CN115068412A - Valnemulin hydrochloride nano gel for treating animal proliferative enteritis and preparation method thereof - Google Patents
Valnemulin hydrochloride nano gel for treating animal proliferative enteritis and preparation method thereof Download PDFInfo
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract
The invention discloses a valnemulin hydrochloride nanogel for treating animal proliferative enteritis, which is prepared from the following raw materials in parts by weight: 0.2-1 part of valnemulin hydrochloride; 1-4 parts of poloxamer; 0.5-2 parts of pectin; 30-80 parts of distilled water; 20-70 parts of cane sugar. The invention is used for treating the proliferative enteritis of animals for the first time by combining the advantages of the inclusion technology, the nanotechnology and the gel technology; the stability of the valnemulin hydrochloride in gastric acid is enhanced; the bitter taste of valnemulin hydrochloride is covered; the target effect and the sustained-release effect of the valnemulin hydrochloride in the intestinal tract are improved through the hydrolysis effect of the pectinase and the inclusion effect of the poloxamer; can improve the clinical curative effect of the valnemulin hydrochloride on the proliferative enteritis of animals.
Description
Technical Field
The invention belongs to the technical field of veterinary medicine preparation, and particularly relates to valnemulin hydrochloride nanogel for treating animal proliferative enteritis and a preparation method thereof.
Background
Proliferative Enteritis (PE) caused by Lawsonia intracellularis (l.intracellularis) is a contact digestive tract infectious disease characterized by adenomatous hyperplasia of immature intestinal cells in the ileum and colon crypt, leading to thickening of the intestinal mucosa. At present, a plurality of animals can suffer from the disease, the diseased animals are the main diseases in the intensive pig breeding at present, and are mostly manifested as anorexia, mental depression, pale skin, intermittent diarrhea, and soft and thin feces, and sometimes blood or necrotic tissue fragments are mixed, and simultaneously, as the intestinal wall of ileum is obviously thickened, the digestion and absorption capacity of ileum is disordered, so that the production performance is reduced, the weight is slowly increased, the feed conversion rate is reduced, and serious economic loss is caused.
Valnemulin hydrochloride belongs to a special antibiotic for a new generation of pleuromutilin animals, and is approved by the European Union to prevent and treat swine colonic spirochaete disease and swine proliferative enteritis in 1 month in 2004. Because of the characteristics of safety, low toxicity, wide antibacterial spectrum, strong antibacterial activity and the like, the composition is widely applied to the prevention and treatment of gram-positive bacteria such as staphylococcus aureus, streptococcus and the like and pathogens such as mycoplasma pneumoniae, brachyspira hyodysenteriae, brachyspira colophonium pili and lawsonia intracellularis and the like. Researches show that valnemulin hydrochloride can obviously relieve the clinical symptoms of proliferative enteritis, inhibit infection and control diarrhea. For digestive tract diseases, oral administration is often adopted, but valnemulin hydrochloride is bitter in taste and has strong irritation to gastrointestinal tracts. Therefore, a valnemulin hydrochloride preparation suitable for treating animal proliferative enteritis is needed at present, so that the treatment effect can be improved while the stimulation reaction of the medicine to gastrointestinal tracts is avoided.
Disclosure of Invention
In order to improve the palatability of valnemulin hydrochloride, reduce irritation and improve stability, the invention prepares the pectinase response type valnemulin hydrochloride nanogel by taking high-ester pectin with natural non-toxicity as a material and adding cane sugar to wrap poloxamer-valnemulin hydrochloride nano microspheres, thereby overcoming the problem of poor palatability of valnemulin hydrochloride, prolonging the release time of a medicament in a body and improving the stability of the medicament, and further achieving the aim of enhancing the curative effect.
In order to achieve the purpose, the invention provides the following technical scheme:
a valnemulin hydrochloride nano gel for treating animal proliferative enteritis is prepared from the following raw materials in parts by mass: 0.2-1 part of valnemulin hydrochloride; 1-4 parts of poloxamer; 0.5-2 parts of pectin; 30-80 parts of distilled water; 20-70 parts of cane sugar.
Preferably, the feed is prepared from the following raw materials in parts by mass: 0.2-1 part of valnemulin hydrochloride; 1-4 parts of poloxamer; 0.5-2 parts of pectin; 50-70 parts of distilled water; 30-50 parts of cane sugar.
Most preferably, the feed is prepared from the following raw materials in parts by mass: 0.4 part of valnemulin hydrochloride; 2 parts of poloxamer; 0.8 part of pectin; 62.5 parts of distilled water; 34.3 parts of sucrose.
The nanogel has the characteristics of excellent drug loading capacity, good structural stability, biocompatibility and the like, can deliver the antibacterial drug to a bacterial infection part, obviously improves the targeted biological distribution of the antibacterial drug in a microenvironment, and is expected to enhance the treatment effect on lawsonia intracellularis due to the nanoscale and easy passage of biological barriers such as a cell membrane.
The poloxamer can wrap the valnemulin hydrochloride to form the nano-microspheres, so that the slow-release effect is achieved.
Pectin is a natural and nontoxic food additive and health product, is widely applied to the fields of food and medicine, is very stable in an acidic environment, and can be prevented from being damaged by gastric acid after being coated with a medicine, so that the stability of the medicine is improved. Bacteroides thetaiotaomicron in intestinal microorganisms can specifically decompose pectin, so that the medicament achieves the targeted release effect at the infected parts of ileum and colon.
The sucrose can promote the high-ester pectin to form a three-dimensional mesh gel structure, and meanwhile, the bitter taste of valnemulin hydrochloride can be covered, so that the palatability of animals is improved.
The preparation method of the valnemulin hydrochloride nano gel for treating the proliferative enteritis of the animals comprises the following steps:
s110, dividing the distilled water into two parts, namely distilled water 1 and distilled water 2; dissolving pectin in distilled water 1 to obtain solution 1;
s120, sequentially adding the valnemulin hydrochloride and the poloxamer into distilled water 2, and uniformly mixing to obtain a solution 2;
s130, dropwise adding the solution 2 into the solution 1, and uniformly mixing to obtain a solution 3;
s140, adding sucrose into the solution 3, heating to dissolve (preferably 50 ℃), adjusting the pH value to 2-3 to obtain a solution 4, and continuously stirring to form nanogel, namely the valnemulin hydrochloride nanogel.
The invention has the beneficial effects that:
1. the composition is used for treating animal proliferative enteritis by combining the advantages of an inclusion technology, a nanotechnology and a gel technology for the first time;
2. the stability of the valnemulin hydrochloride in gastric acid is enhanced;
3. the bitter taste of valnemulin hydrochloride is covered;
4. the target effect and the sustained-release effect of the valnemulin hydrochloride in the intestinal tract are improved through the hydrolysis effect of the pectinase and the inclusion effect of the poloxamer;
5. can improve the clinical curative effect of the valnemulin hydrochloride on the hyperplastic enteritis of animals.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that need to be used are briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a schematic diagram of the appearance of valnemulin hydrochloride nanogel in example 3;
FIG. 2 is a schematic scanning electron microscope of valnemulin hydrochloride nanogel in example 3;
FIG. 3 is a schematic illustration of the particle size distribution of valnemulin hydrochloride nanogel in example 3;
FIG. 4 is a Zeta potential distribution diagram of a valnemulin hydrochloride nanogel in example 3;
FIG. 5 is a graph showing the swelling behavior of valnemulin hydrochloride nanogel in simulated gastric and intestinal fluids in example 3;
figure 6 is a schematic representation of the in vitro release of valnemulin hydrochloride nanogel in example 3 in simulated gastric and intestinal fluids;
FIG. 7 is a schematic representation of a mouse model tissue section of a positive control group in a treatment trial;
FIG. 8 is a schematic representation of a tissue section of a mouse model of a negative control group in a treatment trial;
FIG. 9 is a schematic representation of tissue sections of a valnemulin hydrochloride premix treatment infected mouse model in a therapeutic trial;
figure 10 is a schematic of a tissue section of a mouse model infected with valnemulin hydrochloride nanogel treatment in a therapeutic trial.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.
Example 1
The valnemulin hydrochloride nano gel is prepared from the following raw materials in parts by mass: 0.5 part of valnemulin hydrochloride; 2 parts of poloxamer; 1 part of pectin; 60.5 parts of distilled water; 36 parts of sucrose. The preparation method specifically comprises the following steps:
s110, dividing the distillation level into two parts, namely distilled water 1 and distilled water 2; dissolving pectin in distilled water 1 to obtain solution 1;
s120, sequentially adding the valnemulin hydrochloride and the poloxamer into distilled water 2, and uniformly mixing to obtain a solution 2;
s130, dropwise adding the solution 2 into the solution 1, and uniformly mixing to obtain a solution 3;
s140, adding sucrose into the solution 3, heating to dissolve (50 ℃), adjusting the pH value to 2.5 to obtain a solution 4, and continuously stirring to form nano gel, namely the valnemulin hydrochloride nano gel.
Example 2
The valnemulin hydrochloride nano gel is prepared from the following raw materials in parts by mass: 0.4 part of valnemulin hydrochloride; 2 parts of poloxamer; 1 part of pectin; 62 parts of distilled water; 34.6 parts of sucrose. The preparation process is referred to example 1.
Example 3
The valnemulin hydrochloride nano gel is prepared from the following raw materials in parts by mass: 0.4 part of valnemulin hydrochloride; 2 parts of poloxamer; 0.8 part of pectin; 62.5 parts of distilled water; 34.3 parts of sucrose. The preparation process is referred to example 1.
1. A proper amount of the nanogel in the examples 1 to 3 was taken, and the produced gel material was observed by eye to see whether particles or bubbles having uneven sizes were generated. In example 1, the color was not uniform, no gel was formed, and particles of different sizes were present; example 2 color was uniform but did not form a gel; the valnemulin hydrochloride nanogel prepared in the embodiment 3 has good uniformity, can form stable gel, and can be used as a therapeutic test medicament of a subsequent mouse model.
2. And (3) morphology observation: the valnemulin hydrochloride nanogel obtained in example 3 was diluted by 100 times, and then observed for microscopic morphology by a scanning electron microscope. The results show that: the prepared valnemulin hydrochloride nanogel is clear and transparent, appears as a gel in an inclined bottle, and is not found with floccules and precipitates, as shown in figure 1. Scanning electron micrographs of the nanogels are shown in figure 2. Through an inclusion technology, the valnemulin hydrochloride is wrapped in poloxamer to form a valnemulin hydrochloride inclusion compound; through the nanometer technology and the gel technology, the valnemulin hydrochloride is wrapped in the pectin and sucrose hydrogel to form the valnemulin hydrochloride composite nanometer gel. Therefore, the valnemulin hydrochloride composite nanogel is successfully prepared by the inclusion technology, the nanotechnology and the gel technology.
3. Zeta potential and particle size measurement: diluting the prepared valnemulin hydrochloride nanogel by 100 times, measuring the Zeta potential and the particle size of the valnemulin hydrochloride nanogel by a Malvern nanometer laser particle size analyzer, and repeating the steps for 3 times to obtain an average value. The results show that: the average particle diameter and the Zeta potential were 454.22. + -. 5.63nm and-32.3. + -. 3.64mV, respectively, as shown in FIGS. 3 and 4.
4. Swelling property: simulated gastric fluid (pH 1.2) and intestinal fluid (pH 7.4, pectinase was added) were prepared separately. Subsequently, the valnemulin hydrochloride nanogel is respectively placed into simulated gastric juice and intestinal juice, and the swelling performance of the valnemulin hydrochloride nanogel is observed at different time points. The results show that: in gastric juice, at 24h, the valnemulin hydrochloride nano gel is still in a stable state, which shows that the prepared gel has higher stability in gastric acid; in intestinal juice, the valnemulin hydrochloride nano gel is obviously swelled after 3 hours, which shows that the prepared gel releases the medicament after swelling in the intestinal juice, as shown in figure 5. Therefore, the prepared valnemulin hydrochloride nano gel can enhance the stability of valnemulin hydrochloride in gastric acid.
5. In vitro release: the valnemulin hydrochloride nano gel is respectively put into simulated gastric juice and intestinal juice, and the drug release rate is calculated at different time points. The results show that: in gastric juice, 95.5% +/-2.1% of the drug is released at 3 hours; in intestinal fluid, only 68.2% + -2.8% of the drug was released at 3h, and 83.8% + -3.0% of the drug was released at 12h, as shown in fig. 6. The swelling performance and in-vitro release are integrated, and the targeted effect and the sustained release effect of the valnemulin hydrochloride in intestinal tracts are improved through the hydrolysis effect of pectinase and the inclusion effect of poloxamer.
6. Palatability testing: mixing the valnemulin hydrochloride nano gel (an additive group 1) and the valnemulin hydrochloride premix (an additive group 2) in water, and observing the water drinking conditions of the additive group and the mice without the additive group. The results show that: the medicine adding group 1 and the medicine not adding group have no obvious difference in the water drinking condition of mice and no obvious difference in weight. The water drinking of the medicine adding group 2 is obviously reduced, almost no water is drunk, and the weight is reduced. Therefore, the prepared valnemulin hydrochloride nano gel covers the bitter taste of valnemulin hydrochloride.
7. Treatment trials of mouse models:
1. materials and methods
1.1 medicine valnemulin hydrochloride premix (10%, water-soluble) and valnemulin hydrochloride nano gel (0.5%).
1.2 test animals 24 clean-grade (ICR) Kunming mice, purchased from the animal laboratory site at Tarim university.
1.3 instruments including laser nanometer particle analyzer, heat-collecting constant temperature magnetic stirrer, heating magnetic stirrer, freeze drier, variable vacuum ultrahigh resolution field emission scanning electron microscope, ultraviolet-visible spectrophotometer, nanometer particle size and Zeta potential analyzer.
1.4 test methods
1.4.1 establishment of mouse proliferative enteritis model
24 mice (20 + -1.2 g) were randomly divided into 4 groups (valnemulin hydrochloride premix treatment group, valnemulin hydrochloride nanogel treatment group, positive control group, negative control group), and 6 mice each. In which 1-3 groups of mice were inoculated with 0.6mL of bacterial suspension (10) 5 TCID 50 mL), continuously infecting for 3 days, and constructing a mouse proliferative enteritis model. Group 4 mice were not infected (negative control group). Mice infected with lawsonia intracellularis had decreased dietary water consumption, lost weight, and significantly leaned, and tissue sections showed significant proliferation of intestinal cells in the crypt of the ileum. And (5) if the negative control group mice drink normal water and have no symptoms, judging that the proliferative enteritis model of the mice is successfully established.
1.4.2 therapeutic experiments
The infected mice were treated with valnemulin hydrochloride nanogel in group 1, the infected mice were treated with valnemulin hydrochloride premix in group 2, after the mice were infected in group 3, no treatment was done (positive control group), and group 4 was not infected and no treatment was done (negative control group), and the treatment was observed. The valnemulin hydrochloride nano gel and the valnemulin hydrochloride premix are used for treating infected mice through intragastric administration for 7 days continuously, the weight and clinical symptoms of the mice are observed and recorded, and the tail ends of ileum of each group of mice are collected for HE dyeing.
1.4.3 determination of results
And (3) judging clinical symptoms: after confirming the success of the infection in the mice, the mice were observed 1 time every 24h, during which the mice were observed for clinical symptoms. After treatment, the infected mice have less spirit, activity, diet and drinking water, and recover to normal without obvious change of body weight, and the treatment success is judged from the clinical perspective.
And (3) judging tissue sections: the terminal ileum of the mice of the positive control group is obviously proliferated, and intestinal cells in crypts are obviously proliferated. The terminal ileum of the mice of the treatment group has no obvious hyperplasia, and has no obvious difference with the negative control group.
1.5 test results
The infected mice have the phenomena of reduction of drinking water and diet, weight loss, obvious emaciation, obvious proliferation of the terminal of ileum and the like, and then a mouse proliferative enteritis model is successfully established.
After the mouse proliferative enteritis model is treated by the valnemulin hydrochloride premix and the valnemulin hydrochloride nano gel, the drinking water and diet are recovered to be normal, the weight is not obviously different from the negative control, and the treatment is judged to be successful from the clinical symptom angle. After tissue section, if no pathological change is obvious, the treatment success is judged from the pathological point of view, as shown in fig. 7, fig. 8, fig. 9 and fig. 10. The cure rate of the group 1 is 83.3 percent, and the cure rate of the group 2 is 50.0 percent, thereby showing that the valnemulin hydrochloride nano gel can improve the clinical curative effect of the valnemulin hydrochloride on the animal proliferative enteritis.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (5)
1. The valnemulin hydrochloride nano gel for treating the proliferative enteritis of animals is characterized by being prepared from the following raw materials in parts by mass: 0.2-1 part of valnemulin hydrochloride; 1-4 parts of poloxamer; 0.5-2 parts of pectin; 30-80 parts of distilled water; 20-70 parts of cane sugar.
2. The valnemulin hydrochloride nanogel for treating the proliferative enteritis of animals according to claim 1, is prepared from the following raw materials in parts by mass: 0.2-1 part of valnemulin hydrochloride; 1-4 parts of poloxamer; 0.5-2 parts of pectin; 50-70 parts of distilled water; 30-50 parts of cane sugar.
3. The valnemulin hydrochloride nanogel for treating the proliferative enteritis of animals according to claim 2 is prepared from the following raw materials in parts by mass: 0.4 part of valnemulin hydrochloride; 2 parts of poloxamer; 0.8 part of pectin; 62.5 parts of distilled water; 34.3 parts of sucrose.
4. The preparation method of the valnemulin hydrochloride nanogel for treating the proliferative enteritis of the animals as claimed in any one of claims 1 to 3, is characterized by comprising the following steps:
s110, dividing the distilled water into two parts, namely distilled water 1 and distilled water 2; dissolving pectin in distilled water 1 to obtain solution 1;
s120, sequentially adding the valnemulin hydrochloride and the poloxamer into distilled water 2, and uniformly mixing to obtain a solution 2;
s130, dropwise adding the solution 2 into the solution 1, and uniformly mixing to obtain a solution 3;
s140, adding sucrose into the solution 3, heating to dissolve, adjusting the pH value to 2-3 to obtain a solution 4, and continuously stirring to form nano gel, namely the valnemulin hydrochloride nano gel.
5. The method of claim 4, wherein: the heating temperature in step S140 is 50 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101057966A (en) * | 2007-05-16 | 2007-10-24 | 中国科学院上海药物研究所 | Liposome nanometer carrier situ gel preparation used for eye epidermal growth factor |
| CN103705454A (en) * | 2014-01-07 | 2014-04-09 | 王玉万 | Oily injection containing valnemulin hydrochloride/poloxamer 407 |
| CN105878176A (en) * | 2016-04-06 | 2016-08-24 | 山东胜利生物工程有限公司 | Valnemulin hydrochloride injection in-situ gel preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101057966A (en) * | 2007-05-16 | 2007-10-24 | 中国科学院上海药物研究所 | Liposome nanometer carrier situ gel preparation used for eye epidermal growth factor |
| CN103705454A (en) * | 2014-01-07 | 2014-04-09 | 王玉万 | Oily injection containing valnemulin hydrochloride/poloxamer 407 |
| CN105878176A (en) * | 2016-04-06 | 2016-08-24 | 山东胜利生物工程有限公司 | Valnemulin hydrochloride injection in-situ gel preparation and preparation method thereof |
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