US 20100203126A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0203126 A1 Park et al. (43) Pub. Date: Aug. 12, 2010
(54) MULTILAYERED VITAMIN COMPLEX Publication Classification TABLET CONTAINING UBDECARENONE (51) Int. Cl. A69/20 (2006.01) A6II 3/34 (2006.01) (76) Inventors: Jong-Woo Park, Gyeonggi-do A 6LX 3L/355 (2006.01) (KR); Jin-Woo Han, Gyeonggi-do A6II 3L/23 (2006.01) (KR); Yae-Young Choi, Seoul (KR) A63L/7056 (2006.01) A6II 3/4406 (2006.01) A63/675 (2006.01) Correspondence Address: A6II 3L/22 (2006.01) DCKSTEIN SHAPRO LLP A633/30 (2006.01) 1825. EYE STREET NW A633/26 (2006.01) Washington, DC 20006-5403 (US) A633/42 (2006.01) A6IR 9/28 (2006.01) (52) U.S. Cl...... 424/465: 514/474; 424/464: 514/458: (21) Appl. No.: 12/668,328 514/552; 514/52: 514/355; 514/89: 514/678: 424/643; 424/646; 424/602; 424/474 (22) PCT Filed: Jul. 11, 2008 (57) ABSTRACT The present invention relates to a multi-layered vitamin/min eral complex tablet having enhanced stability of ubide (86). PCT No.: PCT/KRO8/04111 carenone. The present invention is characterized in that ubidecarenone is contained in a first layer, and ingredients S371 (c)(1), decreasing the stability of ubidecarenone are contained in an (2), (4) Date: Jan. 8, 2010 additional layer separated from the first layer. The method is a convenient process, and the formulation prepared by the method can maintain a high content of ubidecarenone during (30) Foreign Application Priority Data long-term storage, thereby providing a simultaneous intake of ubidecarenone and nutritional ingredients such as various Jul. 11, 2007 (KR) ...... 10-2007-OO69558 Vitamins. US 2010/0203126 A1 Aug. 12, 2010
MULTILAYERED VITAMIN COMPLEX 0008 JP P2004-1601 1A discloses that a drink, which con TABLET CONTAINING UBDECARENONE tains ubidecarenone stabilized by using one or more Sugar alcohols and organic acids, and JP P2003-169630A discloses TECHNICAL FIELD that dispersion and stability of ubidecarenone and other vita mins are improved by using Sodium caseinate and dextrin. JP 0001. The present invention relates to a vitamin complex P2004-81 158A discloses that coenzyme Q is emulsified in an tablet containing ubidecarenone. aqueous solution, and organic acids are added thereto to increase its stability. BACKGROUND ART 0009. On the other hand, U.S. Pat. No. 5,443,842, U.S. Pat. No. 6,740,338, and U.S. Pat. No. 6,855,733 disclose that 0002 Ubidecarenone (Coenzyme Qo; molecular formula Soft or hard oral capsules, filled into gelatin capsule. In par CsoHooO, molecular weight 863.36) is one of coenzyme ticular, U.S. Pat. No. 6,995,820 and JP P2001-354553A dis synthesized by the human body, and functions as a transmitter close that ubidecarenone stabilized in capsule is disclosed in. component in the electron transfer system through repeated When ubidecarenone is present with gelatin, its degradation oxidation and reduction in mitochondria. Generally, about 40 is generally accelerated due to contact with soluble vitamins. to 90% thereof occurs in reduced form in living bodies, and Therefore, organic acids, mixtures thereof, and other stabi the reduced ubidecarenone is known to have antioxidant lizers are used in the above references.JP 2005-124482 dis effect. closes a nutrient composition containing beta carotene and 0003. Examples of the physiological functions of ubide enzyme treated rutin. carenone include the activation of energy production through 0010 All of the above references disclose that the stability activating mitochondrial function, activation of cardiopulmo and bioavailability of ubidecarenone are enhanced by formu nary function, stabilization of cellular membranes, produc lations and additives. However, there is still a need for solid tion of cells through an anti-oxidative effect, myocardial pro tablet formulations, in which they contain various vitamins tection action, prevention of carcinogenesis, anti-aging with minimized amount of other excipients, and thus their action, and LDL oxidation Suppression in blood, Suppression size is Small and various vitamins and minerals and ubide of elevation in blood pressure, and amelioration in oxygen carenone can be taken all at once, as an alternative of Sus utilization efficiency in myocardial ischemia. In medical pended liquids or big-sized capsules. fields, ubidecarenone is used as a metabolic cardiotonic drug, 0011. Meanwhile, JP P2005-2005A discloses stabiliza and applied for the treatment of diseases such as heart failure, tion techniques for treating ubidecarenone itself have been aging, arteriosclerosis, diabetes, hypertension, hypotension, studied, and exemplified by encapsulation with cyclodextrin, angina pectoris, ischaemic heart disease, and degenerative and KP2002-0080370A discloses a technique for enhancing muscular atrophy. the solubility and stability by complex formation of ubide 0004 Ubidecarenone is generally found in fish, meat, or carenone and gamma cyclodextrin. seaweed, but rarely in natural foods. Thus, since ubide (0012 JP 2006-182770A discloses a preparation method carenone cannot be sufficiently taken by typical meals, it is of Solid formulations, in which one group containing ubide commercially available as a nutrient additive or drug. carenone along with organic acid as Stabilizer, and the other 0005. In particular, ubidecarenone directly removes oxy group containing vitamin B1 are granulated separately, and gen free radical which causes cancer, adult diseases, or aging, then mixed together to improve the stability of ubide and facilitates functions of other antioxidants (vitamin C, E), carenone. However, the separation of ubidecarenone and Vita and thus it is usually taken along with other antioxidant Vita min B1 by the granulation process has a problem that of large mins. When ubidecarenone is administered with other anti contact area, which leads to low stability. Accordingly, the oxidants including beta-carotene, selenium, vitamin C, and stability can be enhanced by using organic acids that is known vitamin E, the efficacy is increased to 2-3 fold or more than to suppress the degradation of ubidecarenone. that of its single administration. It has been reported that the 0013 As described above, the known techniques of stabi coexistence of ubidecarenone is very important for vitamin E lizing ubidecarenone generally require either an additional to exert its antioxidative activity. process of directly treating ubidecarenone, or stabilizers such 0006 Ubidecarenone is an oil-soluble substance, and thus as organic acids as an essential component. is insoluble in water and alcohol, but highly soluble in ether. 0014 Problematically, organic acids are expensive, and In addition, ubidecarenone is very unstable and degrades to artificial use thereof causes blood acidification whichthus produce hydroquinone when it reacts with light, air, or other may generate headache, dizziness, insomnia, fatigue or the vitamins. Therefore, in order to increase the uptake of ubide like. In addition, organic acids stimulate intestinal Secretion, carenone, it is needed to increase its solubility and stability. causing diarrhea. Organic acids such as oxalate and phytate Generally, it is taken in a form of a stabilized tablet or capsule, bind with calcium in the digestive organs to produce insoluble or a solubilized and/or stabilized liquid formulation with salts, thereby inhibiting calcium absorption. lipids. 0015. Furthermore, when organic acids co-exist with 0007. Its oral liquid formulations having enhanced solu unstable vitamins and minerals under acidic conditions. Such bility and bioavailability are disclosed in U.S. Pat. No. 5,035, as vitamin K, folic acid, VitaminA, etc., they may increase the 895, U.S. Pat. No. 6,300,377, U.S. Pat. No. 6,441,050, U.S. risk of reducing their stability. Pat. No. 6,652,891, JP P2003-169630A, and JP P2005-43A. 0016. In the preparation of single formulations containing Specifically, GB 1112568 discloses that the liquid formula nutritional ingredients such as ubidecarenone, Vitamins and tion is stabilized by using a Suspending agent and a non-ionic minerals, the prior arts are limited to vitamins such as Vitamin surfactant, U.S. Pat. No. 7,026,361 discloses that its stabili Band E. There is no mention of the stability of ubidecarenone Zation and bioavailability is improved by using a water with respect to other vitamins and minerals that are contained soluble polymer, an emulsifier, and a suspending agent. in the typical vitamin complex tablet. US 2010/0203126 A1 Aug. 12, 2010
0017. Accordingly, the present inventors have examined tate, cyanocobalamine, nicotinamide, pyridoxine hydrochlo other nutritional ingredients (vitamins, minerals, amino ride, chole-calciferol, fursultiamine, inositol, derivatives acids, etc.) decreasing the stability of ubidecarenone under thereof and mixtures thereof. the co-existence, and they have developed a multi-layered 0023. Further, the present invention provides an ubide tablet, in which a layer containing the nutritional ingredients carenone-containing multi-layered vitamin complex tablet, and other layer containing ubidecarenone are separated, and characterized by maintaining at 90% or more of the content of thus ubidecarenone is stably separated and stored in one solid ubidecarenone upon long-term storage stability test (24 formulation without an additional complex process or addi months: 25+2°C., 60+5% RH) or accelerated stability test (6 tion of stabilizers such as organic acids, thereby completing months: 40+2°C., 75+5% RH). the present invention. 0024. Further, the present invention provides an ubide carenone-containing multi-layered vitamin complex tablet, DISCLOSURE OF INVENTION characterized in that the second layer further contains a min Technical Problem eral selected from Zinc sulfate, iron sulfate, cholinebitartrate, calcium hydrogen phosphate and mixtures thereof, amino 0018. In order to overcome the limitations of the prior art, acids selected from L-cysteine, derivatives thereof and mix the present invention provides a vitamin complex tablet com tures thereof, and herbal extracts selected from gamma prising both ubidecarenone and nutritional ingredients of oryzanol, derivative thereof and mixtures thereof. various vitamins, in which the vitamin complex tablet is a 0025. Further, the present invention provides an ubide multi-layered oral vitamin complex tablet containing ubide carenone-containing multi-layered vitamin complex tablet, carenone, prepared by a simple and inexpensive process, characterized in that the first and second layers have a struc capable of maintaining a high content of ubidecarenone dur ture of upper/lower layers or inner/outer layers. ing long-term storage. 0026. Further, the present invention provides an ubide carenone-containing multi-layered vitamin complex tablet, Technical Solution characterized in that the complex tablet is in a form of three 0019. In order to overcome the limitations of the prior art, layered tablet, where the second layer is divided by at least it is an object of the present invention to provide a vitamin two Sublayers, so that the vitamin exists in one Sublayer and complex tablet comprising both ubidecarenone and nutri the mineral exists in the other sublayer. tional ingredients such as various vitamins and minerals, in 0027. Further, the present invention provides an ubide which the vitamin complex tablet is a multi-layered oral carenone-containing multi-layered Vitamin complex tablet, Vitamin/mineral complex tablet containing ubidecarenone, characterized by further comprising at least one excipients, prepared by a simple and inexpensive process, capable of disintegrants, binders, glidants and Sweetening agents. maintaining a high content of ubidecarenone during long 0028. Further, the present invention provides an ubide term storage. carenone-containing multi-layered vitamin complex tablet, 0020. Further, it is another object of the present invention characterized in that at least one moisture-proof coating and to provide a multi-layered oral vitamin/mineral complex tab light-shielding coating are applied to the complex tablet. let containing ubidecarenone, capable of maintaining the sta 0029. Further, the present invention provides a method of bility of ubidecarenone for a long period time, even though it preparing the ubidecarenone-containing multi-layered vita comprises an excessive amount of vitamin, mineral or the min complex tablet, characterized in that one of the raw like. materials for the first layer containing ubidecarenone (as a first ingredient) and for the second layer containing at least Advantageous Effects one active ingredient (as a second ingredient) that decrease the stability of ubidecarenone is Subjected to compression, 0021. The present invention is characterized in that ubide and then the other raw material is subjected to compression on carenone is contained in a first layer, and other ingredients to the above compressed raw material in a form of upper/ decreasing the stability of ubidecarenone are contained in an lower layers or inner/outer layers, so as to obtain a multi additional layer being separated from the first layer. The layered tablet. The second ingredient contains a vitamin method is convenient and the formulation prepared by the selected from ascorbic acid, alpha-tocopherol acetate, fursul method can maintain a high content of ubidecarenone during tiamine, retinol palmitate, cyanocobalamine, nicotinamide, long-term storage, thereby providing a simultaneous intake of pyridoxine hydrochloride, cholecalciferol, inositol, deriva ubidecarenone and nutritional ingredients such as various tives thereof and mixtures thereof, and the first and second Vitamins and minerals. ingredients are not simultaneously present in the same layer. BEST MODE FOR CARRYING OUT THE 0030 Hereinafter, the present invention will be described in more detail. INVENTION 0031. The multi-layered tablet of the present invention is a 0022. In order to achieve the above objects, the present multi-layered vitamin complex tablet comprising ubide invention provides an ubidecarenone-containing multi-lay carenone in a first layer and the active ingredients decreasing ered vitamin complex tablet, characterized in that it is a multi the stability of ubidecarenone such as minerals and vitamins layered tablet comprising a first layer containing ubide in other separated layer. The present invention provides a carenone (first ingredient) and a separated second layer convenient process, which does not require addition of stabi containing an active ingredient (second ingredient) decreas lizer improving the stability of each raw material, and pre ing the stability of ubidecarenone, the first ingredient and the treatment Such as shielding and encapsulation, and also pro second ingredient are not simultaneously present in the same vides a convenient tablet formulation, which has a small size layer, and the second ingredient contains a vitamin selected since it contains various vitamins with minimized amount of from ascorbic acid, alpha-tocopherol acetate, retinol palmi other excipients, and by which a patient can take various US 2010/0203126 A1 Aug. 12, 2010
Vitamins and minerals along with ubidecarenone at once, having the functions of moisture-proof and light-shielding for instead of Suspended liquids or big-sized soft capsules. the purpose of maintaining the stability of ubidecarenone and 0032. The mixture of ubidecarenone and other vitamins/ Vitamin. minerals may be prepared according to the typical methods, 0041. The coating base used in the coating agent include cellulose derivatives such as hydroxypropylcellulose, and the mixture may contain pharmaceutically acceptable hydroxypropylmethylcellulose, ethylcellulose, hydroxypro excipients, disintegrants, binders, glidants, Sweetening pyl-methylcellulose phthalate, hydroxypropylmethylcellu agents or the like, in addition to ubidecarenone and other lose acetate Succinate, carboxymethylethylcellulose, and cel Vitamins/minerals. The multi-layered tablet prepared using lulose acetate phthalate, synthetic copolymers such as the mixture may be coated with film or Sugar. polyvinylacetaldiethylaminoacetate and aminoalkyl 0033. The layer containing ubidecarenone of the present methacrylate copolymer E. methacrylic acid copolymer L or invention may include ubidecarenone, ubidecarenone deriva LD, aminoalkylacrylate copolymer RS, and polyvinylpyr tives and ingredients that do not decrease the stability of rolidone, dextrin, fluran, Zein, Sodium alginate, white Sugar, ubidecarenone under the co-existence, and ingredients gelatin, and serac. Examples of the plasticizer include mac decreasing the stability of ubidecarenone may be used, as rogol, trimethyl citrate, triacetin, medium-chain triglycer long as they do not inhibit the stability of ubidecarenone in a ides, and glycerin. Examples of the glidants include talc, formulation. Stearic acid, magnesium Stearate, and Sucrose esters of fatty 0034. The ingredients of the layer containing vitamin and acid, and examples of the light-shielding agent or coloring mineral may include orally administrable vitamins that agent include metal oxide Such as titanium oxide, yellow 3 inhibit the stability of ubidecarenone under the co-existence, ferric oxide, red 3 ferric oxide, and black 3 ferric oxide, and Such as vitamins including ascorbic acid, alpha-tocopherol tar colors. acetate, fursultiamine, retinol palmitate, cyanocobalamine, 0042. The pharmaceutical composition according to the nicotinamide, pyridoxine hydrochloride, chole-calciferol, present invention may be formulated into an orally adminis and inositol, and derivatives thereof, orally administrable trable solid multi-layered tablet such as bilayered tablets, minerals that inhibit the stability of ubidecarenone under the three-layered tablets, and core tablets. co-existence, such as minerals including Zinc sulfate, iron 0043. The tableting method applied for the preparation of Sulfate, choline bitartrate, and calcium hydrogen phosphate, the multi-layered tablet may include any known methods. and derivatives thereof, orally administrable amino acids and However, with respect to the multi-layered tablet, a pressure herbal extracts that inhibit the stability of ubidecarenone of 4.9 kN (kilo Newton, 10 ton=98 kN) or less is preferably under the co-existence, Such as minerals including L-cysteine applied upon first tableting. When a higher pressure is applied and gamma-oryZanol, and derivatives thereof, or mixtures thereto, the tablet becomes too hard to bind with the second thereof. layer. Upon second tableting, a pressure of 1 to 2 ton, that is, 0035. The excipients used in the present invention may 11.76 to 14.7 kN is applied. include at least one selected from the group consisting of orally administrable lactose, white Sugar, glucose, fructose, MODE FOR THE INVENTION mannitol, corn starch, potato starch, wheat starch, pregelati 0044. Hereinafter, the present invention will be described nized starch, micro-crystalline cellulose or cellulose deriva in more detail with reference to Examples. However, these tives, dextrin, calcium hydrogen phosphate, calcium phos Examples are for illustrative purposes only, and the invention phate monobasic, ethylcellulose, and methylcellulose. is not intended to be limited by these Examples. 0036. The binders used in the present invention may 0045 I. Examination of Ingredients Decreasing Stability include one or more selected from the group consisting of of Ubidecarenone orally administrable polyvinylpyrrolidone or derivatives 0046. In order to examine the ingredients decreasing the thereof, vinylpyrrolidone/vinylacetate copolymer, hydroxy stability of ubidecarenone, monolayered tablets containing cellulose, methylcellulose, ethyl-cellulose, polyvinylalcohol, various ingredients of vitamin/mineral/herbal extract/amino gelatin, corn starch, potato starch, wheat starch, pregelati acid and ubidecarenone were prepared (Preparation nized Starch, hydroxypropylmethylcellulose, and hydrox Examples 1-1 to 1-7), their stability was evaluated (Experi ypropylcellulose. mental Example 1). The detailed description is as follows. 0037. The disintegrants used in the present invention may 0047 1. Preparation of Ubidecarenone-Containing include at least one selected from the group consisting of Monolayered Tablets by Various Formulation Methods orally administrable croScarmellose Sodium, Sodium starch glycolate, sodium carboxymethylcellulose, calcium car (1) Preparation Example 1-1 boxymethylcellulose, crospovidone, and etc. Formulation of Ubidecarenone-Containing Monolay 0038. The glidants used in the present invention may ered Tablet include at least one selected from the group consisting of orally administrable magnesium Stearate, calcium Stearate, 0048 Sodium Stearyl fumarate, Stearic acid, talc, and silicone diox ide. TABLE 1 0039. The sweetening agents used in the present invention Ingredient Weight (per one tablet) may include at least one selected from the group consisting of acesulfame potassium, Sucralose, aspartame, Stevioside, and Ubidecarenone 5.0 mg Low-substituted hydroxymethyl cellulose 20.0 mg saccharin. Ludipress 200.0 mg 0040. The coating agent used in the present invention is Povidone 2.5 mg not specifically limited, and more preferably a coating agent US 2010/0203126 A1 Aug. 12, 2010
0053 Ubidecarenone were mixed with thiamine nitrate, TABLE 1-continued biotin, riboflavin, low-substituted hydroxymethyl cellulose, and ludipress for 10 minutes, and then magnesium Stearate, Ingredient Weight (per one tablet) talc, and anhydrous silicic acid were added thereto, followed Magnesium stearate 10.7 mg by mixing for 5 minutes. The mixed powder was filled into a Talc 1.7 mg lower punch below a die using a feeder. Then, compression was performed using an upper punch, and a tablet was dis 0049. Ubidecarenone and low-substituted hydroxymethyl charged from the die to prepare an ubidecarenone-containing cellulose, ludipress, povidone were mixed for 10 minutes, monolayered tablet and then magnesium Stearate, talc, and silicone dioxide were added thereto. The mixture was blended for 5 minutes to (4) Preparation Example 1-4 prepare a powder. The mixed powder was filled into a lower Formulation of Ubidecarenone-Containing Monolay punch below a die using a feeder. Then, compression was ered Tablet performed using an upper punch, and a tablet was discharged from the die to prepare an ubidecarenone-containing mono 0054 layered tablet. TABLE 4 (2) Preparation Example 1-2 Ingredient Weight (per one tablet) Formulation of Ubidecarenone-Containing Monolay Ubidecarenone 5.0 mg ered Tablet Ascorbic acid 100.0 mg Alpha-tocopherol acetate 1O.O I.U. 0050 Low-substituted hydroxymethyl cellulose 20.0 mg Lactose 200.0 mg TABLE 2 Povidone 2.5 mg Magnesium stearate 10.7 mg Ingredient Weight (per one tablet) Talc 1.7 mg Silicone dioxide 3.2 mg Calcium pantothenate 30.0 mg Selenium (dried yeast) 18.0 mg Ubidecarenone 5.0 mg 0055 Ubidecarenone, alpha-tocopherol acetate, and lac Low-substituted hydroxymethyl cellulose 20.0 mg tose were granulated using povidone as a binder, and then Lactose 200.0 mg Povidone 2.5 mg sieved. Then, low-substituted hydroxymethyl cellulose and Magnesium stearate 10.7 mg ascorbic acid were added thereto, and mixed for 10 minutes. Talc 1.7 mg Magnesium Stearate, talc, and silicone dioxide were added thereto, and mixed for 5 minutes. The mixed powder was filled into a lower punch below a die using a feeder. Then, 0051 Ubidecarenone and lactose were granulated using compression was performed using an upper punch, and a poVidone as a binder, and then sieved. Selenium, calcium tablet was discharged from the die to prepare a ubide pantothenate, and low-substituted hydroxymethyl cellulose carenone-containing monolayered tablet. were added thereto, and mixed for 10 minutes. Then, magne sium stearate and talc were added thereto, and mixed for 5 (5) Preparation Example 1-5 minutes to prepare a powder. The powder was filled into a lower punch below a die using a feeder. Then, compression Formulation of Ubidecarenone-Containing Monolay was performed using an upper punch, and a tablet was dis ered Tablet charged from the die to prepare an ubidecarenone-containing monolayered tablet. 0056 (3) Preparation Example 1-3 TABLE 5 Formulation of Ubidecarenone-Containing Monolay Ingredient Weight (per one tablet) ered Tablet Ubidecarenone 5.0 mg Cholinebitaritrate 50.0 mg 0052 Alpha-tocopherol acetate 1O.O I.U. Low-substituted hydroxymethyl cellulose 20.0 mg Lactose 200.0 mg TABLE 3 Povidone 2.5 mg Magnesium stearate 10.7 mg Ingredient Weight (per one tablet) Talc 1.7 mg Thiamine nitrate 30.0 mg Silicone dioxide 3.2 mg Biotin 45.0 Ig Riboflavin 200.0 mg Ubidecarenone 5.0 mg 0057 Ubidecarenone, cholinebitartrate, alpha-tocopherol Low-substituted hydroxymethyl cellulose 20.0 mg acetate, and lactose were granulated using povidone as a Ludipress 200.0 mg Magnesium stearate 10.7 mg binder, and then sieved. Low-substituted hydroxymethyl cel Talc 1.7 mg lulose was added thereto, and mixed for 10 minutes. Magne Silicone dioxide 1.2 mg sium Stearate, talc, and silicone dioxide were added thereto, and mixed for 5 minutes. The mixed powder was filled into a lower punch below a die using a feeder. Then, compression US 2010/0203126 A1 Aug. 12, 2010 was performed using an upper punch, and a tablet was dis charged from the die to prepare an ubidecarenone-containing TABLE 8 monolayered tablet. (6) Preparation Example 1-6 Test Sample Initiation day 2 months 4 months 6 months Formulation of Ubidecarenone-Containing Monolay ered Tablet Preparation OO.O 98.3 95.6 92.1 0058 Example 1-1 Preparation OO.O 97.8 94.5 91.7 TABLE 6 Example 1-2 Ingredient Weight (per one tablet) Preparation OO.O 96.5 93.7 90.2 Example 1-3 Ubidecarenone 5.0 mg Cholinebitaritrate 50.0 mg Preparation OO.O 777 S8.1 39.4 Retinol palmitate SOO.O I.U. Example 1-4 Low-substituted hydroxymethyl cellulose 20.0 mg Preparation OO.O 78.9 64.4 46.3 Lactose 200.0 mg Povidone 2.5 mg Example 1-5 Magnesium stearate 10.7 mg Preparation OO.O 86.3 74.8 68.6 Talc 1.7 mg Silicone dioxide 3.2 mg Example 1-6 Preparation OO.O 76.2 61.4 40.1 0059. Ubidecarenone, cholinebitartrate, and lactose were Example 1-7 granulated using povidone as a binder, and then sieved. Ret inol palmitate and low-substituted hydroxymethyl cellulose were added thereto, and mixed for 10 minutes. Magnesium 0063 (2) Result of Long-Term Stability Test for Ubide Stearate, talc, and silicone dioxide were added thereto, and carenone in Monolayered Tablet (Unit:% Residual Amount mixed fro 5 minutes. The mixed powder was filled into a of Ubidecarenone) lower punch below a die using a feeder. Then, compression was performed using an upper punch, and a tablet was dis TABLE 9 charged from the die to prepare a ubidecarenone-containing TeS Initiation 3 6 12 18 24 monolayered tablet. Sample day months months months months months (7) Preparation Example 1-7 Preparation 1OO.O 99.7 99.4 98.6 97.3 96.8 Formulation of Ubidecarenone-Containing Monolay Example 1-1 ered Tablet Preparation 1OO.O 98.8 98.0 96.8 95.8 94.2 Example 1-2 0060 Preparation 1OO.O 99.5 97.7 97.2 95.2 94.8 Example 1-3 Preparation 1OO.O 82.7 67.6 49.7 32.4 15.2 TABLE 7 Example 1-4 Preparation 1OO.O 88.9 73.1 54.5 48.9 21.8 Ingredient Weight (per one tablet) Example 1-5 Ubidecarenone 5.0 mg Preparation 1OO.O 95.3 90.8 86.O 74.6 59.8 0.1% Cyanocobalamine 5.0 mg Example 1-6 Cholinebitaritrate 50.0 mg Preparation 1OO.O 89.2 76.7 57.8 37.4 22.6 Low-substituted hydroxymethyl Cellulose 20.0 mg Example 1-7 Ludipress 200.0 mg Povidone 2.5 mg Magnesium stearate 10.7 mg 0064. As shown in Table 8 and Table 9, the tablets Talc 1.7 mg Silicone dioxide 3.2 mg prepared by the formulations of Preparation Examples 1-1, 1-2, and 1-3 were subjected to the accelerated stability test for 6 months or long-term stability test for 24 months. As a result, 0061 Ubidecarenone was mixed with 0.1% cyanocobal amine, cholinebitartrate, low-substituted hydroxymethylcel high stability of 90% or more was maintained, and thus they lulose, ludipress, and povidone for 10 minutes, and magne can be used as a composition of the ubidecarenone-contain sium Stearate, talc, and silicone dioxide were added thereto, ing layer of the present invention. followed by mixing for 5 minutes. The mixed powder was 0065. The tablets prepared by the formulations of Prepa filled into a lower punch below a die using a feeder. Then, ration Examples 1-4, 1-5, 1-6, and 1-7 were also subjected to compression was performed using an upper punch, and a the accelerated stability test for 6 months or long-term stabil tablet was discharged from the die to prepare a ubide ity test for 24 months. However, the content of ubidecarenone carenone-containing monolayered tablet. was excessively reduced, and thus they cannot be used as a 2. Test Example 1 composition of the ubidecarenone-containing layer of the Stability Test for Each Formulation of Preparation present invention. Accordingly, these results suggest that Examples 1-1 to 1-7 Some or all of other active ingredients than ubidecarenone 0062 (1) Result of Accelerated Stability Test for Ubide should be contained in the other layer separated from the carenone in Monolayered Tablet (Unit:% Residual Amount ubidecarenone-containing layer in the multi-layered tablets of Ubidecarenone) of the present invention. US 2010/0203126 A1 Aug. 12, 2010
0066 II. Preparation of Multi-Layered Tablet of the min and mineral-containing layer (B) was filled, and Sub Present Invention and Monolayered Tablet of Prior Art and jected to final compression. A tablet was discharged from the their Stability Test die to prepare an oral bilayered vitamin complex tablet con 0067. 1. Preparation of Multi-Layered Tablet of the taining ubidecarenone. Present Invention (2) Preparation Example 3 (1) Preparation Example 2 Preparation of Bilayered Tablet B Consisting of Preparation of Bilayered Tablet A Consisting of Ubidecarenone-Containing Layer/Vitamin and Min Ubidecarenone-Containing Layer/Vitamin and Min eral-Containing Layer eral-Containing Layer 0073 (A) Ubidecarenone-Containing Layer 0068 (A) Ubidecarenone-Containing Layer TABLE 12 TABLE 10 Ingredient Weight (per one tablet) Ingredient Weight (per one tablet) Low-substituted hydroxymethyl Cellulose 20.0 mg Low-substituted hydroxymethyl Cellulose 20.0 mg Ludipress 200.0 mg Ludipress 200.0 mg Ubidecarenone 5.0 mg Thiamine nitrate 30.0 mg Magnesium stearate 10.7 mg Biotin 45.0 Ig Talc 1.7 mg Ubidecarenone 5.0 mg Silicone dioxide 1.2 mg Magnesium stearate 10.7 mg Talc 1.7 mg Silicone dioxide 1.2 mg 0074 (B) Vitamin and Mineral-Containing Layer
0069 (B) Vitamin and Mineral-Containing Layer TABLE 13 Ingredient Weight (per one tablet) TABLE 11 Thiamine nitrate 30.0 mg Ingredient Weight (per one tablet) Retinol palmitate SOO.O I.U. Biotin 45.0 ug Retinol palmitate SOO.O I.U. Riboflavin 12.0 mg Riboflavin 12.0 mg Nicotinamide 10.0 mg Nicotinamide 10.0 mg Calcium pantothenate 30.0 mg Calcium pantothenate 30.0 mg Pyridoxine hydrochloride 10.0 mg Pyridoxine hydrochloride 10.0 mg Dried Cholecalciferol 1.0 mg Dried cholecalciferol 1.0 mg 0.1% Cyanocobalamine 5.0 mg 0.1% Cyanocobalamine 5.0 mg Alpha-tocopherol acetate 1O.O I.U. Alpha-tocopherol acetate 1O.O I.U. Cholinebitaritrate 25.0 mg Cholinebitaritrate 25.0 mg Calcium hydrogen phosphate 50.0 mg Calcium hydrogen phosphate 50.0 mg Low-substituted hydroxymethyl cellulose 20.9 mg Low-substituted hydroxymethyl cellulose 20.9 mg Lactose 110.2 mg Lactose 110.2 mg Ludipress 173.4 mg Ludipress 173.4 mg Povidone 2.5 mg Povidone 2.5 mg Magnesium stearate 25.5 mg Magnesium stearate 25.5 mg Talc 4.1 mg Talc 4.1 mg Silicone dioxide 2.9 mg Silicone dioxide 2.9 mg (0075 (C) Preparation Method 0070 (C) Preparation Method 0076 Ubidecarenone was mixed with low-substituted 0071 Ubidecarenone was mixed with thiamine nitrate, hydroxymethyl cellulose, and ludipress for 10 minutes, and biotin, low-substituted hydroxymethyl cellulose, and magnesium Stearate, talc, and silicone dioxide were added ludipress for 10 minutes, and magnesium Stearate, talc, and thereto, followed by mixing for 5 minutes to prepare a mix silicone dioxide were added thereto, followed by mixing for 5 ture of the ubidecarenone-containing layer (A). Biotin, cho minutes to prepare a mixture of the ubidecarenone-containing line bitartrate, calcium hydrogen phosphate and lactose were layer (A). Choline bitartrate, calcium hydrogen phosphate, granulated using povidone as a binder, and sieved. Calcium and lactose were granulated using povidone as a binder, and pantothenate, retinol palmitate, thiamine nitrate, riboflavin, sieved. Riboflavin, nicotinamide, calcium pantothenate, pyri nicotinamide, pyridoxine hydrochloride, dried cholecalcif doxine hydrochloride, dried cholecalciferol, 0.1% cyanoco erol, 0.1% cyanocobalamine, alpha-tocopherol acetate, low balamine, alpha-tocopherol acetate, ludipress, low-substi substituted hydroxymethyl cellulose, and ludipress were tuted hydroxymethyl cellulose, and povidone were added added thereto, and mixed for 10 minutes. Then, magnesium thereto, and mixed for 10 minutes. Then, magnesium Stearate, Stearate, talc, and silicone dioxide were added thereto, and talc, and silicone dioxide were added thereto, and mixed to mixed for 5 minutes to prepare a mixture of the vitamin and prepare a mixture of the Vitamin and mineral-containing layer mineral-containing layer (B). (B). 0077. The mixture of the ubidecarenone-containing layer 0072 The mixture of the ubidecarenone-containing layer (A) was filled into a lower punch below a die, and a predeter (A) was filled into a lower punch below a die, and a predeter mined pressure was applied thereto using an upper punch for mined pressure was applied thereto using an upper punch for a primary tableting. Subsequently, the mixed powder of Vita a primary tableting. Subsequently, the mixed powder of Vita min and mineral-containing layer (B) was filled, and Sub US 2010/0203126 A1 Aug. 12, 2010 jected to final compression. A tablet was discharged from the mineral-containing outer layer (B) was mixed and filled into die to prepare an oral bilayered vitamin complex tablet con a lower punch, and Subjected to final compression using an taining ubidecarenone. upper punch. A tablet was discharged from the die to prepare (3) Preparation Example 4 an oral Vitamin complex core tablet containing ubide CaO. Preparation of Core Tablet A Consisting of Ubide carenone-Containing Inner Layer/Vitamin and Min eral-Containing Outer Layer (4) Preparation Example 5 0078 (A) Ingredients and Weight of Ubidecarenone-Con Preparation of Core Tablet B Consisting of Ubide taining Inner Layer carenone-Containing Inner Layer/Vitamin and Min eral-Containing Outer Layer TABLE 1.4 Ingredient Weight (per one tablet) I0084 (A) Ubidecarenone-Containing Inner Layer Low-substituted hydroxymethyl cellulose 20.0 mg TABLE 16 Lactose 200.0 mg Calcium pantothenate 30.0 mg Ingredient Weight (per one tablet) Selenium (dried yeast) 18.0 mg Ubidecarenone 5.0 mg Low-substituted hydroxymethyl cellulose 20.0 mg Povidone 2.5 mg Lactose 200.0 mg Magnesium stearate 10.7 mg Ubidecarenone 5.0 mg Talc 1.7 mg Povidone 2.5 mg Magnesium stearate 10.7 mg 0079 (B) Vitamin and Mineral-Containing Outer Layer Talc 1.7 mg
TABLE 1.5 I0085 (B) Vitamin and Mineral-Containing Outer Layer ngredient Weight (per one tablet) TABLE 17 Fursultiamine 50.0 mg Riboflavin 12.0 mg Weight Nicotinamide 10.0 mg Pyridoxine hydrochloride 10.0 mg Ingredient (per one tablet) Dried cholecalciferol 1.0 mg Ascorbic acid 200.0 mg 0.1% Cyanocobalamine 5.0 mg L-cysteine 120.0 mg Alpha-tocopherol acetate 1O.O I.U. Calcium pantothenate 12.0 mg Retinol palmitate SOO.O I.U. Microcrystalline cellulose 50.0 mg Gamma-ory Zanol 5.0 mg Ludipress 93.4 mg Ascorbic acid 500.0 mg Low-substituted hydroxymethyl cellulose 20.9 mg nositol 30.0 mg Magnesium stearate 25.5 mg Low-substituted hydroxymethyl cellulose 20.9 mg Talc 4.1 mg LactOSe 110.2 mg Silicone dioxide 2.9 mg Microcrystalline cellulose 173.4 mg Povidone 5.0 mg Magnesium stearate 25.5 mg Talc 4.1 mg I0086) (C) Preparation Method Silicone dioxide 2.9 mg 0087 Ubidecarenone was mixed with lactose and low substituted hydroxymethyl cellulose for 10 minutes, and then 0080 (C) Preparation Method poVidone, magnesium Stearate, and talc were added thereto, 0081 Ubidecarenone was mixed with selenium, calcium followed by mixing for 5 minutes to prepare a mixture of pantothenate, lactose, low-substituted hydroxymethyl cellu ubidecarenone-containing inner layer (A). lose for 10 minutes, and povidone, magnesium Stearate, and talc were added thereto, followed by mixing for 5 minutes to I0088 Separately, ascorbic acid, L-cysteine, calcium pan prepare a mixture of the ubidecarenone-containing inner tothenate, microcrystalline cellulose, ludipress, and low-Sub layer (A). stituted hydroxymethyl cellulose were added, and mixed for 0082 Separately, fursultiamine, riboflavin, nicotinamide, 10 minutes. Magnesium Stearate, talc, and silicone dioxide pyridoxine hydrochloride, dried cholecalciferol, 0.1% cyano were added thereto, and mixed for 5 minutes to prepare a cobalamine, alpha-tocopherol acetate, retinol palmitate, mixture of vitamin and mineral-containing outer layer (B). v(gamma)-ory Zanol, ascorbic acid, inositol, lactose, low I0089. The mixture of the ubidecarenone-containing inner substituted hydroxymethyl cellulose, microcrystalline cellu layer (A) was filled into a lower punch below a die, and a lose, and povidone were added, and mixed for 10 minutes. predetermined pressure was applied thereto using an upper Magnesium Stearate, talc, and silicone dioxide were added thereto, and mixed to prepare a mixture of vitamin and min punch for tableting. Subsequently, the mixture of vitaminand eral-containing outer layer (B). mineral-containing outer layer (B) was mixed and filled into 0083. The mixture of the ubidecarenone-containing inner a lower punch, and Subjected to final compression using an layer (A) was filled into a lower punch below a die, and a upper punch. A tablet was discharged from the die to prepare predetermined pressure was applied thereto using an upper an oral Vitamin complex core tablet containing ubide punch for tableting. Subsequently, the mixture of vitaminand CaO. US 2010/0203126 A1 Aug. 12, 2010
(5) Preparation Example 6 0.095 Riboflavin, nicotinamide, calcium pantothenate, pyridoxine hydrochloride, dried cholecalciferol, 0.1% cyano Preparation of Three-Layered Tablet Consisting of cobalamine, alpha-tocopherol acetate, retinol palmitate, Ubidecarenone Layer/Vitamin Layer/Mineral Layer ascorbic acid, inositol, low-substituted hydroxymethyl cellu 0090 (A) Ubidecarenone-Containing Layer lose, lactose, micro-crystalline cellulose, povidone were mixed for 10 minutes, and magnesium Stearate, talc, and silicone dioxide were added thereto, followed by mixing for 5 TABLE 18 minutes to prepare a mixture of layer containing vitamin Weight except ubidecarenone (B). Ingredient (per one tablet) 0096 Separately, choline bitartrate, calcium hydrogen Low-substituted hydroxymethyl Cellulose 20.0 mg phosphate, Zinc sulfate, dried iron Sulfate, selenium, lactose Lactose 200.0 mg were granulated using povidone as a binder, and sieved. Ubidecarenone 5.0 mg Microcrystalline cellulose and low-substituted hydroxym Povidone 2.5 mg Magnesium stearate 10.7 mg ethyl cellulose were mixed, and then magnesium Stearate, Talc 1.7 mg talc, and silicone dioxide were added thereto, followed by Silicone dioxide 3.2 mg mixing for 5 minutes to prepare a mixture of mineral-con taining layer (C). 0097. The mixture of the ubidecarenone-containing inner 0091 (B) Layer Containing Vitamin Except Ubide layer (A) was filled into a lower punch below a die, and a CaO. predetermined pressure was applied thereto using an upper punch for a primary tableting. Subsequently, the mixed pow TABLE 19 der of vitamin-containing layer (B) was filled, and Subjected to compression. Then, the mixed powder of mineral-contain ngredient Weight (per one tablet) ing layer (C) was filled, and Subjected to compression, and a Riboflavin 12.0 mg tablet was discharged from the die to prepare an oral three Nicotinamide 10.0 mg Calcium pantothenate 30.0 mg layered vitamin complex tablet containing ubidecarenone. Pyridoxine hydrochloride 10.0 mg Dried cholecalciferol 1.0 mg (6) Preparation Example 7 0.1% Cyanocobalamine 5.0 mg Alpha-tocopherol acetate 1O.O I.U. Preparation of Film Coated Bilayered Tablet Con Retinol palmitate SOO.O I.U. taining Ubidecarenone Ascorbic acid 500.0 mg nositol 30.0 mg 0098. A bilayered tablet was prepared according to the Low-substituted hydroxymethyl cellulose 20.9 mg LactOSe 110.2 mg formulation of Preparation Example 2, and then 44.0 g of Microcrystalline cellulose 173.4 mg polyvinyl alcohol. 20.0 g of talc, 15.7 g of allura red AC Povidone 5.0 mg aluminum lake, 12.4 g of polyethylene glycol, 3.5g of leci Magnesium stearate 25.5 mg thin, 3.0 g of titanium oxide, 1.2 g of erythrosine, and 0.3 g of Talc 4.1 mg indigo carmine aluminum lake were dissolved in purified Silicone dioxide 2.9 mg water, and film-coated to prepare a coated tablet with 32 mg coating (per tablet). 0092 (C) Layer Containing Mineral Except Ubide (0099 2. Preparation of Multi-Layered Tablet by Prior Art CaO. (1) Comparative Preparation Example 1 TABLE 20 Preparation of Monolayered Tablet Containing Weight Ubidecarenone, Vitamin and Mineral (Comparison Ingredient (per one tablet) with Bilayered Tablet A of Preparation Example 2) Cholinebitaritrate 25.0 mg 0100. The mixture of ubidecarenone-containing layer (A) Calcium hydrogen phosphate 10.0 mg Zinc sulfate 50.0 mg of Table 10 prepared in Preparation Example 2 and the mix Dried iron sulfate 12.0 mg ture of layer containing vitamin and mineral except ubide Selenium (dried yeast) 18.0 mg carenone (B) of Table 11 were mixed with each other, and Low-substituted hydroxymethyl cellulose 20.9 mg then filled into the lowerpunch below the die using the feeder, Lactose 110.2 mg Microcrystalline cellulose 173.4 mg and then Subjected to compression using the upper punch. A Povidone 5.0 mg tablet was discharged from the die to prepare a monolayered Magnesium stearate 25.5 mg tablet containing ubidecarenone. Talc 4.1 mg Silicone dioxide 2.9 mg (2) Comparative Preparation Example 2 Preparation of Monolayered Tablet Containing 0093 (D) Preparation Method Ubidecarenone, Vitamin and Mineral (Comparison 0094 Ubidecarenone and lactose were granulated using with Core Tablet A of Preparation Example 4) poVidone as a binder, and sieved. Low-substituted hydroxym ethyl cellulose was added thereto, and mixed for 10 minutes. 0101 The mixture of ubidecarenone-containing layer (A) Magnesium Stearate, talc, and silicone dioxide were added of Table 14 prepared in Preparation Example 4 and the mix thereto, and mixed for 5 minutes to prepare a mixture of ture of layer containing vitamin and mineral except ubide ubidecarenone-containing layer (A). carenone (B) of Table 15 were mixed with each other, and US 2010/0203126 A1 Aug. 12, 2010
then filled into the lowerpunch below the die using the feeder, 0107 The mixed powder was filled into the lower punch and then Subjected to compression using the upper punch. A below the die using a feeder, and then Subjected to compres tablet was discharged from the die to prepare a monolayered sion using the upper punch. A tablet was discharged from the tablet containing ubidecarenone. die to prepare a monolayered tablet containing ubide CaO. (3) Comparative Preparation Example 3 Preparation of Monolayered Tablet Containing (B) Comparative Preparation Example 5-2 Ubidecarenone, Vitamin and Mineral (Comparison Monolayered Tablet II Prepared by Separating with Core Tablet B of Preparation Example 5) Ubidecarenone from Vitamins According to Granula tion Method 0102 The mixture of ubidecarenone-containing layer (A) of Table 16 prepared in Preparation Example 5 and the mix 0108 ture of layer containing vitamin and mineral except ubide carenone (B) of Table 17 were mixed with each other, and TABLE 22 then filled into the lowerpunch below the die using the feeder, and then Subjected to compression using the upper punch. A Ingredient Weight (per one tablet) tablet was discharged from the die to prepare a monolayered Ubidecarenone 5.0 mg Ascorbic acid 100.0 mg tablet containing ubidecarenone. Alpha-tocopherol acetate 100 IU Cholinebitaritrate 50.0 mg (4) Comparative Preparation Example 4 Low-substituted hydroxymethyl cellulose 20.0 mg Lactose 200.0 mg Preparation of Monolayered Tablet Containing Povidone 2.5 mg Ubidecarenone, Vitamin and Mineral (Comparison Magnesium stearate 10.7 mg with Three-Layered Tablet of Preparation Example Talc 1.7 mg 6) Silicone dioxide 3.2 mg 0103) The mixture of ubidecarenone-containing layer (A) 0109 Ubidecarenone and low-substituted hydroxymethyl of Table 18 prepared in Preparation Example 6, the mixture of cellulose were granulated using povidone as a binder, and layer containing vitamin except ubidecarenone (B) of Table sieved. Lactose, ascorbic acid, alpha-tocopherol acetate, and 19, and the mixture of layer containing mineral (C) of Table choline bitartrate were added thereto, and mixed for 10 min 20 were mixed with each other, and then filled into the lower utes. Magnesium Stearate, talc, and silicone dioxide were punch below the die using the feeder, and then subjected to added thereto, and mixed for 5 minutes to prepare a mixture compression using the upper punch. A tablet was discharged containing ubidecarenone. from the die to prepare a monolayered tablet containing 0110. The mixture was filled into the lower punch below ubidecarenone. the die using a feeder, and then Subjected to compression 0104 3. Preparation of Monolayered Tablet by Separating using the upperpunch. A tablet was discharged from the die to Ubidecarenone from Vitamins According to Granulation Method in Prior Art prepare a monolayered tablet containing ubidecarenone. (C) Comparative Preparation Example 5-3 (A) Comparative Preparation Example 5-1 Monolayered Tablet III Prepared by Separating Monolayered Tablet I Prepared by Separating Ubide Ubidecarenone from Vitamins According to Granula carenone from Vitamins According to Granulation tion Method Method 0111 01.05 TABLE 23 TABLE 21 Ingredient Weight (per one tablet) Ingredient Weight (per one tablet) Ubidecarenone 5.0 mg Ubidecarenone 5.0 mg Cholinebitaritrate 50.0 mg Ascorbic acid 100.0 mg Alpha-tocopherol acetate 1O.O I.U. Alpha-tocopherol acetate 1O.O I.U. Ascorbic acid 100.0 mg Low-substituted hydroxymethyl cellulose 20.0 mg Low-substituted hydroxymethyl cellulose 20.0 mg Lactose 200.0 mg Microcrystalline cellulose 200.0 mg Povidone 2.5 mg Povidone 2.5 mg Magnesium stearate 10.7 mg Magnesium stearate 10.7 mg Talc 1.7 mg Talc 1.7 mg Silicone dioxide 3.2 mg Silicone dioxide 3.2 mg
0106 Ubidecarenone and lactose were granulated using 0112 Ubidecarenone and microcrystalline cellulose were poVidone as a binder, and sieved. Low-substituted hydroxym granulated using povidone as a binder, and sieved. Low ethyl cellulose, ascorbic acid, and alpha-tocopherol acetate Substituted hydroxymethyl cellulose, ascorbic acid, alpha were added thereto, and mixed for 10 minutes. Magnesium tocopherolacetate, and cholinebitartrate were added thereto, Stearate, talc, and silicone dioxide were added thereto, and and mixed for 10 minutes. Magnesium Stearate, talc, and mixed for 5 minutes to prepare a mixture containing ubide silicone dioxide were added thereto, and mixed for 5 minutes CaO. to prepare a mixture containing ubidecarenone. US 2010/0203126 A1 Aug. 12, 2010
0113. The mixture was filled into the lower punch below 5. Test Example 3 the die using a feeder, and then Subjected to compression using the upperpunch. A tablet was discharged from the die to Accelerated Stability Test of Monolayered Tablets prepare a monolayered tablet containing ubidecarenone. (Prior Art) Separated by Granulation Method
4. Test Example 2 0116 TABLE 25 Accelerated Stability Test of Preparation Examples 2 to 6 (Present Invention) and Comparative Prepara Table 25: Result of accelerated stability test for compositions of tion Examples 1 to 4 (Prior Art) ubidecarenone layer Test Sample Initiation day 2 months 4 months 6 months 0114. The tablets prepared in Preparation Examples 2, 3, Preparation Example 1OO.O 777 S8.1 39.4 4, 5, and 6 were subjected to the accelerated stability test with 1-4 the tablets prepared in Comparative Preparation Examples 1, Comparative 1OO.O 86.2 74.5 58.3 Preparation Example 2, 3, and 4 as control groups. The prepared tablets was pack S-1 aged into a HDPE (High density polyethylene) bottle, and Comparative 1OO.O 82.1 70.4 61.3 stored under the conditions of 40+2°C., 75+5% RH, respec Preparation Example S-2 tively. Then, changes in the content were measured at initia Comparative 1OO.O 84.8 71.1 52.7 tion day, 2, 4, and 6 month. The result was represented by a Preparation Example relative residual amount, when the content of ubidecarenone S-3 on the initiation day of accelerated Stability test was regarded Preparation Example 3 1OO.O 98.6 96.1 93.9 as 100.0%. (Unit:% residual amount of ubidecarenone)
TABLE 24 0117 Tablets prepared in Comparative Preparation Examples 5-1 to 5-3 were stabilized by granulating ubide Table 24: Result of accelerated stability test for tablets containing carenone with excipients. They are more stable than that ubidecarenone prepared in Preparation Example 1-4, but the content of ubidecarenone was found to be excessively reduced in 6 Initiation month accelerated stability test, and less stable than the bilay Test Sample day 2 months 4 months 6 months ered tablet prepared in Preparation Example 3. Thus, these results suggest that the stabilization of ubidecarenone in the Preparation Example 2 OO.O 97.0 94.2 90.7 complex vitamin tablet cannot be achieved by the simple (bilayered tablet A) granulation method. Preparation Example 3 OO.O 98.6 96.1 93.9 (bilayered tablet B) 0118 III. Result of Stability Test and Relationship with Preparation Example 4 OO.O 97.3 93.5 91.4 Contents of Ubidecarenone and Vitamins Under Co-Exist (core tablet A) CC Preparation Example 5 OO.O 96.5 91.7 91.1 0119. In accordance with the regulations set forth by the (core tablet B) Korea Pharmacopeia, preparation of medicines Such vitamins Preparation Example 6 OO.O 97.7 93.8 92.0 and minerals should meet the preparation standard. In par (three-layered tablet) ticular, the efficacy and effect of the ingredient can be labeled Comparative Preparation OO.O 68.9 32.4 15.2 on the product, when the content of the ingredients in the Example 1 (monolayered product is more than a predetermined amount. Thus, the ablet) present inventors examined the ingredients decreasing the Comparative Preparation OO.O 74.3 51.8 33.6 stability of ubidecarenone, which are regarded as reference. Example 2 (monolayered That is, even though the ingredients rarely inhibit the stability ablet) of ubidecarenone when used in a small amount, the ingredi Comparative Preparation OO.O 77.5 60.9 43.1 ents that inhibit the stability of ubidecarenone when used in Example 3 (monolayered an amount over the standard were regarded as ingredients ablet) Comparative Preparation OO.O 67.0 40.1 22.7 decreasing the stability of ubidecarenone. Example 4 (monolayered 0.120. The detailed description is as follows. ablet) I0121 1. Stability Test for Ubidecarenone and Vitamins/ Minerals Under Co-Existence (Unit:% residual amount of ubidecarenone) 0.122 First, ubidecarenone was mixed with vitamins or minerals that are typically used for formulation at a ratio of 0115. When the total ingredients of Preparation Examples 1:1, and the changes in the content of ubidecarenone were 2 to 6 were compared to the monolayered tablets in Compara measured under the conditions of 40+2°C., 75-5 RH% for 6 tive Preparation Examples 1, 2, 3, and 4, the stability of weeks. The result was expressed as a relative residual amount, ubidecarenone was found to be improved in Preparation when the content of ubidecarenone on the initiation day of Examples 2,3,4,5, and 6, where the ubidecarenone layer was accelerated stability test was regarded as 100.0%, as shown in separated from the vitamin/mineral layer. the following Table 26. US 2010/0203126 A1 Aug. 12, 2010 11
tocopherol acetate, dried cholecalciferol, and retinol palmi TABLE 26 tate were found to excessively reduce the stability of ubide CaO. Table 26: Result of stability test for ubidecarenone and vitamins under co-existence 0.124 2. Stability Test for Ubidecarenone and Vitamins/ 2 4 6 Minerals Under Co-Existence According to Typical Formu Mixture Initial weeks weeks weeks lation Ratio Ubidecarenone 100 99.2 97.2 96.4 (0125 Ubidecarenone and vitamins/minerals were under Ubidecarenone + Retinol palmitate 100 97.7 90.7 76.2 co-existence at a typical formulation amount and ratio, and Ubidecarenone + Choline bitaritrate 100 84.4 73.0 S8.0 then the accelerated stability test for ubidecarenone was per Ubidecarenone + AscorbicBiotin acid 100 94.798.3 92.294.2 90.287.2 formed. The results are as follows. In the following table, Ubidecarenone + 0.1% 100 83.5 76.6 744 ubidecarenone is contained at the same amount of 50 mg in Cyanocobalamine each formulation. The amount of ubidecarenone was omitted in the column of preparation formulation.
TABLE 27 Preparation formulation Initial 2 weeks 4 weeks 6 weeks Mixture (mg) (%) (%) (%) (%) Ubidecarenone alone 50 OO 99.2 97.2 96.4 Thiamine nitrate- 3OOSO OO 97.2 97.0 96.8 Obidecarenone Fursultiamine 3OOSO OO 90.4 834 74.3 Obidecarenone Riboflavin Jbidecarenone 12OSO OO 98.5 98.0 96.4 NicotinamideUbidecarenone 1OOSO OO 85.2 79.1 71.4 Calcium pantothenate- 12OSO OO 97.9 96.6 94.4 Obidecarenone Pyridoxine hydrochloride- 1OOSO OO 91.8 85.8 73.2 Ubidecarenone Dried cholecalciferol- 1 OSO OO 92.1 84.4 76.4 Obidecarenone 0.1% Cyanocobalamine- 5050 OO 83.5 76.6 74.4 Obidecarenone 90% Ascorbic acid- 500050 OO 89.4 73.6 54.2 Obidecarenone Alpha-tocopherol 2OOSO OO 90.7 742 68.3 acetateUbidecarenone Retinol palmitate- 1 OSO OO 93.4 87.3 76.4 Obidecarenone BiotinUbidecarenone 4550 OO 98.9 96.2 94.7 nositol Ubidecarenone 1OOOSO OO 85.2 73.8 61.4
0.126 The content of ingredients such as vitamins and the TABLE 26-continued content of ubidecarenone (50 mg equally) under the co-ex Table 26: Result of stability test for ubidecarenone and vitamins istence were represented in the column of preparation formu under co-existence lation of Table 27.
2 4 6 I0127. As such, when the amount contained in the product Mixture Initial weeks weeks weeks was regarded as content, the relative residual amount of Ubidecarenone + Dried 100 90.8 89.9 75.5 ubidecarenone was found to be reduced by 90% or less in the cholecalciferol accelerated Stability test for some ingredients. Accordingly, it Ubidecarenone + Thiamine nitrate 100 98.6 94.7 90.4 Ubidecarenone + Fursultiamine 100 84.5 79.4 75.4 can be seen that the multi-layered tablet of the present inven Ubidecarenone + Pyridoxine 100 91.1 84.9 74.6 tion should be prepared by separating the ingredients from the hydrochloride ubidecarenone-containing layer. Ubidecarenone + Nicotinamide 100 92.5 86.2 80.2 Ubidecarenone + Calcium 100 98.3 96.O 92.3 I0128. 3. Stability Test for Ubidecarenone According to pantothenate Ubidecarenone + Riboflavin 100 97.7 95.3 90.6 Change in the Content (%) of Vitamin C Having a High Daily Ubidecarenone + Alpha-tocopherol 100 96.4 93.9 72.3 Dosage acetate Ubidecarenone + Inositol 100 90.5 80.1 72.6 I0129. 10 mg of ubidecarenone and 50 mg, 100 mg, 500 mg, 1000 mg, and 1500 mg of 90% ascorbic acid were con (Unit:% residual amount of ubidecarenone) tained under the co-existence to prepare each sample, and the 0123. As shown in Table 26, when each ingredient was accelerated stability test was performed. The results are as singly mixed with ubidecarenone, choline bitartrate, alpha follows. US 2010/0203126 A1 Aug. 12, 2010 12
period of a 24 months long-term stability test performed at TABLE 28 25+2° C. and 60+5% RH, or a 6 months accelerated stability test performed at 40+2° C. and 75+5% RH. Content of 90% Initial (% 2 weeks (% 4 weeks (% 6 weeks (% ascorbic acid in residual residual residual residual 3. The ubidecarenone-containing multi-layered vitamin sample (mg) amount) amount) amount) amount) complex tablet according to claim 1, wherein the second layer O 100 99.2 97.2 96.4 further contains at least one active ingredient selected from 50 100 96.4 92.5 84.3 the group consisting of 100 100 89.4 73.6 54.2 500 100 73.7 48.1 42.2 a mineral selected from Zinc sulfate, iron Sulfate, choline 1OOO 100 78.9 34.4 36.3 bitartrate, calcium hydrogen phosphate and mixtures 1SOO 100 71.3 58.8 28.6 thereof; an amino acid selected from L-cysteine, derivatives thereof 0130. As such, it was found that as the content of ascorbic and mixtures thereof, and acid in the sample tablet increases, the residual amount of a herbal extracts comprisingy-ory Zanol, derivative thereof ubidecarenone was remarkably reduced. Considering that the or mixtures thereof. typical vitamin formulation contains vitamin C in an amount 4. The ubidecarenone-containing multi-layered vitamin of 500 to 5000 mg. vitamin C should be regarded as the complex tablet according to any one of claims 1 to 3, wherein ingredient decreasing the stability of ubidecarenone, demon the first and the second layers together forms a structure of strating that the multi-layered tablet of the present invention upper/lower layers or inner/outer layers. should be prepared by separating ubidecarenone therefrom. 5. The ubidecarenone-containing multi-layered vitamin complex tablet according to claim 4, wherein the second layer INDUSTRIAL APPLICABILITY is divided into two separate Sublayers, each of said Sublayers 0131 The present invention provides a vitamin/mineral comprises vitamin and mineral respectively, thereby the complex tablet comprising ubidecarenone useful for the multi-layered tablet is in the form of three-layered tablet. human body, in particular, an oral Solid formulation having 6. The ubidecarenone-containing multi-layered vitamin enhanced stability and bioavailability of ubidecarenone. In complex tablet according to claim 1, wherein the multi-lay the present invention, the multi-layered tablet is prepared by ered tablet further comprises at least one selected from the a simple process without addition of stabilizer Such as organic group consisting of excipients, disintegrants, binders, acids, thereby increasing the stability of ubidecarenone. glidants and Sweetening agents. 0132. The effect can be achieved in such a manner that a 7. The ubidecarenone-containing multi-layered vitamin first layer contains ubidecarenone and other pharmaceutical complex tablet according to claim 1, wherein at least one of a composition not decreasing the stability of ubidecarenone, moisture-proof coating and a light-shielding coating are and other layer contains vitamins and minerals decreasing the applied to the multi-layered tablet. stability of ubidecarenone, thereby minimizing the contact of each ingredient. In addition, moisture-proof coating is 8. A method for preparing an ubidecarenone-containing applied to the tablet, and thus provides the effect of preventing multi-layered vitamin complex tablet, comprising the steps additional degradation and oxidation of ubidecarenone due to of: moisture. compressing one of raw materials for a first layer and for a 1. An ubidecarenone-containing multi-layered vitamin second layer to form a compressed layer, said first layer complex tablet, comprising: containing ubidecarenone and said second layer con a first layer containing ubidecarenone as a first ingredient; taining at least one active ingredient, as a second ingre and dient, said active ingredient decreasing the stability of a second layer containing an active ingredient as a second ubidecarenone; and ingredient, said active ingredient decreasing the stability compressing the other raw material onto the compressed ofubidecarenone; layer to form a structure of upper/lower layers or inner/ wherein said second ingredient contains vitamin selected outer layers to obtain a multi-layered tablet: from the group consisting of ascorbic acid, alpha-toco wherein the second ingredient contains a vitamin selected pherol acetate, retinol palmitate, cyanocobalamine, from the grouped consisting of ascorbic acid, alpha nicotinamide, pyridoxine hydrochloride, cholecalcif tocopherol acetate, fursultiamine, retinol palmitate, erol, fur-sultiamine, inositol, derivatives thereof and cyanocobalamine, nicotinamide, pyridoxine hydrochlo mixtures thereof. ride, chole-calciferol, inositol, derivatives thereof and 2. The ubidecarenone-containing multi-layered vitamin mixtures thereof. complex tablet according to claim 1, wherein the ubide carenone content is maintained at 90% or more over the