JP4601934B2 - Ubidecarenone tablets - Google Patents

Description

  The present invention relates to a tablet containing a high content of ubilecarenone.

で表される化合物であって、ユビキノン−１０またはコエンチームＱ₁₀、ＣｏＱ₁₀の別称でも知られた物質である。水には殆ど不溶であるが、エーテルなどには高い溶解性を示し、光によって分解し、ヒドロキノン体やユビクロメールなどの分解生成物を形成する。従来から、心筋の代謝障害を改善する薬物として知られ、代謝性強心薬として軽度および中程度のうっ血性心不全の浮腫、肺うっ血および狭心症状などに対する有効な医薬品として処方されていたが、最近では食品として認可されたこともあり、手軽に購入できる健康食品として健康に関心の高い消費者に有望な健康素材となっている。 Ubidecarenone has the following formula

It is a compound represented by the formula, and is also known as ubiquinone-10 or another name for coenteam Q ₁₀ and CoQ ₁₀ . Although it is almost insoluble in water, it is highly soluble in ether and decomposes by light to form decomposition products such as hydroquinone and ubichrome. Formerly known as a drug that improves myocardial metabolic disorders, it has been prescribed as an effective drug for edema, pulmonary congestion, and angina symptoms of mild and moderate congestive heart failure as a metabolic cardiotonic drug. Since it has been approved as a food, it is a promising health material for consumers interested in health as a health food that can be easily purchased.

Ubidecarenone is a fat-soluble chemical, has a low melting point and high adhesion, so capping and sticking occur during tableting, and tablet hardness does not increase. Various problems occur in the formulation of tablets with a high content ratio of ubidecarenone. Therefore, it is very difficult to produce a high content of Ubidecarenone tablets. In the pharmaceutical field, ubidecarenone is formulated as a tablet, but commercially available ubidecarenone tablets for pharmaceutical use are mainly 10 mg / tablet (100 mg).
For the manufacture of tablets containing a high content of ubidecarenone, the purpose can be achieved by increasing the size of the tablet, but if the tablet size increases, swallowing becomes difficult, especially in the elderly and children, and the swallowing function is reduced. Patients can not take.

For this reason, in the formulation of ubidecarenone, it is often used as a capsule formulation in which ubidecarenone is filled in a capsule film. In making capsules, ubidecalenone is poorly soluble, so absorption in the body and skin is extremely poor, so it can be dissolved in liquid edible natural oils and triglycerides of medium chain fatty acids at room temperature to improve absorption. It has been proposed (see Patent Document 1).
However, ubidecalenone dissolved in these solvents has poor stability, and the ubidecalenone composition is emulsified and encapsulated and sold as a product such as increased convenience and appearance. It was not enough.
JP 54-92616 A

  An object of the present invention is to provide a tablet containing a high content of ubidecarenone.

  As a tablet manufacturing method, there is a wet granulation method. When the tableting property by the direct tableting method is poor, it is found that the tableting property is improved by wet granulating the drug with an appropriate excipient. ing. However, selection of excipients and binders is not easy due to the physical properties of drugs and physical properties such as excipients and binders. In the pharmaceutical field, the range of selectivity of excipients and binders is wide, but in the food field, only a very limited selectivity is available at present. Under these circumstances, the present inventors have examined various excipients and binders that can be used, and in order to improve the tabletability of ubidecarenone, ubidecalenone was formed into an intragranular shape at 12 to 30 w / w%. Capping and sticking, especially when using non-digestible water-soluble cellulose or soluble dextrin as a binder by mixing and tableting granules containing an agent and binder and extragranular excipients The inventors have found that a tablet having no hardness, moderate hardness, and a high content of ubidecarenone can be obtained, and further studies have been made to complete the present invention.

That is, the present invention
(1) A tablet comprising ubidecalenone 12-30 w / w%, a granule containing an intragranular excipient and a binder, and an extragranular excipient,
(2) The tablet according to (1), wherein the intragranular excipient is at least one compound selected from lactose, sucrose, D-mannitol and xylitol,
(3) The tablet according to (1) or (2) above, wherein the binder is at least one compound selected from water-soluble polysaccharides, water-soluble celluloses and water-soluble polymers.
(4) The tablet according to (3) above, wherein the water-soluble polysaccharide is maltodextrin or pullulan.
(5) The tablet according to the above (3), wherein the water-soluble cellulose is at least one compound selected from non-digestible water-soluble dietary fiber, hydroxypropylcellulose and hydroxypropylmethylcellulose,
(6) The tablet according to (3), wherein the water-soluble polymer is polyvinylpyrrolidone,
(7) The tablet according to any one of the above (1) to (6), wherein the extragranular excipient is a disintegrant or / and a lubricant,
(8) The tablet according to (7) above, wherein the disintegrant is carmellose calcium or croscarmellose sodium,
(9) The tablet according to (7) above, wherein the lubricant is sucrose fatty acid ester or magnesium stearate, and (10) 12-30 w / w% of ubidecalenone, 55-80 w / w% of lactose, and maltodextrin The present invention relates to a ubidecalenone tablet containing 3 to 15 w / w%, wherein the ubidecalenone, lactose and maltodextrin granules are tableted together with a disintegrant and a lubricant. The present invention also relates to a method for producing a ubilecarenone tablet containing a high content of ubilecarenone.
In addition, unless otherwise indicated,% in this invention shall show the compounding quantity in a tablet, and weight% (w / w%).

  According to the present invention, a stable tablet containing a high content of ubidecarenone can be supplied.

  If the amount of ubidecarenone in the tablet of the present invention is about 12 to 30%, capping or the like does not occur, and a tablet having sufficient hardness as a tablet can be obtained. According to the present invention, if the weight of one tablet is 100 mg, ubidecalenone 12-30 mg, and if the weight of one tablet is 200 mg, ubicarenone tablets containing 24-60 mg of ubidecalenone can be produced. Preferably, the weight of one tablet is 150 to 170 mg and a ubilecarenone tablet containing 20 to 50 mg of ubidecarenone, more preferably a ubilecarenone tablet having a weight of 150 to 160 mg and containing 30 to 45 mg of ubidecarenone.

As the intragranular excipient of the ubidecarenone tablet of the present invention, saccharides such as lactose, sucrose, D-mannitol, xylitol, erythritol and trehalose are preferable, and lactose, sucrose, D-mannitol and xylitol are particularly preferable. In addition to these saccharides, other excipients such as sugar alcohols, corn starch, potato starch, partially pregelatinized starch and the like may be used as long as they do not affect the granulation properties of the granules constituting the tablet of the present invention. Inorganic substances such as starches, crystalline cellulose, calcium hydrogen phosphate, talc, light anhydrous silicic acid and hydrous silicon dioxide may be added as appropriate.
The compounding ratio of the intragranular excipient is usually about 50 to 85%, preferably about 55 to 80%. It is about 2 to 6.5 weight ratio with respect to 1 weight of ubidecarenone.

Among the binders of the ubidecalenone tablet of the present invention, examples of the water-soluble polysaccharide include maltodextrin, pullulan and ersilane, but maltodextrin is preferred. More specifically, as maltodextrin, for example, Amicol No. 3-L, Amicole No. 1, Amicole No. 1 5-L, Amicole No. 6-L, Amicole No. 10 and the like. 6-L, Amicole No. 10 is preferred. Examples of water-soluble cellulose include non-digestible water-soluble dietary fiber, hydroxypropylcellulose, hydroxypropylmethylcellulose and the like. Of these, non-digestible water-soluble fibers, more specifically, Fiber Sol 2 (manufactured by Matsutani Chemical Industry Co., Ltd.) and the like are preferable. Examples of the water-soluble polymer include polyvinyl pyrrolidone (for example, polyvinyl pyrrolidone K15, polyvinyl pyrrolidone K30, polyvinyl pyrrolidone K90, etc.).
One of the above binders may be used alone, or two or more of the above binders may be appropriately mixed and used.
The blending ratio of the binder is generally about 1 to 25%, but varies depending on the binder used. For example, in the case of maltodextrin, about 3 to 15% is preferable. Is preferably about 0.5 to 6.5%.
The binder is preferably used as an aqueous solution of 10 w / w% or more and 60 w / w% or less. Specifically, in the case of a maltodextrin aqueous solution, about 20 to about 60 w / w%, and Fiber Sol 2 aqueous solution Also in this case, it is preferable to add appropriately from the concentration range of about 10 to about 60 w / w% so as to achieve the above blending ratio.

As the disintegrant of the extragranular excipient of the ubidecarenone tablet of the present invention, carmellose calcium, low-substituted hydroxypropyl cellulose, cellulose derivatives such as croscarmellose sodium, corn starch, carboxymethyl starch sodium, hydroxypropyl starch, Examples thereof include starch and starch derivatives such as partially pregelatinized starch, and synthetic polymers such as crospovidone. Carmellose calcium and croscarmellose sodium are preferred. The mixing ratio of the disintegrant is about 1.5 to 5%.
As the lubricant, sucrose fatty acid ester and magnesium stearate are preferable. The blending ratio of the lubricant is about 1.5 to 6.5%.

Further, as an extragranular excipient, unless it is contrary to the object of the present invention, other medicinal ingredients and other excipients such as crystalline cellulose (Avicel), fine silicon dioxide, wheat starch, corn starch, etc. You may mix | blend.
Moreover, you may add the component normally mix | blended as additives, such as pharmaceuticals and foodstuffs, such as a coloring agent and a flavoring agent.

Next, the preferable manufacturing method of the ubidecarenone tablet of this invention is demonstrated below.
First, ubidecarenone and an intragranular excipient are sieved and mixed to prepare a raw powder for granules, and then mixed with an aqueous solution of the binder. The granulated wet granule is taken out from the granulator and blown or dried with heat on a shelf or charged into a fluidized bed dryer and dried. After drying, a sieve (20 mesh) is passed through to obtain granules having a particle size of about 850 μm or less.
As the binding liquid at the time of granulation, an aqueous solution of the binder described above may be prepared and added to the powder by dropping or spraying. In this case, the addition ratio of the aqueous solution of the binder to the bulk powder is different depending on the concentration of the aqueous solution, but when it is about 0.1 to 0.6 g (aqueous solution weight) with respect to 1 g of the bulk powder, The hardness of ubidecarenone tablets is preferred. In addition, the fluidity of the granules is good and the variation in tablet weight is small. Especially preferably, it is 0.15-0.3g as binder aqueous solution with respect to 1g of raw materials for granules. More specifically, a maltodextrin about 20 to about 60 w / w% solution or a non-digestible water-soluble dietary fiber (Fibersol 2) about 5 to about 40 w / w% solution is used so that it may become the said addition ratio. Is preferred.
The disintegrant and lubricant are added to and mixed with the obtained granule, and the tablet containing a high content of ubidecarenone can be obtained by tableting with a tableting machine using a conventional method.
The hardness of the tablet obtained by the present invention is about 2 to 10, preferably about 4 to 10, more preferably about 5 to 10.
The tablets of the present invention can be sugar-coated to give sugar-coated tablets.

  Preferred examples and test examples in the present invention will be described below, but the present invention is not limited to the following examples.

[Example 1]
Ubidecarenone 60 g and lactose 137.25 g are stirred, passed through a sieve (42 mesh), and then put into a universal mixing stirrer (Dalton Co., Ltd.). While stirring, 60% Amicol No. Add 56.25 mL of 6-L aqueous solution and stir further. After confirming that the whole was well mixed, transfer to a blower dryer (manufactured by Ikeda Rika) and dry at 40 ° C. After drying, it was sieved with a 20 mesh sieve. RT-S-9 type tablet machine, to which 4.5 g of carmellose calcium (ECG-505; manufactured by Gotoku Pharmaceutical Co., Ltd.) and 4.5 g of sucrose fatty acid ester are added to the sieved granules, and after mixing, 1 tablet is 160 mg. Tableting was carried out (manufactured by Kikusui Seisakusho Co., Ltd.) to produce 1500 ubidecalenone 40 mg / tablet.
No capping was observed during tableting. When the hardness of the manufactured tablet was measured with a tablet hardness meter TS-50N (Okada Seiko Co., Ltd.), the average hardness of the manufactured tablet was 7.9 kgf.
Moreover, when the disintegration time of this tablet was measured according to the disintegration test method of the 14th revised Japanese Pharmacopoeia General Test Method, the disintegration time was 60 minutes or less.

[Example 2-10]
The formulations shown in Tables 1 and 2 were tableted in the same manner as in Example 1. Further, the hardness and disintegration time of the tablets produced in the same manner as in Example 1 were measured. In addition, the occurrence of sticking and capping during tableting was observed (Tables 1 and 2). In the ubilecarenone tablet of Example 2-10, neither sticking nor capping occurred during tableting, and a tablet having a hardness in the range of 2.3 to 6 kgf was obtained. Moreover, the disintegration time by the disintegration test of the tablet of these Examples was 30 minutes or less.

The ubidecalenone tablet of the present invention contains ubidecalenone in a high content, so that it can be used to improve heart disease such as palpitations and shortness of breath, improvement of periodontal disease, and activation of the immune system, etc. it can. It is also useful for improving exercise capacity, recovering from fatigue, cooling, preventing aging, and improving skin wrinkles. Furthermore, since adjustment of blood pressure, reduction of risks such as diabetes, and suppression of progression of Alzheimer's disease and the like can be expected, it can be advantageously used as pharmaceuticals, health foods, quasi drugs.

Claims (7)

12-25 w / w of ubidecarenone, an intragranular excipient that is at least one compound selected from lactose, sucrose, D-mannitol, and xylitol, and a binder that is maltodextrin or / and indigestible dextrin A tablet comprising: a granule containing a non-granular excipient that is a disintegrant or / and a lubricant.   The tablet according to claim 1, wherein the intragranular excipient is at least one compound selected from lactose, sucrose and D-mannitol. The tablet according to claim 1 , wherein the disintegrant is carmellose calcium or croscarmellose sodium. The tablet according to claim 1 , wherein the lubricant is a sucrose fatty acid ester or magnesium stearate.   A tablet containing ubidecalenone 12-25 w / w%, lactose 55-80 w / w%, maltodextrin 3-15 w / w%, wherein the granule containing ubidecalenone, lactose and maltodextrin is used as a disintegrant and Ubidecarenone tablets that are tableted together with lubricants. Ubidecalenone and an intragranular excipient which is at least one compound selected from lactose, sucrose, D-mannitol and xylitol are sieved and mixed to obtain a bulk powder, and then the bulk powder , A step of obtaining granules by mixing and granulating an aqueous solution of a binder that is maltodextrin or / and an indigestible dextrin , and an extragranular excipient that is a disintegrant or / and a lubricant is mixed with the granules The manufacturing method of the tablet as described in any one of Claims 1-5 characterized by including a process.   The production method according to claim 6, wherein the intragranular excipient is at least one compound selected from lactose, sucrose, and D-mannitol.