Streptomyces avermitilis
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produces four homologous pairs of closely related compounds: avermectins A1, A2, B1, and B2. The four pairs are further divided into the major components A1A, A2A, B1A, and B2A. These subtle differences in the chemical structure were found to have significant functional consequences: while initial trials found that all four avermectins showed some efficacy against gastrointestinal nematodes of sheep, avermectins of the &#;B&#; series showed the highest activity [Mycobacterium tuberculosis
, including multidrug-resistant clinical strains, but there is no strong evidence of their activity against other bacterial species. The advantage of this class of molecules is that it is already approved for clinical and veterinary use and already has well-documented pharmacokinetic and safety profiles [Mycobacterium bovis
BCG andM. tuberculosis
laboratory strains (H37Rv, CDC , and Erdman) at concentrations ranging from 1 to 8 μg/mL [The avermectin structure is closely related to complex 16-membered macrocyclic lactones. Although they share structural features with the antibacterial macrolides and the antifungal macrocyclic polyenes, avermectins are not usually grouped with those compounds [ 16 17 ]. Chemically, the fermentation of the actinomyceteproduces four homologous pairs of closely related compounds: avermectins A1, A2, B1, and B2. The four pairs are further divided into the major components A1A, A2A, B1A, and B2A. These subtle differences in the chemical structure were found to have significant functional consequences: while initial trials found that all four avermectins showed some efficacy against gastrointestinal nematodes of sheep, avermectins of the &#;B&#; series showed the highest activity [ 18 ]. Further, when given orally, avermectin B1 was more active than B2, while with parenteral administration, avermectins B2 was more active than B1 [ 19 ]. Surprisingly, despite being macrocyclic lactones, their antibacterial activity is quite limited. More precisely, avermectins are reported to be very effective in killing, including multidrug-resistant clinical strains, but there is no strong evidence of their activity against other bacterial species. The advantage of this class of molecules is that it is already approved for clinical and veterinary use and already has well-documented pharmacokinetic and safety profiles [ 5 ]. Lim and colleagues, on top of performing extensive literature research on the possible antibacterial activity of avermectins, performed a panel of experiments in which both Gram-positive and Gram-negative bacteria were exposed to different avermectins (doramectin, ivermectin, moxidectin, and selamectin) at concentrations as high as 256 μg/mL. The results concluded that no inhibitory effect was observed [ 5 ]. On the other hand, in the same research thread, the authors tested the inhibitory activity of avermectins against several different mycobacterial strains. The obtained results clearly demonstrated their role in inhibiting the growth ofBCG andlaboratory strains (H37Rv, CDC , and Erdman) at concentrations ranging from 1 to 8 μg/mL [ 5 ].
Chlamydia trachomatis
infection of epithelial cells has also been demonstrated [Regarding the same topic of bacterial growth inhibition, its efficacy againstinfection of epithelial cells has also been demonstrated [ 6 ].
S. aureus
), one Gram-negative bacterial species (E. coli
), and one mycobacterium (Mycobacterium avium
sub.paratuberculosis
) to concentrations of IVM equal to the ones used for anthelmintic control. At the same time, the minimum inhibitory concentration of a macrolide antibiotic (MIC) should be evaluated for each species before and after IVM exposure. One possible experimental scheme to provide answers to this point is shown inAs aforementioned, the antibacterial properties of IVM have been clearly demonstrated for mycobacterial species, but there is still a large gap in knowledge to be filled on other bacterial species. Future work on IVM should aim to clarify these scientific findings towards the additional research on Gram-positive, Gram-negative, and acid-fast bacteria behaviour after exposure to IVM at therapeutic concentrations. Such a research thread comes from the urgent need to evaluate all the possible benefits and side effects of this widely used drug. Among the side effects, the possible induction of macrolides antibiotic resistance should be investigated. This task could be accomplished by exposing one Gram-positive bacterial species (), one Gram-negative bacterial species (), and one mycobacterium (sub.) to concentrations of IVM equal to the ones used for anthelmintic control. At the same time, the minimum inhibitory concentration of a macrolide antibiotic (MIC) should be evaluated for each species before and after IVM exposure. One possible experimental scheme to provide answers to this point is shown in Figure 1 . As visible in the figure, if IVM is demonstrated to be capable of inducing resistance to macrolides, the previously saved bacterial pellets (before and after IVM exposure) will be analysed through NGS sequencing and in-depth proteomics approaches to uncover the eventual mechanisms generating antibiotic resistance [ 20 21 ]. This proteo-genomics approach will allow the analytical steps to be performed with extreme additional depth. The FASTA database necessary for the proteomics analysis will be generated specifically for each of the analysed strains.
E.coli
isolates growing with a concentration of 10 µg/mL of enrofloxacin [This investigation may contribute to clarifying the potential of IVM to induce antibiotic resistance in Gram-positive, Gram-negative, and acid-fast bacteria and could uncover the molecular mechanisms adopted by mycobacterial species to survive sublethal IVM concentrations. This last point is particularly relevant considering the emerging concern regarding multidrug-resistant tuberculosis and the fact that IVM might represent one of the last possibilities to fight multidrug-resistant strains [ 22 23 ]. Label-free proteomics is very effective in the discovery of antibiotic resistance mechanisms and intrinsic resistance [ 24 ]. This has been previously demonstrated inisolates growing with a concentration of 10 µg/mL of enrofloxacin [ 21 ]. This evidence demonstrates that the evaluation of differential protein expression may be useful in studying resistance mechanisms. As designed, the contribution of a parallel metagenomic approach will provide a tool to improve the coverage of the proteomics dataset by reducing the gap between the analysed strains and the publicly available genomes and will also provide the possibility to search the genome for ab-resistant gene sequences.
Technical Field
The invention relates to the field of veterinary drug preparations, in particular to a compound abamectin transdermal solution for pets and a preparation and application method thereof.
Background
Parasitic diseases caused by infection with ectoparasites (ticks, mites, fleas, lice, etc.) and nematodes in the body are one of the common diseases of pets. Various parasites in vivo and in vitro can deprive the organism of the animal of nutrition to different degrees, damage the histiocyte of the animal, secrete toxin, influence the growth and development of pets and transmit various diseases. These are serious hazards to the health of pets and even threaten the health of human beings. The parasite species are many, the effective prevention and treatment difficulty is large, and some parasites cause animal infection and disease, and even cause animal death in serious conditions. Therefore, there is a great need to develop broad-spectrum, highly effective, safe antiparasitic drugs for pet health and public health safety.
Avermectin is a macrolide antibiotic with sixteen-membered ring structure and insecticidal, acaricidal and nematicidal activities, has extremely strong killing activity on endoparasites and ectoparasites, and has no antifungal and bacterial activities. The avermectin has the characteristics of novel structure, high efficiency, broad spectrum, low residue, safety to people and livestock and the like, and is a 'three-in-one' type medicament (Liweiping, Chinese medicine, 21(19), 108 + 110()) which can be used in the fields of human medicine, pesticide and veterinary medicine. The existing formulations of abamectin applied to the field of veterinary drugs comprise injection, powder, tablets, capsules and the like, and although the formulations can meet the requirements of animals for medication to different degrees, the formulations still have the defects of inconvenient administration route, large first-pass effect, easy poisoning and the like. Chinese patents CN.8 and CN.4 both disclose an external avermectin transdermal agent and a preparation method thereof, but the two inventions are single avermectin transdermal agent, and the two inventions still have limitations in clinical use, such as limited insect-resistant spectrum, slow effect taking and incapability of simultaneously meeting the treatment requirements of parasitic diseases, secondary infection bacteria and fungal skin diseases.
The plant-derived pesticide has the characteristics of difficult generation of drug resistance, self-degradation in the environment, relative safety to people, livestock and the environment and the like, and is concerned. Pyrethrin (pyrenthrins) is an extract from pyrethrum, has higher insecticidal activity and wider insecticidal spectrum, can quickly knock down pests, has no toxic or side effect on human beings, livestock and the like, is quickly metabolized, does not accumulate in the bodies of mammals, and has no residue (Liu Yu Qing, etc., Henan science, 31(8), - ()). The cortex pseudolaricis extract is derived from root bark and near-root bark of Pinaceae plant Pseudolarix kaempferi gord, contains various diterpenoid compounds such as pseudolaric acid, pseudolaric acetic acid glucoside and the like, and has various biological activities such as disinsection, fungus resistance, tumor resistance and the like (Wangqiyu and the like, Nature science edition of university of Liaoning, 43 (3)), 258-. The cortex Meliae extract is derived from dried bark and root bark of Melia azedarach L, and has biological activities of expelling parasites, treating tinea, relieving itching, relieving pain, resisting inflammation, and resisting tumor (Zhang Ming dynasty, Shanghai medicine, 28(11), 506 ()). Menthol is derived from mint (Methhalicacalyx Briq.) and has the effects of resisting inflammation, easing pain, relieving itching, resisting fungi, resisting tumors, promoting transdermal absorption and the like (Wangmafeng et al, China modern Chinese medicine, ()).
With the increasing severity of problems such as destruction of environmental microbial balance and drug resistance caused by overuse of antibiotics, antibiotic reduction and use plans are in force. The plant-derived insecticides and the abamectin are scientifically formulated, and are synergized through combination of Chinese and Western medicines, so that advantage complementation is realized, the parasitic diseases and the secondary skin diseases inside and outside a pet can be effectively treated, and the using amount of the abamectin can be reduced, so that resistance reduction and ecological safety are realized.
Disclosure of Invention
The invention aims to solve the technical problem of providing a compound abamectin transdermal solution for pets and a preparation method and a using method thereof, and solves the problems that the existing single abamectin transdermal agent still has limitations such as limited insect resistance spectrum, slow effect and incapability of meeting the treatment requirements on parasitic diseases, secondary infection bacteria and fungal skin diseases simultaneously during clinical use.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a compound avermectin transdermal solution for pets comprises the following raw materials in parts by weight:
10.5 percent of abamectin B, 10 to 25 percent of pyrethrin, 1 to 5 percent of pseudolarix extract, 0.5 to 5 percent of chinaberry bark extract, 0.5 to 3 percent of menthol, 2 to 8 percent of azone, 3 to 15 percent of propylene glycol and the balance of organic solvent.
Preferably, the pyrethrin accounts for 15% -25%.
Preferably, the pseudolarix extract accounts for 2-5%.
Preferably, the cortex meliae extract accounts for 1-5%.
Preferably, the menthol is 1% to 3%.
Preferably, the azone is 2 to 6 percent.
Preferably, the propylene glycol accounts for 5 to 15 percent.
Preferably, the organic solvent is at least one of ethanol, polyethylene glycol, glycerol, isopropanol or ethyl acetate.
A preparation method of the compound avermectin transdermal solution for pets comprises the following steps:
(1) weighing 2/3 parts by weight of organic solvent, and preheating to 40-50 &#;;
(2) adding the required weight parts of propylene glycol and azone, and stirring to completely dissolve the propylene glycol and the azone;
(3) adding required weight parts of avermectin B1, pyrethrin, cortex pseudolaricis extract, cortex Meliae extract and menthol, and stirring to dissolve completely;
(4) the volume is determined by the remaining 1/3 parts by weight of organic solvent.
The application method of the compound avermectin transdermal solution for the pets comprises the step of smearing the compound avermectin transdermal solution on the inner sides of ears of the pets or dripping the compound avermectin transdermal solution along spinal cords of the pets.
By adopting the technical scheme, the avermectin, the pseudolarix extract, the melia azedarach extract, the abamectin B1 and the menthol are synergistic, meanwhile, the azone and the propylene glycol have good permeation promoting effect, and the menthol has the effect of promoting the permeation as a multi-active substance, so that the compound abamectin transdermal solution has good effects of treating parasitic diseases of pets, secondary infection bacteria, fungal skin diseases and the like, has obvious effects on the secondary infection bacteria and fungal skin diseases of pets caused by the parasitic diseases, has the effects of relieving pain and swelling, diminishing inflammation and relieving itching, and can obviously improve the symptoms of the skin diseases of the pets; compared with the single abamectin transdermal solution, the compound abamectin transdermal solution has the advantages that the anti-insect spectrum and the anti-insect activity are enhanced, the compound abamectin transdermal solution also has a good treatment effect on secondary bacterial and fungal skin diseases, the anti-insect spectrum is wider, and the anti-insect activity is stronger; the invention is a transdermal solution, the transdermal absorption is fast, and the effect is fast; the preparation method is simple and low in cost.
Detailed Description
The following further describes the embodiments of the present invention. It should be noted that the description of the embodiments is provided to help understanding of the present invention, but the present invention is not limited thereto. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
A compound avermectin transdermal solution comprises the following components in percentage by weight:
the preparation amount is 100ml, and the preparation method comprises the following steps:
(1) firstly weighing 2/3 formula amount of ethanol, and preheating to 40-50 &#;;
(2) sequentially adding the propylene glycol and the azone with the formula amount, and stirring to completely dissolve;
(3) accurately weighing abamectin B1, pyrethrin, cortex pseudolaricis extract, cortex Meliae extract and menthol, sequentially adding into the above solution, and stirring to completely dissolve the components;
(4) the volume is determined by the residual ethanol.
Example 2
A compound avermectin transdermal solution comprises the following components in percentage by weight:
the preparation amount is 100ml, and the preparation method comprises the following steps:
(1) firstly weighing 2/3 formula amount of ethanol, and preheating to 40-50 &#;;
(2) sequentially adding the propylene glycol and the azone with the formula amount, and stirring to completely dissolve;
(3) accurately weighing abamectin B1, pyrethrin, cortex pseudolaricis extract, cortex Meliae extract and menthol, sequentially adding into the above solution, and stirring to completely dissolve the components;
(4) the volume is determined by the residual ethanol.
Example 3
A compound avermectin transdermal solution comprises the following components in percentage by weight:
the preparation amount is 100ml, and the preparation method comprises the following steps:
(1) firstly weighing 2/3 formula amount of ethanol, and preheating to 40-50 &#;;
(2) sequentially adding the propylene glycol and the azone with the formula amount, and stirring to completely dissolve;
(3) accurately weighing abamectin B1, pyrethrin, cortex pseudolaricis extract, cortex Meliae extract and menthol, sequentially adding into the above solution, and stirring to completely dissolve the components;
(4) the volume is determined by the residual ethanol.
Example 4
A compound avermectin transdermal solution comprises the following components in percentage by weight:
the preparation amount is 100ml, and the preparation method comprises the following steps:
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(1) firstly weighing 2/3 formula amount of ethanol, and preheating to 40-50 &#;;
(2) sequentially adding the propylene glycol and the azone with the formula amount, and stirring to completely dissolve;
(3) accurately weighing abamectin B1, pyrethrin, cortex pseudolaricis extract, cortex Meliae extract and menthol, sequentially adding into the above solution, and stirring to completely dissolve the components;
(4) the volume is determined by the residual ethanol.
Example 5
A compound avermectin transdermal solution comprises the following components in percentage by weight:
the preparation amount is 100ml, and the preparation method comprises the following steps:
(1) firstly weighing 2/3 formula amount of ethyl acetate, and preheating to 40-50 &#;;
(2) sequentially adding the propylene glycol and the azone with the formula amount, and stirring to completely dissolve;
(3) accurately weighing abamectin B1, pyrethrin, cortex pseudolaricis extract, cortex Meliae extract and menthol, sequentially adding into the above solution, and stirring to completely dissolve the components;
(4) the volume is determined by the balance of ethyl acetate.
Example 6
A compound avermectin transdermal solution comprises the following components in percentage by weight:
the preparation amount is 100ml, and the preparation method comprises the following steps:
(1) firstly weighing 2/3 formula amount of isopropanol, and preheating to 40-50 &#;;
(2) sequentially adding the propylene glycol and the azone with the formula amount, and stirring to completely dissolve;
(3) accurately weighing abamectin B1, pyrethrin, cortex pseudolaricis extract, cortex Meliae extract and menthol, sequentially adding into the above solution, and stirring to completely dissolve the components;
(4) the volume is determined by the residual isopropanol.
Example 7
Clinical efficacy test of compound avermectin transdermal solution on ectoparasite
(I) test materials
(1) Test drugs: the compound avermectin transdermal solution prepared in embodiment 3 of the invention
(2) Control drugs: avermectin transdermal solution (content 0.5%, commercial product)
(3) Test animals: the south Beijing one wandering dog housing center is examined by ectoparasites to confirm that dogs infected by ticks, fleas and the like are diagnosed.
(II) test grouping and administration
Test groups: the composition is administered by applying 0.1ml/kg body weight to the inner side of ear of two ears.
Drug control group: the composition is administered by applying 0.1ml/kg body weight to the inner side of ear of two ears.
(III) determination of therapeutic Effect
The number of fleas and ticks was measured every 7 days before and 14 days after administration, classified and counted, and the occurrence, development, regression and disappearance of symptoms of the infected dog with the parasitic disease were recorded. The negative conversion rate and the reduction rate of each insect body (and insect egg) of each animal in each group are respectively calculated according to the following formulas by taking the change index of the number of ectoparasites as a main judgment standard.
The insect body negative conversion rate is equal to the number of the insect body negative conversion animals/the number of the experimental animals multiplied by 100 percent
The reduction rate of the insect body is (number of the insects before insect repelling-number of the insects after insect repelling)/number of the insects before insect repelling × 100%
(IV) test results
The results are shown in the table below, and the results of the compound abamectin transdermal solution on the killing of canine epizoon show that 30min after the compound abamectin transdermal solution is used, the pruritus symptoms of a test group are obviously relieved, fleas can fall off after 2-4 h after the compound abamectin transdermal solution is used, and no fleas or ticks can be found 24h after the compound abamectin transdermal solution is used. At 7d after the application, the insect body negative turning rate and the insect body reduction rate of the scabies and the fleas of the test group reach 100 percent, the skin lesion disappears, and the scabies and the fleas basically recover to normal. After the drug control group is used, the rate of turning negative of the insect bodies of the ticks and fleas at the 7 th day and the rate of reduction of the insect bodies are 90%, and the skin lesions disappear at the 14 th day after the drug control group is used, and the skin lesions basically return to normal.
Example 8
Clinical curative effect test of compound avermectin transdermal solution on dog intestinal roundworm
(I) test materials
(1) Test drugs: the compound avermectin transdermal solution prepared in the embodiment 4 of the invention.
(2) Control drugs: avermectin transdermal solution (content 0.5%, commercial product).
(3) Test animals: a certain Nanjing wandering dog is collected in a central dog, and 30 dogs are selected for testing through fecal ova examination.
(II) test grouping and administration
Test groups: the composition is administered by applying 0.1ml/kg body weight to the inner side of ear of two ears.
Drug control group: the composition is administered by applying 0.1ml/kg body weight to the inner side of ear of two ears.
Positive control group: 10, no drug was administered.
About 5g of fresh feces is collected from each dog before and 7d after the administration, nematode eggs are checked by a saturated saline floating method, and the number of Eggs (EPG) in each gram of feces is calculated and counted.
(III) determination of therapeutic Effect
According to the change of the nematode eggs in vivo before and after the administration, the negative turning rate and the reduction rate of the eggs are calculated according to the following formula.
The rate of negative conversion of eggs is equal to the number of animals with negative conversion of eggs/number of experimental animals multiplied by 100 percent
The egg reduction rate is (before insect repelling EPG-after insect repelling EPG)/before insect repelling EPG X100%
(IV) test results
The results are shown in the table below, and clinical efficacy tests of the compound avermectin transdermal solution on dog intestinal ascaris show that the results of two times of fecal examinations of a positive control group are positive, and the EPG has no obvious change. The negative conversion rate and the egg reduction rate of the test group at the 7d after the administration are both 100.0 percent and are better than the negative conversion rate (85.11 percent) and the egg reduction rate (87.94 percent) of the drug control group at the 7d after the administration.
Example 9
Clinical curative effect test of compound avermectin transdermal solution on dog psoriasis
(I) test materials
(1) Test drugs: the compound avermectin transdermal solution prepared in the embodiment 5 of the invention.
(2) Control drugs: avermectin transdermal solution (content 0.5%, commercial product).
(3) Test animals: the south Beijing certain wandering dog housing center, a sick dog with psoriasis.
(II) test grouping and administration
Test groups: 45 patients are administered by applying on the inner side of ears at a dose of 0.1ml/kg body weight.
Drug control group: 48 of the above-mentioned medicinal materials are applied on the inner side of ears in a single dose of 0.1ml/kg body weight.
(III) determination of therapeutic Effect
And (4) invalidation: compared with the prior art, the clinical symptoms are not reduced or even increased, and a large amount of mites and fungi are still found in microscopic examination.
The method has the following advantages: reduced symptoms, reduced lesion size, reduced or absent microscopic pathogens, but sometimes recurrent.
And (3) curing: the skin lesion disappears, the itch feeling is avoided, new quilt hair grows out, the recurrence and the rebound are avoided, and no acarid and fungus are found in microscopic examination.
(IV) test results
The results are shown in the table below, and clinical efficacy tests of the compound avermectin transdermal solution on dog psoriasis show that the treatment effect of the test group is obviously better than that of the drug control group, and after the compound avermectin transdermal solution is used by a critically ill dog, the itching feeling is obviously relieved 30min after the compound avermectin transdermal solution is used. After 24 hours of administration, the disease condition is obviously controlled, the lesion is reduced, the depilation is stopped, the pustule herpes disappears, and no mites and fungi are found in microscopic examination. New hair begins to grow on the affected part 5 days after the application of the medicine. The drug can be used for mild disease dogs or simple fungus disease dogs for 2-3 days to recover to normal. The symptoms of the drug control group are relieved 3-5 days after the drug is taken, and the mild infected cases begin to grow new hairs 14 days after the drug is taken, tinea spots still exist, and fungi can still be seen in microscopic examination.
The embodiments of the present invention have been described in detail, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, and the scope of protection is still within the scope of the invention.
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