Coated composition comprising a pH-sensitive polymer

Abstract

The present disclosure relates to a pH-sensitive polymer comprising hydrophilic amino acids, hydrophobic amino acids, and fatty acids as monomers, a coating composition comprising the pH-sensitive polymer, and a feed additive coated with the coating composition to prevent its decomposition in the ruminant stomach.

Description

Technical Field

[0001] The present disclosure relates to a pH-sensitive polymer comprising hydrophilic amino acids, hydrophobic amino acids, and fatty acids as monomers, a coating composition comprising the pH-sensitive polymer, and a feed additive coated with the coating composition to prevent its decomposition in the ruminant stomach.

Background Art

[0002] All animals, especially livestock, require sufficient nutrition to grow. Amino acids are organic compounds that make up proteins, and amino acids and proteins are components of living organisms. Proteins are digested or broken down to produce amino acids. Living organisms consume amino acids to produce proteins, break down food, grow, repair body tissues, and perform many other functions. Amino acids can also be used as an energy source. These amino acids are classified into essential amino acids, non-essential amino acids, and conditional amino acids. Among them, the nine essential amino acids are "histidine", "lysine", "tryptophan", "methionine", "threonine", "valine", "leucine", "isoleucine", and "phenylalanine". These essential amino acids are not synthesized in the body and must be ingested through food. Therefore, these essential amino acids are synthesized in vitro by methods such as fermentation and then provided in the form of feed or food additives.

[0003] However, when these amino acids are orally administered to ruminants, the amino acids are destroyed by the action of digestive enzymes and microorganisms present in the forestomach. Therefore, in order for these active ingredients to be useful and beneficial to animals, it is necessary to protect these active ingredients with a substance that allows the active ingredients to pass through the forestomach without damage and decompose in or after the fourth stomach chamber, thereby releasing them in the intestine.

[0004] Methods known so far for protecting amino acids in the ruminant stomach include amino acid mineral chelation methods, methods in which amino acids are coated with pH-sensitive polymers, methods in which amino acids are coated with lipid matrices, etc., and commercial products using these methods include Smartamine MTM, Mepron M85, METHIO-BY. However, the disadvantage of these products is that they are very expensive due to the use of excipients and expensive coating materials. These products also have potential toxicity problems due to the use of petroleum-derived materials.

Summary of the Invention

[0005]

Technical Problem

[0006] As a result of intensive research efforts to find coating compositions for preventing the decomposition of active ingredients such as amino acids in the ruminant stomach, the present applicant has confirmed that an amino acid polymer containing hydrophilic amino acids, hydrophobic amino acids, fatty acids, and optionally a chain extender in a predetermined molar ratio exhibits pH sensitivity, i.e., the amino acid polymer is insoluble at neutral pH but selectively soluble in an acidic solution having a pH of about 2, and thus a feed additive for preventing decomposition in the ruminant stomach can be provided by coating particles containing an active ingredient with a coating composition containing the amino acid polymer, thereby completing the present disclosure.

[0007]

Technical Solution

[0008] An object of the present disclosure is to provide a pH-sensitive polymer including hydrophilic amino acids, hydrophobic amino acids, and fatty acids as monomers.

[0009] Another object of the present disclosure is to provide a coating composition for preventing decomposition in the ruminant stomach, including a pH-sensitive polymer, a fatty acid, and cellulose or its derivative.

[0010] Yet another object of the present disclosure is to provide a feed additive for preventing decomposition in the ruminant stomach, which includes: a core particle containing an active ingredient, and a coating layer formed on the core particle using the coating composition.

[0011]

Advantageous Effects

[0012] The pH-sensitive amino acid polymer of the present disclosure includes a predetermined ratio of hydrophilic amino acids, hydrophobic amino acids, and fatty acids, and thus is almost insoluble under neutral conditions but selectively decomposes under strong acid conditions of about pH 2 as its solubility rapidly increases, and can be effectively used as a coating material for protecting the ruminant stomach of ruminant feed additives.

Brief Description of the Drawings

[0014] Figure 1 is a diagram showing the result of visually confirming the degree of dissolution of the pH-sensitive amino acid polymer according to an embodiment of the present disclosure.

[0015] Figure 2 is a diagram showing the result of visually confirming the degree of dissolution of the pH-sensitive amino acid polymer according to an embodiment of the present disclosure.

Detailed Description of the Invention

[0017] The present invention is as follows. Each description and example disclosed in the present application can also be applied to other descriptions and examples. That is, all combinations of various elements disclosed in the present disclosure fall within the scope of the present disclosure. In addition, the scope of the present disclosure is not limited by the following specific description.

[0018] One aspect of the present disclosure provides a pH-sensitive polymer comprising hydrophilic amino acids, hydrophobic amino acids, and fatty acids as monomers.

[0019] As used herein, a "hydrophilic amino acid" is an amino acid that has a relatively high solubility in water and tends to be located mainly on the outside and in contact with the aqueous environment in the three-dimensional structure of a protein. The hydrophilicity of an amino acid can be quantitatively represented by a numerical value called the hydrophobicity index proposed by Jack Kyte and Russell F. Doolittle. This quantifies the degree of hydrophilicity (hydrophobicity) of an amino acid. For example, the values of arginine and lysine, which are the most hydrophilic, are -4.5 and -3.9, respectively.

[0020] The hydrophilic amino acid used in the pH-sensitive polymer according to the present disclosure can be one or more selected from lysine, arginine, glutamic acid, aspartic acid, glutamine, asparagine, and histidine. For example, lysine, arginine, or a combination of lysine and arginine can be used, but the hydrophilic amino acid is not limited thereto. In this case, the content of the hydrophilic amino acid can be 50 mol% to 75 mol% relative to the total monomers contained in the pH-sensitive polymer according to the present disclosure, but is not limited thereto.

[0021] As used herein, a "hydrophobic amino acid" is an amino acid that has a relatively low solubility in water and participates in van der Waals interactions and contributes to the stabilization of the protein core. The hydrophobicity of an amino acid, like the degree of hydrophilicity, can be quantitatively represented by a numerical value called the hydrophobicity index. This quantifies the degree of hydrophobicity (hydrophilicity) of an amino acid. For example, the values of isoleucine and valine, which have the greatest hydrophobicity, are 4.5 and 4.2, respectively.

[0022] The hydrophobic amino acid used in the pH-sensitive polymer according to the present disclosure can be one or more selected from phenylalanine, tryptophan, isoleucine, leucine, valine, alanine, methionine, cysteine, and tyrosine. The hydrophobic amino acid can be, for example, one or more selected from the group consisting of phenylalanine, tryptophan, valine, and tyrosine, but is not limited thereto. In this case, the content of the hydrophobic amino acid can be 10 mol% to 35 mol% relative to the total monomers contained in the pH-sensitive polymer according to the present disclosure, but is not limited thereto.

[0023] As used herein, the term "fatty acid" refers to, in chemistry, especially in biochemistry, a carboxylic acid having an unsaturated or saturated long aliphatic chain and is an amphoteric substance, the structure of which can be divided into a hydrophilic and water-soluble polar head group and a hydrophobic and insoluble non-polar tail group. Fatty acid is a weak acidic substance, so pK aIt varies little according to the length of the fatty acid chain. Most naturally occurring fatty acids are unbranched hydrocarbon chains with an even number of carbon atoms from 4 to 28. Fatty acids usually exist in organisms in the form of three major types of esters: triglycerides, phospholipids, and cholesterol esters, rather than in an independent form. However, the fatty acids contained in the pH-sensitive amino acid polymers of the present disclosure can be in the form of free fatty acids, rather than in the form of these esters.

[0024] For example, the fatty acid can be a fatty acid having 12 to 18 carbon atoms. Specifically, the fatty acid can be one or more selected from the group consisting of stearic acid, palmitic acid, and lauric acid, but is not limited thereto.

[0025] In this case, the fatty acid can be contained in an amount of 5 mol% to 20 mol% relative to the total monomers contained in the pH-sensitive polymer of the present disclosure, but is not limited thereto.

[0026] The term "chain extender" as used herein refers to a small molecule having two or more functional groups (such as hydroxyl groups, amino groups, or carboxyl groups) in one molecule, and can be added to a polymerization reaction by connecting monomers to monomers in polymer polymerization to form a polymer with a high molecular weight.

[0027] When considering hydrophilic amino acids having a large number of amino groups in the polymer, the chain extender used in the pH-sensitive polymer according to the present disclosure can be glutamic acid or aspartic acid having two carboxyl groups, or a combination of glutamic acid and aspartic acid, thereby facilitating the condensation reaction with hydrophilic amino acids, but is not limited thereto.

[0028] In this case, the chain extender can be contained in an amount of 0 mol% to 15 mol% relative to the total monomers in the pH-sensitive polymer of the present disclosure. The chain extender can be contained, for example, in an amount of 2 mol% to 15 mol%, 3 mol% to 13 mol%, or 5 mol% to 12 mol%, but the content is not limited thereto.

[0029] The content ratios of the hydrophilic amino acids, hydrophobic amino acids, fatty acids, and optional chain extender contained in the pH-sensitive polymer of the present disclosure can be adjusted according to the polymerization of the polymer and / or pH sensitivity, etc.

[0030] As used herein, the term "pH sensitivity" refers to a state that selectively exhibits a predetermined property within a specific pH range. For example, a pH-sensitive polymer may swell or collapse as the pH value of the surrounding medium changes, or its properties may change in various ways. Such pH-sensitive polymers are also used in controlled drug delivery systems, bionics, microelectromechanical systems, separation processes, surface functionalization, etc. As an example, the pH-sensitive polymer of the present disclosure is almost insoluble under neutral conditions similar to about pH 7 in the ruminant stomach, but has significantly excellent solubility under strongly acidic conditions similar to pH 2 in the fourth stomach chamber.

[0031] Another aspect of the present disclosure provides a coating composition comprising a pH-sensitive polymer, a fatty acid, and cellulose or a derivative thereof.

[0032] The coating composition can be applied to feed additives, etc., to provide a coating for protecting the active ingredients contained in feed additives, etc., from decomposition in the ruminant stomach.

[0033] "Cellulose" as used herein is the most abundant polysaccharide existing in nature and is a linear polymer composed of 6-membered ether rings (D-glucose or glucose) covalently linked to each other through ether groups called glycosidic bonds. Cellulose and its derivatives can be regarded as condensation polymers because they are usually composed of thousands of glucose repeating units and produce glucose molecules by hydrolysis. Derivatives of cellulose refer to substances in which some or all of the hydrogen atoms of the hydroxyl groups present in glucose (the monomers constituting cellulose) are replaced by substituents. Derivatives of cellulose (such as ester cellulose, ether cellulose, and nitrated cellulose (nitrocellulose, celluloid) in which the substituents are alkylcarbonyl, alkyl, and nitro, respectively) are commercially available. For example, the cellulose or its derivative contained in the coating composition of the present disclosure may be one or more selected from the group consisting of cellulose itself, ethyl cellulose, and methyl cellulose, which are ether derivatives of cellulose, but are not limited thereto.

[0034] As used herein, the "rumen stomach" refers to the stomach of mammals of the order Artiodactyla, and is also known as the stomach for rumination. Since herbivores mainly ingest roughage, certain parts of the digestive system are particularly well-developed. For example, horses and rabbits have well-developed cecums and colons, but the stomachs of cows and goats are particularly well-developed, forming rumen stomachs, which account for approximately 70% of the entire digestive system. They are also large in volume. The stomach volume of a cow is 200L, while the stomach volume of a pig or a horse is only 6L - 15L. The rumen stomach is divided into four gastric chambers: the first gastric chamber, the rumen; the second gastric chamber, the reticulum; the third gastric chamber, the omasum; and the fourth gastric chamber, the abomasum. The rumen and the reticulum are modified esophaguses, and the omasum and the abomasum correspond to the primitive stomach. The rumen is particularly large, accounting for 80% of the entire stomach, and there are countless papillae on the inner wall of the rumen wall. At the same time, the reticulum mucosa is honeycombed and wrinkled, the omasum has a large number of papillae and wrinkles, and the abomasum has large wrinkles, 13 - 15 for goats and 16 for dairy cows. These four gastric chambers are interconnected, and the digestion process in the rumen stomach is as follows: The coarsely chewed food is sent to the reticulum through the rumen, then agglomerated in the reticulum, sent back to the mouth, undergoes the rumination process, and then enters the omasum, where it is crushed into small pieces and digested in the abomasum. At this time, the only stomach that secretes digestive juice is the abomasum, the fourth gastric chamber, but the crude fiber is fermented by the action of microorganisms in the rumen.

[0035] In another aspect, there is provided a feed additive coated in a manner to prevent decomposition in the rumen stomach, which comprises: a core particle containing an active ingredient, and a coating layer formed on the core particle using a coating composition.

[0036] The active ingredient used in the feed additive of the present disclosure can be an amino acid, an enzyme, a probiotic, a prebiotic, a phage, a vitamin, an organic acid, or a mixture thereof, but is not limited thereto.

[0037] In addition, the feed additive of the present disclosure can be for ruminants, but is not limited thereto.

[0038] As used herein, the term "ruminant" refers to an animal that has a ruminant stomach and ruminates, and is a herbivorous mammal, also known as a ruminant. Animals in the families Camelidae, Tragulidae, Cervidae, Giraffidae, and Bovidae in the mammalian order Artiodactyla belong to this category. The digestion of these ruminants has two characteristics: rumination and microbial decomposition of food. When a monogastric animal ingests food, the monogastric mixes with saliva, crushes the food into small pieces, and swallows the small pieces. However, ruminants do not have incisors, so they roughly chew the food with their tongues and lips, then swallow the roughly chewed food, and then ruminate the roughly chewed food for digestion. It is believed that this rumination mainly occurs at night because ruminants are often preyed upon by carnivores, so they eat a large amount of food in a given time, store the food, and then slowly digest the food in a safe place. As described above, there are several types of microorganisms that ferment food in the first stomach chamber (i.e., the rumen) of ruminants. These microorganisms are digested and absorbed after being decomposed with the food in the fourth stomach chamber and become the nutrients necessary for ruminants.

[0039] In the feed additive of the present disclosure, the coating layer does not decompose in the ruminant stomach with a pH value of 6-8, but selectively decomposes in the fourth stomach chamber with a pH value of less than 3 to release the active ingredient.

[0040] As with other animals, in the case of ruminants, it is necessary to provide nutrients, such as feed containing essential amino acids, to promote growth or endow functions. However, when the nutrients are supplied as unprocessed ingredients, a large amount of the nutrients are decomposed through a series of rumination, such as being decomposed by microorganisms in the rumen, and the nutrients are not transported to the fourth stomach chamber where digestive enzymes work or the small intestine that absorbs nutrients, and are easily lost. Therefore, according to the present disclosure, a feed additive in which the active ingredient is coated with a coating composition containing a pH-sensitive polymer may be suitable as a formulation for supplying amino acids to ruminants because the feed additive does not decompose under neutral conditions like the rumen, but selectively decomposes under strongly acidic conditions similar to the environment of the fourth stomach chamber to dissolve the active ingredient.

Examples

[0041] Hereinafter, the present disclosure will be described in more detail with reference to the following examples. However, the following examples are only for illustrative purposes of the present disclosure, and the scope of the present disclosure is not limited to these.

[0042]

Experimental Example 1: Preparation of pH-sensitive amino acid polymer

[0043]

Experimental Example 1-1: Preparation of pH-sensitive amino acid polymer

[0044] Hydrophilic amino acids and hydrophobic amino acids are used as monomers, and a pH-sensitive amino acid polymer is prepared by thermal condensation polymerization. Specifically, the hydrophilic amino acids and hydrophobic amino acids are placed in a reactor equipped with a stirrer and a condenser, and then stirred and reacted while the temperature is raised to 185 °C. The condensed water generated at this time is discharged through the condenser. At the time point when no more condensed water is generated, the pressure is reduced, and stirring and reaction are carried out under vacuum for 2 to 3 hours. After the reaction is completed, the content is discharged to obtain the title polymer.

[0045]

Experimental Example 1-2: Preparation of a pH-sensitive amino acid polymer incorporating a fatty acid

[0046] Hydrophilic amino acids, hydrophobic amino acids, and fatty acids are used as monomers, and a pH-sensitive amino acid polymer incorporating a fatty acid is prepared by thermal condensation polymerization. Specifically, similar to Experimental Example 1-1, the condensed water generated during the reaction of the hydrophilic amino acids and hydrophobic amino acids is removed through the condenser. At the time point when no more condensed water is generated, the fatty acid is placed in the reactor, then the pressure is reduced, and the mixture is stirred and reacted under vacuum for 2 to 3 hours. After the reaction is completed, the content is discharged to obtain the title polymer.

[0047]

Experimental Example 2: Preparation of a methionine preparation coated in a manner to prevent decomposition in the ruminant stomach

[0048]

Experimental Example 2-1: Preparation of a methionine core

[0049] The active ingredient methionine and polylysine (binder) are mixed with water, and the mixture is extruded using a twin-screw extruder (L / D = 15, screw diameter: 100 mm). The temperature of the extruder is set to room temperature and maintained at a rate of 0.1 ton / day. The extrudate is formed into spherical or cylindrical methionine cores with a particle size of 2.3 mm to 2.8 mm using a conventional ball filter.

[0050]

Experimental Example 2-2: Coating for preventing decomposition in the ruminant stomach

[0051] A coating composition is prepared by dissolving a pH-sensitive amino acid polymer without introducing a fatty acid or a fatty acid, ethyl cellulose, and stearic acid prepared according to Experimental Example 1-1 or 1-2 in an aqueous ethanol solution at 65 °C. The methionine core prepared in Experimental Example 2-1 is placed in a cylindrical pan coater, and the previously prepared coating composition is sprayed at a rate of 4 mL / minute. The coated preparation is dried at room temperature.

[0052]

Experimental Example 3: Preparation of a histidine preparation coated in a manner to prevent decomposition in the ruminant stomach

[0053]

Experimental Example 3-1: Preparation of a histidine core

[0054] The preparation method of the spherical or cylindrical histidine core is the same as that of Experimental Example 2-1, except that histidine in the form of hydrochloride or free form is used instead of methionine as the active ingredient, and further contains defatted soy flour and stearic acid as excipients.

[0055]

Experimental Example 3-2: Coating for preventing decomposition in the ruminant stomach

[0056] The pH-sensitive amino acid polymer is coated in the same manner as Experimental Example 2-2, except that the histidine core prepared according to Experimental Example 3-1 is used instead of the methionine core.

[0057]

Experimental Example 4: Evaluation of bioavailability

[0058]

Experimental Example 4-1: Evaluation of in-situ rumen bypass

[0059] The coated preparation to be protected prepared according to Experimental Examples 2 and 3 was placed and sealed in a nylon bag (R510 from ANKOM Technology). This was incubated in the rumen of 3 rumen-cannulated Holstein castrated cattle (weight: about 630 kg - 650 kg). After the experiment was completed, the nylon bag was washed with water and dried, and the DM and active ingredient contents were measured, and the relative residual amounts were compared.

[0060]

Experimental Example 4-2: Evaluation of in-vitro digestion and decomposition

[0061] The rumen and small intestine were simulated by treating the preparation prepared successively with pepsin, pancreatin, and lipase under phosphate buffer conditions. Specifically, the pH was adjusted to pH 2 by adding 1M HCl to 0.1M KH2PO4 buffer, and then a 25 mg / mL pepsin solution was added. The sample was placed in a nylon bag (F57 from ANKOM Technology) for rumen bypass evaluation, sealed, placed in the solution, mixed, then sealed, and incubated at 39 °C in an incubator (DaisyII from ANKOM Technology). After 2 hours, 0.5 L of 0.2M KH2PO4 was added, the pH was adjusted to pH 7.8 with 1M NaOH, and a 10 mg / mL pancreatin solution was added, and then incubated at 39 °C. After the experiment was completed, the nylon bag was washed with water and dried, and the DM and active ingredient contents were measured.

[0062]

Experimental Example 4-3: Calculation of bioavailability

[0063] The rumen bypass rate is calculated as the ratio of the residual sample after rumen bypass evaluation to the sample before the experiment, and the digestion and decomposition rate is calculated as the ratio of the loss of the active ingredient before evaluation to the lost active ingredient. The bioavailability is calculated based on these values using the following formula:

[0064] Bioavailability (%) = Rumen bypass rate × Digestion and decomposition rate × Active ingredient content (%)

[0065]

Example 1: Analyze the physical properties of a pH-sensitive amino acid polymer that also includes a chain extender

[0066] A pH-sensitive amino acid polymer was prepared according to Experimental Example 1-1, except that a chain extender was also included, and its physical properties were measured and shown in Table 1 below. At this time, lysine was used as a hydrophilic amino acid, phenylalanine and tryptophan were used as hydrophobic amino acids, and glutamic acid was used as a chain extender, and 5 polymers (Polymers A to E) were synthesized in the proportions shown in Table 1 below.

[0067] Specifically, a gel permeation chromatography system (GPC, Waters) equipped with a refractive index detector (RID) was used to analyze the weight-average molecular weight and molecular weight distribution. At this time, polystyrene was used as a standard substance. Meanwhile, a differential scanning calorimeter (DSC, TA Instruments Q20) was used to measure the heat capacity from -20°C to 280°C in a nitrogen atmosphere to calculate the melting temperature (Tm), crystallization temperature (Tc), and glass transition temperature (Tg). In addition, the pH sensitivity was confirmed by immersing the polymer in 0.1 M phosphate buffer (KH2PO4) at pH 2 and pH 7 at a concentration of 20 g / L and observing their changes over time. Each result is shown in Table 1 below, and the changes over time depend on the pH value, and these changes have been confirmed with the naked eye, as Figure 1 shown.

[0068]

Table 1

[0069]

[0070] As shown in Table 1, the microstructure of the pH-sensitive amino acid polymer prepared by changing the proportions of hydrophilic amino acids, hydrophobic amino acids, and chain extender was measured using a differential scanning calorimeter, and it was confirmed that the pH-sensitive amino acid polymer has an amorphous structure. When comparing the solubility of the pH-sensitive amino acid polymer by observing the changes over time, when the content of lysine as a hydrophilic amino acid is as high as more than 57 mol%, and / or when a chain extender is included, a stronger pH sensitivity is exhibited.

[0071]

Example 2: Analyze the physical properties of a pH-sensitive amino acid polymer that also includes a chain extender

[0072] Similar to Example 1, the physical properties of the pH-sensitive amino acid polymers prepared by further including a chain extender were measured and shown in Table 2 below. At this time, lysine was used as the hydrophilic amino acid, phenylalanine or tryptophan as the hydrophobic amino acid, and glutamic acid as the chain extender, and four polymers (Polymers F-I) were synthesized at the ratios shown in Table 2 below.

[0073]

Table 2

[0074]

[0075] As shown in Table 2, the microstructure of the pH-sensitive amino acid polymers prepared by changing the ratios of the hydrophilic amino acid, hydrophobic amino acid, and chain extender was measured using a differential scanning calorimeter, and it was confirmed that the pH-sensitive amino acid polymers had an amorphous structure.

[0076] In addition, the dissolution degree depending on the pH value was confirmed by observing the changes over time of Polymers G and H selected from the polymers, and the results are shown in Table 3 below and Figure 2 .

[0077]

Table 3

[0078]

[0079] As shown in Table 3 and Figure 2 shown, when all the polymers composed of hydrophilic amino acids, hydrophobic amino acids, and chain extenders were prepared at controlled ratios, strong pH sensitivity was exhibited regardless of the type of hydrophobic amino acid.

[0080]

Example 3: Analysis of the Physical Properties of pH-Sensitive Amino Acid Polymers Incorporating Fatty Acids

[0081] pH-sensitive amino acid polymers incorporating fatty acids were prepared according to Experimental Examples 1-2, except that a chain extender was also included, and their physical properties were measured and shown in Table 4 below. At this time, lysine was used as the hydrophilic amino acid, phenylalanine and / or tryptophan as the hydrophobic amino acid, glutamic acid as the chain extender, and stearic acid as the fatty acid, and five polymers (Polymers J-N) were synthesized at the ratios shown in Table 4 below.

[0082] Specifically, as in Example 1, the weight-average molecular weight, molecular weight distribution, melting temperature (Tm), and glass transition temperature (Tg) were calculated, respectively. In addition, the pH sensitivity was confirmed by observing the changes over time of the polymers in solutions at pH 2 and pH 7. Each result is shown in Table 4 below.

[0083]

Table 4

[0084]

[0085]

[0086] As shown in Table 4, the melting temperature found in pure fatty acids was not observed in the pH-sensitive amino acid polymers into which fatty acids were introduced as monomers, indicating that the fatty acids exist in the polymer chain in the form of covalent bonds.

[0087] For the methionine preparations (hereinafter referred to as preparations a to d) for preventing decomposition in the ruminant stomach prepared according to Experimental Example 2, polymers J, K, L, and N were used in the coating composition, the ratio of the coating to the active ingredient was changed, and the bioavailability was evaluated according to Experimental Example 4. The results are shown in Table 5 below. In situ rumen bypass was evaluated by incubating for 48 hours, and all experimental results were calculated based on the product of the DM and active ingredient contents.

[0088]

Table 5

[0089]

[0090] As shown in Table 5, when the preparation was coated with a polymer containing fatty acids, compared with the case where the preparation was coated with a pH-sensitive amino acid polymer having a similar composition but not containing fatty acids, even though the digestion and decomposition rates were slightly lower, the bypass rate was significantly increased and an improvement in bioavailability was expected.

[0091]

Example 4: Evaluation of pH Sensitivity According to Fatty Acid Type

[0092] In the polymerization, 2 different types of fatty acids were used and glutamate was also included as a chain extender. A pH-sensitive amino acid polymer into which fatty acids were introduced was prepared according to Experimental Examples 1-2. At this time, the ratio of each monomer was adjusted to be the same as that in polymer K, and C 18 stearic acid and C 12 lauric acid were used as fatty acids. The pH sensitivity was confirmed by measuring and comparing the solubilities of the polymers prepared above under different pH conditions. Specifically, the polymers were dissolved at a constant concentration in 0.1 M KH2PO4 buffer solutions adjusted to pH 2 and pH 7 with hydrochloric acid and sodium hydroxide, respectively. The supernatant was taken over time and diluted 1000 times, and the absorbance at a wavelength of 200 nm was measured using a UV / visible spectrometer. The absorbances measured over time under each pH condition are shown in Table 6 below.

[0093]

Table 6

[0094]

[0095]

[0096] As shown in Table 6, compared with the polymer containing stearic acid with a relatively higher carbon atom number, in the polymer containing lauric acid, the absorbance at pH 2 is higher and the absorbance at pH 7 is lower. However, although there are differences in degree, regardless of the type of fatty acid, both polymers are almost insoluble under neutral conditions of pH 7, but have significantly high solubility under acidic conditions of pH 2, that is, both exhibit pH sensitivity.

[0097]

Example 5: Physical Property Analysis of pH-Sensitive Amino Acid Polymers Incorporating Fatty Acids in Large Quantities

[0098] The pH-sensitive amino acid polymers incorporating fatty acids according to the present disclosure were mass-produced in a 50 L reactor. As monomers, lysine as a hydrophilic amino acid, tryptophan as a hydrophobic amino acid, glutamic acid as a chain extender, and stearic acid as a fatty acid were used for polymerization, and three polymers (hereinafter referred to as polymers Q, R, and S) were synthesized. The physical properties of these polymers were measured and shown in Table 7 below. At this time, polymers R and S were subjected to continuous batch polymerization. The weight-average molecular weight and glass transition temperature were measured in the same manner as in Example 1. Regarding viscosity, the relative viscosity was measured using a rotational rheometer (rheometer, Anton Paar). In the measurement, the polymer material was placed between the shaft with a gap of 1.0 mm and the parallel plate, and while heating at a rate of 2.5 °C / min in the temperature range of 70 to 190 °C, the shaft was rotated at a constant shear rate. At this time, the relative viscosity at 150 °C was measured based on the behavior of the polymer material. Using a melt flow indexer (Meltflowindexer, Toyoseiki), the melt flow index was measured at 150 °C and a load of 2160 g according to the international standards ISO E1133 and ASTM D1238.

[0099]

Table 7

[0100]

[0101] For the use of polymers Q, R, and S in coating compositions, methionine preparations (hereinafter referred to as preparations e, f, and g) coated in a manner to prevent decomposition in the ruminant stomach prepared according to Experimental Example 2 were subjected to bioavailability evaluation according to Experimental Example 4, and the results are shown in Table 8 below. In situ rumen bypass was evaluated by incubating for 48 hours, and all experimental results were calculated based on the product of the DM and active ingredient content.

[0102]

Table 8

[0103]

[0104]

Example 6: Evaluation of Bioavailability According to the Type of Active Ingredient

[0105] Using the polymer R disclosed in Example 5 in a coating composition, methionine preparations and histidine preparations coated in a manner to prevent decomposition in the ruminant stomach were prepared according to Experimental Examples 2 and 3, respectively, containing methionine and histidine as active ingredients. Three preparations (hereinafter referred to as preparations h, i, and j, respectively) were prepared by adjusting to contain the coating and the active ingredient in the proportions shown in Table 9 below. The bioavailability of these preparations was evaluated according to Experimental Example 4, and the results are shown in Table 9 below. The in situ rumen bypass was evaluated by incubating for 24 hours, and all experimental results were calculated based on the product of the DM and the active ingredient content.

[0106]

Table 9

[0107]

[0108] As shown in Table 9, excellent bioavailability can be achieved regardless of the type of active ingredient by adjusting the proportion of the coating.

[0109] Based on the above description, those skilled in the art can understand that the present disclosure can be implemented in different specific forms without changing its technical spirit or essential features. Therefore, it should be understood that the above embodiments are not restrictive but illustrative in all aspects. The scope of the disclosure is defined by the appended claims rather than by the description preceding them, and thus all changes and modifications belonging to the scope and range of the claims or equivalents of such scope and boundaries are therefore intended to be embraced by the claims.

Claims

1. A pH-sensitive polymer comprising hydrophilic amino acids, hydrophobic amino acids, and fatty acids as monomers, wherein the hydrophilic amino acids are lysine, arginine, or both lysine and arginine, wherein the hydrophobic amino acids are one or more selected from the following: phenylalanine, tryptophan, isoleucine, leucine, valine, alanine, methionine, cysteine, and tyrosine, wherein the hydrophilic amino acids are included at 50 mol% to 75 mol% in the total monomers, wherein the hydrophobic amino acids are included at 10 mol% to 35 mol% in the total monomers, and wherein the fatty acids are included at 5 mol% to 20 mol% in the total monomers.

2. The pH-sensitive polymer according to claim 1, wherein the hydrophilic amino acid is lysine, and wherein the hydrophobic amino acids are phenylalanine, tryptophan, or both phenylalanine and tryptophan.

3. The pH-sensitive polymer according to claim 1, wherein the hydrophobic amino acids are one or more selected from the following: phenylalanine, tryptophan, valine, and tyrosine.

4. The pH-sensitive polymer according to claim 1, wherein the fatty acids are selected from one or more of the following: stearic acid, palmitic acid, and lauric acid.

5. The pH-sensitive polymer according to claim 1, which further includes a chain extender.

6. The pH-sensitive polymer according to claim 5, wherein the chain extender is glutamic acid, aspartic acid, or both glutamic acid and aspartic acid.

7. The pH-sensitive polymer according to claim 1, wherein the hydrophilic amino acids are included at 57 mol% to 75 mol% in the total monomers.

8. The pH-sensitive polymer according to claim 5, wherein the chain extender is included at 0 mol% to 15 mol% in the total monomers.

9. A coating composition comprising the pH-sensitive polymer according to any one of claims 1 to 8, a fatty acid, and cellulose or a derivative thereof.

10. The coating composition according to claim 9, wherein the coating composition is used to prevent decomposition in the ruminant stomach.

11. The coating composition according to claim 9, wherein the fatty acids are selected from one or more of the following: stearic acid, lauric acid, and palmitic acid.

12. The coating composition according to claim 9, wherein the cellulose derivatives are selected from one or more of the following: cellulose, ethyl cellulose, and methyl cellulose.

13. A feed additive coated to prevent decomposition in the ruminant stomach, comprising: a core particle containing an active ingredient, and a coating layer formed on the core particle using the coating composition according to claim 9.

14. The feed additive according to claim 13, wherein the feed additive is for ruminants.

15. The feed additive according to claim 13, wherein the coating layer does not decompose in the ruminant stomach with a pH value of 6 to 8, but rather selectively decomposes in the abomasum with a pH value of less than 3, thereby releasing the active ingredient.

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