TABLETTABLE FORMULATION OF LUTEIN AND/OR ZEAXANTHIN

Abstract

Solid formulations include a milled carotenoid, at least one hydrocolloid, a glucose syrup, sucrose and at least one water-soluble antioxidant (preferably sodium ascorbate), wherein the carotenoid is selected from the group consisting of lutein and zeaxanthin and any mixture thereof, wherein the hydrocolloid is selected from the group consisting of modified food starches and any mixtures thereof, and wherein the milled carotenoid has the following particle size distribution: D [3,2] in the range of from 0.6 to 1.5 m and D [v, 0.5] in the range of from 1.1 to 3.5 m, all D values as measured by laser diffraction (Malvern Instruments Ltd, Malvern, UK, Mastersizer 3000) according to the Fraunhofer scattering model. The solid formulation is in form of granules which are used for dietary supplements and pharmaceuticals, such as e.g. multi-vitamin and/or multi-mineral tablets and surprisingly show a low compression loss.

Claims

1. A solid formulation comprising a milled carotenoid, at least one hydrocolloid, a glucose syrup, sucrose and a water-soluble antioxidant, wherein the carotenoid is selected from the group consisting of lutein and zeaxanthin and any mixture thereof, wherein the hydrocolloid is selected from the group consisting of modified food starches and any mixture thereof, and wherein the milled carotenoid has the following particle size distribution: D [3,2] in the range of from 0.6 to 1.5 m, and D [v, 0.5] in the range of from 1.1 to 3.5 m, all D values as measured by laser diffraction according to the Fraunhofer scattering model.

2. The solid formulation according to claim 1, wherein the solid formulation is in the form of granules.

3. The solid formulation according to claim 2, wherein the solid formulation is obtained according to the following process: a) providing an aqueous solution of at least one modified food starch, a glucose syrup and sucrose; b) adding the carotenoid to the solution of step a) hereby obtaining a suspension; c) milling the suspension of step b) until the particle size distribution of the milled carotenoid according to claim 1 is reached; d) spray-granulating the suspension of step c) to obtain the solid formulation; whereby a water-soluble antioxidant (being preferably sodium ascorbate) is added during the process.

4. The solid formulation according to claim 2, wherein the granules have the following particle size distribution: D [3,2] in the range of from 200 to 300 m (preferably in the range of from 230 to 270 m) and D [v, 0.5] in the range of from 220 to 320 m (preferably in the range of from 240 to 290 m), all D values as measured by laser diffraction according to the Fraunhofer scattering model.

5. The solid formulation according to claim 1, wherein the amount of sucrose is in the range of from 0.1 to 40 weight-%, preferably in the range of from 10 to 30 weight-%, more preferably in the range of from 15 to 25 weight-%, based on the total weight of the formulation.

6. The solid formulation according to claim 1, wherein the amount of carotenoid is in the range of from 1 to 30 weight-%, preferably in the range of from 5 to 25 weight-%, more preferably in the range of from 5 to 17 weight-%, most preferably in the range of from 10 to 17 weight-%, based on the total weight of the formulation.

7. The solid formulation according to claim 1, wherein the carotenoid is a mixture of lutein and zeaxanthin, and wherein the molar ratio of lutein to zeaxanthin is in the range of from 20:1 to 2:1, preferably the molar ratio is in the range of from 10:1 to 4:1.

8. The solid formulation according to claim 1, wherein the amount of the modified food starch is in the range of from 10 to 50 weight-%, preferably in the range of from 25 to 45 weight-%, based on the total weight of the formulation.

9. The solid formulation according to claim 1, wherein the amount of glucose syrup is in the range of from 0.1 to 40 weight-%, preferably in the range of from 10 to 30 weight-%, more preferably in the range of from 15 to 25 weight-%, based on the total weight of the formulation.

10. The solid formulation according to claim 1, wherein the amount of the water-soluble antioxidant (preferably being sodium ascorbate) is in the range of from 0.1 to 10 weight-%, preferably in the range of from 2 to 7 weight-%, more preferably in the range of from 4 to 6 weight-%, based on the total weight of the formulation.

11. The solid formulation according to claim 1, wherein the amount of the milled carotenoid, the amount of the at least one modified food starch, the amount of the glucose syrup, the amount of sucrose and the amount of the water-soluble antioxidant (preferably being sodium ascorbate) sum up to an amount of at least 90 weight-%, preferably of at least 95 weight-%, based on the total weight of the formulation.

12. The solid formulation according to claim 1, wherein the formulation does not contain any oil.

13. The solid formulation according to claim 1, wherein the formulation does not comprise any of the following compounds: hydrolyzed lecithin products, Gum Arabic, fat-soluble antioxidants, isomalt, -zeacarotene and -zeacarotene.

14. A dietary supplement comprising a solid formulation according to claim 1.

15. The dietary supplement according to claim 14 further comprising vitamins, mineral salts and/or trace elements.

16. The dietary supplement according to claim 14, wherein the dietary supplement is in the form of a tablet.

17. The tablet according to claim 16, wherein the tablet has a compression loss of less than 12% of carotenoid, based on the total amount of carotenoid.

18. The tablet according to claim 16, wherein the tablet has a hardness as crushing force of at least 160 N when a compression force of 20-25 kN is applied.

19. Use of a solid formulation according to claim 1 as additive for dietary supplements, especially for dietary supplements in form of tablets.

Description

EXAMPLES

[0123] The following abbreviations are used: RH=room humidity.

[0124] Measurement of Particle Size

[0125] All particle sizes of the solid particles of 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.

[0126] Analytical Equipment that was Used for Powder and Tablet Characterization

[0127] Powder characteristics included the analyses of powder density (bulk and tapped) and flowability. Bulk (bulk) and tapped densities (tapped) are determined with an Engelsmann JEL powder tap density tester (J. Engelsmann AG, Ludwigshafen, Germany) according to EP<2.9.34> and USP <616> via the measurement in a graduated cylinder. The powder flowability is determined with a Pharmatest PTG-S4 automated powder characterization instrument (Pharma Test Apparatebau AG, Hainburg, Germany). Mass flow rate (g/min) is determined via the method of flow through an orifice. Flow rate is interpreted as the time needed for a specified amount of powder (100 g) to flow through an orifice with different diameters. A free flowing powder should be able to flow through the whole set of diameters 5, 7, 9, 10, and 15 mm. The plot of flow rate vs. orifice diameter is referred as flow curve. Three parallel measurements are performed to determine the flow rate.

[0128] Following tableting, the characterization of compressed tablets including tablet hardness, friability, disintegration, and content uniformity is done. The breaking strengths of tablets (hardness) are measured as described in USP <1217> and EP <2.9.8.> with a Krmer UTS4 1 tester (Kraemer Elektronik GmbH, Darmstadt, Germany). The force needed to break a tablet axially is measured. Presented are always average values of 10 measurements.

[0129] Friability, that is closely related to tablet hardness, refers to the extent of weight loss during mechanical abrasion. A maximum loss of no more than 1% of the initial tablet weight is considered acceptable (USP <1216>, EP<2.9.7.>). 10 tablets are tested in an AE-1 Friabilator (Charles Ischi AG Pharma Prftechnik, Zuchwill, Switzerland) at a rotation speed of 25 rpm for 4 minutes. The weight loss of the tablets is recorded.

[0130] Tablet disintegration is characterized according to USP<701, 2040> by using a DISI-1 disintegration tester (Charles Ischi PG Pharma Prftechnik, Zuchwill, Switzerland) in 900 mL demineralized water at 37 C. Six parallel measurements are carried out. Upper limit of disintegration time is 30 min for uncoated tablets (USP <2040>).

[0131] Content uniformity is evaluated via the standard deviation RSD (%) calculated out of individual determinations per series.

[0132] Stability of prototypes in tablet application has been monitored at 25 C./60% RH (long-term study, up to 36 months), 30 C./65% RH (intermediate stability, 12 months) and at 40 C./75% RH (accelerated/stress test, 6 months). The tablets are stored in sealed polyethylene (PE) boxes, and analyzed at pre-determined time-points.

[0133] Measurement of the Particle Size Distribution

[0134] The particle size distribution was measured after the re-dispersed formulation of example 1, 2 and 3, respectively, was treated with ultrasound and centrifuged.

Example 1: Manufacture of a Solid Formulation of Lutein and Zeaxanthin According to the Present Invention

[0135] 150 kg of OSA-Starch, 75 kg of dried glucose syrup and 75 kg of sucrose are dissolved in 440 l of preheated water at 72 C. for at least 30 minutes (matrix). 60 kg of FloraGlo lutein crystals (as available from Kemin Foods, Des Moines, US) are then added to the matrix under stirring at a temperature between 36 C. and 20 C. After pH adjustment of the resulting suspension to a pH of 3.5 the resulting pH-adjusted suspension is added to the milling beads (diameter of 0.3 mm) and milling is carried out in several passages. To the resulting suspension 18 kg of sodium ascorbate are added. Then water is added and spray dry granulation started. 275 kg of the solid formulation are obtained.

Example 2: Manufacture of a Solid Formulation of Lutein and Zeaxanthin According to the Present Invention

[0136] 160 kg of OSA-Starch, 80 kg of dried glucose syrup and 80 kg of sucrose are dissolved in 480 l of preheated water at 72 C. for at least 30 minutes (matrix). 60 kg of FloraGlo lutein crystals (as available from Kemin Foods, Des Moines, US) are then added to the matrix under stirring at a temperature between 36 C. and 29 C. After pH adjustment of the resulting suspension to a pH of 2.9 the resulting pH-adjusted suspension is added to the milling beads (diameter of 0.3 mm) and milling is carried out in several passages. To the resulting suspension 20 kg of sodium ascorbate are added. Then water is added and spray dry granulation started. 305 kg of the solid formulation are obtained.

Example 3: Manufacture of a Solid Formulation of Lutein and Zeaxanthin According to the Present Invention

[0137] 160 kg of OSA-Starch, 80 kg of dried glucose syrup and 80 kg of sucrose are dissolved in 480 l of preheated water at 72 C. for at least 30 minutes (matrix). 60 kg of FloraGlo lutein crystals (as available from Kemin Foods, Des Moines, US) are then added to the matrix under stirring at a temperature between 39 C. and 21 C. After pH adjustment of the resulting suspension to a pH of 3.03 the resulting pH-adjusted suspension is added to the milling beads (diameter of 0.3 mm) and milling is carried out in several passages. To the resulting suspension 18 kg of sodium ascorbate are added. Then water is added and spray dry granulation started. 330 kg of the solid formulation are obtained.

Example 4: Comparison Example

[0138] As comparison example the commercially available Lutemax2020 (Lutein & Zeaxanthin Vegetarian Multifunctional beadlets 5%) (OmniActive Health Technologies, India) is used. It is a standardized extract of dried flowers of Marigold (Tagetes species) in the form of purified Free Lutein concentrate encapsulated in a matrix of hydrophilic carriers, cellulose derivatives and natural anti-oxidants.

[0139] Flowability

[0140] All three formulations manufactured according to examples 1-3 showed an excellent flowability (see table 1 below).

TABLE-US-00001 TABLE 1 Flow [g/min] through an orifice with a Example 1 - Example 2 - Example 3 - diameter of Flow [g/min] Flow [g/min] Flow [g/min] 15 mm 2308 2308 2368 10 mm 789 789 796 9 mm 571 657 672 7 mm 300 299 305 5 mm 126 126 124

[0141] Density

[0142] The bulk density and the tapped density of all three examples is high as can be seen in the following table 2.

TABLE-US-00002 TABLE 2 Example 1 Example 2 Example 3 Bulk density 0.71 g/cm.sup.3 0.71 g/cm.sup.3 0.71 g/cm.sup.3 Tapped density 0.79 g/cm.sup.3 0.79 g/cm.sup.3 0.79 g/cm.sup.3

Example 5: Tableting Process and Equipment

[0143] Tablet mixtures are prepared by mixing and sieving (1 mm diameter of the sieve) the ingredients as given in table 3 and 4, respectively, in a Turbula mixer (Willy A. Bachofen Maschinenfabrik) at 23 rpm for 15 min followed by mixing in a drum (7.5 l) for 15 min at 20 rpm (rotations per minute).

TABLE-US-00003 TABLE 3 Vitamin premix (dose in mg per tablet) As Amount of Total commercially ingredient Dose amount Amount Ingredient available form in form [mg] in [g] in [%] Beta Beta Tab 20% S 20% 7.50 90.00 3.89 carotene Vitamin A Vitamin A 500000 IU 8.10 97.20 4.21 Acetate 500 Vitamin D3 Vitamin D3 100 100000 IU 5.40 64.80 2.80 SD/S Vitamin C Ascorbic Acid 90% 70.00 840.00 36.35 90% granulation Vitamin E Vitamin E 75 750 IU 42.00 504.00 21.81 HP Vitamin B1 Thiamine 100% 2.03 24.35 1.05 mononitrate Vitamin B2 Riboflavin TG 100% 1.87 22.44 0.97 Vitamin B3 Niacinamide 100% 21.00 252.00 10.90 Vitamin B5 Calcium D- 100% 14.72 176.58 7.64 Panthothenate Vitamin B6 Pyridoxine 100% 2.68 32.21 1.39 Hydrochloride Vitamin B8 Biotin 1% on 1% 3.75 45.00 1.95 Potato maltodextrin Vitamin B9 Folic acid 10% 10% 5.00 60.00 2.60 on Potato maltodextrin Vitamin B12 Vitamin B12 0.1% 7.80 93.60 4.05 0.1% WS N Vitamin K1 Vitamin K1 5% 5% 0.75 9.00 0.39 SD = 192.60 = 2311.18 = 100.00

TABLE-US-00004 TABLE 4 Mineral premix (dose in mg per tablet) As Amount of commercially ingredient Total available in form Dose amount Amount Ingredient form [%] [mg] in [g] in [%] iron Ferrous 31.52 57.11 611.04 28.60 fumarate copper Copper (II) 39.82 5.02 53.74 2.51 sulphate anhydrous manganese Manganese 32.50 6.15 65.85 3.08 sulphate monohydrate zinc Zinc sulphate 36.40 41.21 440.93 20.63 monohydrate iodine Potassium 7.43 2.02 21.60 1.01 iodide 10% on Potato maltodextrin chrome Chromic 19.52 0.31 3.29 0.15 chloride hexahydrate selenium Sodium 0.44 11.36 121.59 5.69 selenite 1% on corn maltodextrin molybdene Sodium 39.60 0.19 2.03 0.09 molybdate dihydrate Potassium Potassium 52.40 76.34 816.79 38.22 chloride chloride = 199.71 = 2136.86 = 100.00

[0144] Tablets are compressed with a Korsch XL 100 rotary tablet press (Korsch AG, Berlin, Germany). During tableting, the tablet mixtures are compressed with different compression forces (10-40 kN) and the breaking force of the tablets is measured. Tablet hardness vs. compression force is plotted to construct the compression profiles. Based on the obtained compression profiles, the optimal compression force was determined (20 kN) and the tablets are produced with the composition as given in the following table 5.

TABLE-US-00005 TABLE 5 Tablet composition of the multivitamin-multimineral tablets 1-3 and comparison table 4 comprising either of the formulations according to example 1, 2 or 3 or the formulation according to comparison example 4 Comparison tablet 4 with Tablet 1 with Tablet 2 with Tablet 3 with formulation formulation formulation formulation according to according to according to according to comparison Ingredient example 1 example 2 example 3 example 4 Lutein/zeaxanthin In form of In form of In form of In form of formulation formulation formulation formulation according to according to according to according to example 1: example 2: example 3: example 4: 60.00 mg 60.00 mg 60.00 mg 120.00 mg Vitamin premix 192.60 mg 192.60 mg 192.60 mg 192.60 mg according to table 6 mineral premix 199.71 mg 199.71 mg 199.71 mg 199.71 mg according to table 7 Magnesium as 166.67 mg 166.67 mg 166.67 mg 166.67 mg magnesium oxide tornita Calcium and phosphorous 594.90 mg 594.90 mg 594.90 mg 594.90 mg as calcium phosphate anhydrous (Emcompress) Crospovidone NF 7.00 mg 7.00 mg 7.00 mg 7.00 mg as Polyplasdone XL Silicium as 4.28 mg 4.28 mg 4.28 mg 4.28 mg Aerosil 200 Stearic Acid powder 4.00 mg 4.00 mg 4.00 mg 4.00 mg Magnesium stearate 4.00 mg 4.00 mg 4.00 mg 4.00 mg Cellulose, 311.85 mg 311.85 mg 311.85 mg 311.85 mg microcrystalline as Avicel PH 102 ad 1500.00 mg 1500.00 mg 1500.00 mg 1500.00 mg

[0145] Compression Profile (See Table 6)

[0146] The compression profiles of all three tablets 1-3 are similar to each other. The comparison example exhibited lower compressibility what was reflected in higher compression force needed for tabletingat least 25 kN for the comparison tablet 4 versus 20 kN for the tablets 1-3 according to the invention.

TABLE-US-00006 TABLE 6 Tablet 1 with Tablet 2 with Tablet 3 with formulation formulation formulation according to according to according to Compression example 1 - example 2- example 3 - force F.sub.press average of average of average of [kN] hardness [N] hardness [N] hardness [N] 10.0 78 75 79 15.0 128 122 123 17.5 144 148 149 20.0 178 175 175 25.0 207 207 208 30.0 246 239 242 35.0 266 269 261 40.0 299 290 298

[0147] Tablet Characteristics

[0148] All three tablets 1-3 according to the present invention show satisfactory tablet properties in terms of hardness, friability and disintegration (see table 7). That means that multivitamin-multimineral tablets with the formulations according to the present invention show a hardness as crushing force of at least 160 N when a compression force of 20 kN-25 kN is applied.

[0149] The comparison tablet 4 exhibits a longer disintegration time compared to the tablets 1-3 according to the present invention. The content uniformity within all produced tablets according to the present invention is satisfactory (RSD<5%).

TABLE-US-00007 TABLE 7 Comparison Tablet 1 Tablet 2 Tablet 3 tablet 4 Tablet press Korsch XL Korsch XL Korsch XL Korsch XL 100 100 100 100 Punch 22 9 mm 22 9 mm 22 9 mm 22 9 mm kN 20 20 20 25 Weight of 1509.3 (1501.0- 1505.7 (1499.9- 1507.1 (1500.4- 1499.1 (1490.7- cores [mg] 1515.5) 1512.0) 1514.1) 1507.3) Hardness [N] 175 (166-180) 172 (166-182) 170 (162-179) 166 (156-176) Friability [%] 0.16 0.13 0.12 0.09 Disintegration 1 min 26 sec 1 min 28 sec 1 min 29 sec 5 min 58 sec of cores in (1 min 20 sec- (1 min 22 sec- (1 min 16 sec- (4 min 50 sec- deionized 1 min 32 sec) 1 min 40 sec) 1 min 44 sec) 7 min 36 sec) water at 37 C.

[0150] Stability Trials with the Tablets Comprising the Formulations Manufactured According to Example 1, 2 and 3, Respectively

[0151] The lutein and zeaxanthin contents of the three tablets comprising the formulations according to the examples 1-3 and the lutein and zeaxanthin contents of the tablet comprising the form of the comparison example 4 have been measured at the following conditions:

[0152] 25 C. at 60% RH, 30 C. at 65% RH and 40 C. at 75% RH.

[0153] The results are shown in the following tables 8-10.

TABLE-US-00008 TABLE 8 25 C. at 60% RH Lutein content in % of initial Zeaxanthin content in % of initial amount amount Sample 1 2 3 1 2 3 Time 0 month months months 0 month months months Tablet 1 98.5 85.5 80.3 80.3 100.5 86.5 81.4 84.8 Tablet 2 97.9 88.6 85.7 83.5 97.6 87.3 85.7 87.3 Tablet 3 96.7 84.9 83.3 80.8 96.6 84.1 84.5 84.1 Comparison 99.7 75.9 68.3 55.5 100.3 77.3 71.3 61.5 tablet 4

TABLE-US-00009 TABLE 9 30 C. at 65% RH Lutein content in % of initial Zeaxanthin content in % of initial amount amount Sample 1 2 3 1 2 3 Time 0 month months months 0 month months months Tablet 1 98.5 82.7 80.6 78.5 100.5 83.1 81.4 81.4 Tablet 2 97.9 86.2 83.2 83 97.6 84.1 83.7 87.3 Tablet 3 96.7 84.5 81 79.7 96.6 82.5 81.9 84.1 Comparison 99.7 73.9 60.3 55.4 100.3 76.1 64.1 60.4 tablet 4

TABLE-US-00010 TABLE 10 40 C. at 75% RH Lutein content in % of initial Zeaxanthin content in % of initial amount amount Sample 1 2 3 1 2 3 Time 0 month months months 0 month months months Tablet 1 98.5 84.8 81 76.8 100.5 84.8 81.4 81.4 Tablet 2 97.9 86.6 84.4 81.3 97.6 85.7 85.1 85.7 Tablet 3 96.7 83.3 80.4 79.1 96.6 82.5 82.8 82.5 Comparison 99.7 56.7 45.9 25.6 100.3 62.8 52 33.2 tablet 4