Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K50/00—Feeding-stuffs specially adapted for particular animals
  • A23K50/10—Feeding-stuffs specially adapted for particular animals for ruminants
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/142—Amino acids; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/163—Sugars; Polysaccharides
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K40/00—Shaping or working-up of animal feeding-stuffs
  • A23K40/10—Shaping or working-up of animal feeding-stuffs by agglomeration; by granulation, e.g. making powders
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K40/00—Shaping or working-up of animal feeding-stuffs
  • A23K40/20—Shaping or working-up of animal feeding-stuffs by moulding, e.g. making cakes or briquettes
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K40/00—Shaping or working-up of animal feeding-stuffs
  • A23K40/25—Shaping or working-up of animal feeding-stuffs by extrusion
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to hydrophilic amino acid granule cores.
• the present invention also relates to hydrophilic amino acid granules for feeding or treating ruminants.
• Some compounds for example vitamins, minerals and amino acids (or amino acids) are essential in the diet of ruminants because they are limiting in the daily nutritional intake. The feeding of ruminants with these compounds is therefore generally supplemented.
• these compounds when administered orally to ruminants are destroyed in the rumen by the action of digestive enzymes. Also in order to be beneficial and assimilable by animals, these compounds are protected by a coating that allows them to cross the rumen without damage and to be disintegrated in the abomasum, so as to release the active ingredient in the intestine .
• Extrusion devices are devices that use both heat and pressure by forcing the mixture to extrude through a die. During this step, the active ingredients undergo an irreversible degradation.
• patent FR 2,663,818 proposes the use of a fusible binder agent.
• a fusible binder agent As such, one generally uses a fatty substance, for example stearic acid. These have the advantage of easily mixing with the hydrophobic active ingredients.
• hydrophilic active ingredient present in a high content in the mixture, with one of the known fusible binders, one encounters difficulties in homogenization.
• the present invention has sought to allow the easy extrusion of hydrophilic active principles.
• the inventors have surprisingly realized that by adding a compound selected from starches to known fuse binders, this goal was achieved.
• the present invention therefore relates to granulated cores intended for animal feed, said granule cores comprising:
• hydrophilic amino acid present at an active content of greater than 60% by weight of the granule core
• At least one plasticizer characterized in that said cores further comprise a compound chosen from starches.
• EP 1 405 570 describes a feed additive for ruminants comprising a magnesium phosphate of lysine. Nevertheless, the additive described in this document has a lysine content of not more than 43% by weight in the finished product.
• the application WO 02/10208 relates to a process for the preparation of amino acid by fermentation.
• the amino acid thus obtained is then shaped.
• US Patent 5,279,832 relates to a preparation of active substance, especially amino acid, for oral administration. This document does not describe a composition allowing the easy extrusion of the hydrophilic amino acids present in a high content in the composition.
• the inventors have furthermore advantageously realized that the active ingredient cores of the present invention, as well as the granules comprising said cores, have numerous advantages which will be set forth throughout the description which follows.
• the hydrophilic amino acids have an established physiological activity in animals. They come in particular in the category of food supplements. Animal feed supplements are products intended to be ingested, in addition to the current diet, in order to compensate for the insufficiency of daily intake of certain compounds. It is for example generally known to supplement the feed rations of farm animals with amino acids, so as to increase the zootechnical performance of the animals raised.
• the amino acid is selected from the group consisting of lysine, arginine, tyrosine, their salts and esters.
• the hydrophilic amino acid is L-lysine or its commercial form: L-lysine hydrochloride. It may also be L-arginine hydrochloride or L-tyrosine hydrochloride.
• the hydrophilic amino acid is furthermore present at an active content greater than or equal to 60% by weight of the granule core.
• the hydrophilic amino acid is present at an active content greater than or equal to 64% by weight of the granule core.
• active content is meant the actual content of amino acid itself, that is to say the amino acid in the basic form having the physiological activity in the animal whose effect is sought. It may be the form completely assimilated by the body of the animal. It may be that amino acids are in commercial form more interesting and easy to handle than the active form. This is particularly the case when the amino acid is in salt form or the like.
• the actual active amino acid content may, for example, represent a certain percentage of the content of active form, belonging to the mixture of starting compounds.
• the contents are expressed in% by weight of the granule core or, as the case may be, in% by weight of the granule itself.
• the granule core further comprises at least one fusible binder.
• the fusible binder is selected from the group consisting of polyethylene glycol waxes, paraffins, oils or fats, fatty acids having from 10 to 32 carbon atoms, esters and the corresponding alcohols, and di and corresponding triesters. As an indication, it may in particular be stearic acid.
• Précirol ® and Compritol ® are examples of stearic acid.
• the granule cores according to the present invention also comprise at least one plasticizer. This is preferably selected from cellulose or its derivatives, and especially ethylcellulose.
• the granule cores of the present invention are characterized in that they comprise a starch.
• starch is meant any polysaccharide formed from the combination of two polymers: amylose and amylopectin.
• the starch can be in the form of powder or in the form of pits. As an indication, it may be native wheat starch, native corn starch, native rice starch or potato starch. It can also be the same physically treated starches, for example pregelatinized.
• Granules cores may also be provided with a disintegrating agent which accelerates the disintegration of the tablet in the digestive tract. It may especially be talc, silica, carbonate, polyphosphate, for example Na 2 O, CaO, P 2 O 5 or AI 2 O 3 .
• the cores may further comprise another active ingredient or several others, in addition to the hydrophilic amino acid present at an active content greater than or equal to 60% by weight.
• active ingredient any substance having an established physiological activity in the animal.
• active ingredient according to the invention include dietary supplements.
• Animal feed supplements are products intended to be ingested, in addition to the current diet, in order to compensate for the insufficiency of daily intake of certain compounds. It is for example generally known to supplement the feed rations of farm animals with active ingredients, so as to increase the zootechnical performance of the animals raised. It may especially be vitamins, mineral salts, amino acids, trace elements, hormones or antibiotics.
• said other active ingredient is an amino acid.
• methionine, tryptophan or 2-hydroxy-4-methylthiobutanoic acid hydroxy-methionine analogue
• Mention may also be made of the salts and esters of these compounds.
• Said other active ingredient is preferably present at a very low active content, less than or equal to 1% by weight of the granule core.
• the present invention also relates to a granule core in which the active ingredients, that is to say the hydrophilic amino acid and optionally at least one other active ingredient, are present at an active content greater than 64% by weight. granule core weight.
• the hydrophilic amino acid is present at an active content greater than or equal to 64% by weight of the granule core.
• Pellet cores are conventionally obtained by a melt extrusion process. This process is completely described in patent FR 2,663,818.
• the ingredients are first mixed and then kneaded.
• the process for preparing the cores of granules comprises a preliminary step of dry co-grinding of the ingredients before extrusion, said co-grinding being preferably carried out at a temperature at most equal to 50 ° C.
• grinding is meant more particularly the mechanical action which consists in reducing the starting ingredients to a given size.
• co-grinding involves the grinding of several ingredients at the same time. The co-grinding is therefore carried out “dry”, that is to say that all the ingredients are in dry form, most often in the form of powder.
• a liquid ingredient to the mixture, or to put one or all of the ingredients in solution.
• the co-grinding of the ingredients requires the use of a grinder, which may be chosen from among knife, rotor, bar, grids, disc or ball mills. The choice of mill is mainly a function of the particle size of the crushed product expected.
• water to the mixture after grinding and before extrusion.
• less than 10% by weight of the mixture is added before extruding water.
• Preferably, between 3 and 5% by weight of the mixture is added before extruding water.
• the mass to be extruded is then forced through an extruder, preferably single screw or twin screw, provided with one or more dies having orifices of the desired granule diameter.
• composition of the granule cores according to the present invention allows a better extrusion rate or "extrudability” (see examples).
• the rods undergo a step of spheronization whose object is to make the rods perfectly spherical, without irregularity or surface roughness (the smoothest possible). It is also important to specify that the quality of the subsequent coating step, and therefore the protection of the active ingredient, lies mainly in the spheronization step.
• the spheronized granulated cores are coated to obtain protected granules.
• the present invention also relates to a hydrophilic amino acid granule which comprises:
• the contents are expressed in% by weight of the granule core or, as the case may be, in% by weight of the granule itself. Because of the presence of the coating, this percentage differs from the percentage by weight of the granulated core and the person skilled in the art must then calculate this new percentage.
• hydrophilic active principle is present, from equivalent way in the granule itself, with an active content greater than or equal to 51% by weight of the granule.
• the present invention advantageously covers an active hydrophilic amino acid content greater than or equal to 64% by weight of the granule core, or under the same hypothesis as previously (That is to say a coating representing 15% by weight of the granule), with an active content greater than 54.4% by weight of the granule.
• said other active ingredient is preferably present at a very low active content, less than or equal to 1% by weight of the granule core.
• said other active ingredient is present, in an equivalent manner, with an active content less than or equal to 0.85% by weight of the granule itself.
• the coating step is carried out in accordance with the teaching described in patents EP 462 015 and EP 447 298, by a pH sensitive polymer-based composition.
• This composition has many advantages and in particular it is not degraded in the rumen but it is releasable in the abomasum and / or intestine.
• the coating process comprises a first aqueous emulsion monomer polymerization step, a second step of preparing the coating emulsion and a third step of depositing said aqueous emulsion on the active principle cores.
• the pH sensitive polymers are chosen from:
• the copolymer based on styrene and vinyl-2-pyridine is preferably used.
• the polymer is prepared by contacting the monomer (s) in the presence of a surfactant and a polymerization initiator.
• the surfactants are preferably chosen from alkaline salts of fatty acids, for example the sodium salt of oleic acid and the sodium salt of stearic acid.
• the polymerization initiator is chosen from the soluble initiators conventionally used in emulsion processes, for example sodium persulfate.
• the pH during the polymerization is preferably set between 10 and 14.
• the coating emulsion is prepared.
• An aqueous emulsion containing the sensitive pH polymer obtained in the preceding step and a hydrophobic substance are preferably used as coating composition.
• the hydrophobic substance is especially chosen from fatty acids containing 12 to 22 carbon atoms, their esters (mono-, di- and triesters in particular) and their salts. It may especially be stearic acid.
• the aqueous emulsion may also contain additives such as antistatic agents, fungicides, plasticizers, colorants, palatability agents, for example olfactory additives, and complementary emulsifying agents.
• additives such as antistatic agents, fungicides, plasticizers, colorants, palatability agents, for example olfactory additives, and complementary emulsifying agents.
• the emulsion is then deposited on the cores to be coated. For example, this emulsion is sprayed on the granules of active principle.
• the quality of the extrudates is evaluated by a friability test.
• the friability test is carried out on a Sotax Friabilitor USP F1 device with 10 g of extrudates for 5 min at 50 rpm.
• the friability is given by the following formula: (initial weight - weight of rods recovered at the end of the test) / initial weight.
• the granules of active ingredient of the present invention have many advantages. Among these, and as can be seen from the following examples, include protection levels and improved release rates vis-à-vis pellets not advantageously containing starch or derivatives.
• the rate of release of granules containing methionine is measured under these conditions by iodometry, while that of lysine is measured by argentimetry.
• HPLC or any other chromatographic method (ion exchanger in particular) is used.
• the appearance of the pellets, especially their size and shape, is very important.
• the spheronized granule cores should be round, spherical and smooth (as smooth as possible), so that the coating step takes place under the best conditions, and that the active ingredient is properly and uniformly protected .
• Figures 1 to 4 are photographs of granulated cores and granules:
• FIG. 1 shows hearts of lysine granules without starch.
• FIG. 2 shows lysine granule cores with starch, as obtained according to the present invention.
• Figure 3 shows granules of lysine without starch.
• Figure 4 shows lysine granules with starch, as obtained according to the present invention.
• the granulometry of the granules is also an important industrial characteristic.
• the granules of the present invention have a diameter of 1 to 3 mm and a length of 1 to 5 mm.
• Example 1 Lysine granules without starch
• the material used to prepare the hearts of granules and granules of lysine without starch is as follows:
• Haake Rheomex TW 100 Bivis extruder configured with two coarse-rotating screws (diameter 19.7 mm and length 331 mm) and a die with 9 holes (2 mm in diameter);
• the friability test is carried out on a Sotax friabilator USP F1 with 10 g of extrudates for 5 min at 50 rpm.
• the operating conditions are as follows:
• the mixture obtained is rehomogenized with the Böhle mixer for 15 minutes still at 50 rpm.
• This mixture is introduced via a hopper into the extruder Bivis, the temperatures of the three sections were previously set at: - 72 0 C in the food compartment;
• the extrusion rate is about 1 kg / h.
• the extrudates obtained are cut to a length of 2 mm. They are then characterized in terms of friability. The friability of the extrudates is measured: it is between 1, 5 and 2%.
• the extrudates are then spheronized at 500 rpm, for 8 min and at 90 0 C and sieved between 1, 4 and 2.5 mm. The yield of this operation is 87%.
• the sieved extrudates are then coated with the emulsion prepared by polytron stirring at a temperature between 75 and 90 ° C.
• the 25% dry extract emulsion has the following composition:
• the spraying rate is 10 g / min and the efficiency is 98%.
• the extrudates are characterized in terms of protection rate and lysine release rate.
• protection rate for a coating rate of 14.6%, the content of lysine base is 54.2%, the degree of protection measured in vitro varies between 61 and 89%, and the release rate is 95%.
• Example 2 Lysine granules with corn starch
• Example 1 is repeated with the same apparatus but substituting a portion of the stearic acid with standard native corn starch.
• the mixture is cobbled identically to Example 1.
• the granulometry of the laboratory mill output mixture is such that one has a powder with 50% of particles ⁇ 50 ⁇ m and less than 10% of particles> 200 ⁇ m.
• the extrusion rate is about 2 kg / h.
• the extrusion rate is therefore much higher than that of Example 1, in which the starch is not used.
• the extrusion rate is doubled. We can therefore consider doubling productivity by using starch. This is an advantage of the present invention.
• the extrudates obtained are cut to a length of 2 mm and then characterized in terms of friability.
• the friability of the extrudates is measured: it is between 0.5 and 0.8%.
• the friability of the extrudates comprising lysine and starch is better than that of the extrudates comprising only lysine (Example 1), which is a guarantee of quality of the extrudates obtained.
• the extrudates are then spheronized at 500 rpm, for 6 min and at 90 ° C. and sieved between 1, 4 and 2.5 mm. The yield of this operation is 88%.
• Example 1 Compared with Example 1, for an equivalent coating rate (14.6% of the weight of the granule), the granules of lysine with corn starch had a degree of protection of 96%, much higher than that of the granules without starch (61 to 89%). With a higher coating rate (16.4% of the weight of the granule), the protection level of lysine granules with starch increases to 99%.
• Starch granules also have a release rate of 100%, compared with 95% for lysine cores without starch.
• Example 3 granules of lysine with wheat starch
• Example 2 is repeated with the same apparatus but replacing the cornstarch with wheat starch.
• the extrusion rate is about 1.4 kg / h.
• the extrusion rate is therefore greater than that of Example 1, in which the starch is not used.
• the extrudates obtained are cut to a length of 2 mm and then characterized in terms of friability.
• the friability of the extrudates is between 0.6 and 1%.
• the extrudates are then spheronized at 500 rpm, for 7 min and at 90 0 C and sieved between 1, 4 and 2.5 mm.
• the yield of this operation is 85%.
• the spraying rate is 10 g / min and the yield is 98%.
• the lysine base content is 56.2%
• the degree of protection measured in vitro is 88%
• the release rate is 100%.
• Example 4 Granules of lysine with potato starch
• Example 2 is repeated with the same apparatus but replacing the cornstarch with potato starch.
• the extrusion rate is about 1.5 kg / h.
• the extrusion rate is also higher than that of Example 1, in which the starch is not used.
• the extrudates obtained are cut to a length of 2 mm and then characterized in terms of friability.
• the friability of the extrudates is between 0.5 and 0.7%.
• the extrudates are then spheronized at 500 rpm, for 6 min and at 90 0 C and sieved between 1, 4 and 2.5 mm. The yield of this operation is 89%.
• the spraying rate is 10 g / min and the yield is 99%.
• the lysine base content is 56.2%
• the degree of protection measured in vitro is 96%
• the release rate is 100%.
• Example 5 lysine granules with Arbocel cellulose
• Example 2 is repeated with the same apparatus but replacing the cornstarch with Arbocel cellulose.
• the extrusion rate is about 0.5 kg / h.
• the extrusion rate is lower than that of Example 1, using no starch either.
• the advantageous property of the starch or its derivatives on the extrusion rate is not reproduced here.
• the extrudates obtained are cut to a length of 2 mm and then characterized in terms of friability.
• the friability of the extrudates is between 1, 5 and 2%. It is therefore higher than that of the extrudates which comprise starch (Examples 2,3 and 4).
• extrudates are then spheronized at 500 rpm, for 6 minutes and at
• the spraying rate is 10 g / min and the yield is 98%.
• Example 2 is reproduced with the same apparatus but incorporating 0.35% of methionine to the detriment of stearic acid.
• the extrusion rate is about 1.6 kg / h.
• the extrudates obtained are cut to a length of 2 mm and then characterized in terms of friability.
• the friability of the extrudates is between 0.4 and 0.6%. Their apparent density is between 0.62 and 0.64 g / cm 3 . The calculated true density of the granules of 1.24 g / cm3.
• the extrudates are then spheronized at 500 rpm, for 8 min and at 90 0 C and sieved between 1, 4 and 2.5 mm. The yield of this operation is 92%.
• the spraying rate is 11 g / min and the yield is 96%.
• the lysine base content is 55%
• the degree of protection measured in vitro is 96%
• the release rate is 100%.
• the equipment used is as follows: - an industrial 3000 liter ribbon mixer;
• the extrudates are therefore prepared, spheronized and coated using industrial equipment.
• the friability test is carried out on a Sotax friabilator USP F1 carried out with 10 g of extrudates for 5 min at 50 rpm.
• the operating conditions are as follows:
• the stearic acid assayed in the mixture is 12.07% (for 1 1, 65% theoretical).
• This mixture is used to feed an industrial extruder operating at
• this flow rate can be between 5 and 10% of the mixture (ie 3 to 6 kg / h for an extrusion rate of 60 kg / h).
• the extrusion yield defined as the% of extrudates longer than 1.4 mm, is 99%.
• the measured friability of these extrudates is between 0.5 and 0.7%.
• the extrudates are spheronized in a batch of 25 kg.
• the industrial apparatus with a diameter of 700 mm is set at 350 rpm for an extrudate temperature of 90 ° C.
• the spheronization time is 12 min.
• the extrusion yield, defined as the% of granules between 1.4 and 2.5 mm, is 83%.
• the spheronized granules are then coated under the following conditions:
• the content of lysine base is 51.2%
• the degree of protection measured in vitro is 94%
• the release rate is 98%.

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  • 2004-12-15 FR FR0413346A patent/FR2879074B1/fr not_active Expired - Fee Related
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