阅读说明：本技术 一种替抗包衣复合酸化剂 (Anti-coating compound acidifier ) 是由 罗云 徐涌 于 2020-12-14 设计创作，主要内容包括：公开了一种包衣复合酸化剂,复合酸化剂为延胡索酸和二甲酸钾的组合,并且,包衣复合酸化剂包括载药丸芯和酸不溶性树脂包衣层；延胡索酸和二甲酸钾的重量比为6：(2-6)。该包衣复合酸化剂不仅能降低胃中酸化剂吸收率,又能提高小肠和大肠中的吸收均匀性。(Discloses a coating compound acidifier, which is a combination of fumaric acid and potassium diformate, and comprises a drug-loaded pill core and an acid-insoluble resin coating layer; the weight ratio of fumaric acid to potassium diformate is 6: (2-6). The coated compound acidifier can reduce the absorption rate of acidifier in stomach, and improve the absorption uniformity in small intestine and large intestine.)

1. The coated compound acidifier is a combination of fumaric acid and potassium diformate, and is characterized by comprising a drug-loaded pellet core and an acid-insoluble resin coating layer.

2. The coated compounded acidulant of claim 1 wherein the weight ratio of fumaric acid to potassium diformate is 6: (2-6).

3. The coated compounded acidulant of claim 1 or 2 wherein the solid raw material of the drag pellet core comprises compounded acidulant, corn starch, sodium carboxymethyl starch, white carbon black and microcrystalline cellulose.

4. The coated compounded acidulant according to claim 3 wherein the weight ratio of compounded acidulant, corn starch, sodium carboxymethyl starch, white carbon black and microcrystalline cellulose is (25-35): (25-35): (2-6): (6-10): (24-32).

5. The coated compounded acidulant of claim 3 wherein the drag-loaded pellet core is prepared by mixing the solid material with a binder to prepare a soft mass and then performing an extrusion-spheronization operation.

6. The coated compounded acidulant of claim 5 wherein the binder is selected from 0.5-4wt% hydroxypropyl methylcellulose (HPMC E3) aqueous solution; the addition amount is 20-50v% of the solid material volume.

7. The coated compounded acidulant of claim 1 wherein the acid insoluble resin is selected from acrylic resins which are insoluble at pH 5 or less.

8. The coated compounded acidulant of claim 7 wherein the acrylic resin is selected from the group consisting of a combination of Eudragit L100 and Eudragit S100; the weight ratio of the two is (4-8): (2-4).

9. The coated compounded acidulant of claim 8 wherein the coating solution of the acid insoluble resin coating layer is: 6-12 parts of acrylic resin; 80-120 parts by weight of 90v% ethanol aqueous solution; 1-3 parts of talcum powder; 0.5 to 1.5 weight portions of triethyl citrate.

10. The coated compounded acidulant of claim 1 wherein the acid insoluble resin coating layer weight gain is 18-26 wt%.

Technical Field

The invention belongs to the technical field of animal feed additives, and relates to a substitute-antibody coating compound acidifier.

Background

In recent years, due to the influence of environmental protection, epidemic situation and upstream raw feed cost, the pig raising industry in China is generally in a situation of insufficient supply. In order to maximize the reproductive performance of adult sows, early weaning of piglets (3-4 weeks old) is a common practice. However, since the digestive system of piglets has not developed to maturity at this time, the nervous and endocrine regulatory systems have not been fully established.

In 3-4 weeks after weaning, the yield of lactic acid in the digestive tract of the piglet is greatly reduced, and the endogenous gastric acid secretion is not enough to make up the reduction of the lactic acid; furthermore, part of the gastric acid is easy to combine with the feed raw materials. The pH value of the digestive tract of the weaned piglets is higher than the level after weaning, and the stress response of the piglets, including poor appetite, slow growth speed, diarrhea rate and increased mortality rate after weaning, can be caused in the transition stage from sucking breast milk to eating solid feed by adding factors such as pathogenic microorganisms and inadaptation of feeding environment. These stress responses are collectively referred to as "early weaning stress syndrome".

In order to prevent and treat the above-mentioned stress response of piglets, antibiotics are usually added to pig feed to control inflammatory reactions caused by various types of infections other than viral diseases. However, the use of antibiotics is twofold, which brings great benefits and also recycles into human body through food intake or environmental residue, thus endangering human health and environmental safety. In this large background, countries around the world continue to develop rather strict legislation on the use of antibiotics in livestock breeding. Taking the European Union as an example, the addition of antibiotic growth-promoting feed additives to animal-derived foods was totally prohibited in 2006. The comprehensive treatment scheme (2015-2019) for the five-year action in national veterinary drug (antibacterial) in China forbids antibiotics from being added into the feed. Accordingly, there is an increasing demand by stockbreeders for antibiotic substitutes (abbreviated as surrogate antibiotics) that are highly effective and are beneficial to food safety.

As antibiotic substitutes, plant extracts (e.g., chinese herbal medicines and essential oils), microbial agents (e.g., enzyme preparations and probiotics), acidifying agents (e.g., inorganic acids and organic acids and salts thereof), and metal ion-based antibacterial agents (e.g., high zinc and high copper products), and the like are used in many cases.

Chinese patent CN107319131B discloses a preparation method and application of a natural anti-functional feed additiveThe amorphous powder solid preparation contains drug-resistant bacteria and anti-inflammatory components, and the weight ratio of the amorphous powder solid preparation is 2: 1, peony seed meal powder and soybean meal powder; wherein, the peony seed meal powder contains 2.5-3.0% of drug-resistant bacteria and anti-inflammatory components. The natural feed additive for replacing antibiotics disclosed by the invention contains anti-G in raw materials⁺A bactericidal compound with a bacterium positive bacterium and simultaneously has bactericidal efficacy, namely a stilbene compound. The feed additive provided by the invention is used for livestock and poultry, even ruminants, can improve the growth performance and has the antibiotic-like effect. However, the invention needs to extract oil from peony seed fruit and soybean through screw press, pulverize and sieve the residual cake dregs, mix them, and then dry and sterilize them to obtain amorphous powder solid preparation, the whole process is complicated, and the process applicability is complex.

Chinese patent application CN109511811A discloses a substituted medium-short chain fatty acid essential oil preparation and a preparation method and application thereof, the substituted medium-short chain fatty acid essential oil preparation is mainly prepared from the following raw materials, by weight, 5-20 parts of formic acid, 5-20 parts of butyric acid, 1-5 parts of caproic acid, 1-5 parts of caprylic acid, 1-5 parts of capric acid, 5-20 parts of lauric acid, 3-10 parts of ammonia gas, 5-15 parts of glycerol, 1-5 parts of origanum oil and 20-40 parts of silicon dioxide, and the substituted medium-short chain fatty acid essential oil preparation can replace antibiotics to play a good role in sterilization and bacteriostasis, promote animal growth and does not pollute the environment. However, the preparation of the anti-medium-short chain fatty acid essential oil contains up to 6 kinds of acids, and contains gaseous raw materials such as ammonia gas and solid raw materials of silicon dioxide, and the formula stability is not satisfactory.

In summary, acidulants are the preferred antibiotic substitutes from the standpoint of formulation stability and process suitability of the feed additive.

The acidifying agent includes organic acidifying agents and inorganic acidifying agents. The former mainly comprises citric acid, fumaric acid, lactic acid, formic acid, propionic acid, etc.; the organic acid has good flavor and can directly enter the tricarboxylic acid cycle in vivo. The latter mainly includes sulfuric acid, hydrochloric acid, phosphoric acid, etc.; the inorganic acid has better effects of reducing the pH value and sterilizing.

However, any acidulant is corrosive and affects mineral metabolism in animals. In addition, the formula of the acidifier also has the defect of unstable use effect, and mainly comprises: the absorption speed of the acidifier in the stomach is too high, so that the gastric acid secretion and the normal development of the stomach function are inhibited; only a small part of the acidifying agent reaches the small intestine and the large intestine, and cannot effectively reduce the pH value in the small intestine, so that the growth of Escherichia coli is difficult to inhibit.

In response to the above technical deficiencies, there remains a need to find a tiantian coated acidulant that not only reduces the absorption rate of the acidulant in the stomach, but also improves the uniformity of absorption in the small and large intestine.

On the other hand, there are also a few complex acidifiers in the prior art. The acidifier can realize broad-spectrum bacteriostasis and bacterium regulation in a wider pH value range. There are differences in the effect of different kinds of acidifying agents on the palatability of feed.

The inventor finds that the combination of fumaric acid and potassium diformate is not reported as a compound acidifier through scientific and technological investigation. Fumaric acid is known to improve the production performance of piglets by adding organic acid into the daily ration of weaned piglets; potassium diformate is the first non-antibiotic feed additive approved by the European Union to replace antibiotics. Both the two have certain effects of resisting bacterial infection, improving the nutrient digestibility of the feed and the like, and have obvious growth promoting effect on piglets and growing-finishing pigs.

The inventor finds that the effect of the compound acidifier obtained by combining the two acidifiers on improving the production performance of animals is better than that of the single acidifier.

In combination with the above two reasons, there is a need to find a tiantian coated complex acidifier that not only reduces the absorption rate of acidifier in stomach but also improves the absorption uniformity in small and large intestine.

Disclosure of Invention

The invention aims to provide a substitute anti-coating compound acidifier. The tiantian coated compound acidifier provided by the invention can reduce the absorptivity of an acidifier in stomach and improve the absorption uniformity in small intestine and large intestine. In particular, the absorption of the gastric acidifying agent is reduced to below 10%, while the absorption in both the small and large intestine is above 30%. The absorption characteristics described above are effective in reducing the pH in the small intestine while inhibiting the growth of E.coli.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

the coated compound acidifier is a combination of fumaric acid and potassium diformate, and is characterized by comprising a drug-loaded pellet core and an acid-insoluble resin coating layer.

The coating compound acidifier provided by the invention is characterized in that the weight ratio of fumaric acid to potassium diformate is 6: (2-6).

Preferably, the weight ratio of fumaric acid to potassium diformate is 6: (3-5).

In a specific embodiment, the weight ratio of fumaric acid to potassium diformate is 3: 2.

the coated compound acidifier comprises a solid raw material of a drug-loaded pellet core, wherein the solid raw material comprises a compound acidifier, corn starch, sodium carboxymethyl starch, white carbon black and microcrystalline cellulose.

The coated compound acidulant provided by the invention is prepared from the following components in parts by weight: (25-35): (2-6): (6-10): (24-32).

Preferably, the weight ratio of the compound acidifier to the corn starch to the sodium carboxymethyl starch to the white carbon black to the microcrystalline cellulose is (20-30): (20-30): (3-5): (7-9): (26-30).

In a specific embodiment, the weight ratio of the compound acidulant to the corn starch to the sodium carboxymethyl starch to the white carbon black to the microcrystalline cellulose is 25: 25: 4: 8: 28.

the coated compound acidifier is prepared by mixing the solid raw materials and the adhesive to prepare a soft material and then performing extrusion-spheronization operation on the soft material.

The coated compounded acidulant according to the invention wherein the binder is selected from 0.5-4wt% hydroxypropyl methylcellulose (HPMC E3) aqueous solution; the addition amount is 20-50v% of the solid material volume.

Preferably, the binder is selected from 1-3 wt% HPMC E3 aqueous solution; the addition amount is 30-40 v% of the solid material volume.

In a specific embodiment, the binder is selected from a 2 wt% HPMC E3 aqueous solution; the amount added was one third of the volume of the solid material.

The coating compound acidifier is characterized in that the acid-insoluble resin is selected from acrylic resins which are insoluble under the condition of pH less than or equal to 5.

Preferably, the acid-insoluble resin is selected from acrylic resins that do not dissolve at a pH of 5.5 or less.

In one embodiment, the acid-insoluble resin is selected from acrylic resins that do not dissolve at a pH of 6 or less.

The coated compounded acidulant of the invention wherein the acrylic resin is selected from the group consisting of Eudragit L100 and Eudragit S100 in combination; the weight ratio of the two is (4-8): (2-4).

Preferably, the acrylic resin is selected from the group consisting of Eudragit L100 and Eudragit S100; the weight ratio of the two is (5-7): (2.5-3.5).

In a specific embodiment, the acrylic resin is selected from the group consisting of Eudragit L100 and Eudragit S100; the weight ratio of the two is 2: 1.

the coating compound acidifying agent of the present invention comprises the following components in parts by weight: 6-12 parts of acrylic resin; 80-120 parts by weight of 90v% ethanol aqueous solution; 1-3 parts of talcum powder; 0.5 to 1.5 weight portions of triethyl citrate.

Preferably, the coating solution of the acid-insoluble composite resin coating layer is: 8-10 parts of acrylic resin; 90-110 parts by weight of 90v% ethanol aqueous solution; 1.5-2.5 parts of talcum powder; 0.8 to 1.2 weight portions of triethyl citrate.

In a specific embodiment, the coating solution of the acid-insoluble resin coating layer is: 9 parts of acrylic resin; 100 parts by weight of 90v% ethanol aqueous solution; 2 parts of talcum powder; 1 part by weight of triethyl citrate.

The coating compound acidifier comprises an acid-insoluble resin coating layer, wherein the weight of the acid-insoluble resin coating layer is increased by 18-26 wt%.

Preferably, the weight increase of the acid-insoluble resin coating layer is 20 to 24 wt%.

In a specific embodiment, the weight gain of the acid-insoluble resin coating layer is 22 wt%.

The preparation method of the coated compound acidulant comprises the following steps:

mixing the solid raw material and an adhesive to prepare a soft material, and performing extrusion-rounding operation to prepare a drug-loaded pill core;

coating the drug-loaded pellets by using the coating solution to prepare the coating compound acidifier.

The preparation method provided by the invention is characterized in that the process parameters of the rounding operation are as follows: the rolling speed is 300-700rpm, and the rolling time is 1-5 min.

Preferably, the rounding rotating speed is 400-600rpm, and the rounding time is 2-4 min.

In a specific embodiment, the spheronization speed is 500rpm and the spheronization time is 3 min.

The preparation method provided by the invention comprises the following process parameters of bottom spraying coating: the air inlet temperature is 40-60 ℃, the material temperature is 35-55 ℃, the working frequency is 40-60Hz, the spraying pressure is 0.08-0.18MPa, and the liquid spraying speed is 0.5-1.5 mL/min.

Preferably, the air inlet temperature is 45-55 ℃, the material temperature is 40-50 ℃, the working frequency is 45-55Hz, the spraying pressure is 0.1-0.15MPa, and the liquid spraying speed is 0.8-1.2 mL/min.

In a specific embodiment, the air inlet temperature is 50 ℃, the material temperature is 45 ℃, the working frequency is 50Hz, the spraying pressure is 0.12MPa, and the liquid spraying speed is 1 mL/min.

The beneficial technical effects of the invention are as follows: the tegaserod coating compound acidifier not only can reduce the absorptivity of the acidifier in the stomach, but also can improve the absorption uniformity in the small intestine and the large intestine; in particular, the absorption of the gastric acidifying agent is reduced to below 10%, while the absorption in both the small and large intestine is above 30%. The absorption characteristics described above are effective in reducing the pH in the small intestine while inhibiting the growth of E.coli.

Without wishing to be bound by any theory, the specific formulation of the dragee core and the coating layer produce a synergistic effect, thereby achieving the above-described effect.

Detailed Description

The examples are provided for better illustration of the present invention, but the present invention is not limited to the examples.

Example 1

Fumaric acid and potassium diformate are added according to the weight ratio of 3: 2 mixing to form the compound acidifying agent. According to the following steps of 25: 25: 4: 8: 28 weight percent, sieving the compound acidulant, corn starch, sodium carboxymethyl starch, white carbon black and microcrystalline cellulose through a 100 mesh sieve and mixing well, then adding a 2 wt% hydroxypropyl methyl cellulose (HPMC E3) aqueous solution one third of the solid material volume to prepare a soft mass. Putting the uniformly mixed soft material into an extrusion-rounding machine, and extruding the soft material into strip soft material through a screen with the aperture of 0.8mm at the rotating speed of 50 rpm; rolling the strip-shaped soft material into a circle; the rolling speed is 500rpm, and the rolling time is 3 min; obtain the drug-loaded pellet with high sphericity. Drying the drug-loaded pellets at 50 ℃ for 2h, sieving and retaining the 20-30 mesh drug-loaded pellets to obtain the drug-loaded pellets.

Adding 6 parts by weight and 3 parts by weight of each of Eudragit L100 and Eudragit S100 into 100 parts by weight of 90v% ethanol aqueous solution, and stirring to completely dissolve the mixture; then adding 2 parts by weight and 1 part by weight of each of talcum powder and triethyl citrate, and uniformly mixing to obtain the coating liquid. And (3) placing the drug-loaded pellets in a fluidized bed granulation coating machine for bottom spraying coating, and controlling the weight gain of the coating to be 22 wt%. The air inlet temperature is 50 ℃, the material temperature is 45 ℃, the working frequency is 50Hz, the spraying pressure is 0.12MPa, and the spraying speed is 1 mL/min. The coating solution was stirred continuously during the coating process, and after coating, it was dried at 50 ℃ for 10min to obtain the tiantian coating compound acidifier of example 1.

Comparative example 1

Otherwise, the procedure was as in example 1 except that Eudragit L100 was not used and only Eudragit S1009 parts by weight was used.

Comparative example 2

The other conditions were the same as in example 1, but the drug-loaded pellets were not coated.

Digestion and absorption test

According to the invention, simulated pig gastric juice, pig small intestine liquid and pig large intestine liquid, as well as pig stomach buffer solution, small intestine buffer solution and large intestine buffer solution are prepared by referring to a bionic method of Chengliang et al (Chinese agricultural science, 2013, 46(15) and 3199-page 3205) for evaluating influence factors of feed dry matter digestibility. The digestibility of the present invention in example 1 and comparative examples 1-2 was then evaluated on a monogastric bionic digestion system SDS-2. After the digestion period of each stage is finished, accurately sucking 1mL of buffer solution, placing the buffer solution in a 10mL volumetric flask, and fixing the volume to the scale by using 0.4 wt% phosphoric acid solution. 20 μ L of the extract was measured using a pipette and injected into a liquid chromatograph. The chromatographic conditions are as follows: c18 silica gel column (250 mm. times.4.6 mm. times.5 μm), 0.4 wt% phosphoric acid solution-methanol (80:20), detection wavelength 210 nm; the flow rate is 1 mL/min; column temperature: at 25 ℃. Calculating the absorption rate of fumaric acid in pig stomach, small intestine and large intestine by using standard reference substance according to external standard method; further, considering that potassium diformate has been mostly decomposed into formic acid and potassium formate in the small intestine and the large intestine, the absorption rates thereof in the small intestine and the large intestine are calculated by using respective controls of potassium diformate and potassium formate and then converted by adding them.

The results are shown in Table 1.

TABLE 1

As can be seen from the results, the tiantian coating complex acidulant according to example 1 of the present invention can not only reduce the absorption rate of the acidulant in the stomach but also improve the absorption uniformity in the small and large intestines as compared with comparative examples 1-2. The absorption characteristics described above are effective in reducing the pH in the small intestine while inhibiting the growth of E.coli.

It should be understood that the detailed description of the invention is merely illustrative of the spirit and principles of the invention and is not intended to limit the scope of the invention. Furthermore, it should be understood that various changes, substitutions, deletions, modifications or adjustments may be made by those skilled in the art after reading the disclosure of the present invention, and such equivalents are also within the scope of the invention as defined in the appended claims.