Powderous formulations

Abstract

The present invention relates to improved carrier systems for 3-nitrooxypropanol and derivatives thereof as well as to the production of such formulations.

Description

[0001] Powderous formulations

[0002] The present invention relates to improved carrier systems for 3-nitrooxypropanol and derivatives thereof as well as to the production of such formulations.

[0003] The temperature of the air surrounding the earth is increasing, a process referred to as global warming. One of the main focuses to reduce this warming effect is to reduce the amount of greenhouse gases emitted into the atmosphere. Greenhouse gases are emitted from several different sources, both natural and artificial; however, the two sources with the most emphasis are the agricultural and fossil fuel industries. Within agriculture, ruminants and in particular cattle are the major contributors to the biogenic methane formation, and it has been estimated that the prevention of methane formation from ruminants would almost stabilize atmospheric methane concentrations.

[0004] 3-Nitrooxy propanol and structural analogues thereof have been reported to be highly efficient in reducing the formation of methane in ruminants without affecting microbial fermentation in a way that would be detrimental to the host animal (WO2012 / 084629).

[0005] However, 3-nitrooxypropanol and structural analogues, to be mixable with other components in premixes on in the feed mix, need to provide the supplement as free flowing powder and have been found to require specialized carrier systems, such as being adsorbed onto porous carrier particles. Dependent on the type of carrier material, brittleness of the particles increases with increasing porosity. They are prone to break into smaller pieces, when exposed to mechanical stress. Such stress could arise during transportation, processing, or further handling. Other carriers may have a smaller particle size. A high content of smaller particles or pieces, may cause handling issues, safety issues, such as dust explosions, and health problems.

[0006] Thus, there is an ongoing need to develop a product form, which overcomes the above- mentioned problem, i.e. , a product form with a reduced the amount of fine particles, while having a good flowability and easily being admixed with other components commonly used in feed products for ruminants.

[0007] Surprisingly, it has been found that when the appropriate amount of liquid and a polymer- based binder is added during the production process of the final product form, even if the binder contains a high proportion of fine particles, it leads to a powder with a lower overall concentration of fine particles in the mixture. However, adding excessive amounts of these components will reduce the flowability of the final product.

[0008] Thus, in a first embodiment the present invention relates to a carrier system, powderous formulation (I), with reduced fines content comprising a carrier, and a binder.

[0009] Specifically, A powderous formulation (I) comprising

[0010] (i) at least 25 wt-%, based on the total weight of the powderous formulation, of a carrier, and

[0011] (ii) 0.5 to 10 wt-%, based on the total weight of the powderous formulation, of a binder.

[0012] The powderous formulation (I) may further comprise

[0013] (iii) At least 0.1 weight-% (wt-%), based on the total weight of the powderous formulation, of a compound of formula (X) formula (X) wherein n is an integer from 1 to 15

[0014] R1is selected from the group consisting of H, Ci-Cealkyl, phenyl, -OH, -NH2, - CN, -COOH, -O(C=O)R8, -NHC(=O)R8, SO2NHR8, and -ONO2, and R8is Ci-Cealkyl, phenyl, pyridyl such as preferably 2-pyridyl, and

[0015] (iv) 0 to 60 wt-%, based on the total weight of the powderous formulation, of one or more edible solvents or mixtures thereof.

[0016] The formulations according to the present invention are powders, which depending on the process of production as well as the storage conditions, may additionally comprise some water. The water content, if not used as a solvent, is usually below 5 wt-%, based on the total weight of the formulation. Therefore, a further embodiment of the present invention relates to formulations as described above, wherein 0 to 5 wt-%, based on the total weight of the formulation, of water is present.

[0017] The formulations according to the present invention may furthermore contain small amounts of customary additives commonly used in the preparation of powderous formulations for feed application. Therefore, a further embodiment of the present invention relates to formu- lations according to the present invention, wherein 0 to 5 wt-%, based on the total weight of the formulation, of an additive is present.

[0018] It is clear that in all embodiments of the present invention the addition of all the wt-% always add up to 100. However, it cannot be excluded that small amount of impurities may be present such as e.g. in amounts of less than 5 wt.-%, preferably less than 3 wt.-% which are introduced via the respective raw materials or processes used.

[0019] Particular advantageous compounds of formula (X) in all embodiments of the present invention are compounds of formula (Y) wherein n is an integer between 3 and 9 and R1is OH, COOH or -ONO2.

[0020] Even more advantageous compounds of formula (X) are 3-nitrooxypropanol (CAS-No: 100502-66-7), 9-nitrooxynonanol, 5-nitrooxy pentanoic acid (CAS 74754-56-6), 6-nitrooxy hexanoic acid (CAS 74754-55-5), Bis(2-hydroxyethyl)amine dinitrate (CAS 20830-49-3), 1 ,4-bis-nitrooxybutane (CAS 3457-91-8) and 1 ,5-bis-nitrooxypentane (CAS 3457-92-9). Most preferred in all embodiments of the present invention is 3-nitrooxypropanol.

[0021] The compounds of formula (X) preferably have a boiling point below 250°C at 760 Torr, preferably a boiling point between 100 and 200°C at 760Torr.

[0022] The compounds according to the present invention are known and either commercially available or can be prepared in analogy to the processes as e.g. disclosed in WO2012 / 084629.

[0023] The term carrier as used herein refers to any porous carrier material suitable to absorb active ingredient to be supplemented to animals (including humans). The carriers may be composed of porous particles of any pharmacologically inert material or combinations of materials which is acceptable for inhalation. Particular suitable carriers according to the present invention, to adsorb compounds of formula (X), encompass silicon dioxide, sepiolite, bentonite, kaolinite, limestone, cosal, plant coal, activated plant coal, wheat, di- atomececous earth as well as mixtures thereof. Particularly preferred in all embodiments is the use of silica (silicone dioxide) as carrier.

[0024] Silica is a well-known carrier material in the feed and food industry and refers to white microspheres of amorphous silica (also referred to as silicone dioxide) and is available in a great variety of particle sizes. Particular suitable silica according to the present invention is amorphous precipitated silica, such as e.g. Sipernat 2200 from Evonik, or Tixosil 68 from Solvay.

[0025] Preferably in all embodiments of the present invention the carrier according to the present invention has an average (mean) particle size D(v, 0.5) selected in the range of 10 to 1000pm, more preferably in the range of 50 to 900 pm, more preferably 90 to 850 pm, more preferably in the range of 100 to 850 pm and most preferably 200 to 850 or 100 to 500 pm, or 100 to 300 pm.

[0026] In the context of the present invention, binders maybe polymeric materials showing glass transition and therefore sticky behaviour in a temperature range between material specific glass transition temperature (Tg) and material specific sticky temperature (Tsticky).

[0027] Examples for binders are polysaccharides, and proteins. Preferred binders according to the invention are polysaccharides.

[0028] In the context of the present invention, the term polysaccharide as used herein includes xanthan gum, gum acacia, pectin, guar gum, caroub gum, alginates, celluloses, cellulose derivatives, starch, and starch derivatives. Preferred polysaccharides according to the present invention are starch derivatives and cellulose derivatives, more preferred are gelatinized starch, starch hydrolysates and cellulose ethers, and especially preferred are starch hydrolysates, such as dextrins, maltodextins and dry glucose syrups.

[0029] In the context of the present invention, the term protein as used herein includes plant protein, whey protein, caseines / caseinates gelatin of low bloom, medium bloom or high bloom from fish, pork or bovine and other proteinaceous hydrocolloids.

[0030] Suitable binders according to the present invention have an stickiness factor (SF) between 23 and 86, calculated according to formula (2):

[0031] SF = Tgx aw + Toeita, when

[0032] Tg10 - 70°C, aw 0.3 - 0.8 and Toeita 20 - 30°C.

[0033] Such particular suitable binders according to the present invention are polysaccharides with a Dextrose equivalent (DE) between 3 and 95, preferably between 3 and 50, more preferably between 3 and 47, more preferably between 3 and 20, most preferably between 6 and 20 in case of starch hydrolysates, such as e.g. Glucidex 6, Glucidex 21 and Glucidex IT47 from Roquette, or equivalent polysaccharide chain lengths like Methocel E7 from DuPont.

[0034] In the context of the present invention, glass transition is a gradual and reversible transition of an amorphous or semicrystalline material from hard and glassy state to a viscous and rubbery state. Glass transition of a material is dependent of temperature and water activity (aw), while glass transition temperature of a material (Tg) decreases with increasing water activity. Glass transition can be measured by use of differential scanning calorimetry DSC.

[0035] In the context of the present invention, the sticky zone is defined as the temperature range in which a material shows sticky behaviour, defined as water activity dependent glass transition temperature (Tgx aw) of a material plus a material specific temperature range Toeita. The upper limit of the sticky zone is defined as material specific sticky temperature curve.

[0036] In the context of the present invention, water activity aw is the quotient of the partial vapor pressure over the material and the partial vapor pressure over pure water at the same temperature. Water activity can be derived from hygrometer measurements.

[0037] The particle sizes as given herein are measured by a Malvern Master Sizer 3000 following the recommendations outlined in ISO13320-1 for particle size analysis via laser diffraction methods (laser diffraction light scattering). During this laser diffraction measurement, particles are passed through a focused laser beam. The particles scatter light at an angle that is inversely proportional to their size. The angular intensity of the scattered light is then measured by a series of photosensitive detectors. The map of scattering intensity versus angle is the primary source of information used to calculate the particle size. For the measurement of the silica according to the present invention a dry powder feeder (Malvern Aero S) was used at a dispersion pressure of 0.2 bar.

[0038] The term edible oil refers to oils commonly used in feed applications. Preferred edible oils in all embodiments of the present invention are propyleneglycol, corn oil, rapeseed oil, sunflower oil, middle chain triglyceride (MCT) and glycerol as well as mixtures thereof. Most preferred in all embodiments of the present inventions is the use of propyleneglycol.

[0039] The term additive as used herein refers to additives commonly used in the preparation of powderous formulations for feed application such as in particular to thickeners which are advantageously selected from gums or cellulose derivatives such as xanthan gum, karaya gum and / or ethylcellulose.

[0040] Preferred embodiments of the present invention are formulations (I) which are formulations (II), which comprise

[0041] (i) A powderous formulation (I) comprising

[0042] (i) at least 35 wt-%, based on the total weight of the powderous formulation, of a carrier, and (ii) 0.5 to 8 wt-%, based on the total weight of the powderous formulation, of a binder.

[0043] The powderous formulation (II) may further comprise

[0044] (iii) At least 2 to 20 weight-% (wt-%), based on the total weight of the powderous formulation, of a compound of formula (X) formula (X) wherein n is an integer from 1 to 15

[0045] R1is selected from the group consisting of H, Ci-Cealkyl, phenyl, -OH, -NH2, - CN, -COOH, -O(C=O)R8, -NHC(=O)R8, SO2NHR8, and -ONO2, and

[0046] R8is Ci-Cealkyl, phenyl, pyridyl such as preferably 2-pyridyl, and

[0047] (iv) 10 to 60 wt-%, based on the total weight of the powderous formulation, of one or more edible solvents or mixtures thereof.

[0048] A more preferred embodiment of the present invention relates to a formulation (III) consisting of

[0049] (i) at least 35 wt-%, based on the total weight of the powderous formulation, of a carrier, and

[0050] (ii) 1 to 8 wt-%, based on the total weight of the powderous formulation, of a binder, and

[0051] (iii) to 15 wt-%, based on the total weight of the powderous formulation, of a compound of formula (X), and

[0052] (iv) 20 to 55 wt-%, based on the total weight of the powderous formulation, of one or more edible solvents or mixtures thereof.

[0053] A very specific formulation of the present invention is a formulation (IV) consisting of

[0054] (i) at least 40 wt-%, based on the total weight of the powderous formulation, of a carrier, and

[0055] (ii) 1 to 6 wt-%, based on the total weight of the powderous formulation, of a binder, and

[0056] (iii) 2 to 12 wt-%, based on the total weight of the powderous formulation, of

[0057] 3-nitrooxypropanol, and

[0058] (iv) 20 to 50 wt-%, based on the total weight of the powderous formulation, of propyleneglycol. Generally, in order to produce a powder according to the present invention (formulations (I), (II), (III), (IV), (V)) the compound of formula (X) is, optionally diluted in the edible solvent and, if present, the additive, sprayed onto or admixed to a composition of a carrier and a binder according to the present invention.

[0059] It is also possible that the compound of formula (X) is, optionally in the presence of an edible solvent, such as an oil, and, if present, the additive, diluted in water or an organic solvent suitable for the preparation of food or feed products such as e.g. dichloromethane, sprayed onto or admixed with a carrier and a binder according to the present invention added later during the adsorption process followed by evaporation of the organic solvent.

[0060] It is also possible, in order to produce a powder according to the present invention (formulations (I), (II), (III), (IV), (V)) the compound of formula (X) is, optionally diluted in the edible solvent, if present, the additive, sprayed onto or admixed to a composition of a carrier according to the present invention and a binder according to the present invention is added later during the adsorption process.

[0061] The powderous formulation according to the present invention can comprise from 0.5 wt.-%, preferably from 1 wt.-%, more preferably 2 wt.-%, and up to 8 wt.-%, preferably 6 wt.-% of the total weight of the powderous form of a binder according to the present invention.

[0062] The powderous formulation according to the present invention can additionally be coated with customary coatings in the art such as wax or fats. If present, such coating is generally applied in amounts of 5 to 50 wt.-% based on the total weight of the powderous form. Advantageously, the coating comprises at least one wax and / or at least one fat, which has a dropping point of from 30 to 85 °C.

[0063] The dropping point of a material as used herein refers to the temperature (in °C) when the material begins to melt under standardized conditions. Thus, the material is heated so long until it changes the state of matter from solid to liquid. The dropping point is the temperature when the first dropping is released from the material. The determination of the dropping point (Tropfpunkt) is carried out as described in the standard norm DIN ISO 2176.

[0064] Particularly suitable waxes to be used as coating in the context of the present invention include organic compounds such as long alkyl chains, natural waxes (plant, animal) which are typically esters of fatty acids and long chain alcohols as well as synthetic waxes, which are long-chain hydrocarbons lacking functional groups.

[0065] Particularly suitable fats to be used as coating in the context of the present invention include a wide group of compounds which are soluble in organic solvents and largely insoluble in water such as hydrogenated fats (or saturated fats) which are generally triesters of glycerol and fatty acids. Suitable fats can have natural or synthetic origin. It is possible to hydrogenate a (poly)unsaturated fat to obtain a hydrogenated (saturated) fat.

[0066] Preferred examples of waxes and fats to be used as coating according to the present invention are glycerine monostearate, carnauba wax, candelilla wax, sugarcane wax, palmitic acid, stearic acid hydrogenated cottonseed oil, hydrogenated palm oil and hydrogenated rapeseed oil as well as mixtures thereof.

[0067] All the above disclosed formulations (I), (II), (III), (IV), (V) can be used as such or incorporated in feed products.

[0068] Additionally, all the above disclosed formulations (I), (II), (III), (IV) and (V) can be used as such in the production of feed products.

[0069] The invention is illustrated by the following Examples. All temperatures are given in °C and all parts and percentages are related to the weight.

[0070] Examples

[0071] Example 1

[0072] Particle size determination: The methodology described below followed the recommendations outlined in ISO13320-1 for diffraction light scattering techniques: the particle sizes of various powderous compositions have been measured by a Malvern Master Sizer 3000 following the recommendation of ISO13320-1. An aliquot of the material tempered at 25°C- 35 to 55% r.H is sampled into the vibrator hopper of the (Aero S) dry dispersion unit. The flow aperture of the dispenser gate is set up on the way that the product flows for 10 seconds through the measurement zone, at a vibration feed rate of 35%. A sample measurement at 0.2 bar of disperser pressure is taken for 10 seconds (on the Malvern Mastersizer 3000). The sample pass through the focused beams of light (Helium-neon laser for the red light and solid-state light source for the blue) and scatter the light allowing a measurement of particles between 0.02 and 2000 micrometers. The particle diameters in volume (as outlined in table 1), are determined using Fraunhofer approximation.

[0073] Materials: Carriers used were SiO2 precipitated silica with a particle size (D50) of 230-300 pm. For the purpose of this example different amounts of fines (2% and 3%) were added to simulate increased fines content, resulting from e.g. storage, product handling, added mechanical stress, or process variations. Binders used were maltodextrin Malto DE0508 (Glu- cidex 6 from Roquette with a dextrose equivalent of 6), dried glucose syrup Malto DE2023 (Glucidex 21 from Roquette with a dextrose equivalent of 21) and Malto DE47 (Glucidex IT47 from Roquette with a dextrose equivalent of 47, agglomerated).

[0074] Preparation of the formulation 'Dry blending of polymeric binder and carrier before liquid addition”: Different type of carriers are mixed with different amounts and types of binders (as outlined in table 1). To 80g of said mixtures placed on a beaker, is added ACT-02, a 80g of a 20 wt.-% 3-nitrooxypropanol solution in propyleneglycol, under gentle agitation at room temperature. After 5 minutes agitation, the adsorption is completed and a free flowing powder is obtained. Other mixtures than ACT-02, a 80g of a 20 wt.-% 3-nitrooxypropanol solution in propyleneglycol, are possible, such as pure 3-nitrooxypropanol, pure propyleneglycol or other solvents and mixtures thereof.

[0075] Preparation of the formulation 'Dispersion of the binder in the liquid before addition to carrier”: To 80g of different type of carriers (as outlined in table 1) placed on a beaker, is added ACT-02, 80g of a 20 wt.-% 3-nitrooxypropanol solution the binder in propyleneglycol, under gentle agitation at room temperature (ACT-02). After 5 minutes agitation, the adsorption is completed and a free-flowing powder is obtained. Other mixtures than ACT-02, a 80g of a 20 wt.-% 3-nitrooxypropanol solution in propyleneglycol, are possible, such as pure 3- nitrooxypropanol, pure propyleneglycol or other solvents and mixtures thereof.

[0076] Table 1

[0077] Theoretically, the binder should contribute to fine particle concentration, due to its own particle size distribution and high amount of fine particles.

[0078] Surprisingly, as can be seen (table 1), an increase in binder concentration can lead to de- crease in fine particle concentration and an decrease in binder chain length, in case of starch hydrolysates indicated by an increase in DE value, can lead to decrease in fine particle concentration. A reduction of fine particle concentration can also be achieved, when the binder is pre-dispersed in liquid before adsorption. An increase in binder concentration to 10% lead to lumping and the powder becoming sticky, reducing flowabilty of the powder.

Claims

Claims1. A powderous formulation (I) comprising(i) at least 25 wt-%, based on the total weight of the powderous formulation, of a carrier, and(ii) 0.5 to 10 wt-%, based on the total weight of the powderous formulation, of a binder.

2. The powderous formulation according to claim 1 further comprising(iii) At least 0.1 weight-% (wt-%), based on the total weight of the powderous formulation, of a compound of formula (X)formula (X) wherein n is an integer from 1 to 15R1is selected from the group consisting of H, Ci-Cealkyl, phenyl, -OH, -NH2, - CN, -COOH, -O(C=O)R8, -NHC(=O)R8, SO2NHR8, and -ONO2, andR8is Ci-Cealkyl, phenyl, pyridyl such as preferably 2-pyridyl, and(iv) 0 to 60 wt-%, based on the total weight of the powderous formulation, of one or more edible solvents or mixtures thereof.

3. The powderous formulation according to claim 1 or 2 further comprising(iv) 0 to 10 wt-%, based on the total weight of the powderous formulation, of water and / or an additive.

4. The powderous formulation according to claim 1 or 2, wherein the carrier is selected from the group of silicon dioxide, sepiolite, bentonite, kaolinite, limestone, cosal, plant coal, activated plant coal, wheat as well as mixtures thereof.

5. The powderous formulation according to any of the preceding claims, wherein n is an integer between 3 and 9 and R1is OH, COOH or -ONO2.

6. The powderous formulation according to any of the preceding claims wherein the compound of formula (X) is selected from the group consisting of 3-nitrooxypropanol, 9-nitrooxynonanol, 5-nitroxy pentanoic acid, 6-nitroxy hexanoicacid, bis(2-hydroxyethyl)amine dinitrate, 1 ,4-bis-nitrooxybutane and 1 ,5-bis- nitrooxypentane.

7. The powderous formulation according to any of the preceding claims, further comprising an edible oil.

8. The powderous formulation according to claim 7, wherein the edible oil is selected from the group consisting of propyleneglycol, corn oil, rapeseed oil, sunflower oil, middle chain triglyceride (MCT) and glycerol as well as mixtures thereof.

9. The powderous formulation according to any of the preceding claims wherein the additive is a thickener selected from the group consisting of gums and / or cellulose derivatives, preferably from xanthan gum, karaya gum and / or ethylcellulose.

10. The powderous formulation according to any of the preceding claims wherein the binder has a stickiness factor (SF) between 23 and 86, calculated according to formula (2): SF = Tgx aw + Toeita, when Tg10 - 70°C, aw 0.3 - 0.8 and TDeita20 - 30°C.11 . The powderous formulation according to any of the preceding claims wherein the binder is a polymeric material selected from polysaccharides and proteins, preferably polysaccharides.

12. The powderous formulation according to any of the preceding claims wherein the binder is selected from xanthan gum, gum acacia, pectin, guar gum, caroub gum, alginates, celluloses, cellulose derivatives, starch, and starch derivatives, preferably starch derivatives and cellulose derivatives, more preferably gelatinized starch, starch hydrolysates and cellulose ethers, preferably starch hydrolysates, such as dextrins, maltodextins and dry glucose syrups.

13. The powderous formulation according to any of the preceding claims wherein the binder has a Dextrose equivalent (DE) between 3 and 95, preferably between 3 and 50, more preferably between 3 and 47, more preferably between 3 and 20, most preferably between 6 and 20.

14. Use of formulations according to anyone of claims 1 to 13 in feed products.

15. Feed products comprising a formulation according to anyone of claims 1 to 13.

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