JP4249847B2 - Orally disintegrating tablets containing vitamin K - Google Patents
Orally disintegrating tablets containing vitamin K Download PDFInfo
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- JP4249847B2 JP4249847B2 JP15183599A JP15183599A JP4249847B2 JP 4249847 B2 JP4249847 B2 JP 4249847B2 JP 15183599 A JP15183599 A JP 15183599A JP 15183599 A JP15183599 A JP 15183599A JP 4249847 B2 JP4249847 B2 JP 4249847B2
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- Prior art keywords
- vitamin
- crystalline cellulose
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Description
【０００１】
【産業上の利用分野】
本発明は、ビタミンＫを含有する錠剤、更に詳しくはビタミンＫを含有し口腔内での崩壊が早い錠剤またはその製造方法に関する。
【０００２】
【発明の背景及び従来技術】
ビタミンＫは、止血機構賦活ビタミンであり、数種の同族体が知られている。これらのうちビタミンＫ１はフィトナジオンとも呼ばれ、ビタミンＫ欠乏症の予防治療剤として広く使用されている。また、ビタミンＫ２は、メナテトレノンとも呼ばれ、低トロンビン血症の治療予防に用いられており、また、最近では、骨粗鬆症の治療剤としてもその有用性が高く評価されている。
一方、口腔内において速やかに崩壊する錠剤の研究が進み、例えば、特開平５ー２７１０５４号公報には薬効成分と糖類の粒子表面が湿る程度の水分を含む混合物を打錠する口腔内溶解型錠剤の製造法が開示されている。
【０００３】
【発明が解決しようとする課題】
ビタミンＫ製剤は、錠剤、カプセル剤、注射剤、シロップ剤等多くの剤形により治療に供されているが、特に骨粗鬆症は高齢者が服用するために、更に服用しやすい製剤が求められている。従来の口腔内溶解型錠剤には、水溶性薬物が使用される場合が多く、脂溶性薬物に応用された例は多くない。特にビタミンＫは脂溶性である上に安定性が悪いために口腔内溶解型錠剤とすることは一層困難である。本発明者は、ビタミンＫを口腔内において容易に溶解する錠剤とすべく鋭意検討した結果、以下に示す手段により目的を達成できることを見出し本発明を完成した。
【０００４】
【課題を解決するための手段】
本発明は、ビタミンＫを吸着した結晶セルロースと糖類及び溶媒からなる湿潤粉体を製錠した錠剤である。本発明はまた、ビタミンＫを吸着した結晶セルロースと糖類及び溶媒からなる湿潤粉体を製錠した口腔内の崩壊時間が３０秒以内の錠剤である。本発明は更に、ビタミンＫを結晶セルロースに吸着後、水及びアルコール混液により造粒し、次いで糖類と混合後水及び／又はアルコール類により湿潤し、製錠する錠剤の製造方法である。
【０００５】
本発明において、ビタミンKとは血液の凝固を促す脂溶性ビタミンであり、天然にはビタミンＫ１及びＫ２がある。Ｋ１は黄色油状、Ｋ２は黄色結晶である。ビタミンＫ１はフィトナジオン、Ｋ２はメナテトレノンと称され、どちらも医薬品として広く用いられている。本発明においては、ビタミンＫ１又はＫ２のどちらを用いてもよい。
【０００６】
本発明においては、ビタミンＫを結晶セルロースに吸着させる。一般に、脂溶性薬物を吸着させるには、比表面積の大きな二酸化ケイ素等の吸着剤が用いられるがビタミンＫは、ケイ酸類と接触すると分解するため使用できない。吸着は結晶セルロースとビタミンＫを室温又は加温下で混練合することにより達成される。結晶セルロースにはいろいろな種類があるが、本発明おいて使用されるものは特に限定されず、例えば、アビセル（商品名、旭化成工業株式会社製）として容易に入手できる。
ビタミンＫと結晶セルロースとの比は、通常、ビタミンＫ１重量部に対し、結晶セルロース１〜５重量部である。
【０００７】
本発明においては、ビタミンKを結晶セルロースに吸着した粉体を用いることもできるし、ビタミンKを結晶セルロースに吸着した後造粒した粉体を用いることもできる。造粒とは、通常使用される意味の造粒であり、例えばビタミンＫを吸着させた結晶セルロースに、結合剤を混合し溶媒を添加して混練合するか、又はビタミンＫを吸着させた結晶セルロースに、結合剤を溶解した溶液を添加しながら混練合して得ることができる。
【０００８】
本発明における湿潤粉体とは、ビタミンＫを吸着させた結晶セルロースに、糖類を混合後、水及び／又は水と混和する有機溶媒を添加して粉体表面を湿潤した粉体である。水又は水を混和した湿潤粉体中の水分含量は、０．１〜１５重量％であり、好ましくは０．５〜１２重量％である。
本発明で使用される糖は、例えばショ糖、乳糖、ブドウ糖、マンニトール、エリスリトール、キシリトール、ソルビトール等であり、１種又は２種以上を混合して使用することができる。
【０００９】
本発明ではビタミンＫを吸着した結晶セルロースと糖類に更に結合剤を加えることができる。即ち本発明は、ビタミンＫを吸着した結晶セルロース、糖類、結合剤及び溶媒からなる湿潤粉体を製錠した錠剤である。結合剤とは、例えばポリビニルピロリドン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、メチルセルロース、エチルセルロース、カルボキシビニルポリマー、デンプン等であり、１種又は２種以上を混合して用いることができる。結合剤を加えることにより錠剤の硬度を上げることができる。
【００１０】
本発明において製錠とは、鋳型若しくは臼に摺込むようにして上記湿潤粉体を充填し、必要に応じて低圧で圧縮することであり、通常使用される打錠機による打錠とは異なる。圧縮を行わなくても製錠可能であるが、錠剤の硬度を増し、輸送中の摩損を防ぐために２〜１５０ｋｇの低圧、好ましくは１０〜１００ｋｇの低圧により圧縮することができる。一般に湿潤粉体の製錠は、ハリツキやスティッキングを起こすが、特開平８ー１９５８９号公報に開示される製錠機を使用すると効率よく高品質の錠剤が得られる。
得られた錠剤は、乾燥後、次の包装工程に供される。
【００１１】
【効果】
本発明により従来不可能であった、ビタミンKを含有し水等を飲まずに口腔内で３０秒以内に溶解する錠剤が得られる。以下に示す実施例１、２及び参考例１で得られた錠剤の口腔内における崩壊時間は、６錠の平均でそれぞれ、７．９秒、４．２秒、５．９秒であった（表１）。
【００１２】
【表１】
【実施例】
以下に実施例を挙げて本発明を更に詳細に説明するが、本発明がこれらに限定されるわけではない。
【００１４】
実施例１
ビタミンK（メナテトレノン）３００ｇを約５０℃に加温し結晶セルロース（アビセル１０１；商品名）６００ｇに混合して吸着させた。続いて水・エタノール（１：１）混合液４５０ｍｌを徐々に加えて造粒を行った。その後、４０℃で約１０時間乾燥し、乾燥後、整粒を行い吸着顆粒を調製した。得られた顆粒３１５ｇにマンニトール１６２５．４gと１０％ポリビニルピロリドンＫ−３０を含有する水１９６ｇを加え混練合し、鋳型に充填、フィルムを介して低圧で圧縮して３５℃で乾燥し１錠約２８０ｍｇの錠剤を得た。
【００１５】
参考例１
ビタミンK（メナテトレノン）３００ｇを約５０℃に加温し、結晶セルロース（アビセル１０１；商品名）６００ｇ及びコーンスターチ２２０ｇに混合し、ビタミンKを結晶セルロースに吸着させ、次いで水・エタノール（１：１）混合液８９０ｍｌを徐々に加えて造粒後、４０℃で約１０時間乾燥した。得られた顆粒を整粒後、その３８５ｇにマンニトール１５５５．４gを加え混合し、１０％ポリビニルピロリドンＫ−３０を含有する水１９６ｇを加えて混練合し、鋳型に充填、フィルムを介して低圧で圧縮して３５℃で乾燥して１錠約２８０ｍｇの錠剤を得た。
【００１６】
実施例２
ビタミンK（メナテトレノン）３００ｇを約５０℃に加温し、結晶セルロース（アビセル１０１；商品名）５８０ｇに混合して、ビタミンKを結晶セルロースに吸着させ、次いでポリビニルピロリドン２０ｇを添加・混合した。その後、水・エタノール（１：１）混合液６００ｍｌを徐々に加えて造粒を行った。４０℃で約１０時間乾燥後整粒を行い顆粒を調製した。得られた顆粒３１５ｇにマンニトール１６２５．４gを加え混合し、１０％ポリビニルピロリドンＫ−３０を含有する水１９６ｇを添加して混練合し、鋳型に充填、フィルムを介して低圧で圧縮し３５℃で乾燥して１錠約２８０ｍｇの錠剤を得た。[0001]
[Industrial application fields]
The present invention relates to a tablet containing vitamin K, and more particularly to a tablet containing vitamin K and rapidly disintegrating in the oral cavity or a method for producing the same.
[0002]
BACKGROUND OF THE INVENTION AND PRIOR ART
Vitamin K is a hemostatic mechanism-activating vitamin, and several types of homologs are known. Of these, vitamin K1 is also called phytonadione and is widely used as a preventive and therapeutic agent for vitamin K deficiency. Vitamin K2, also called menatetrenone, is used for the treatment and prevention of hypothrombinemia, and recently, its usefulness is highly evaluated as a therapeutic agent for osteoporosis.
On the other hand, research on tablets that disintegrate rapidly in the oral cavity has progressed. For example, JP-A-5-271054 discloses an oral dissolution type tablet that compresses a mixture containing a medicinal component and water that moistens the surface of saccharide particles. A method for manufacturing tablets is disclosed.
[0003]
[Problems to be solved by the invention]
Vitamin K preparations are used for treatment in many dosage forms such as tablets, capsules, injections, syrups, etc. Especially for elderly people, osteoporosis is required to be easy to take. . In conventional oral-dissolving tablets, water-soluble drugs are often used, and there are not many examples applied to fat-soluble drugs. In particular, vitamin K is more soluble in the oral cavity because it is fat-soluble and has poor stability. As a result of intensive studies to make vitamin K into a tablet that easily dissolves in the oral cavity, the present inventor has found that the object can be achieved by the following means, and has completed the present invention.
[0004]
[Means for Solving the Problems]
The present invention is a tablet obtained by tableting a wet powder comprising crystalline cellulose adsorbing vitamin K, a saccharide and a solvent. The present invention is also a tablet having a disintegration time in the oral cavity of 30 seconds or less in which a wet powder comprising crystalline cellulose adsorbing vitamin K, a saccharide and a solvent is tableted. The present invention further relates to a method for producing a tablet in which vitamin K is adsorbed on crystalline cellulose, granulated with a mixture of water and alcohol, then mixed with sugars, wetted with water and / or alcohols, and tableted.
[0005]
In the present invention, vitamin K is a fat-soluble vitamin that promotes blood coagulation, and naturally there are vitamins K1 and K2. K1 is a yellow oil and K2 is a yellow crystal. Vitamin K1 is called phytonadione and K2 is called menatetrenone, both of which are widely used as pharmaceuticals. In the present invention, either vitamin K1 or K2 may be used.
[0006]
In the present invention, vitamin K is adsorbed on crystalline cellulose. In general, an adsorbent such as silicon dioxide having a large specific surface area is used to adsorb fat-soluble drugs, but vitamin K cannot be used because it decomposes when it comes into contact with silicic acids. Adsorption is achieved by kneading crystalline cellulose and vitamin K at room temperature or under heating. There are various types of crystalline cellulose, but those used in the present invention are not particularly limited, and can be easily obtained as, for example, Avicel (trade name, manufactured by Asahi Kasei Kogyo Co., Ltd.).
The ratio of vitamin K to crystalline cellulose is usually 1 to 5 parts by weight of crystalline cellulose with respect to 1 part by weight of vitamin K.
[0007]
In the present invention, a powder in which vitamin K is adsorbed on crystalline cellulose can be used, or a powder granulated after adsorbing vitamin K on crystalline cellulose can also be used. Granulation is granulation in the meaning normally used. For example, a crystal in which vitamin K is adsorbed is mixed with a binder and a solvent is added and kneaded, or a crystal in which vitamin K is adsorbed. It can be obtained by kneading with cellulose while adding a solution in which a binder is dissolved.
[0008]
The wet powder in the present invention is a powder obtained by mixing saccharides with crystalline cellulose adsorbed with vitamin K and then adding water and / or an organic solvent miscible with water to wet the powder surface. The water content in water or wet powder mixed with water is 0.1 to 15% by weight, preferably 0.5 to 12% by weight.
Examples of the sugar used in the present invention include sucrose, lactose, glucose, mannitol, erythritol, xylitol, sorbitol, and the like, and one or more kinds can be used in combination.
[0009]
In the present invention, a binder can be further added to crystalline cellulose and saccharide adsorbed with vitamin K. That is, the present invention is a tablet obtained by tableting a wet powder composed of crystalline cellulose adsorbed with vitamin K, saccharide, binder and solvent. Examples of the binder include polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, methyl cellulose, ethyl cellulose, carboxyvinyl polymer, starch, and the like, and one or a mixture of two or more can be used. The hardness of the tablet can be increased by adding a binder.
[0010]
In the present invention, tableting refers to filling the wet powder as if it is slid into a mold or mortar and compressing at a low pressure as necessary, and is different from tableting by a normally used tableting machine. Tablets can be produced without compression, but can be compressed with a low pressure of 2 to 150 kg, preferably 10 to 100 kg in order to increase the hardness of the tablet and prevent abrasion during transportation. In general, wet powder tableting causes stickiness and sticking, but high-quality tablets can be obtained efficiently by using a tableting machine disclosed in JP-A-8-19589.
The obtained tablet is subjected to the next packaging step after drying.
[0011]
【effect】
According to the present invention, a tablet containing vitamin K and dissolving within 30 seconds in the oral cavity without drinking water or the like, which has been impossible in the past, is obtained. The disintegration time in the oral cavity of the tablets obtained in Examples 1 and 2 and Reference Example 1 shown below was 7.9 seconds, 4.2 seconds, and 5.9 seconds, respectively, on the average of 6 tablets ( Table 1).
[0012]
[Table 1]
【Example】
The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
[0014]
Example 1
300 g of vitamin K (menatetrenone) was heated to about 50 ° C., mixed with 600 g of crystalline cellulose (Avicel 101; trade name), and adsorbed. Subsequently, 450 ml of a water / ethanol (1: 1) mixed solution was gradually added to perform granulation. Then, it dried at 40 degreeC for about 10 hours, and after drying, it sized and prepared the adsorption granule. To 315 g of the obtained granules, 1965.4 g of mannitol and 196 g of water containing 10% polyvinylpyrrolidone K-30 were added and kneaded, filled into a mold, compressed at a low pressure through a film, dried at 35 ° C., and about 1 tablet. 280 mg tablets were obtained.
[0015]
Reference example 1
300 g of vitamin K (menatetrenone) is heated to about 50 ° C., mixed with 600 g of crystalline cellulose (Avicel 101; trade name) and 220 g of corn starch, adsorbed to crystalline cellulose, and then water / ethanol (1: 1) After 890 ml of the mixed solution was gradually added and granulated, it was dried at 40 ° C. for about 10 hours. After sizing the obtained granules, 1555.4 g of mannitol was added to 385 g of the granules, mixed, 196 g of water containing 10% polyvinylpyrrolidone K-30 was added and kneaded, filled into a mold, and passed through a film at low pressure. Compressed and dried at 35 ° C. to obtain about 280 mg tablets.
[0016]
Example 2
300 g of vitamin K (menatetrenone) was heated to about 50 ° C. and mixed with 580 g of crystalline cellulose (Avicel 101; trade name) to adsorb vitamin K to the crystalline cellulose, and then 20 g of polyvinylpyrrolidone was added and mixed. Thereafter, 600 ml of a water / ethanol (1: 1) mixed solution was gradually added to perform granulation. After drying at 40 ° C. for about 10 hours, granulation was performed to prepare granules. Add 1625.4 g of mannitol to 315 g of the obtained granule, add 196 g of water containing 10% polyvinylpyrrolidone K-30, knead and mix, fill in the mold, compress at low pressure through the film, and at 35 ° C. The tablet was dried to obtain about 280 mg tablets.
Claims (8)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15183599A JP4249847B2 (en) | 1999-05-31 | 1999-05-31 | Orally disintegrating tablets containing vitamin K |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15183599A JP4249847B2 (en) | 1999-05-31 | 1999-05-31 | Orally disintegrating tablets containing vitamin K |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2000344664A JP2000344664A (en) | 2000-12-12 |
| JP4249847B2 true JP4249847B2 (en) | 2009-04-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15183599A Expired - Fee Related JP4249847B2 (en) | 1999-05-31 | 1999-05-31 | Orally disintegrating tablets containing vitamin K |
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| Country | Link |
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| JP (1) | JP4249847B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003238393A (en) * | 2002-02-15 | 2003-08-27 | Otsuka Pharmaceut Co Ltd | Tablet with improved tableting property and method for producing the same |
| FI3473251T3 (en) * | 2002-12-20 | 2024-01-09 | Niconovum Ab | A nicotine-cellulose combination |
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1999
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| Publication number | Publication date |
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| JP2000344664A (en) | 2000-12-12 |
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| LAPS | Cancellation because of no payment of annual fees |