Vitamin formulation

Abstract

The present patent application relates to solid particles comprising at least one fatsoluble vitamin, which are more stable when compressed into tablets.

Claims

1. A compressed tablet consisting of: (a) about 24.48 wt. %, based on total weight of the compressed table, of solid particles; (b) about 30.14 wt. %, based on total weight of the compressed tablet, of microcrystalline cellulose, (c) about 45.20 wt. %, based on total weight of the compressed tablet, of calcium phosphate, and (d) about 0.18 wt. %, based on total weight of the compressed tablet, of magnesium stearate, wherein the solid particles consist of, based on the total weight of the solid particles, of: (i) 27.00 wt. % of vitamin A acetate, (ii) 0.75 wt. % of dl-α-tocopherol; (iii) 0.75 wt. % of butylated hydroxytoluene (BHT); (iii) 47.31 wt. % of food modified starch; (iv) 18.19 wt. % of trehalose as a non-reducing sugar; (v) 4.00 wt. % of corn starch; and (vi) 2.00 wt. % of water, wherein the compressed tablet is a compression product of compressing the components (a)-(d) at a pressure between 5-40 kN, and wherein the compressed tablet has greater retention of the vitamin A acetate as compared to a similar compressed tablet that does not contain the trehalose after storage in a closed brown-glass bottle at room temperature for 35 days.

2. The compressed tablet according to claim 1, wherein the solid particles have a size Dv90 between 50-1000 μm.

3. The compressed tablet according to claim 2, wherein the solid particles have a size Dv90 between 100-800 μm.

4. The compressed tablet according to claim 1, wherein the tablet is a compression product of compressing the components (a)-(d) at a pressure between 10-40 kN.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1-3 are each graphs of the data in Tables 5-7, respectively, below showing vitamin A retention (IU/g) versus days of storage.

DETAILED DESCRIPTION

(2) The embodiments disclosed herein relate to solid particles (SP) comprising: (i) at least 20 weight-% (wt-%), based on the total weight of the solid particles, of least one fat soluble vitamin, (ii) at least one emulsifier, and (iii) at least one non-reducing sugar.

(3) These solid particles show better storage stability (of the fat-soluble vitamin) when compressed into tablets.

(4) It also possible to produce solid particles with only these three kind of ingredients.

(5) Therefore, the present invention relates to solid particles (SP′) consisting of (i) at least 20 weight-% (wt-%), based on the total weight of the solid particles, of least one fat soluble vitamin, (ii) at least one emulsifier, and (iii) at least one non-reducing sugar.

(6) Preferred non-reducing sugars are non-reducing disaccharides; more preferably sucrose and/or trehalose, most preferred is trehalose.

(7) Sucrose is a disaccharide combination of the monosaccharides glucose and fructose with the formula C.sub.12H.sub.22O.sub.11. It is commercially available from many suppliers.

(8) Sucrose is often extracted and refined from either cane or beet sugar for human

(9) Trehalose, also known as mycose or tremalose, is a natural alpha-linked disaccharide formed by an α,α-1,1-glucoside bond between two α-glucose units. There is an industrial process where trehalose is derived from corn starch. There are known biological pathways for trehalose biosynthesis.

(10) Trehalose is available commercially from various suppliers.

(11) The amount of non-reducing sugar in the solid particles is from 5-55 weight-% (wt-%), based on the total weight of the solid particles. Preferably 10-50 wt-%, based on the total weight of the solid particles; more preferably 15-45 wt-%, based on the total weight of the solid particles.

(12) Therefore the present invention relates to solid particles (SP1), which are solid particles (SP) or (SP′) comprising 5-55 wt-%, based on the total weight of the solid particles, of at least one non-reducing sugar.

(13) Therefore the present invention relates to solid particles (SP2), which are solid particles (SP) or (SP′) comprising 10-50 wt-%, based on the total weight of the solid particles, of at least one non-reducing sugar.

(14) Therefore the present invention relates to solid particles (SP3), which are solid particles (SP) or (SP′) comprising 15-45 wt-%, based on the total weight of the solid particles, of at least one non-reducing sugar.

(15) The solid particles according to the present invention comprise at least one fat-soluble vitamin.

(16) Fat-soluble vitamins are vitamin A, D, E, and K (as well as derivatives thereof). In a preferred embodiment of the present invention, vitamin A and/or its derivatives (such as vitamin A acetate and vitamin A palmitate) are used.

(17) Therefore, the present invention relates to solid particles (SP4), which are solid particles (SP), (SP′), (SP1) or (SP2), wherein the fat-soluble vitamin is vitamin A and/or a derivative of vitamin A (especially vitamin A acetate or vitamin A palmitate).

(18) The solid particles according to the present invention comprise usually comprise 20-75 wt-%, based on the total weight of the solid particles, of at least one fat soluble vitamin, preferably, 25-70 wt-%, based on the total weight of the solid particles.

(19) Therefore, the present invention relates to solid particles (SP5), which are solid particles (SP), (SP′), (SP1), (SP2), (SP3) or (SP4), wherein the solid particles comprise 20-75 wt-%, based on the total weight of the solid particles, of the fat-soluble vitamin(s).

(20) Therefore, the present invention relates to solid particles (SP6), which are solid particles (SP), (SP′), (SP1), (SP2), (SP3), (SP4) or (SP5), wherein the solid particles comprise 25-70 wt-%, based on the total weight of the solid particles, of the fat-soluble vitamin(s).

(21) Furthermore, the solid particles according to the present invention comprise at least one emulsifier. Any commonly known and used emulsifier can be used. A single emulsifier as well as a mixture of emulsifiers can be used.

(22) Suitable emulsifiers are modified (food) starches, ascorbyl palmitate, pectin, alginate, carrageenan, furcellaran, dextrin derivatives, celluloses and cellulose derivatives (e.g. cellulose acetate, methyl cellulose, hydroxypropyl methyl cellulose), lignosulfonate, polysaccharide gums (such as gum acacia (=gum arabic), modified gum acacia, TIC gum, flaxseed gum, ghatti gum, tamarind gum and arabinogalactan), gelatine (bovine, fish, pork, poultry), plant proteins (such as are for example peas, soybeans, castor beans, cotton, potatoes, sweet potatoes, manioc, rapeseed, sunflowers, sesame, linseed, safflower, lentils, nuts, wheat, rice, maize, barley, rye, oats, lupin and sorghum), animal proteins including milk or whey proteins, lecithin, polyglycerol ester of fatty acids, monoglycerides of fatty acids, diglycerides of fatty acids, sorbitan ester, and sugar ester (as well as derivatives thereof).

(23) Preferred are emulsifiers, which are not derived from an animal source.

(24) More preferred emulsifiers are modified (food) starches, polysaccharide gums and plant proteins.

(25) The starches can be modified physically and chemically. Pregelatinized starches are examples of physically modified starches. Acidic modified, oxidized, cross-linked, starch esters, starch ethers and cationic starches are examples of chemically modified starches.

(26) The amount of the emulsifier(s) in the solid particles is usually from 20-70 wt-%, based on the total weight of the solid particles; preferably 25-65 wt-%, based on the total weight of the solid particles.

(27) Therefore the present invention relates to solid particles (SP7), which are solid particles (SP), (SP′), (SP1), (SP2), (SP3), (SP4), (SP5) or (SP6), wherein the at least emulsifier is chosen from the group consisting of modified (food) starches, ascorbyl palmitate, pectin, alginate, carrageenan, furcellaran, dextrin derivatives, celluloses and cellulose derivatives (e.g. cellulose acetate, methyl cellulose, hydroxypropyl methyl cellulose), lignosulfonate, polysaccharide gums (such as gum acacia (=gum arabic), modified gum acacia, TIC gum, flaxseed gum, ghatti gum, tamarind gum and arabinogalactan), gelatine (bovine, fish, pork, poultry), plant proteins (such as are for example peas, soybeans, castor beans, cotton, potatoes, sweet potatoes, manioc, rapeseed, sunflowers, sesame, linseed, safflower, lentils, nuts, wheat, rice, maize, barley, rye, oats, lupin and sorghum), animal proteins including milk or whey proteins, lecithin, polyglycerol ester of fatty acids, monoglycerides of fatty acids, diglycerides of fatty acids, sorbitan ester, and sugar ester (as well as derivatives thereof).

(28) Therefore the present invention relates to solid particles (SP7′), which are solid particles (SP), (SP′), (SP1), (SP2), (SP3), (SP4), (SP5) or (SP6), wherein the at least emulsifier is not derived from an animal source.

(29) Therefore the present invention relates to solid particles (SP7″), which are solid particles (SP), (SP′), (SP1), (SP2), (SP3), (SP4), (SP5) or (SP6), wherein the at least emulsifier is chosen from the group consisting of modified (food) starches, polysaccharide gums and plant proteins.

(30) Therefore the present invention relates to solid particles (SP8), which are solid particles (SP), (SP′), (SP1), (SP2), (SP3), (SP4), (SP5), (SP6), (SP7), (SP7′) or (SP7″), wherein the amount of the emulsifier(s) in the solid particles is 20-70 wt-%, based on the total weight of the solid particles.

(31) Therefore the present invention relates to solid particles (SP9), which are solid particles SP), (SP′), (SP1), (SP2), (SP3), (SP4), (SP5), (SP6), (SP7), (SP7′) or (SP7″), wherein the amount of the emulsifier(s) in the solid particles is 25-65 wt-%, based on the total weight of the solid particles.

(32) Furthermore, the solid particles can comprise further ingredients (auxiliary agents). Such auxiliary agents are for example antioxidants (such as ascorbic acid or salts thereof, tocopherol (synthetic or natural)), butylated hydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxyanisole (BHA), propyl gallate, tert. butyl hydroxyquinoline, ethoxyquin and/or ascorbic acid esters of a fatty acid); stabilisers (such as gel-forming agents as xanthan gum, gellan gum); humectants (such as glycerine, sorbitol, polyethylene glycol); dyes; fragrances; fillers and buffers.

(33) These auxiliary agents can be useful for the solid particles, for their production, for the final product (for what the solid particles used) and/or for the production of the final product.

(34) These compounds can optionally be used in an amount of up to 15 wt-%, based on the solid particles.

(35) Therefore the present invention relates to solid particles (SP10), which are solid particles (SP), (SP1), (SP2), (SP3), (SP4), (SP5), (SP6), (SP7), (SP7′), (SP7″), (SP8) or (SP9), comprising up to 15 wt-%, based on the solid particles, of at least one auxiliary agents.

(36) Therefore the present invention relates to solid particles (SP11), which are solid particles (SP10), wherein the auxiliary agent (or auxiliary agents) is chosen from the group consisting of antioxidants (such as ascorbic acid or salts thereof, tocopherol (synthetic or natural)), butylated hydroxytoluene (BHT), ascorbyl palmitate, butylated hydroxyanisole (BHA), propyl gallate, tert. butyl hydroxyquinoline, ethoxyquin and/or ascorbic acid esters of a fatty acid); stabilisers (such as gel-forming agents as xanthan gum, gellan gum); humectants (such as glycerine, sorbitol, polyethylene glycol); dyes; fragrances; fillers and buffers.

(37) Depending on the way of the production of the solid particles according to the present invention it also possible that they are coated with a powder, which is used in the powder catch process. Such a powder can be for example corn starch.

(38) The amount of the powder (especially of corn starch) can be up to 15 wt-%, based on the total weight of the powder coated particles. Usually the content of the powder coating is kept as low as possible, so that another coating layer can be created.

(39) Furthermore, it is also possible to coat the solid particles with a coating layer. This layer can be of any known and used coating material.

(40) A suitable size of the solid particles of the present invention is between 50-1000 μm (preferably 100-800 μm); the size is defined by the diameter of the longest dimension of the particle and measured by commonly known method (like laser diffraction) All particle sizes of the solid particles according to the present invention are determined by laser diffraction technique using a “Mastersizer 3000” of Malvern Instruments Ltd., UK. Further information on this particle size characterization method can e.g. be found in “Basic principles of particle size analytics”, Dr. Alan Rawle, Malvern Instruments Limited, Enigma Business Part, Grovewood Road, Malvern, Worcestershire, WR14 1XZ, UK and the “Manual of Malvern particle size analyzer”. Particular reference is made to the user manual number MAN 0096, Issue 1.0, November 1994. If nothing else is stated all particle sizes referring to the coarse particles of the solid particles according to the present invention are Dv90 values (volume diameter, 90% of the population resides below this point, and 10% resides above this point) determined by laser diffraction. The particle size can be determined in the dry form, i.e. as powder or in suspension. Preferably, the particle size of the solid particles according to the present invention is determined as powder.

(41) The distribution of the particle size of the solid particles is also no essential feature of the present invention.

(42) The shape of the solid particles is also not an essential feature of the present invention. The shape can be sphere-like or any other form (also mixtures of shapes). Usually and preferably, the particles are sphere-like.

(43) The particles can be produced by any commonly known process, which are used to produce such particles (spray drying, spray chilling, etc.).

(44) The process of coating such small particles is well known. It is usually done by fluidized bed spray granulation, film coating or wet granulation.

(45) The solid particles according to the present invention are mainly used for producing compressed tablet.

(46) Therefore the present invention relates to the use of at least one solid particle (SP), (SP′), (SP1), (SP2), (SP3), (SP4), (SP5), (SP6), (SP7), (SP7′), (SP7″), (SP8), (SP9), (SP10) and/or (SP11) in the production of compressed tablets.

(47) The pressure, which is used to producing tablets, is at least 5 kN

(48) The pressure, which is used to producing tablets, is usually between 5 and 40 kN, preferably between 10-40 kN, more preferably between 5-40 kN.

(49) Therefore the present invention relates to the process (P) of producing compressed tables wherein at least one solid particle (SP), (SP′), (SP1), (SP2), (SP3), (SP4), (SP5), (SP6), (SP7), (SP7′), (SP7″), (SP8), (SP9), (SP10) and/or (SP11) are compressed with at pressure of at least 5 kN.

(50) Therefore the present invention relates to the process (P′) of producing compressed tables wherein at least one solid particle (SP), (SP′), (SP1), (SP2), (SP3), (SP4), (SP5), (SP6), (SP7), (SP7′), (SP7″), (SP8), (SP9), (SP10) and/or (SP11) are compressed with at pressure of between 5 and 40 kN.

(51) Therefore the present invention relates to the process (P″) of producing compressed tables wherein at least one solid particle (SP), (SP′), (SP1), (SP2), (SP3), (SP4), (SP5), (SP6), (SP7), (SP7′), (SP7″), (SP8), (SP9), (SP10) and/or (SP11) are compressed with at pressure of between 10-40 kN.

(52) Therefore the present invention relates to the process (P′″) of producing compressed tables wherein at least one solid particle (SP), (SP′), (SP1), (SP2), (SP3), (SP4), (SP5), (SP6), (SP7), (SP7′), (SP7″), (SP8), (SP9), (SP10) and/or (SP11) are compressed with at pressure of between 15-40 kN.

(53) It is also possible to add any further ingredients (such as fillers, dyestuffs, antioxidants, flavours, etc.) to the solid particles according to the present invention before compressing the particles into the tablet.

(54) Therefore the present invention relates to the process (P1), which is process (P), (P′), (P″) or (P′″), wherein at least one further ingredient is added.

(55) The tablet can be a dietary supplement or a pharmaceutical product. This depends what is added to the compressed tablets additionally.

(56) Furthermore the present invention also relates to compressed tablets comprising at least one solid particle (SP), (SP′), (SP1), (SP2), (SP3), (SP4), (SP5), (SP6), (SP7), (SP7′), (SP7″), (SP8), (SP9), (SP10) and/or (SP11).

(57) The invention is illustrated by the following Example. All temperatures are given in ° C. and all parts and percentages are related to the weight.

EXAMPLES

Example 1: Food Modified Starch and Trehalose

(58) 370.6 g of deionized water were heated up to 60° C.-65° C. in a vessel. 316.75 g of food modified starch and 121.2 g of trehalose were added and the mixture was brought into solution while stirring at 60-65° C. The obtained solution was cooled to 50-55° C. and degassed for 1 hour. Thereupon, 190.82 g of an oil mixture (180.78 g vitamin A acetate, 5.02 g BHT and 5.02 g dl-alpha-tocopherol) were added to the matrix system and emulsified. The temperature of the process was always kept below 65° C. After emulsification the inner phase of the emulsion had an average particle size of about 272 nm (Dv(0.1)=100 nm, Dv(0.5)=272 nm, Dv(0.9)=559 nm), measurement realized by laser diffraction (Malvern 3000). After emulsification the moisture of the emulsion, determined by a halogen moisture analyzer (Mettler Toledo, Type HR73-P), was checked and adapted if necessary. Afterwards 150 g of the emulsion were sprayed into a spray pan containing 1500 g of corn starch using a rotating spray nozzle. The obtained particles were sieved off (150 to 600 μm) from the excess of corn starch and dried at room temperature using a stream off air. The final product particle size after drying was in average 246 μm (Dv(0.1)=198 μm, Dv(0.5)=246 μm, Dv(0.9)=303 μm) measured by laser diffraction (Malvern 3000).

(59) Solid particles with the composition as listed in table 1 have been obtained.

(60) TABLE-US-00001 TABLE 1 Composition [wt %] Vit. A Ac. 2.8 Mio I.U/g 27.00 dl-alpha-Tocopherol 0.75 BHT 0.75 Food modified starch 47.31 Trehalose 18.19 Corn Starch 4.00 Water 2.00 Total 100.00

Example: 2 Food Modified Starch and Trehalose

(61) 381 g of deionized water were heated up to 60° C.-65° C. in a vessel. 316.75 g of food modified starch and 122.2 g of trehalose were added and the mixture was brought into solution while stirring at 60-65° C. The obtained solution was cooled to 50-55° C. and degassed for 1 hour. Thereupon, 190.78 g of vitamin A acetate were added to the matrix system and emulsified. The temperature of the process was always kept below 65° C. After emulsification the inner phase of the emulsion had an average particle size of about 333 nm (Dv(0.1)=175 nm, Dv(0.5)=333 nm, Dv(0.9)=558 nm), measurement realized by laser diffraction (Malvern 3000). After emulsification the moisture of the emulsion, determined by a halogen moisture analyzer (Mettler Toledo, Type HR73-P), was checked and adapted if necessary. Afterwards 150 g of the emulsion were sprayed into a spray pan containing 1500 g of corn starch using a rotating spray nozzle. The obtained particles were sieved off (150 to 600 μm) from the excess of corn starch and dried at room temperature using a stream off air. The final product particle size after drying was in average 180 μm (Dv(0.1)=180 μm, Dv(0.5)=240 μm, Dv(0.9)=321 μm) measured by laser diffraction (Malvern 3000).

(62) Solid particles with the composition as listed in table 21 have been obtained.

(63) TABLE-US-00002 TABLE 2 Composition [wt %] Vit. A Ac. 2.8 Mio I.U/g 27.00 Food modified starch 48.31 Trehalose 18.19 Corn Starch 4.00 Water 2.00 Total 100.00

Example 3: Food Modified Starch and Sucrose

(64) 370.6 g of deionized water were heated up to 60° C.-65° C. in a vessel. 317.4 g of food modified starch and 122.1 g of sucrose were added and the mixture was brought into solution while stirring at 60-65° C. The obtained solution was cooled to 50-55° C. and degassed for 1 hour. Thereupon, 197.3 g of an oil mixture (186.9 g vitamin A acetate, 10.4 g BHT) were added to the matrix system and emulsified. The temperature of the process was always kept below 65° C. After emulsification the inner phase of the emulsion had an average particle size of about 276 nm (Dv(0.1)=112 nm, Dv(0.5)=276 nm, Dv(0.9)=516 nm), measurement realized by laser diffraction (Malvern 3000). After emulsification the moisture of the emulsion, determined by a halogen moisture analyzer (Mettler Toledo, Type HR73-P), was checked and adapted if necessary. Afterwards 150 g of the emulsion were sprayed into a spray pan containing 1500 g of corn starch using a rotating spray nozzle. The obtained particles were sieved off (150 to 600 μm) from the excess of corn starch and dried at room temperature using a stream off air. The final product particle size after drying was in average 272 μm (Dv(0.1)=197 μm, Dv(0.5)=272 μm, Dv(0.9)=377 μm) measured by laser diffraction (Malvern 3000).

(65) Solid particles with the composition as listed in Table 3 have been obtained

(66) TABLE-US-00003 TABLE 3 Composition [wt %] Vit. A Ac. 2.8 Mio I.U/g 27.00 BHT 1.50 Food modified starch 45.86 Sucrose 17.64 Corn Starch 5.00 Water 3.00 Total 100.00

Example 4: Gum Acacia and Trehalose

(67) 381 g of deionized water were heated up to 60° C.-65° C. in a vessel. 143.78 g of food modified starch and 287.56 g of trehalose were added and the mixture was brought into solution while stirring at 60-65° C. The obtained solution was cooled to 50-55° C. and degassed for 1 hour. Thereupon, 187.68 g of an oil mixture (177.80 g vitamin A acetate, 4.94 g BHT and 4.94 g dl-alpha-tocopherol) were added to the matrix system and emulsified. The temperature of the process was always kept below 65° C. After emulsification the inner phase of the emulsion had an average particle size of about 493 nm (Dv(0.1)=215 nm, Dv(0.5)=493 nm, Dv(0.9)=987 nm), measurement realized by laser diffraction (Malvern 3000). After emulsification the moisture of the emulsion, determined by a halogen moisture analyzer (Mettler Toledo, Type HR73-P), was checked and adapted if necessary. Afterwards 150 g of the emulsion were sprayed into a spray pan containing 1500 g of cornstarch using a rotating spray nozzle. The obtained particles were sieved off (150 to 600 μm) from the excess of corn starch and dried at room temperature using a stream off air. The final product particle size after drying was in average 234 μm (Dv(0.1)=189 μm, Dv(0.5)=234 μm, Dv(0.9)=293 μm) measured by laser diffraction (Malvern 3000).

(68) Solid particles with the composition as listed in Table 4 have been obtained.

(69) TABLE-US-00004 TABLE 4 Composition [wt %] Vit. A Ac. 2.8 Mio I.U/g 27.00 dl-alpha-Tocopherol 0.75 BHT 0.75 Gum acacia 21.83 Trehalose 43.67 Corn Starch 4.00 Water 2.00 Total 100.00

Example 5: Stability in Stress Tablets

(70) 110.3 g of powder consisting of 27 g of vitamin A acetate particles (as obtained in Example 1), 33.24 g microcrystalline cellulose, 49.86 g calcium phosphate and 0.2 g of magnesium stearate was mixed during 10 min. This end preparation was then compressed with a pressure of 35 KN. The tablets (common disk-shaped; 0.2 g) were stored at room temperature in a closed brown-glass bottle and the vitamin A acetate content determined after 1, 7 and 35 days of storage.

(71) For the purpose to show the superior property of the particles according to the present invention, comparative examples were also carried, wherein instead of trehalose or sucrose other sugars, which are no non-reducing sugars, have been used. These comparative solid particles were prepare as described in Example 1.

(72) The impact of the use of trehalose is far better than other types of plasticizer. This can be seen on the FIGS. 1, 2, and 3. (in tables 5-7, the solid particles are listed. The concentration of the ingredients is the same as in Example 1).

(73) TABLE-US-00005 TABLE 5 Compressed tablets as on FIG. 1: Graph Composition of the solid particles 1 Vitamin A acetate Food Maltodextrin12 BHT/toco modified starch 2 Vitamin A acetate Food trehalose BHT/toco modified starch 3 Vitamin A acetate Food sucrose BHT/toco modified starch

(74) TABLE-US-00006 TABLE 6 Compressed tablets as on FIG. 2: Graph Composition of the solid particles 1 Vitamin A acetate Food Maltodextrin BHT/toco modified starches 20-23 2 Vitamin A acetate Food Maltodextrin BHT/toco modified starches 12 3 Vitamin A acetate Food trehalose BHT/toco modified starch

(75) TABLE-US-00007 TABLE 7 Compressed tablets as on FIG. 3: Graph Composition of the solid particles 1 Vitamin A acetate Gum acacia Maltodextrin BHT/toco 20-23 2 Vitamin A acetate Gum acacia Maltodextrin BHT/toco 12 3 Vitamin A acetate Gum acacia trehalose BHT/toco