Formulation of fat-soluble vitamin

Abstract

The invention relates to a composition comprising A) microcapsules comprising at least one fat-soluble active substance selected from a vitamin K compound or a provitamin or a prodrug of a vitamin K compound embedded in a matrix comprising a hydrocolloid and optionally one or more other matrix components, and B) at least one dietary mineral; as well as uses and products comprising such compositions.

Claims

1. A composition comprising: A) a first component being microcapsules consisting of at least one fat-soluble active substance selected from a vitamin K compound or a provitamin or a prodrug of a vitamin K compound embedded in a matrix comprising a hydrocolloid and optionally one or more other matrix components; and B) a separate second component being at least one dietary mineral, wherein the dietary mineral is selected from a calcium salt, a magnesium salt, calcium carbonate or magnesium oxide.

2. The composition according to claim 1, wherein said at least one fat-soluble active substance is vitamin K1, vitamin K2, provitamins and prodrugs of vitamin K1 or vitamin K2, MK-6, MK-7, MK-8, or a mixture thereof.

3. The composition according to claim 1, wherein the content of said active substance is from 0.01 to 15%, 0.1 to 10%, 0.2 to 5%, or 1 to 3% of the total weight of the microcapsules.

4. The composition according to claim 1, wherein the content of said microcapsules is from 0.001 to 15%, 0.01 to 10%, or 0.1 to 6% of the total weight of the composition.

5. The composition according to claim 1, wherein the content of said at least one dietary mineral is at least 10%, at least 20%, or at least 30% of the total weight of the composition.

6. The composition according to claim 1, further comprising one or more additional active substances selected from the group consisting of vitamin D2, vitamin D3, vitamin E, vitamin E-acetate, vitamin A, a monounsaturated fatty acid, a polyunsaturated fatty acid (PUFA), a PUFA oil, β-carotene, zeaxanthin, lycopene, lutein and Q10.

7. The composition according to claim 1, wherein said microcapsules comprise vitamin K2 in the MK-7 form as the at least one fat-soluble active substance, and wherein said at least one dietary mineral is calcium carbonate or magnesium oxide.

8. The composition according to claim 1, wherein said microcapsules comprise vitamin K1 as the at least one fat-soluble active substance, and wherein said at least one dietary mineral is calcium carbonate or magnesium oxide.

9. A unit dosage form comprising the composition according to claim 1, wherein the content of said active substance is from 10 to 500 μg, 25 to 250 μg, or 50 to 200 μg, and wherein the content of said at least one dietary mineral is at least 10%, at least 20%, or at least 30% of the total weight of the dosage form.

10. The unit dosage form according to claim 9 which is a daily unit dosage form.

11. A process for preparing the unit dosage form according to claim 9 in the form of a tablet, comprising: a) blending microcapsules comprising at least one fat-soluble active substance selected from a vitamin K compound or a provitamin or a prodrug of a vitamin K compound embedded in a matrix comprising a hydrocolloid and optionally one or more other matrix components in an amount of from 10 to 500 μg with at least 10% by weight of the total weight of the dosage form of at least one dietary mineral; and b) compressing the resulting blend to form a tablet.

12. The composition according to claim 1, wherein said hydrocolloid is an acacia gum, a protein or a starch.

13. The composition according to claim 1, wherein said matrix further contains antioxidants and/or carbohydrates.

14. A product comprising the composition according to claim 1.

15. The product according to claim 14, which is a food, a food supplement, a beverage, a pharmaceutical or veterinary product, a feed or feed supplement, a personal care product, or a household product.

16. The product according to claim 14, which is a nutraceutical or pharmaceutical product for oral administration.

17. The product according to claim 14 for use: a) in the treatment of a condition associated with vitamin K deficiencies; b) in the treatment of osteoporosis; c) in the treatment of conditions of the cardiovascular system; d) in the treatment of arteriosclerosis; or e) in assisting blood clotting.

18. A method of treating a condition associated with vitamin K1 or K2, comprising administering to a patient in need thereof an effective amount of the composition according to claim 1.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) In one embodiment of the composition of the invention the at least one fat-soluble active substance is selected from vitamin K1, vitamin K2 and provitamins and prodrugs of vitamin K1 or vitamin K2, such as MK-6, MK-7 or MK-8, in particular K1 and MK-7, or a mixture thereof.

(2) In another embodiment the content of said active substance(s) is from 0.01 to 15%, such as 0.1 to 10%, e.g. 0.2 to 5% or 0.5 to 3% or 1 to 2%, of the total weight of the microcapsules.

(3) In one embodiment of the composition of the invention the at least one dietary mineral is selected from a salt of Li, Na, Mg, K, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Mo or Se, preferably Ca and/or Mg.

(4) In another embodiment the at least one dietary mineral salt is any pharmaceutically acceptable salt, such as a halide, oxide, nitrate, stearate, sulphate, carbonate, glycerophosphate, hydrogen carbonate, dihydro- or anhydro-phosphate, e.g. a calcium salt, such as calcium carbonate, or a magnesium salt, such as magnesium oxide.

(5) In one of such embodiments the composition comprises microcapsules comprising vitamin K2 in the MK-7 form as the at least one active substance and calcium carbonate or magnesium oxide as one of the at least one dietary mineral.

(6) In another of such embodiments the composition comprises microcapsules comprising vitamin K1 as the at least one active substance and calcium carbonate or magnesium oxide as one of the at least one dietary mineral.

(7) In yet another embodiment the content of said microcapsules is from 0.001 to 15%, such as 0.01 to 10%, e.g. 0.1 to 6%, of the total weight of the composition.

(8) The content of said at least one dietary mineral may e.g. be at least 10% of the total weight of the composition, such as at least 20% or even at least 30%.

(9) The composition of the invention may further comprise one or more additional active substances selected from vitamin E or E-acetate, vitamin A, D2 or D3, a monounsaturated or polyunsaturated fatty acid or a PUFA oil comprising mono-, di- and/or triglycerides of linoleic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid and/or docosahexaenoic acid in combination with other fatty acids or the free fatty acids itself, β-carotene, zeaxanthin, lycopene, lutein or Q10, such as vitamin E or E-acetate, vitamin A, D2 or D3, a monounsaturated or PUFA oil, β-carotene, lycopene, lutein or Q10.

(10) In one embodiment of the unit dosage form of the invention is a daily unit dosage form.

(11) In one embodiment of the microcapsule of the invention the at least one fat-soluble active substance is selected from vitamin K1, vitamin K2 and provitamins and prodrugs of vitamin K1 or vitamin K2.

(12) In another embodiment the content of the active substance(s) is 0.1 to 10%, e.g. 0.2 to 5% or 0.5 to 3% or 1 to 2%, of the total weight of the microcapsules.

(13) In another embodiment the microcapsules comprising at least one fat-soluble active substance selected from a vitamin K compound or a provitamin or a prodrug of a vitamin K compound and comprised in the composition of the invention is obtained by a process according to the invention.

(14) In a third embodiment the microcapsule of the invention is for use in a composition according to the invention.

(15) The additional oil for solution of the active substance(s) is a conventional oil, such as a medium chained triglyceride, any vegetable edible oil, soy bean oil, olive oil, palm oil, sunflower oil, etc.

(16) The fat-soluble active substances comprised in the microcapsule according to the invention or the microcapsule included in the composition according to the invention may be any substance selected from vitamin K1, vitamin K2 and provitamins or prodrugs of vitamin K1 or vitamin K2, viz. any substance of the vitamin K type which during storage, transport, handling and use requires protection, e.g. from oxygen, moisture, light radiation, and physical influences, in order to avoid physical and chemical decomposition of the substance. These active substances are further defined as being active in either a chemical or biological system. A provitamin, or a prodrug, of vitamin K will in vivo convert to the active vitamin and may be selected from any one of the substances disclosed in WO2010/035000 or WO2013/128037. These publications, which are referred to as a whole also disclose processes for manufacture of vitamin K compounds.

(17) In one embodiment the microcapsule is made from a crystalline form of the actual vitamin K2 compound. In another embodiment the microcapsule is made from the oil of the actual vitamin K1 compound. In further another embodiment the microcapsule is made of crystalline form of the actual vitamin K1 and K2 alone or in combination with other vitamins, carotenoids or monounsaturated or polyunsaturated fatty acids.

(18) The matrix hydrocolloid used according to the invention may be any hydrocolloid with emulsifying properties, such as an gum acacia, a protein, e.g. caseinate, whey protein, milk protein or hydrolysates, naturally occurring and modified polysaccharides and naturally occurring hydrocolloids, e.g. alginate, carrageenan, gelatine, gum ghatti, xanthan gum, gellan gum, modified gum acacia, carboxy methyl cellulose, pectins, modified pectins or mixtures. Starch derived from a natural source, such as potato, wheat, maize, tapioca, barley and rice, and modified starch are other examples of suitable matrix hydrocolloids, e.g. sodium octenyl succinate modified starch. The amount may e.g. make up from 15 to 80% by weight of the microcapsule, such as from 20 to 70% or from 25 to 60%.

(19) The matrix can optionally comprise further components, such as dissolved carbohydrates, e.g. fructose, glucose, glucose syrup, high fructose corn syrup, sorbitol and sucrose or combinations thereof, and/or an antioxidant. The use of sorbitol and sucrose and/or an antioxidant is therefore an option. The use of the combination of a hydrocolloid and a carbohydrate is especially preferred.

(20) The microcapsule may further contain conventional additives such as antioxidants, e.g. t-butylhydroxytoluene (BHT), t-butylhydroxyanisole (BHA), ascorbic acid, ascorbyl palmitate, sodium ascorbate, citric acid, sodium citrate, EDTA or its salts, tocopherols, TBHQ, ethoxyquine, propyl gallate, and extracts from herbs, i.a. rosemary or oregano extract; anti-caking agents, e.g. tri-calcium phosphate and silicates, i.a. silicon dioxide and sodium aluminium silicate; plasticizers, e.g. carbohydrates and carbohydrate alcohols, examples of which are saccharose, glucose, fructose, lactose, invert sugar, sorbitol, mannitol, Trehalose, Tagatose, Pullulan, Raftilose (oligofructose), dextrin, maltodextrin, glycerin, and mixtures thereof, such as saccharose, Trehalose, Pullulan, dextrin and Raftilose and mixtures thereof, emulsifiers and surfactants, e.g. ascorbyl palmitate, sucrose esters, mono- and diglycerides of fatty acids and derivatives thereof, and lecithin.

(21) The microencapsulation process typically involves dissolution of the fat-soluble active ingredient in an oil such as MCT oil. The hydrocolloid is then dissolved in a solvent such as water, optionally together with other excipients such as sugar. The two phases are then mixed and homogenised in a homogeniser such as a rotor stator. The homogeniser composition may then be sprayed. In order to facilitate spraying, it may be necessary to dilute the homogenised mixture.

(22) The homogenised mixture is then preferably spray dried, but also other methods of drying can be used. The dividing and drying of the solution or dispersion to produce a mass of particles can be done in any conventional way, such as spray cooling, spray drying or sheet drying and crushing, see e.g. WO 91/06292.

(23) In one embodiment of the process of the invention a powdering agent, such as native corn starch, is fed to the microcapsules during the finely dividing and drying step.

(24) In another embodiment of the process a further step of treatment of the solution or dispersion in a high pressure homogenisator is included, such as treatment in a Niro Soavi High Pressure Homogenisator or Rannie.

(25) In one embodiment the product of the invention is a food, a food supplement, a beverage, a pharmaceutical or veterinary product, a feed or feed supplement, a personal care product or a household product, such as a nutraceutical or pharmaceutical product for oral administration.

(26) For instance a sucrose product can be fortified with the composition of the invention.

(27) The product may for instance be for use in the treatment of a condition associated with vitamin K deficiencies, such as for the treatment of osteoporosis and conditions of the cardiovascular system such as arteriosclerosis or in assisting blood clotting.

(28) In one embodiment the invention relates to use of the composition of the invention for the manufacture of tablets containing the active substance selected from vitamin K products.

(29) The composition of the invention may also be used in a method of treatment of a condition associated with vitamin K deficiencies comprising administering to a patient in need thereof an effective amount of a composition according to the invention.

(30) The process of the invention may be carried out in accordance with the following general recipe or as shown in the examples.

(31) The water soluble ingredients, including some of the matrix components, are added to water, optionally at elevated temperature, and dissolved under agitation. The fat-soluble ingredients are mixed and then added to the aqueous phase and the mixture is homogenised in a rotor/stator dissolver to prepare a solution or dispersion. The solution or dispersion is diluted, if necessary, to an appropriate viscosity before the solution or dispersion is finely divided and dried by a conventional method. If applicable a powdering agent is added during the diving and drying.

(32) If applicable the solution or dispersion is subjected to an additional treatment in a high pressure homogenisator.

(33) The composition of the invention is suitable for use in the treatment of a condition associated with vitamin K1 or K2 such as for the treatment of osteoporosis and conditions of the cardiovascular system such as arteriosclerosis or in assisting blood clotting.

(34) The composition of the invention is also suitable for use in a method of treating a condition associated with vitamin K1 or K2 comprising administering to a patient in need thereof an effective amount of a composition of the invention.

(35) Whilst the invention has been described in relation to vitamin K, the microencapsulation techniques described herein could be applied to other vitamins and other compounds that are readily degraded during their storage, such as polyunsaturated fatty acids and derivatives thereof, such as omega-3s. Vitamins that could be microencapsulated include vitamin A, vitamins of the B family and vitamin D family of vitamins. The microencapsuled compounds might be used in conjunction with a dietary mineral but can equally be used per se.

(36) Viewed from a further aspect therefore the invention provides a composition comprising

(37) A) microcapsules comprising at least one fat-soluble active substance which degrades on storage, such as a vitamin or a provitamin or a prodrug of a vitamin or a polyunsaturated fatty acid or derivative thereof, embedded in a matrix comprising a hydrocolloid and optionally one or more other matrix components, and

(38) B) at least one dietary mineral.

(39) The microcapsules of part A) above also form a further aspect of the invention.

(40) Viewed from another aspect the invention provides a process of preparing a microcapsule which process comprises the steps of providing a solution or dispersion of a hydrocolloid and optionally other matrix components, adding to said solution or dispersion said at least one fat-soluble active substance which degrades on storage, such as a vitamin or a provitamin or a prodrug of a vitamin or a polyunsaturated fatty acid or derivative thereof; treating the mixture thus obtained to prepare a solution or dispersion of said at least one active substance in said matrix finely dividing and drying the mixture thus obtained to prepare a mass of particles each containing said at least one active substance embedded in said matrix.

(41) The invention will now be described in further detail with reference to the following examples.

EXAMPLES

(42) Stability Testing of Tablets:

(43) The compositions comprising vitamin K and dietary minerals are tested for stability at long term (25° C./60% RH) and accelerated conditions (40° C./75 30% RH). The vitamin K2, MK-7 compound was provided by Kappa Bioscience

Example 1

(44) Preparations of Microcapsules Comprising Vitamin K

(45) Microcapsules Comprising Vitamin K2 in an Amount of 0.2 wt % Crystalline MK-7

(46) 8.9 g Vitamin K2/MK-7 was dissolved in 60 g MCT (medium chain triglycerides) oil at a temperature of 62° C.

(47) 1250 g acacia gum and 1800 g sugar were dissolved in 2200 g water at 62° C. under agitation. The oil phase containing the MK-7 was added to the aqueous solution, and the solution was stirred below 65° C.

(48) The dispersion was homogenized well in a rotor/stator; alternatively a high pressure homogenizer can be applied; and diluted to a sprayable viscosity.

(49) Subsequently, the dispersion was finally divided in a spray drying tower, where the dispersion particles were covered with a thin layer of starch and dried.

(50) The mean droplet size (d0.5, measured by a Master sizer, Malvern instruments) in the final microcapsules was 100-800 nm, the content of MK-7 was 0.2 wt %, the residual water content was 3-5 wt %, and the bulk density, loose/tapped was 0.71/0.86 g/ml.

Comparative Example 1

(51) A Vitamin K2 MK-7 in MCC (microcrystalline cellulose) powder was used.

Example 2

(52) Compositions According to the Invention Containing MgO as Dietary Mineral and Microcapsules Comprising Crystalline MK-7

(53) 16 g microencapsulated Vitamin K2 (0.2 wt % MK7, example 1) was mixed with 274 g MgO (Magnesia 82600), 274 g microcrystalline cellulose powder (MCC) and 5 g magnesium stearate to a homogenous mixture. This mixture was used to produce tablets.

Comparative Example 2

(54) Compositions Containing MgO as Dietary Mineral and MK-7 in MCC Powder

(55) 45 g Vitamin K2, MK7 in MCC powder (0.2%, Kappa Biosceince, comparative example 1) was blended together with 373.5 g MgO (Magnesia 82600), 373.5 g MCC powder and 8 g magnesium stearate to a homogenous mixture. This mixture was used to produce tablets.

(56) Tablet Parameters:

(57) Tablet machine: Killian T 300

(58) Tablet size: 11 mm

(59) Tablet pressure: 39 kN

(60) Stability Testing of Tablets

(61) Stability testing at long term (25° C./60% RH) and accelerated conditions (40° C./75% RH) for tablets containing microcapsules comprising MK7 and MgO (example 2) and compared with tablets containing MK7 in MCC (non-coated) and MgO (comparative example 2) have been carried out. Table 1 below shows the stability results (% w/w):

(62) TABLE-US-00001 TABLE 1 Amount of MK-7 recovered after storage (% w/w) Temperature 25° C. 40° C. Time Initial 1 month 3 month 1 month 3 month Microcapsules of MK-7 100 100 98 96 90 (0.2%) with MgO MK7 (0.2%) in MCC 100  19  8  7  3 powder with MgO

Example 3

(63) Compositions According to the Invention Containing CaCO.sub.3 as Dietary Mineral and Microcapsules Comprising Crystalline MK-7

(64) 16 g microencapsulated Vitamin K2 (0.2% MK7, example 1) was mixed with 459 g CaCO.sub.3 (Presscal 90%), 90 g microcrystalline cellulose powder (MCC) and 5 g magnesium stearate to a homogenous mixture. This mixture was used to produce tablets.

Comparative Example 3

(65) Compositions containing CaCO.sub.3 as dietary mineral and MK-7 in MCC powder 45 g Vitamin K2 MK7 in MCC powder (0.2%, Kappa Biosceince, comparative 15 example 1) was mixed with 645 g CaCO.sub.3 (Presscal 90%), 102 g MCC powder and 8 g magnesium stearate to a homogenous mixture. This mixture was used to produce tablets.

(66) Tablet Parameters:

(67) Tablet machine: Killian T 300

(68) Tablet size: 11 mm

(69) Tablet pressure: 39 kN

(70) Stability Testing of Tablets

(71) Stability testing at long term (25° C./60% RH) and accelerated conditions (40° C./75% RH) for tablets containing microcapsules comprising MK7 and CaCO.sub.3 (example 3) and compared with MK7 in MCC (non-coated) and CaCO.sub.3 (comparative example 3) has been carried out. Table 2 below shows the stability results (% w/w):

(72) TABLE-US-00002 TABLE 2 Amount of MK-7 recovered after storage (% w/w) Temperature 25° C. 40° C. Time Initial 1 month 3 month 1 month 3 month Microencapsulated MK-7 100 100 99 99 95 (0.2%) with CaCO3 MK7 (0.2%) in MCC 100  89 85 76 60 powder with CaCO3

Example 4

(73) Microcapsules Comprising Vitamin K1 in an Amount of 1.0% by Weight

(74) 7.5 g Vitamin K1 is weighed in at a temperature of 65° C.

(75) 176 g acacia gum and 476 g spray dried glucose syrup are dissolved in 490 g water at 65° C. under agitation. The oil phase containing the vitamin K1 is added to the aqueous solution and stirred below 70° C.

(76) The dispersion is homogenized well in a rotor/stator; alternatively a high pressure homogenizer can be applied; and diluted to a sprayable viscosity.

(77) Subsequently, the dispersion is finally divided in a spray drying tower, where 20 the dispersion particles are covered with a thin layer of starch and dried.

(78) The content of MK-7 is 1.0% by weight, and the residual water content 2-3%.

Comparative Example 4

(79) A conventional spray-dried Vitamin K1 product, containing 1.0% K1 is used.

Example 5

(80) Compositions According to the Invention Containing MgO as Dietary Mineral and Microcapsules Comprising Vitamin K1

(81) 10 g microencapsulated Vitamin K1 (1.0%, example 4) is mixed with 274 g MgO (Magnesia 82600), 274 g microcrystalline cellulose powder (MCC) and 5 g magnesium stearate to a homogenous mixture. This mixture is used to produce tablets.

Comparative Example 5

(82) Compositions Containing MgO as Dietary Mineral and Conventional Spray-Dried Vitamin K1 Product

(83) 10 g spray dried Vitamin K1 (1.0%, comparative example 4) is mixed with 20 274 g MgO, 274 g microcrystalline cellulose powder (MCC) and 5 g magnesium stearate to a homogenous mixture. This mixture is used to produce tablets.

(84) Tablet Parameters:

(85) Tablet machine: Killian T 300

(86) Tablet size: 11 mm

(87) Tablet pressure: 39 kN

(88) Stability Testing of Tablets

(89) Stability testing at long term (25° C./60% RH) and accelerated conditions (40° C./75% RH) for tablets containing microcapsules comprising vitamin K1 and MgO (example 5) and spray dried vitamin K1 and MgO (comparative example 5) are on-going.

Example 6

(90) Compositions According to the Invention Containing CaCO3 as Dietary Mineral and Microcapsules Comprising Vitamin K1

(91) 10 g microencapsulated Vitamin K1 (1.0% K1, example 4) is mixed with 858 g CaCO3 (Calci-Press 95MD) 30 g Kollidon CL-F (BASF) and 8.4 g magnesium stearate to a homogenous mixture. This mixture is used to produce tablets.

Comparative Example 6

(92) Compositions Containing CaCO3 as Dietary Mineral and Conventional Spray-Dried Vitamin K1 Product

(93) 10 g vitamin K1 (comparative example 5) is mixed with 858 g CaCO3 (Calci-15 Press 95MD) 30 g Kollidon CL-F (BASF) and 8.4 g magnesium stearate to a homogenous mixture. This mixture is used to produce tablets.

(94) Tablet Parameters:

(95) Tablet machine: Korsch PH 106 20

(96) Tablet size: Oblong Calcium

(97) Tablet pressure: 20 kN

(98) Stability Testing of Tablets

(99) Stability testing at long term (25° C./60% RH) and accelerated conditions (40° C./75% RH) for tablets containing microcapsules comprising vitamin K1 and CaCO3 (example 6) and spray dried vitamin K1 and CaCO3 (comparative example 6) are on-going.

Example 7

(100) Further stability testing has been carried out on the compositions of examples 2 and 3 and comparative compositions 2 and 3, this time for 12 months.

(101) Material

(102) Example 1 microcapsules and MgO, powder and tablets AGF4

(103) Example 1 microcapsules and CaCO.sub.3, powder and tablets AGF5

(104) Vitamin K2 in MCC (Comp Example 1) and MgO, powder and tablets

(105) Vitamin K2 in MCC (Comp Example 1) and CaCO.sub.3, powder and tablets

(106) The tablets were produced as described in example 2. They were either used as such or ground in a mortar to obtain powder.

(107) HPLC Conditions: The samples were analysed by reversed phase HPLC (method ID MK-7 short). MK-7 was quantified using external standard calibration and UV detection at 270 nm. A detector with 60 mm flow celle was used, due to low concentration samples.

(108) Results

(109) The results for Example 2 and 3 products and comparative example 2 and 3 are presented in Table 3 and Table 4, respectively.

(110) TABLE-US-00003 TABLE 3 Stability results for Example 2 powder and tablets T = 1 month T = 3 months T = 12 months T = 0 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. Powder AGF4 with MgO 71 65 62 69 65 67 57 Tablets AGF4 with MgO 66 68 63 65 59 61 53 Powder AGF5 with 76 64 72 77 75 77 71 CaCO3 Tablets AGF5 with 69 70 68 68 65 66 59 CaCO3

(111) TABLE-US-00004 TABLE 4 T = T = 1 month T = 3 months T = 12 months 0 25° C. 40° C. 25° C. 40° C. 25° C. 40° C. Tablets MCC 99 19 7.4 8.4 2.9 1.3 0.7 with MgO Tablets MCC 104 88 84 75 60 62 30 with CaCO3

SUMMARY

(112) The results from the stability testing of MK-7 in powder and tablets with CaCO.sub.3 and MgO show that the formulations of the invention are more stable than the corresponding MCC formulations with respect to MK-7 content.

(113) For the ground powder and tablets with MgO and CaCO.sub.3 only small changes in the result for the MK-7 content is observed during the 12 months testing period, for material stored at 25° C. For material stored at 40° C. the content of MK-7 decreases slightly.

(114) The results for the MCC products with MgO and CaCO.sub.3 show a significant decrease in the amount of MK-7, especially for the material containing MgO. At the 1 months testing time point the amount of MK-7 is reduced to less than 20% of the T=0 results for the tablets with MCC powder and MgO.

(115) For tablets with MCC powder and CaCO.sub.3 the one month results are better than for MgO, however compared to the products of the invention the reduction of MK-7 is significant.

(116) The comparative study of the effect of MgO and CaCO.sub.3 on MK-7 shows that the stability of MK-7 is significantly improved in the microcapsule formulation.