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
• • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
• • 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
• • 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

Definitions

• the present invention relates to a process for the preparation of adsorbates of at least one vitamin E compound in adsorbed form on a silica carrier, comprising as an essential step, the mixing of the corresponding vitamin E compound with the silica carrier under reduced pressure.
• the invention relates to adsorbates which can be prepared by said process.
• the nutritional quality of compound feed is largely determined by its content of essential ingredients such as minerals, trace elements, amino acids or vitamins.
• the respective amounts of said ingredients in feed can be widely within limits by adding réellesl. Additives are adapted to the respective needs.
• the supplements or additives used here contain the desired ingredients or else several different ingredients in a form which is suitable for the production of animal feeds.
• silica gel of supported vitamin E acetate which is available for example under the name Lutavit ® E 50 (BASF Aktiengesellschaft).
• EP 1 018 303 discloses active ingredient adsorbates based on silicic acids which contain precipitated silica and an active substance such as, for example, vitamin E acetate in an amount of from 1 to more than 60% by weight. Furthermore, a process for the preparation of said adsorbates is disclosed, which provides the granulation of an aqueous suspension of precipitated silica and the corresponding active substance in the fluidized bed. However, this process is associated with high energy and thus cost.
• EP 0 984 772 relates to compositions comprising at least one liquid, such as, for example, choline hydrochloride or vitamin E, which is precipitated on a precipitation acid-containing carrier, wherein the precipitated silica is in approximately spherical form, the spheres having a mean size of over 150 ⁇ m, a filling density of less than 0.29; a residue rate in a screen of 75 microns mesh of at least 88% and a specific pore volume.
• the said compositions can be prepared by mixing the corresponding liquid with the carrier in a conventional manner.
• EP 0 966 207 relates to compositions comprising at least one liquid, such as choline hydrochloride or vitamin E, absorbed on a precipitated silica-containing carrier, the precipitated silica being in approximately spherical form, the spheres having an average size greater than 150 ⁇ m, a filling density of less than 0.29; a residue rate in a sieve of 75 ⁇ m mesh of at least 92% and an oil DOP of at least 250 ml / 100 g.
• the compositions mentioned can be prepared by mixing the corresponding liquid with the carrier in a conventional manner. They may have a liquid content of 50 to 65 wt .-%.
• EP 0 345 109 discloses special precipitated silicas which are distinguished by a certain BET surface area, a certain DOP oil absorption, a certain minimum filling density, an average particle diameter between 80 and 150 ⁇ m and a specific granulometric disperse index.
• prepared compositions comprising, in addition to the carrier, an absorbed liquid such as vitamin E, as well as a method for producing said special precipitated silicas are disclosed. The adsorption is carried out in a conventional manner in a mixer.
• EP 0 556 883 discloses a process for producing extruded feed pellets loaded with an active ingredient.
• the feed pellets are mixed after extrusion in a fluid phase with an active substance which would be damaged by the extrusion process, and loaded under reduced pressure.
• the active ingredient is an enzyme, protein, pigment, vitamin, antioxidant, dye or carotenoid.
• WO 00/27362 relates to a process for the preparation of dry, flowable vitamin powders by mixing dried corn starch, silica and at least one vitamin in a mixer. First cornstarch and silica are mixed and then the vitamin is added. The mixing is preferably carried out in a scher performed at a speed of at least 3600 U / min.
• the preferred vitamin is, inter alia, called vitamin E, which is preferably used in an amount of 50 to 80% by weight.
• a process for producing dry, finely divided and flowable powder containing vitamin E or vitamin E acetate is disclosed in US Pat. No. 4,603,143.
• the method comprises adding a silicon-containing adsorbent in the form of substantially discrete, non-amorphous agglomerates having a minimum length and / or width of 300 ⁇ m into a container and then adding Vitamin E or Vitamin E acetate in liquid form in an amount sufficient to obtain about 40 to about 60% by weight powder with simultaneous mixing.
• the present invention was based on the object to provide an economical method that allows to provide adsorbates of vitamin E compounds on suitable carriers, which are characterized by the highest possible content of adsorbed vitamin E compound and beyond at least comparable good Have material properties such as a good flowability and a low tendency to stick, such as the corresponding adsorbates prepared by known methods.
• R 1 , R 2 , R 3 are each independently hydrogen or methyl and
• R 4 is hydrogen or C 2 to C 12 acyl
• the process according to the invention is particularly suitable for producing such adsorbates which are at least 90% by weight, preferably at least 95% by weight and more preferably at least 98% by weight, of at least one, i. from preferably a vitamin E compound or a mixture of several, usually 2 to about 4, in particular 2 or 3 different vitamin E compounds of the formula (I) and a silica carrier exist.
• the adsorbates according to the invention may also contain small amounts of water or other impurities, for example by-products or impurities from the preparation or isolation or purification of the vitamin E compound or compounds used according to the invention.
• the adsorbates which can be prepared by the process according to the invention are preferably characterized in that, based on the amount of the finished adsorbate, they contain from about 30 to about 70% by weight, preferably at least about 40 to about 65% by weight and more preferably from about 50% to about 65% by weight of a vitamin E compound of formula (I).
• adsorbate is to be interpreted broadly in the context of the present invention and generally refers to mixtures of the respective vitamin E compound or vitamin E compounds with the silica carrier used, wherein the respective vitamin E compound is applied to the surface of the silica carrier in the respectively used dosage form is.
• the respective vitamin E compound can therefore also be introduced into the existing cavities of the silica carrier.
• Suitable vitamin E compounds to be adsorbed in the context of the method according to the invention are those of the general formula (I)
• Vitamin E compounds of the formula (I) which are preferred according to the invention are those in which the radicals R 1 , R 2 and R 3 each represent a methyl group.
• the radical R 4 is preferably a straight-chain or branched acyl radical having 2 to 6 carbon atoms, particularly preferably acetyl. Accordingly, adsorbates which are preferably to be prepared in the context of the process according to the invention are those in which the vitamin E compound is present in the form of an acetate. A particularly preferred vitamin E compound in the context of the method according to the invention is ⁇ -tocopherol acetate.
• the vitamin E compounds contained in the adsorbates to be prepared according to the invention can each be isolated from natural sources or prepared by suitable synthesis processes. Preference is given to those vitamin E compounds which are synthetically produced. Enantiomerically pure vitamin E compounds as well as racemic mixtures or mixtures of different diastereomers with respect to the stereogenic centers of the respective vitamin E compound or compounds are equally suitable as starting materials in the context of the method according to the invention. Preferred according to the invention are those vitamin E compounds which are present in liquid or oily form at room temperature.
• the vitamin E compound used as starting material in the process according to the invention is synthetically prepared dl- ⁇ -tocopherol acetate, which is usually in the form of an oil containing from about 90 to about 95% by weight of dl- ⁇ - Tocopherol acetate (hereinafter referred to as "vitamin E oil”), which, like the other vitamin E compounds which can be used according to the invention, can also have a small amount of solvent residues, for example from the production or isolation of the vitamin E compounds used in each case ,
• the second starting material in the context of the process according to the invention is a silica carrier on which the selected vitamin E compound or compounds are adsorbed in accordance with the invention.
• silica carrier is to be interpreted broadly and refers to a fine-grained carrier material based on silica, which is suitable for use as an adsorbent.
• Silica gels sica gels
• precipitated silicas or silicic acids produced by flame hydrolysis may be mentioned as examples of silica carriers.
• suitable siliceous carriers are also minerals consisting essentially of silicon dioxide, such as, for example, silica or kieselguhr, if suitable for use as a feed additive.
• silica sorbent does not include the silicate vermiculite.
• Silica supports which are preferred according to the invention are the precipitated silicas. Silica supports preferred as the starting material in the process according to the invention have an average particle size of from about 50 to about 600, preferably from about 150 to about 400 ⁇ m, and a specific surface area of from about 50 to about 500 m 2 / g, preferably from about 100 to about 300 m 2 / g.
• Precipitated silicas which are particularly preferred for use in the process according to the invention are, for example, those commercially available under the name Sipernat® 2200 (Degussa AG).
• Other preferred silica carriers are, for example: Sipernat® 2300 (Degussa AG), Tixosil® (Rhodia).
• the process according to the invention comprises, as an essential step, the mixing of the at least one vitamin E compound of the formula (I) with the silica carrier under reduced pressure.
• vacuum mixers such as, for example, the discontinuous twin-shaft paddle mixer VC-450 from the company Dinissen (Seveneum, NL) or rotary vacuum mixers from Forberg International AS, such as, for example, the model F-6-RVC models, are suitable for carrying out the process according to the invention in various sizes up to a capacity of 2000 to 7000 liters (F-5000-RVC) are available or similar apparatus.
• the procedure for the vacuum mixture essentially corresponds to the procedure known to those skilled in the art for vacuum coating pelleted feed, as described, for example, in the cited reference Mühle + Mischfutter 138 (8), 2001, pp. 262-264 or also in Matrix Forum, March 2002 under the Title "Processing. High enregy poultry feed "by W. Strauch.
• a vacuum mixer which can be advantageously used has a horizontal housing and bottom flaps which expediently open over the entire length of the mixer and one or more horizontal mixing rotors.
• the rotors preferably have inclined paddles, whereby the transport or replacement of the mixed material particles during the mixing process is ensured.
• the maximum useful mass per mixing process is usually about 250 kg.
• the drive power of the mixer is then, depending on the design of the mixer, up to about 5.5 kW.
• the selected vacuum mixer advantageously has one or more, usually, depending on the size of the selected mixer, about 1 to 10, nozzles, such as single-flat spray nozzles, full cone nozzles or hollow cone nozzles, preferably single-fluid flat jet nozzles, which are usually in the lid of the Mischers are integrated.
• the preparation process according to the invention is advantageously carried out by charging the selected silica carrier, preferably the selected precipitated silica, into the mixer and sealing it tightly. Subsequently, it is expedient to generate a negative pressure in the vacuum mixer with a suitable vacuum pump.
• a negative pressure in the vacuum mixer of from about 0.1 to about 0.5 bar (absolute), preferably from about 0.15 to about 0.3 bar (absolute), and more preferably from about 0.15 to about, is generated 0.25 bar (absolute).
• the power of the vacuum pump used is advantageously selected so that an evacuation time advantageous from an economic point of view of up to about 15 minutes, preferably up to about 5 minutes and particularly preferably up to about 1 minute is achieved. This ensures a satisfactory turnover in discontinuous operation.
• the agitator After setting the desired pressure in the vacuum mixer or, if desired, already during the pressure setting, the agitator can be put into operation.
• speeds of the mixer in the range of about 10 to 100, preferably from about 10 to about 50 and more preferably from about 15 to about 40 revolutions per minute depending on the selected type of mixer, have proven to be advantageous.
• the vitamin E compound to be adsorbed is added to the silica carrier introduced in the vacuum mixer at reduced pressure.
• the ⁇ -tocopherol acetate is preferably sprayed onto the stirred silica carrier by the above-mentioned nozzles.
• the spray pressure is advantageously about 1 to about 15 bar, preferably about 2 to about 10 bar.
• the spraying process is usually completed after about 1 to about 15 minutes, often up to about 10 minutes.
• the vacuum mixer is then advantageously slow in the speed of rotation of the agitator until complete pressure equalization, i. over a period of about 0.5 to about 10 minutes, preferably from 1 to about 10 minutes, and more preferably over a period of about 1 to about 3 minutes aerated.
• the resulting adsorbate for example, be removed by opening the bottom flaps of the mixer and treated as desired.
• the production process according to the invention is characterized in particular by simple technical feasibility and short cycle times, whereby it can also be used as a discontinuous process in an economically advantageous manner.
• the adsorbates produced by the production process according to the invention are usually obtained in the form of stable, dry and fine-grained powders having an average particle diameter of about 0.15 to about 0.6, preferably about 0.3 to about 0.6 mm.
• pulverulent adsorbates having the following particle size distribution: 5% by weight of the grains have an average diameter of up to 100 ⁇ m, and about 40% by weight of the grains have an average particle size Diameters of up to 500 microns, about 95 wt .-% of the grains have an average diameter of up to 2000 microns, preferably up to 1500 microns and more preferably up to 1000 microns and less than 1 wt% of the grains have a mean Diameter of 2000 microns or above.
• adsorbates which can be prepared by the process according to the invention are distinguished by advantageous material properties such as, for example, high mechanical stability, high storage stability and good flow properties, ie. H. a low stickiness even with a high content of adsorbed vitamin E compound, as well as a high Schütt composition. Shake density off.
• the present invention also relates to adsorbates of at least one vitamin E compound of the formula (I)
• R 1 , R 2 , R 3 are each independently hydrogen or methyl and
• R 4 is hydrogen or C 2 - to C 2 acyl
• the present invention relates to adsorbates of ⁇ -tocopherol acetate in adsorbed form on a precipitated silica carrier which can be prepared by a process as described above comprising mixing ⁇ -tocopherol acetate with the precipitated silica under reduced pressure.
• Such adsorbates have a higher content of each vitamin E compound used in the pores of the silica carrier used in each case than adsorbers prepared by conventional methods. This means that in the adsorbates according to the invention there is a greater ratio of the amount of vitamin E compound adsorbed in the pores to the amount of the silica gel support used on the outer surface, which is due to a higher density of the adsorbates according to the invention with otherwise advantageous material properties Good free-flowing and low stickiness is expressed.
• the adsorbates of the invention can be filled and stored in the usual way and are characterized by a good storage stability. In some cases, it has proven advantageous to provide a short ripening time of about 10 to about 30 minutes before filling, for example in sacks.
• the mentioned silica carriers which can be used in the context of the process according to the invention, in particular the precipitated silicas, are furthermore nutritionally harmless and are therefore suitable for use as additives for food or feed.
• the bulk material was piled up in a funnel with sieve to form a cone.
• the specified angle of repose was calculated by trigonometric from the ratio of height to radius of the bulk material cone.
• the flow behavior (discharge behavior) was determined with a cylindrical model container with variable aperture, the fixed height with a constant Mass test material was filled, determined. The smallest aperture is measured at which the test material leaked without bridging.
• the mixer was started at a speed of 30 min " 1 and 166.7 kg of 85.6 ° C preheated vitamin E oil (92 wt .-% racemic vitamin E acetate), corresponding to 62.5 wt. % of the total amount of vitamin E oil and carrier sprayed through four single-jet flat spray nozzles VeeJet® 9570 (5.2 mm bore, Spraying Systems Co.) at a spray pressure of 8 bar within 5.5 min.
• Example 1 The material obtained according to Example 1 was packed in plastic bags and stored at room temperature for 3 weeks, and the flow behavior was examined at weekly intervals. After one week of storage, the flow time was 4.4 s, after two weeks 4.1 s and after four weeks 4.2 s, each with a 30 mm aperture diameter.

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Citations (6)

• 2006
  • 2006-12-11 EP EP06830498A patent/EP1965766A1/de not_active Withdrawn
  • 2006-12-11 JP JP2008546367A patent/JP2010512142A/ja not_active Withdrawn
  • 2006-12-11 WO PCT/EP2006/069524 patent/WO2007074043A1/de active Application Filing
  • 2006-12-11 BR BRPI0620102A patent/BRPI0620102A2/pt not_active IP Right Cessation
  • 2006-12-11 CN CNA2006800488485A patent/CN101346129A/zh active Pending
  • 2006-12-11 KR KR1020087017777A patent/KR20080098586A/ko not_active Application Discontinuation
  • 2006-12-11 RU RU2008129544/15A patent/RU2008129544A/ru not_active Application Discontinuation
  • 2006-12-11 US US12/158,495 patent/US20080293955A1/en not_active Abandoned
  • 2006-12-22 TW TW095148609A patent/TW200731935A/zh unknown

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