JPH0357732B2 - - Google Patents

Description

Claim 1: comprising coating a core material with a coating composition comprising a film-forming polymeric material, a hydrophobic material, and flake particles, the flake particles being brought into frictional contact with the hydrophobic material prior to coating. A method for producing a small coated pill comprising a core material and a film, characterized in that:

2. The method according to claim 1, wherein the flake material and the hydrophobic material are ball milled.

3. The method according to claim 1 or 2, wherein the duration of the frictional contact is between 2 and 28 hours.

4. The method according to claim 3, wherein the frictional contact is performed under a mild shear stress of 0.1 to 20 kg/ ^cm2 .

Specification The present invention generally relates to a method of manufacturing pellets for oral administration to ruminants. More particularly, the present invention relates to a method for producing pellets having a core material, such as a nutrient or drug, and a coating on the core material that protects the core in the rumen environment. The membrane loses its continuity under the more acidic conditions of the abomasum, and the nuclear material becomes available to the animal.

In ruminants, such as beef and dairy cattle, sheep, etc., ingested feed first passes into the proventriculus, where it is predigested by fermentation. The feed ingested during this fermentation period is ruminated. Rumination is part of the digestive process that includes eating back. After the fermentation phase, adsorption (absorption) of digested nutrients begins and continues in the next part of the digestive tract. This digestive process is
Digestive Physiology and Nutrition of Luminants, by DC Church.
and Nutrition of Ruminants, Volume 1, OSU Book Stores, Inc., Corvallis, Oregon.
is described in detail.

When manufacturing nutrients and drugs intended for administration to ruminants, it is important to protect the active ingredients from the environmental conditions of the forestomach, i.e. from microbial degradation, and to maintain a pH in the range of 5.5 to 7.0. It is to protect the active ingredient from influences. When protected in this way, the active substance will be protected until it reaches the predetermined location where absorption occurs. Meat, wool and/or milk production if the essential amino acid sources and/or drugs that control development are protected from modification by microorganisms present in the proventriculus and later available for direct adsorption by the animal in the gastrointestinal tract. It is well known that speed can be increased.

Because proteins are susceptible to degradation in the proventriculus, it has been proposed to process protein-containing nutrients fed to ruminants so that they can pass through the forestomach to the abomasum without being degraded by microorganisms. Ta. The proposed method involves coating the protein material with, for example, fats and vegetable oils; heat treating the protein material; coating the protein material with formaldehyde, acetylenic esters, polymerized unsaturated carbon residues or carboxylic acid anhydrides and nitrided halides. This involved reacting with various compounds such as phosphorus and the like.

The pellets described in US Pat. No. 4,181,708 have a core comprising nutrients and/or drug and a desired coating on the core. This capsule protects the nucleus in the forestomach environment. The continuity of the capsule is broken in the more acidic conditions of the abomasum, thereby releasing the nuclear material. Although this patent discloses a coating comprising a polymer, a hydrophobe, and a flake material, it does not disclose any treatment of the flake material.

These pellets are highly desirable ruminant feed. However, further improvements are needed in the forestomach protection provided by pill capsules. If the coating is improved, U.S. Patent No.
The same forestomach protection could be achieved using less coating material than the pellets described in No. 4181708, or greater protection could be achieved using the same amount of coating material. Thus, the problem to be solved was to provide a coating material that provided greater forestomach protection. The present method solves this problem.

More particularly, the invention comprises coating a core material with a coating composition comprising a film-forming polymeric material, a hydrophobic material, and flake particles, wherein the flake particles are mixed with the hydrophobic material prior to coating. characterized by bringing it into frictional contact with
A method for manufacturing a coated pellet comprising a core material and a film is provided.

According to the present invention, the flake material is treated by bringing the particles into frictional contact with a hydrophobic material, preferably in a liquid medium, for a period of time sufficient to render the flake material more hydrophobic. Generally, at least mild shear stress and/or direct pressure (0.1
~20Kg/ ^cm2 ) for 2 to 28 hours is sufficient. Thus, the surface energy of the flake material is changed to become more hydrophobic. It has been found that the flake material can be substantially improved in forestomach protection by such special treatment.

To bring the flake material and the hydrophobic material into frictional contact, they are preferably ball milled. However, other conventional methods and devices can also be used. For example, other milling methods,
Grinding, vigorous mixing, etc. may also be used. If desired, vehicles such as mineral spirits, volatile hydrocarbons and ketones may be used to disperse the hydrophobic and flake materials.

Preferred ball mills used to carry out the present invention include:
It comprises a cylindrical container mounted horizontally and incompletely filled with ceramic balls. Surface modification of the flake material by hydrophobes in acetone is sufficient to cause the balls to rise to one side and then cause them to roll, slide and fall towards the lower side. This is done by rotating the ball mill and its contents about the horizontal axis of the ball mill at a high speed.

The laboratory method carried out in the present invention is as follows: 1. Weigh out approximately 570 g of ceramic balls and add these balls into a ball mill. The total volume of the bowl is approximately 15-25% of the volume of the cylindrical container.

2 137g mixture of flake material and hydrophobic substance
and 320 ml of acetone are added to the ball mill and the vessel is closed to minimize evaporation of acetone during the operation.

Rotate the ball mill on rollers for 16 hours at a speed of 3 to 90 times/min.

4 Decant the contents and clean the container and bowl with acetone. The dispersion can be used as is for preparing coating compositions, or the dispersion can be dried by evaporating the acetone at 50°C. The dry mixture of flake material/hydrophobe is then redispersed in a polymer solution to make the coating composition.

In the practice of the present invention, the polymeric material can generally be dissolved in a suitable physiologically acceptable organic solvent if a residue is left behind upon evaporation of the solvent. Hydrophobic substances and flake materials are
The polymeric material is mixed in a solution in which it is a dispersed matrix and the additives are dispersed therein. The coating solution can be applied by various known means, such as brushing, dipping, spraying, fluidized bed, and the like.

To illustrate the invention, poly(2-methyl-
A sample of 5-vinylpyridine/styrene, 80/20) can be dissolved in acetone and added to this, with stirring, a dry mixture of flake material/hydrophobe or flake material/hydrophobe/
Add some of the acetone dispersion. Mix the dispersion vigorously for 40 minutes. During the coaching process
A small amount of water (less than 8%) may be added to the dispersion to minimize static charges.

An air suspension coater can be used to spray coat nutrient particles containing methionine, glucose, lysine or other active ingredients. Typical coating temperatures are 50°C and 32°C for inlet and outlet air, respectively. In a typical coaching operation, one
Kg/ ^cm2 hot air ^0.7m3 /min is introduced to circulate the nutrient particles. The coating dispersion was sucked and expelled by a precision pump at a rate of 20 ml/min and 0.15 m ³ /min.
(3 Kg/cm ² ) of compressed air from the nozzle. The product is in the form of pellets encapsulated by a flaky polymer film.

The coating weight is determined by dispersing and rinsing 1 g of the coated pellets several times with 50 ml of acetone until the coating dissolves. Determine the weight loss of the coated pellets and calculate the percent film overlap.

The pellets prepared according to the invention are for oral administration to ruminants. These pellets have suitable dimensions, e.g. US Standard Sieve Dimensions.
Sieve Size) No. 10 to No. 18 is preferable.
In addition, the small pills have an appropriate density, preferably 1 to 1.4
It should have a specific gravity of , and preferably have an acceptable odor, taste, feel, etc. The pellets contain a nucleus and a continuous film or membrane that completely encapsulates the nucleus. Small pills are cylindrical with a diameter of 1.0-2.0 mm and a length-to-diameter ratio of 1-2.0:1 or a diameter of 1.0-2.0 mm.
Preferably, it is 3.0 mm spherical.

The nucleus is made of material that is beneficial to the ruminant as it passes through the forestomach and reaches the abomasum and/or intestine. Typically, the core is a solid material that has been formed into particles, such as by pelletizing. The core must have sufficient stickiness, ie, consistency, to remain intact during handling, especially during coating operations. Suitable core materials include a variety of drugs and nutrients, such as antibiotics, relaxants, drugs, anthelmintics, amino acids, proteins, sugars, carbohydrates, and the like. The core can also include an inert filler such as clay. Other suitable core materials are described in the aforementioned US Pat. No. 4,181,708.

The coating composition can form a continuous film around the core by evaporating the solvent from the coating composition. Preferably, the coating composition material is resistant to PH conditions greater than 5 for 6 to 30 hours. Preferably, the coating composition releases the core material after exposure to abomasal environmental conditions of PH 2 to 3.3. Release occurs within the residence time in the abomasum or later in the intestinal tract, but within at least 6 hours after contact with PH 3.5 or below. The nucleus is
The membrane can be exposed by becoming permeable to the contents of the forestomach, such as by dissolution, disintegration, or expansive swelling. The coating composition is physiologically acceptable. That is, the coating composition should not impair the healthy or normal body functions of the ruminant.

The coating composition can withstand abrasion at relatively high temperatures and/or temperature handling and storage conditions without significant amounts of blocking or sticking. Preferably, the coating composition has a stick temperature greater than 50°C. The adhesion temperature is such that the force of 0.25Kg/ ^cm2 applied over 24 hours causes the film of a small pill to adhere very strongly to the film of an adjacent small pill, causing the film to break when the sticky pills are forcibly separated. Defined as temperature. The coating composition also has a boiling point between 40 and 140 so that conventional coating methods such as spray coating can be used.
Preferably, it can be dissolved or decomposed in an organic solvent at .degree. Particularly suitable solvents include methylene chloride, chloroform, ethanol, methanol, ethyl acetate, acetone, toluene, isopropanol or mixtures thereof.

The coating composition includes a mixture or blend of at least one polymeric material, at least one hydrophobic material, and at least one flake material. In general, the more acidic and more soluble the core material, the higher the ratio of hydrophobic and flake material to polymeric material, while the more basic and more insoluble the core material, the higher the ratio of hydrophobic and flake material to the polymeric material. The ratio to molecular material can be small within a range. The hydrophobe and flake material are typically dispersed in a polymeric matrix. The coating typically contains 16-87% by weight of polymeric material, 0.5-32% by weight of hydrophobic material, and 7-80% by weight of flake material.

Polymers suitable for coaching compositions are described in the aforementioned US Pat. No. 4,181,708. Particularly preferred polymers are poly(vinylpyridine), polymeric derivatives of vinylpyridine, and copolymers of various isomers and derivatives of vinylpyridine copolymerized with one or more addition type monomers. Among them, 2-
Copolymers of methyl-5-vinylpyridine and styrene, especially copolymers of 75-85% by weight of 2-methyl-5-vinylpyridine and 15-25% by weight of styrene and 2-methyl-5-vinylpyridine 55
~65% by weight of acrylonitrile and 35-45% by weight of acrylonitrile. Copolymers of 75-85% by weight of 2-vinylpyridine and 25-15% by weight of styrene are also particularly preferred. These copolymers are commercially available or can be prepared according to conventional methods known in the art.

Hydrophobic materials are commercially available that are physiologically acceptable and have appropriate miscibility with polymers. It is important that the polymer and hydrophobic material have a miscibility that leaves the film intact in the forestomach environment but allows abomasal fluid to penetrate into the nucleus during residence of the pill in the abomasum. be.

Useful hydrophobes include fatty acids having 10 to 32 carbon atoms such as lauric acid, oleic acid, stearic acid, palmitic acid and linoleic acid. It is well known that these substances are water-insoluble due to their long-chain hydrocarbon groups but are water-reactive due to the polarity of their carboxyl groups. In selected basic amino group-containing polymers, the carboxyl groups of fatty acids can react with basic nitrogen groups to form weak salt-type bonds. This bond to the polymer serves to fix the fatty acid within the polymer matrix. The hydrophobic hydrocarbon chains of the fatty acids help make the matrix water resistant, thus reducing swelling of the otherwise water-absorbing polar film. In this way, both the inside and surface of the matrix film have a pH of 5.0.
Water resistant in higher aqueous environments. However, at PH values below 4.5, especially below 3.5, the affinity of the basic nitrogen groups for water and hydrogen ions overcomes the increased water resistance. The film reacts with the acidic environment and loses sufficient barrier properties to allow the nuclear material to escape from the environment.

Polyfunctional carboxylic acids can be obtained from natural products or by organic synthesis, but the ratio of carboxyl groups to hydrophobic organic groups should be at least 1 to 10, based on the molecular weight of the organic groups. . Synthesized hydrophobic organic acids of this type also include monofunctional and Also included are polyfunctional acids. Furthermore, hydrophobic substances of this type include non-toxic polyvalent metal salts of the acids;
For example, the calcium stearates, oleates, fatty acid dimerates and palmitates of aluminum and iron and the higher molecular weight crystalline analogs of said acids;
Also included are magnesium and zinc salts. For aluminum and ferric iron, when the cation is trivalent, the molar ratio of organic acid to metal ion is 2:1 or 3:1, and the acid is bonded to one carboxyl group to the carboxyl group. It can be any monofunctional organic acid having at least 10 carbon atoms in the organic group. When the metal ion is divalent, such as ferrous, calcium, magnesium, or zinc, the organic acid may be a monocarboxylic or polycarboxylic acid, with a The ratio is at least 1:26. Natural and synthetic waxes and resins are useful in the present invention, added in amounts depending on the degree of hydrophobicity and miscibility in the matrix film. "Contact Angle Wettability and Adhesion"
Advances in Chemistry Series No. 43, No. 1
Chapter [Robert F. Gould
Edited by American Chemical Society
Published in 1963 by Zisman.
Waxes and resins having a critical surface tension of less than 31 dynes/cm as measured by the method and having a solubility in the matrix film of less than 5% are useful. These waxes and resins have a solubility of at least 2
30 times the amount and the total weight of the matrix polymer.
% or less in the film. Representative waxes and resins include beeswax, paraffin wax, dammar fat, hard manila resin, phenolic resin, and maleated low molecular weight polyhydrocarbons.
In addition, hydrophobic substances have a weight average molecular weight of 2000~
1,000,000 and a critical surface tension of less than 31 dyne% cm as measured by the method related to Zisman described above. Useful polymers have a solubility or miscibility in the matrix film of 5% by weight.
present in the film in an amount that is at least twice its solubility and less than 30% by weight of the matrix film. Particularly useful are polymers and copolymers containing silicone groups in the main chain or side chains of the polymer and those containing fluorinated carbon atoms in the side chains. Regardless of its nature, the hydrophobic substance must be soluble or colloidally dispersible in the coating solvent during use. The hydrophobe constitutes 1-50% of the total weight of the polymeric material and hydrophobe.

Suitable hydrophobic substances include those with a carbon number of 12 to
32 fatty acids, such as oleic and stearic acids, dimer acids, trimer acids, aluminum salts of fatty acids, waxes, resins, and certain polymers such as those containing very hydrophobic chemical groups, such as silicone groups. Examples include certain polyvalent positive soaps. The hydrophobic substance may be amorphous or crystalline and, if a solvent is used, preferably be essentially dispersible in the coating solvent, in which case it does not substantially affect the solution viscosity. It should not be something that is given.

Aluminum salts of such acids, such as aluminum oleate, aluminum stearate, aluminum dimerate, are also useful.
Also, hydrophobic materials have 10 to 22 per carboxyl group.
The polycarboxylic acid may be one or more polycarboxylic acids having 5 carbon atoms. Blends of these acids and/or salts are also useful.

Suitable inert flake materials include metal flakes, mineral flakes, crosslinked organic polymers, and the like. Particularly suitable are aluminum flakes,
Talc, graphite and mica powder. A preferred flake material is a blend of aluminum and talc.

Aluminum flakes are produced by ball milling aluminum in a liquid medium and in the presence of a lubricant such as stearic acid.
Aluminum flakes are manufactured by Alcon Metal Powders and Division of Alcon Aluminum.
Corporation). The size of the flakes is generally less than 100 microns, preferably about 1
~60 microns. The particle size of talc is generally 0.5
~40 microns.

In a preferred embodiment, the coating composition comprises (a) 16-87% of the film-forming polymeric material, based on the total composition weight; (b) a hydrophobic material dispersed in the polymeric material, based on the total composition weight. and (c) 7 to 80%, by weight of the total composition, of flake material dispersed in the polymeric material.

As previously mentioned, the polymeric materials blended with the hydrophobic materials and flake materials described above can be physiologically tolerated and resistant to pH above 5;
At a pH below 3.5 the pellet core can be released and the film preferably has a sticking temperature of at least 50°C.

The performance of the coated pellets is evaluated by in vitro simulated tests of forestomach protection and abomasal release.

The protection test described in the examples is carried out by stirring 1 g of the coated pellets in a sodium acetate buffer with a pH of 5.4 for 24 hours in a water bath at 37°C. The release test was conducted using 1g of coated small pills.
by extraction in sodium citrate at pH 2.9 for 1 hour in a water bath at 37°C.
The supernatants obtained from the various media are centrifuged to remove undissolved pellets and other insoluble matter. Methionine and chloride ion concentrations in the supernatants obtained from the coated methionine and lysine HCl pellets, respectively, are determined by X-ray fluorescence. Glucose concentration in the supernatant is determined by superimposition or colorimetric methods. Percent protection is calculated from the difference between the initial amount of active ingredient in the coated pill and the amount of active ingredient released into the vehicle.

In order to enhance the understanding of the invention, the following examples are included. Although the examples are based on in vitro studies, the in vitro experiments shown in the examples simulate conditions that exist in ruminants, thus allowing the study of coated pellets without the use of live animals. do. Testing of the pellets in the aqueous medium used in the example, simulating the environmental conditions of the forestomach and abomasum in terms of temperature, pH, etc., revealed the protection afforded by the membrane in the forestomach and of the membrane in the abomasum. Actual in vivo tests have confirmed that reliable data regarding release are provided. Nutrients such as amino acids and proteins available in the core material are known to be beneficial to ruminants when located in the intestinal tract below the forestomach.

Generally, small pills are made from sieve size based on the nutrients applied.
Prepared to size 10 to 18. The nutrients are mixed with conventional additives such as microcrystalline cellulose, binders, inert consistency modifiers, water, and the like. The pellets are formed on a conventional pellet machine, dried, sieved, and coated using the coater described herein. After forming a non-porous film on the pill, the pill has a pH of 2.9.
in a buffer solution of 0.5 hours and in a buffer solution of PH5.4
Test resistance to PH conditions similar to forestomach and abomasum by stirring for 24 hours. The recovery and protection values stated herein for active core components are for initial coated pellets that are not completely soluble in a pH 2.9 buffer containing all undissolved active component in the initial core. Contains all materials.

Example 1 Methionine nucleus (-12/+16 sieve size, US standard.
-12/+16 means that the core passes through a No. 12 sieve with an opening of 1.68 mm, but not through a No. 16 sieve with an opening of 1.19 mm). / styrene, 80/20) [hereinafter,
(referred to as 2M5VP/ST)]/talc/aluminum/calcium stearate (weight ratio 31.5/
38.1/25.4/5.0). Talc, aluminum flakes and calcium stearate ~40% in acetone
A 5% solids coating composition was prepared by ball milling w/v and then mixing with the polymer solution. The pellets were coated using the air suspension coater described above. The protection values for the pellets coated with the surface modified flake formulation showed an improvement over the control pellets that were not ball milled. The ball milled flake material requires only 8.5% by weight of the coating to provide 90% methionine protection, whereas the control pill requires 13% by weight of the coating to achieve the same value.

Example 2 Methionine cores (-12/+16 sieve size) were coated with a coating composition consisting of (2M5VP/ST)/talc/aluminum/stearic acid (weight ratio 31.5/38.1/25.4/5.0). talc,
Aluminum flakes and stearic acid were ball milled at 40% w/v in acetone and then mixed with the polymer solution to prepare a 5% solids coating composition. The pellets were coated as described above. The protection and efficiency of the ball milled coatings showed improvement over the untreated control at all coating levels.

Example 3 Methionine cores (-12/+16 sieve size) were coated with a coating composition consisting of (2M5VP/ST)/talc/stearic acid (31.5/65/3.5). In preparing the coating composition,
Talc and stearic acid were ball milled in acetone, dried, and redispersed in the polymer solution. The results showed that the methionine protection of the pellets coated with the treated membrane was higher than the protection value of the pellets coated without ball milling treatment. Methionine release was not affected by ball milling treatment.

Example 4 Glucose cores (-10/+12 sieve size) were coated with a coating composition consisting of (2M5VP/ST)/talc/stearic acid (31.5/63.6/4.9). In preparing the coating composition, the talc and stearic acid were ball milled in acetone, dried, and redispersed in the polymer solution. Glucose protection is 95% at PH5.4 for small pills coated with 14% film.
The release was completed in 1 hour at pH 2.9.
Protection values are as mentioned above (2M5VP/ST)/talc/aluminum/stearic acid (31.5/39/26/3.5)
The values were comparable to those for pellets coated with the same film.

Examples 5-7 Glucose pellets (-12/+14 sieve size) were coated with a series of coating compositions consisting of 31.5% (2M5VP/ST), 38.1% talc, 25.4% aluminum flakes and 5% stearic acid. In preparing the coating composition, the talc, aluminum and stearic acid were ball milled in acetone, dried, and redispersed in the polymer solution. In another preparation, talc and aluminum were ball milled without the addition of stearic acid, then dried and redispersed in the polymer solution.

At 10% coating weight, the protection values for the various coatings are summarized in the table below. The composition of the film was talc, aluminum flakes and stearic acid in the proportions shown in the table (2MSVP/ST). The ingredients in the bracket were ball milled.

As previously mentioned, the aluminum flakes used in these experiments were prepared using stearic acid.
Therefore, there is stearic acid content from aluminum flakes. Thus, for example, even if 5% by weight of stearic acid is added, the composition actually contains 6% by weight of stearic acid and this is shown in the table.

Table: Ball milled coatings show significantly higher protection values than the control.

Example 8 Lysine/HCl/methionine (8/1) nucleus (-
(2M5VP/ST) talc/aluminum/stearic acid (31.5/31.75/
31.75/5) was coated.
Talc, aluminum flakes and stearic acid were ball milled in acetone and dispersed directly into the polymer solution to prepare two total solids coating compositions. The results show that the protective groups for the ball milled film coated pellets are higher than the control.
The protection values for the pellets coated with the treated coating at 10% solids are much higher than those for the control coating coated at 6% solids. These results clearly demonstrate that treating the flake material with a hydrophobic substance by ball milling improves the coating. That is, ball milling of the flake material and the hydrophobe allows coating at higher composition solids content and provides protection as good as with a dilute coating composition.

Unless otherwise specified, the indicated amounts of ingredients in the composition (e.g., 31.5/38.1/24.4/6) are
Weight percent of polymeric material, talc, aluminum flakes and flake material, respectively, relative to the total weight of the coating composition.

All ratios, percentages, etc. are by weight unless otherwise specified.