阅读说明：本技术 一种适合口服使用的奶牛酮病防治复合配方 (Compound formula for preventing and treating dairy cow ketosis suitable for oral administration ) 是由 贺鑫 于 2021-03-17 设计创作，主要内容包括：奶牛酮病是高发于高产奶牛泌乳初期的代谢性紊乱性疾病,每年给中国奶牛业造成巨大损失,因此需专门防治技术。发明人长期围绕代谢中毒展开研究,针对奶牛酮症涉及的复杂代谢紊乱,筛选出了综合矫正配方,利用标准化高通量细胞和奶牛随机对照实验改进验证,优化出最适合配方,包括：过瘤胃葡萄糖(200-2000g/d)、过瘤胃泛酸(20-500g/d)、氯化钙(10-200g/d)、氯化钠(10-200g/d)、氯化锌(5-50g/d)。本配方价格低廉,避免了过瘤胃问题,可通过消化道吸收,使用方便快捷,降低了泌乳初期奶牛酮病发病率,提高了生产性能和健康水平,有广阔的市场应用前景。(The ketosis of the dairy cows is a metabolic disorder disease which is high in the early lactation stage of high-yield dairy cows and causes great loss to the dairy cows in China every year, so that special prevention and treatment technologies are required. The inventor carries out research around metabolic poisoning for a long time, screens out a comprehensive correction formula aiming at complex metabolic disturbance related to dairy cow ketosis, and optimizes the most suitable formula by utilizing standardized high-flux cells and dairy cow random control experiments for improvement and verification, wherein the formula comprises the following components: rumen bypass glucose (200-2000 g/d), rumen bypass pantothenic acid (20-500 g/d), calcium chloride (10-200 g/d), sodium chloride (10-200 g/d) and zinc chloride (5-50 g/d). The formula has low price, avoids rumen bypass, can be absorbed by the digestive tract, is convenient and quick to use, reduces the incidence of ketosis of the dairy cows in the early lactation period, improves the production performance and the health level, and has wide market application prospect.)

1. The invention provides a compound formula containing rumen-bypass glucose, rumen-bypass pantothenic acid, calcium chloride, sodium chloride and zinc chloride for comprehensively correcting metabolic disorder to prevent dairy cow ketosis.

2. The dosage range of each component of the complex formula of claim 1 is rumen bypass glucose (200-.

3. The complex formulation of claim 1 wherein the calcium chloride, sodium chloride and zinc chloride are replaced by other non-toxic salts of calcium, sodium and zinc, respectively, since absorption in the cow is by way of their respective metal cations.

4. The formulation of claim 1, which is administered primarily through the digestive tract, including but not limited to, feed supplements, drenching and lick blocks, but not including intravenous, intramuscular, topical and aerosol inhalation.

5. The present invention relates to a formulation for rumen bypass glucose and rumen bypass pantothenic acid according to claim 1, wherein rumen bypass technology is an improved technical system which is continuously developed and is commercially available, the present invention only uses the technical system to achieve the purpose of effective absorption, and the specific technology for rumen bypass is not in the scope of protection of the present invention.

Technical Field

The invention belongs to the technical field of animal husbandry and veterinary medicine, and relates to a compound formula for preventing ketosis of dairy cows by comprehensively correcting metabolic disorders, which can be used in a mode of oral administration or feed addition and the like through absorption of digestive tracts.

Background

Cow ketosis is a metabolic disorder widely present in high-producing cows, occurring mainly within 1 month post-partum. Due to energy negative balance and metabolic stress in the early lactation period, if excessive feed containing protein and fat is fed, carbohydrate feed is insufficient and movement is insufficient, forestomach hypofunction is caused, and a large amount of lactation causes lactose consumption, finally, an organism mainly utilizes ketone bodies (such as acetone, acetoacetic acid and beta-hydroxybutyric acid) to supply energy, so that the ketone bodies in blood continuously rise, and a series of metabolic disorders such as metabolic acidosis are caused, at present, the concentration of beta-hydroxybutyric acid (BHBA) in the blood of a cow is generally used as a standard for judging that the cow has subclinical ketosis, and the concentration of beta-hydroxybutyric acid (BHBA) in the blood of the cow is generally used as a standard for judging that the cow has ketosis.

The lactation peak of the dairy cows generally appears at 4-6 weeks after delivery, but the Dry Matter Intake (DMI) can not reach the maximum until 8-10 weeks after delivery, so that the high-yield dairy cows often have energy negative balance in the lactation initial stage, and the nutrition supply must be ensured by a physiological adaptive regulation mechanism to meet the change, and then a large amount of body fat is required to fill the gap of required nutrients, so that energy metabolism disorder diseases are induced, the dairy cows are often in the ketosis risk period in the period, and extra nutrition intake for specially correcting metabolic disorders is required.

Dairy cow ketosis has great economic influence, and is mainly characterized by reduced milk yield, milk waste, treatment cost, prolonged calving interval time, elimination cost and the like; generally speaking, ketosis can cause more than thousand yuan for each sick cow, and the comprehensive analysis of the disease condition of the Chinese dairy cow proves that the ketosis causes about 11 million yuan for the Chinese dairy cow industry every year, so that special development of control measures for the ketosis of the dairy cow is necessary.

At present, a mature dairy cow ketosis treatment scheme is available, but if treatment is started after the onset of disease, the prognosis of the ketosis of the high-yield dairy cow is general, the production performance is greatly influenced, and great economic loss is inevitable. At present, more methods for preventing and treating the ketosis of the dairy cows can be seen in the market. For example, the patent of application No. 201910739279.8 uses lycopene to prevent ketosis of cows, and it is difficult to fundamentally correct nutritional metabolic disorders of cows despite the high price of continuously adding lycopene, so that the prevention effect is limited; the patent of application No. 201810428541.2 utilizes butafosfan to supplement the phosphorus element intake, but reduces the feed calcium phosphorus ratio, is not beneficial to calcium element intake, utilizes molasses to make into lick brick to let the milk cow lick automatically to supplement sugar, but the sugar is decomposed into acid by vitamin through rumen, but promotes the organic acid content in the blood circulation of milk cow, induces and aggravates the attack and progress of ketoacidosis, therefore the effect is not good and the risk is larger; the patent of application No. 201110245114.9 uses a Chinese medicinal composition to prevent ketosis, firstly, the Chinese medicinal composition is continuously added into the feed, the cost is very high, and in addition, the Chinese medicinal composition suitable for human is not suitable for cow, because the effective components of the Chinese medicinal composition are subjected to the fermentation action of rumen microorganisms to produce complex chemical decomposition, the effect is difficult to predict.

In a word, the dairy cow ketosis is a frequently occurring disease which can cause huge economic loss in the dairy cow breeding industry, although a mature treatment scheme is provided at present, the prognosis of the disease is general, the production performance of the dairy cow is greatly influenced, and the large economic loss is inevitably caused, so that the problem can be solved only from the aspect of preventing the disease, but no mature scheme for safely and effectively preventing the dairy cow ketosis exists until the early stage of the patent application.

Disclosure of Invention

The lactation period of the invention is from the birth day of the cow to 21 days after the birth.

The registering unit of the animal medical academy of animal medicine of northwest agriculture and forestry science and technology university of the inventor has a deep historical deposit on the research of the problems of ketosis metabolic poisoning of the dairy cows, the inventor participates in the work for more than ten years, researches are carried out around the problems of metabonomics and ketosis poisoning, the key molecular mechanism of the ketosis metabolic disorder of a plurality of dairy cows is discovered, the correction formula of the ketosis metabolic disorder of the dairy cows is screened in a targeted manner on the basis of long-term experiments, and the compound formula which is most suitable for preventing and treating the ketosis of the dairy cows is obtained through long-term cell experiments and random double-blind control experiments and verification of the dairy cows, and the main components are as follows: rumen bypass glucose (200-. The chemical structures of the components of the formula are clear and definite, the physicochemical properties are stable on the whole, and the theoretical speculation and the experiment prove that the components of the formula do not have the problem of mutual interference, so that the special requirements on the preparation method such as the adding sequence of the components and the like do not exist.

In view of the problems of the dairy cow ketosis which is frequently generated and can cause huge economic loss in the dairy cow breeding industry, the invention provides a method for preparing a functional dairy cow feed additive which can effectively reduce the incidence rate of the ketosis of the dairy cow in the early lactation period. The finished product of the formula is added into the total mixed ration of the dairy cows in the early lactation period in daily use to prepare the functional feed for the dairy cows, and the functional feed can also be used for drenching the dairy cows or used as a digestive tract absorption mode such as lick bricks and the like.

Ketosis in cows involves a complex metabolic disorder, and it is therefore difficult to correct such a metabolic disorder by a single compound. The invention utilizes the synergistic effect of a plurality of small molecular compounds and produces synergy through benign interaction among the components of the formula, thereby comprehensively correcting metabolic disorders. For example, the formula can be supplemented with zinc chloride or other zinc agents, and can be used as enzymes for metabolizing various sugars and inhibiting ketoacidosis and injury, for example, carbonic anhydrase catalyzes carbon dioxide dissolution equilibrium reaction to regulate the pH value of blood so as to inhibit ketoacidosis, copper-zinc superoxide dismutase catalyzes active oxygen decomposition to avoid ketosis injury, and lactate dehydrogenase is an important enzyme for gluconeogenesis.

Until the present patent application, there is no efficient low cost formulation for specifically preventing dairy cow ketosis because the difficulties are manifold and it is necessary to find key molecular mechanisms and select low cost and high effect small molecular compounds through metabonomic analysis. Firstly, the dairy cow is an active metabolic process for more than twenty days in the early lactation period, the nutrition consumption is large, metabolic disorder needs to be corrected, and a certain nutritional supplement needs to be used every day, so that the dairy cow is sensitive to cost; secondly, the milk cow nutritional supplement is fed through the digestive tract, the problems of low technical threshold and the like of convenient use exist, but the problem of microbial decomposition during rumen bypass is solved, or a nutrient with stable chemical properties and no process is selected.

Some of the advantages of the present formulation are listed below:

1. the invention firstly utilizes rumen-bypass glucose and rumen-bypass pantothenic acid to be matched with rumen-bypass stable compounds such as calcium chloride, potassium chloride, zinc chloride and the like, thereby ensuring the absorption rate.

2. In the early lactation period of the postpartum dairy cows, the milk secretion amount of lactose is large, the lactose is converted from glucose, the required amount of glucose is increased greatly, and if the gluconeogenic metabolic substrates, such as propionic acid, are not ingested and generated sufficiently at the moment or metabolic pathway enzymes are abnormal, hepatic gluconeogenesis disorder and ketosis are caused finally, so that the most direct and effective method is to supplement rumen glucose to solve the sugar deficiency.

3. The glycometabolism of ruminants such as dairy cows is mainly regulated by insulin and glucagon, the hormone can influence the gluconeogenesis rate by regulating the activity and substrates of key enzymes of hepatic gluconeogenesis, wherein the glucagon and the like can enhance the gene expression of PEPCK, and the insulin can inhibit or weaken the hepatic gluconeogenesis. Insulin and glucagon are regulated by potassium and zinc ions, so the formulation supplements potassium chloride, zinc chloride to correct metabolic disorders.

4. The components of the formula maintain stability mutually: calcium chloride, sodium chloride and zinc chloride are all compounds with high thermal stability, and can maintain the stability of rumen-bypass glucose and rumen-bypass pantothenic acid systems in the formula. Pantothenic acid and glucose can be packaged in a rumen bypass system, so that the stability is improved, and the technical difficulty is reduced.

5. The cell experiment data show that the formula of the invention has obvious effect. In example 1, the composite formulation has significant effects on standardized high-throughput cellular experiments.

6. From the trial data of the dairy cows, the formula of the invention is obviously stronger than the mainstream scheme in the market. In terms of action and effect, the formula is found to have better effect than certain marketed formulas by comprehensively utilizing experimental methods such as cell viability experiments, multi-center large sample random comparison in the lactation initial stage of dairy cows and the like through statistical analysis on the basis of obtaining a large amount of data (see example 2 for details).

7. In terms of safety, the auxiliary components of the formula come from metabolism regulation nutrient substances with low toxicity recognized in the industry, and the cytotoxicity of the formula is specially checked in a preliminary experiment, so that the use dose is ensured not to exceed 5% of a toxicity threshold; the effect is increased mainly by means of a small dose of the composite formulation. In addition, the early work of the invention accurately proves the action range and the toxicity threshold of each component of the formula through a standardized high-flux cell experiment, thereby ensuring that the use dosage of each component has certain tolerance and being beneficial to the development and marketing of products.

Detailed description of the preferred embodiments.

The technical embodiments of the present invention will be described in further detail with reference to specific examples.

Example 1 efficacy and safety were assessed based on high throughput standardized cellular experiments.

On the basis of earlier work, the dosage ranges of rumen-bypass glucose, rumen-bypass pantothenic acid, calcium chloride, sodium chloride and zinc chloride in the formula are screened by using a high-flux standard cell experiment.

Based on the earlier stage work of the invention, on the basis of gradient treatment, the key enzyme activity of the glycometabolism pathway is determined by using an absorbance method, an average value is taken as an effect index on the basis of data normalization, and T test analysis is carried out on the basis of data of 5 independent experiments; analyzing the range of the effect and the actual effect of the component in the formula by taking the P less than 0.05 as the standard of obvious difference; the data show that the optimal dose, effective range and toxicity threshold of the components of the formula are rumen bypass glucose (500 g/d, 200-2000g/d, 9000 g/d), rumen bypass pantothenic acid (50 g/d, 20-500g/d, 6000 g/d), calcium chloride (60 g/d, 10-200g/d, 5000 g/d), sodium chloride (20 g/d, 10-200g/d, 3000 g/d) and zinc chloride (10 g/d, 5-50g/d, 400 g/d), and the effectiveness and safety of the related components are good.

Example 2 the prevention effect of ketosis in the early lactation period of cows under better concentration according to the formula is compared with a multi-center experiment at random.

435 cows in the early lactation period of each city are respectively selected from a plurality of farms in three cities of Qingyang, Shaanxi Xian and Xiyang in Gansu province from 7 months to 10 months in 2019. Daily topical appearance of the invention formulation a, marketed products B and C (formulation a at the optimum dose given in example 1, products B and C used as per the instructions) was not discernible and the experiments were performed using a randomized double-blind control principle.

The concentration of beta-hydroxybutyric acid (BHBA) in the blood of the cow, the lactation status and the like are respectively measured, and the results are normalized to generate a female reproductive system function damage score. The results show that the formula A group has no dairy cow ketosis, 11 cases and 7 cases respectively appear when the marketed products B and C are used singly, and no additional symptoms appear in the dairy cows using the formula A, the marketed products B and the marketed products C, and no additional abnormality is found in related physical examination.

The above description is only a preferred embodiment of the present invention, and the scope of the present invention is not limited thereto, and any simple modifications or equivalent substitutions of the technical solutions within the scope of the present invention disclosed by the present invention, which can be obviously obtained by those skilled in the art, should also be considered as the scope of the present invention.