MXPA98001512A - Dry particles of flux li - Google Patents

Abstract

The present invention relates to dry particle, easy to flow, consisting of at least one oleophilic substance as active ingredient present in a matrix of at least one support material and a coating. The coating consists of calcium silicate or a mixture of calcium silicate with one or more components, said components being microcrystalline cellulose, magnesium silicate, magnesium oxide, stearic acid, calcium stearate, magnesium stearate, hydrophilic silicic acid, Kaolin and / or Sterot

Description

DRY PARTICLES OF FREE FLOW.

Field of the Invention The invention relates to dry, easily flowable particles composed of at least one oleophilic substance as an active ingredient present in a matrix of at least one support material and a coating.

BACKGROUND OF THE INVENTION They are already known, dry particles, easy to flow, composed of at least one oleophilic substance as an active ingredient present in a matrix of at least one support material and a coating. Its maximum content of oleophilic substance as an active ingredient is 50% by weight. A process for the manufacture of said particles is described, for example, in German Patent 10 35 319 and the corresponding US Patent 2 756 177, in which a dispersion of an oily vitamin as an active ingredient is sprayed into a large excess of starch powder having a water content below 8%, whereby the dry powder of starch REF .: 25316 captures the pulverized particles and these eliminate a quantity of water such that they solidify and simultaneously they are covered with starch powder. A serious drawback of these particles is that approximately 15% of the amount of starch adheres to its surface and therefore the particles contain only a relatively low amount of active ingredient. According to a similar procedure described in the patent US Pat. No. 3 445 563, the starch is replaced by a mixture of inorganic substances that absorb water and others that do not absorb water, in order to eliminate the danger of explosion that is detached from the starch. divided. It is necessary an excess of 20 times of dust collector in order to obtain optimal results. As the water absorbing component of the scavenger powder, mention may be made, inter alia, of calcium silicate, especially calcium aluminum silicate, as an oil-soluble ingredient there may be mentioned vitamin A and vitamin D. In the case of an ingredient activity active 245 000 and 532 000 IU / g, the particles obtained have contained up to 19% dust collector as a coating. Furthermore, from the European Patent Application 0074050, a procedure has been made known that is useful for the preparation of dry powders, easy to flow, easily oxidizable substances, such as vitamins or carotenoids, which are coatings with a colloid. The process comprises the dispersion of these substances in an aqueous solution of a colloid which forms a film, the colloid being the homogeneous phase. After the addition of one or more substances from the group of mono, di or polysaccharides, the dispersion is sprayed in a spray tower with the aid of an auxiliary spraying agent and the pulverized particles are collected in a fluidized bed. With this, a hydrophobic silicic acid or a metal salt of a higher fatty acid or a mixture with silicic acid is introduced in an amount of 0.02 to 0.15 times by weight with respect to the dispersion as auxiliary agent of the dispersion on the bed fluidized with a homogeneous distribution in the spray area at temperatures at which the solidification of the colloid of the pulverized particles does not yet take place. The particles are charged with the auxiliary agent, the colloid mass of which is not essentially gelled, is collected in a fluidized bed and the particles are dried in the fluidized bed in a manner known per se. Although in this process only a thin hydrophobic film of the auxiliary spray agent is produced, the particles formed during the spray are sufficiently stabilized to prevent an agglomeration of the particles when they go together in the non-solidification state, such that the subsequent direct drying is possible on a fluidized bed dryer, the proposed method has the substantial disadvantage that the hydrophobic silicic acid is used as a spray aid. The use of free silicic acid in the pharmaceutical or food industry, which also carries out a whole process, is at least questionable, given that it is dangerous for health and therefore is not allowed for this purpose in many countries. • Therefore, said process and the easily flowable dry particles of the aforementioned type, which are prepared according to the same, are not satisfactory, especially for use in the pharmaceutical or food industry.

Description of the invention The object of the present invention is therefore that of solving the aforementioned disadvantages. In particular, easy-to-flow dry particles of the aforementioned type, containing an active ingredient of 50% by weight and above, especially greater than 70%, ie, particles having a high content of active ingredient, and at the same time should be obtained. find a procedure for the elaboration of said particles. The specific objective of the invention also constitutes a solid form of administration prepared with these dry particles of easy fluidity in order to incorporate an amount of active ingredient that is as high as possible, in the administration form. From the easily flowable particles comprising at least one oleophilic substance as active ingredient present in a matrix of at least one support material and a coating, the proposed objective is achieved by applying a coating based on calcium silicate . The coating may consist of calcium silicate alone, or a mixture of calcium silicate with one of the following components: microcrystalline cellulose, magnesium silicate, magnesium oxide, stearic acid, calcium stearate, magnesium stearate, hydrophilic silicic acid, kaolin and / or Sterotex. Coatings consisting of calcium silicate alone are preferred. The particles according to the invention have an oleophilic substance content of 50% by weight or more, with an average particle size between approximately 80 μm and approximately 1000 μm, especially between approximately loo μm and approximately 800 μm. When the coating consists of calcium silicate alone, the amount of the oleophilic substance may amount to more than 70% by weight without the disadvantageous properties mentioned above being present, even in a small extent. Even particles according to the invention having a content between 74.0 and 78.0% by weight of an oleophilic substance can be processed. In the case of particles according to the invention in which the coating consists of calcium silicate alone, the amount of calcium silicate is between 2 and 12% by weight, preferably about < _7% by weight. In this case, in comparison with the current technique, the low amount of coating substance is the essential reason that a very high amount of active ingredient, that is, a very high amount of oleophilic substance, can be incorporated into the matrix without the manipulation of the particles is influenced. The small amount of coating substance was surprising insofar as it is taken for granted that the substrates which come into consideration for this purpose and which have a chemically inert behavior, all adhere approximately in the same amounts to the matrix support material.

In the case of particles having a coating consisting of a mixture of calcium silicate with one or more of the aforementioned components, the calcium silicate content of the mixture is between 5 and 25% by weight. However, it has been discovered that not only the chemical nature of the calcium silicate particles is important, but also the physical nature thereof. Thus it has surprisingly been found that calcium silicate particles are especially suitable when they have a size of < _ 0.2 μm, especially < _0.1 μm, and a specific surface area of at least about 80 m / g to about 180 m2 / g, preferably about 95 m / g to 120 m2 / g and are agglomerated into aggregates having an average size of about 5-20 μm, preferably 5-10 μm. The Si02 / CaO ratio is between 1.65 and 2.65. Furthermore, it is advantageous when the calcium silicate is completely or parenterally present, in the form of a hydrate. The calcium silicate must be practically free of crystalline silicic acid. Therefore, many calcium silicates which are on the market as coating substances are excluded for the particles according to the invention, since they have been treated with crystalline silicic acid.

The oleophilic substance is at least one of the following group: lipophilic vitamins or their derivatives, carotenoids, especially β-carotene, and polyunsaturated fatty acids such as, for example, arachidonic acid, ecosapentaenoic acid and docosahexaenoic acid, and especially at least one vitamin of the group of vitamins A, D, E and K or a derivative thereof, especially vitamin A acetate, vitamin A palmitate and / or vitamin E acetate, preferably vitamin E or vitamin E acetate. The vitamin And it includes synthetically obtained tocopherols or a mixture of natural tocopherols. The support material is cellulose, water-soluble cellulose derivatives, especially methylcellulose or hydroxypropylmethylcellulose, maltodextrin, especially maltodextrin with an equivalent dextrose value of about 18, an alginic acid derivative, especially sodium alginate, calcium or propylene glycol, lactate calcium, gum arabic, gelatin, especially fish gelatin, sugar, sugar alcohol, glycerin, modified starch or pregelatinized cereal starch, preferably gelatin, especially fish gelatin. Gelatin with a Bloom number between 0 and about 220 has proven to be especially good. The support material or the matrix containing it may additionally contain at least one water-soluble vitamin. The easily flowable dry particles are very suitable for the preparation of solid dosage forms, especially tablets, since they have exceptional fluidity and good compression behavior without the need to add the usual amounts of a compression aid. Taking into account the possibility of incorporating an active ingredient amount of 70% by weight or higher (amounts of 74% by weight and respectively 78% by weight have been incorporated without problems) in the particles according to the invention, they are especially suitable for the preparation of polyvitamin and polyimineral tablets, since in this case there is much demand as high as possible of active ingredient coupled to a volume or weight as low as possible. The term "polyvitaminic and polymineral tablets" also includes effervescent tablets and chewable tablets. A preferred process for the preparation of the particles according to the invention consists in the spraying of an aqueous emulsion of the oleophilic substance (s) and the support material (s) according to the process of capture, especially according to the dust capture method, in a calcium silicate capture medium or a calcium silicate mixture with one or more components as described below in more detail, and the subsequent drying of the resulting particles in a way that is already known per se. The solid dosage forms, in particular the polyvitaminic tablets, contain in addition to at least one water-soluble substance as an active ingredient, preferably at least one oleophilic substance as the active ingredient of the group of carotenoids, especially β-carotene, and vitamins A , D, E and K or a derivative thereof. The vitamin E content is preferably between about 4 and 50% by weight, especially about 5 and 19% by weight. In addition to the usual adjuvants, the dosage form can also contain at least one trace element usually incorporated in the form of a mineral, and / or at least one water-soluble vitamin. As elements in the form of traces, manganese, iodine, potassium, magnesium, calcium, phosphorus, zinc, copper and iron are usually used, of which calcium is already provided at least to a certain extent by the coating of the particles. according to the invention. Of less importance can also be selenium, chromium, chlorine (as chloride), molybdenum, nickel, tin, silicon (in combination), vanadium and boron, with silicon (in combination) being contributed at least in part, such as calcium, by the particles according to the invention. At least one substance from the group of vitamin C, Bj_, B2, B6, B12, pantothenic acid, calcium pantothenate, folic acid, biotin and nicotinamide, is used as a water-soluble substance for the aforementioned purpose. Other details and advantages will be apparent from the following examples. Examples 1-3 describe particles that are coated only with calcium silicate. Example 4 describes a coating with a mixture of calcium silicate and microcrystalline cellulose.

Examples 5-8 describe polyvitamin tablets.

Example 1. 38 g of dried fish gelatin (Bloom number 0) were introduced into a 500 ml container, then 95 ml of deionized water was added and the mixture was dissolved with stirring with a grinding disc, at 1000 revolutions / minute (rpm), at 40-50 ° C, with which the matrix was obtained. Then 154 g of tocopherol acetate were emulsified in this matrix, stirring for 15 minutes. During the emulsification and stirring, the grinding disc was made to work at 4800 rpm. After this time the internal phase of the emulsion had an average particle size of about 250 nm. The emulsion was then diluted with 130 ml of deionized water and heated to 65 ° C. Next, 225 g of calcium silicate (Micro-Cel E from Celite Corp., USA with an Si02 / CaO ratio of 1.65) were placed in a laboratory spray tank cooled to at least 0 ° C. The emulsion was sprayed into the spray tank using a rotary spray nozzle. The calcium-silicate-coated as-adsorbed particles were screened (sieving fraction: 100-800 μm) by removing them from the excess calcium silicate and dried at room temperature using a stream of air. 190 g of calcium silicate coated particles with excellent flow properties were obtained, which were completely dry and could be handled very well. The calcium silicate content was 7% by weight.

Example 2. In an experiment analogous to Example 1, fish gelatin was replaced by gelatin for pharmaceutical uses with a Bloom number of 220, from Croda, England. The yield was 195 g. The product had the same good properties for industrial application as those of the product of example 1.

Example 3. Example 1 was repeated analogously, but using a calcium silicate with an SiO 2 / Cao ratio greater than 2.65. The calcium silicate coated particles having a tocopherol acetate content of only 44.3% by weight were obtained. The weight content of calcium silicate was greater than 7% by weight. A calcium silicate having an SiO / CaO ratio greater than 2.65 is therefore unsuitable.

Example 4. 36 g of dried, large molecule gelatin (Bloom number 0, Norland Products Incorporated) were placed in a 500 ml container. Then, 95 ml of deionized water was added and the mixture was dissolved by shaking with a grinding disc at 1000 revolutions / minute (rpm) at 40-50 ° C, whereby the matrix was obtained. Next, 156 g of tocopherol acetate were emulsified in the matrix by shaking for 15 minutes. During the emulsification and stirring of the grinding disc it was operated at 4800 rpm. After this time the internal phase of the emulsion had an average size of about 300 nm. The emulsion was then diluted with 135 ml of deionized water and heated to 65 ° C. Subsequently, 410 g of a calcium silicate mixture (Micro-Cel E from Celite Corp., USA, with a Si02 / CaO ratio of 1.65) and microcrystalline cellulose (VIVAPUR type 105) were introduced into the reservoir of a spray. laboratory. The ratio of VIVAPUR type 105 to Micro-Cel E was 5.66: 1. The mixture was cooled to at least 0 ° C. The emulsion was sprayed into the spray tank using a rotary spray nozzle. The particles thus obtained coated with calcium silicate cellulose were sieved (screening fraction 100-800 μm) separating them from the excess calcium silicate-cellulose mixture and drying at room temperature using an air stream. 222.1 g of calcium silicate-cellulose silicate-coated particles were obtained which had excellent flow properties, were completely dry and could be handled very well. The calcium silicate content was 21% by weight.

Example 5. Polivitaminic tablets were made from the following components on a COMPRESS II compressing machine with a 16 x 7.42 mm punch and a pressure of 5 to 50 KN. Product of example 1 147.0 mg Beta-Tab 7.5 (ß-carotene 7.5% to compress, origin ROCHE) 96.0 mg Ascorbic acid 90% gr 244.5 mg Avicel PH 102 130.0 mg Lactose DCL 2 1 50.0 mg Total weight of the tablet 668.0 mg The hardness of the resulting tablet was 20 to 140 N. The tablets were dry.

Example 6. Analogously to Example 4, a polyvitaminic tablet (formula E 75%, containing 75% by weight of vitamin E particles) was made using particles according to the invention with a vitamin E content of 75% by weight as an ingredient active and compared with a conventional vitamin tablet (formula E 50%, containing 50% by weight of vitamin E particles) of the same composition. Formula E 75% Formula E 50% Tablet weight 808.3 mg 948.3 mg ß-carotene * 34.5 mg 34.5 mg Vitamin E 280.0 mg 420.0 mg Vitamin C 90 291.7 mg 291.7 mg Avicel 161.6 mg 161.6 mg Microcel C 24.3 mg 24.3 mg PVP XL 16.2 mg 16.2 mg * Beta-Tab 20 (ß-carotene 20% to compress, origin ROCHE) From the foregoing, it is evident that, with the particles according to the invention, tablets with a weight can be made lower (or with correspondingly lower volumes) than with conventionally prepared particles containing vitamin E. Example 7. Analogously to Example 5, a polyvitaminic tablet (formula E 75%, containing 75% by weight of vitamin E particles) was made, using particles according to the invention with a vitamin E content of 75% by weight as an active ingredient and compared with a conventional vitamin E tablet (formula E 50%, containing 50% by weight of vitamin E particles) of the same composition. Formula E 75% Formula E 50% Vitamin / mineral mixture 1294.8 mg 1294.8 mg Vitamin E 70.7 mg 106.0 mg Microcellulose 57.2 mg 0.0 mg PVP XL 6, 6 mg 30, 0 mg Stearic acid 2.0 mg 2, 0 mg Magnesium stearate 4, 2 mg, 2 mg The hardness of the resulting tablet was 210 N. In the case of the formula E 75% the amount of PVP XL disintegrant could be reduced without changing the dissolution time of the tablet (less than 5 minutes ).

Example 8. Analogously to example 5, a polyvitaminic tablet (formula E 75%, containing 75% by weight of vitamin E particles) was made, using particles according to the invention with a vitamin E content of 75% by weight as active ingredient. The tablets did not contain disintegrant and had the following composition: Formula E 75% Vitamin / mineral mixture 1294.8 mg Vitamin E 70.7 mg Microcellulose 58.0 mg Starch 15.0 mg Stearic acid 2.0 mg Magnesium stearate 4, 2 mg The hardness of the resulting tablet was 210 N. The dissolution time of the tablet was less than 5 minutes. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (13)

1. An easily flowable dry particle, comprising at least one oleophilic substance as an active ingredient present in a matrix of at least one support material and a coating, characterized in that the coating consists of calcium silicate or a mixture of sodium silicate. calcium with one of the following components: microcrystalline cellulose, magnesium silicate, magnesium oxide, stearic acid, calcium stearate, magnesium stearate, hydrophilic silicic acid, kaolin and / or Sterotex.

2. The dry particle of easy flowability, according to claim 1, characterized in that the coating 'consists of calcium silicate.

3. The dry particle of easy fluidity, according to claim 1 or claim 2, characterized in that the content of the oleophilic substance amounts to 50% by weight or more, preferably greater than 70% by weight, especially 74.0% by weight. 78.0% by weight, and the average particle size is between about 80 μm and about 1000 μm, especially between about 100 μm and about 800 μm.

4. The dry particle of easy flowability, according to claim 2 or claim 3, characterized in that the content of calcium silicate is between 2 and 12% by weight, especially ... about 7% by weight.

5. The dry particle of easy flowability, according to any one of claims 1-4, characterized in that the calcium silicate, a) has an SiO2 / CaO ratio of 1.65-2.65; b) consists of particles of the size < . 0.2 μm, especially _ 0.1 μm, which are agglomerated forming aggregates with an average size of about 5-20 μm, especially 5-10 μm, and with a specific surface area of at least about 80 m / g approximately 180 m2 / g, preferably between approximately 95 m2 / g and 120 m2 / g; and c) is optionally, all or in part, calcium silicate hydrate.

6. The dry particle of easy flowability, according to any one of claims 1-5, characterized in that the oleophilic substance is at least one substance from the group of lipophilic vitamins or their derivatives, preferably from the group of vitamins A, D, E and K or its derivatives, especially vitamin A acetate, vitamin A palmitate, vitamin E and / or vitamin E acetate; carotenoids, especially β-carotene; and / or a substance from the group of polyunsaturated fatty acids.

7. The dry particle of easy flowability, according to any one of claims 1-6, characterized in that the support material is at least one substance of the cellulose group; water-soluble cellulose derivatives, especially methylcellulose or hydroxypropylmethylcellulose; maltodextrin, especially maltodextrin with an equivalent dextrose value of about 18; alginic acid derivatives, especially sodium, calcium or propylene glycol alginate; calcium lactate; gum arabic; gelatine, especially fish gelatine; sugar; sugar alcohol; glycerin; modified starch and pregelatinized cereal starch.

8. The dry particle of easy flowability, according to any one of claims 1-7, characterized in that at least one water-soluble vitamin is present in the matrix.

9. A process for the preparation of a dry particle of easy flowability, according to any one of claims 1-8, characterized in that it consists of spraying an aqueous emulsion of oleophilic substance (s) and the material (s). ) with the capture method, in particular according to the dust capture method, in a calcium silicate capture medium or a mixture of calcium silicate with one or more components, especially in a capture medium of calcium silicate, and then drying the resulting particles in a manner already known per se.

10. A solid dosage form, especially polyvitaminic tablets, characterized in that they are prepared from dry particles, easy to flow, according to at least one of claims 1-8.

11. The solid dosage form, especially polyvitaminic tablets, according to claim 10, characterized in that the content of vitamin E in the tablet is between 4% by weight and 50% by weight.

12. The use of dry particles, easy to flow, according to any of claims 1-8 for the preparation of a solid dosage form, especially a particular tablet for the production of a polyvitaminic tablet which optionally also contains traces of an element , normally incorporated in the form of a mineral.

13. The use of a dry particle, easy to flow, according to any one of claims 1-8, in the pharmaceutical or food industry.