JPH053864B2 - - Google Patents
Info
- Publication number
- JPH053864B2 JPH053864B2 JP60042432A JP4243285A JPH053864B2 JP H053864 B2 JPH053864 B2 JP H053864B2 JP 60042432 A JP60042432 A JP 60042432A JP 4243285 A JP4243285 A JP 4243285A JP H053864 B2 JPH053864 B2 JP H053864B2
- Authority
- JP
- Japan
- Prior art keywords
- vitamin
- dimethyl
- cyclodextrin
- solubility
- clathrate compound
- Prior art date
- 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
Links
- 229920000858 Cyclodextrin Polymers 0.000 claims description 22
- 239000001116 FEMA 4028 Substances 0.000 claims description 20
- 229960004853 betadex Drugs 0.000 claims description 19
- DKHGMERMDICWDU-GHDNBGIDSA-N menaquinone-4 Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)=C(C)C(=O)C2=C1 DKHGMERMDICWDU-GHDNBGIDSA-N 0.000 claims description 18
- 239000011728 vitamin K2 Substances 0.000 claims description 12
- PFRQBZFETXBLTP-RCIYGOBDSA-N 2-[(2e,6e,10e,14e,18e)-3,7,11,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaen-1-yl]-3-methyl-1,4-dihydronaphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CC/C=C(C)/CC/C=C(C)/CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)=C(C)C(=O)C2=C1 PFRQBZFETXBLTP-RCIYGOBDSA-N 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 18
- 239000000203 mixture Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000008187 granular material Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 235000009491 menaquinone-4 Nutrition 0.000 description 6
- 239000011676 menaquinone-4 Substances 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 238000004898 kneading Methods 0.000 description 5
- 229960005481 menatetrenone Drugs 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 238000004455 differential thermal analysis Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 238000010587 phase diagram Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000002775 capsule Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000006069 physical mixture Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000008279 sol Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000019143 vitamin K2 Nutrition 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HYPYXGZDOYTYDR-HAJWAVTHSA-N 2-methyl-3-[(2e,6e,10e,14e)-3,7,11,15,19-pentamethylicosa-2,6,10,14,18-pentaenyl]naphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(C/C=C(C)/CC/C=C(C)/CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)=C(C)C(=O)C2=C1 HYPYXGZDOYTYDR-HAJWAVTHSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- PFRQBZFETXBLTP-UHFFFAOYSA-N Vitamin K2 Natural products C1=CC=C2C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C(=O)C2=C1 PFRQBZFETXBLTP-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000005280 amorphization Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 238000001782 photodegradation Methods 0.000 description 1
- -1 polyoxyethylene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 229940041603 vitamin k 3 Drugs 0.000 description 1
Landscapes
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は新規なビタミンK2のシクロデキスト
リン包接化合物に関し、更に詳しくは血液凝固に
関与する薬物で医療用に経口剤、注射剤として用
いられるビタミンK2（メナキノン）の水溶性を高
め、かつ経口投与後の吸収性を向上させ、更に光
安定性を増大させたビタミンK2−ジメチル−β
−シクロデキストリン包接化合物に関するもので
ある。[Detailed Description of the Invention] The present invention relates to a novel cyclodextrin clathrate compound of vitamin K 2 , and more specifically, vitamin K 2 (menaquinone), which is a drug involved in blood coagulation and is used for medical purposes as an oral preparation or an injection. Vitamin K 2 -dimethyl-β with increased water solubility, improved absorption after oral administration, and increased photostability.
- Concerning cyclodextrin clathrate compounds.
ビタミンK2は血液の凝固性を保つために必要
とされる物質で黄色結晶性の粉末で水に不溶、有
機溶媒に可溶でアルカリ及び光線（太陽光線、人
口光線、紫外線）によつて容易に分解され、熱に
対しては安定な物質である。 Vitamin K2 is a substance required to maintain the coagulability of blood.It is a yellow crystalline powder that is insoluble in water, soluble in organic solvents, and easily exposed to alkali and light (sunlight, artificial light, ultraviolet light). It is a substance that is stable against heat.
この様に極めて難水溶性で経口投与時のバイオ
アベイラビリテイが低く光分解も著しいためビタ
ミンK2の水への溶解性、光に対する安定性及び
消化管吸収性の改善が強く望まれている。 Since vitamin K2 is extremely poorly water-soluble, has low bioavailability upon oral administration, and is subject to significant photodegradation, it is strongly desired to improve the water solubility, light stability, and gastrointestinal absorption of vitamin K2 . .
従来はビタミンK2を水性媒質中に分散させる
ために非イオン性界面活性剤を使用する方法、レ
シチンによる乳化の方法、リン脂質を用いてリポ
ソームを形成する方法、硬化ヒマシ油、ポリオキ
シエチレン誘導体、中性油及び塩類を配合して水
溶化する方法等が既存の技術として知られている
が本発明者はこれらの方法と全く異なる方法でこ
れらの改善を目的として鋭意研究を重ねた結果ビ
タミンK2−ジメチル−β−シクロデキストリン
包接化合物がビタミンK2の効力を低下させるこ
となく、ビタミンK2の水への溶解性を向上させ
且つ消化管からの吸収性を向上させ更に光安定性
をも著しく改善することを見い出し本発明を完成
するに到つた。 Traditional methods include the use of nonionic surfactants to disperse vitamin K2 in aqueous media, emulsification with lecithin, liposome formation with phospholipids, hydrogenated castor oil, and polyoxyethylene derivatives. , a method of blending neutral oils and salts to make them water-solubilized is known as an existing technique, but the present inventor has conducted extensive research aimed at improving these methods using a method completely different from these methods, and as a result, the vitamin K 2 -dimethyl-β-cyclodextrin clathrate compound improves the solubility of vitamin K 2 in water and absorption from the gastrointestinal tract without reducing the efficacy of vitamin K 2 , and also improves photostability. The present invention has been completed based on the discovery that the present invention can also significantly improve the following properties.
本発明に用いられるジメチル−β−シクロデキ
ストリンはβ−シクロデキストリンの構成単位で
あるグルコースの２，６位の水酸基にメチル基が
導入されたもので融点295〜300℃、水に極めて溶
け易く、低い吸湿性と高い界面活性を有し、有機
溶媒にもよく溶ける性質を有している。 Dimethyl-β-cyclodextrin used in the present invention has a methyl group introduced into the 2- and 6-position hydroxyl groups of glucose, which is a constituent unit of β-cyclodextrin, and has a melting point of 295-300°C and is extremely soluble in water. It has low hygroscopicity and high surface activity, and is highly soluble in organic solvents.
包接化の方法には種々の方法があるが特にビタ
ミンK2に対しては混練法が望ましい。ビタミン
K2の内、代表的なメナテトレノン（メナキノン
−４、MK−４）を例にとり以下説明を行なう。 There are various methods for clathration, but the kneading method is particularly desirable for vitamin K2 . vitamin
Among K2 , a typical example of menatetrenone (menaquinone-4, MK-4) will be explained below.
混練法ではメナテトレノンとジメチル−β−シ
クロデキストリンをモル比１：１〜１：10になる
様に秤量し暗室に於て、ゾル状になる程度の精製
水を加えた后、ペースト状になるまで充分混練を
行つた后、減圧乾燥等で乾燥して粉末状の包接化
合物を得る。混練温度は特に制限はなく、室温で
十分であり混練時間は作成資料の量にもよるが
0.5〜２時間で充分である。このようにして得ら
れた包接化合物は必要に応じて精製することが出
来る。 In the kneading method, menatetrenone and dimethyl-β-cyclodextrin are weighed out at a molar ratio of 1:1 to 1:10, and in a dark room, purified water is added to form a sol, and then the mixture is mixed until it becomes a paste. After thorough kneading, the mixture is dried under reduced pressure to obtain a powdery clathrate compound. There are no particular restrictions on the kneading temperature; room temperature is sufficient, and the kneading time depends on the amount of material to be prepared.
0.5 to 2 hours is sufficient. The clathrate compound thus obtained can be purified if necessary.
以上の方法によつて得られたビタミンK2のジ
メチル−β−シクロデキストリン包接化合物は黄
色結晶性の粉末で水に対する溶解度を著しく増大
する。該包接化合物の形成は溶解度相図、粉末Ｘ
線回折、溶解速度、電顕写真示差熱分析
（DTE）、赤外吸収（IR）等種々の手段により確
認された。 The dimethyl-β-cyclodextrin clathrate compound of vitamin K2 obtained by the above method is a yellow crystalline powder with significantly increased solubility in water. The formation of the clathrate is shown in the solubility phase diagram, powder
It was confirmed by various means such as line diffraction, dissolution rate, electron microscopy differential thermal analysis (DTE), and infrared absorption (IR).
ビタミンK2とジメチル−β−シクロデキスト
リンの25℃における溶解度相図を第１図に示す。
第１図に示した相図の曲線の形はビタミンK2に
関して、高次の水溶性複合体形成を示唆してい
る。ビタミンK2の水への溶解度はジメチル−β
−シクロデキストリン添加により著しく増大し、
例えば0.1Mジメチル−β−シクロデキストリン
水溶液中に於てビタミンK2の溶解度は6.4mg／ml
を示した。 The solubility phase diagram of vitamin K 2 and dimethyl-β-cyclodextrin at 25°C is shown in Figure 1.
The shape of the phase diagram curve shown in Figure 1 suggests the formation of higher order water-soluble complexes with respect to vitamin K2 . The solubility of vitamin K2 in water is dimethyl-β
- Significantly increased by addition of cyclodextrin,
For example, the solubility of vitamin K2 in a 0.1M dimethyl-β-cyclodextrin aqueous solution is 6.4mg/ml.
showed that.
またビタミンK2−ジメチル−β−シクロデキ
ストリンの示差熱分析を第２図に示す。第２図か
ら明らかなようにビタミンK2単独に認められる
35℃付近の融解による吸熱ピークは、複合体では
消失した。こんことは、ビタミンK2がジメチル
−β−シクロデキストリンと熱的に安定な包接化
合物を形成することを示す。 Further, differential thermal analysis of vitamin K 2 -dimethyl-β-cyclodextrin is shown in FIG. As is clear from Figure 2, vitamin K2 is found alone.
The endothermic peak due to melting around 35°C disappeared in the composite. This indicates that vitamin K2 forms a thermally stable clathrate with dimethyl-β-cyclodextrin.
さらにビタミンK2−ジメチル−β−シクロデ
キストリン（モル比１：１）の粉末Ｘ線回折パタ
ーンを第３図および第４図に示す。第３図から明
らかなように物理的混合物のピークは単純に両成
分の和として観察されるが、包接化合物の場合は
第４図に示すように各成分のピークが消失し、新
しいピークの出現による異なつた回折パターンを
示した。また包接化合物のピークは物理的混合物
に比べてブロードニングを起こし、非晶質化を受
けていることを示す。他のモル比（１：３、１：
５、１：10）で調整した複合体についても同様な
性質を示す。 Furthermore, the powder X-ray diffraction pattern of vitamin K 2 -dimethyl-β-cyclodextrin (molar ratio 1:1) is shown in FIGS. 3 and 4. As is clear from Figure 3, the peak of a physical mixture is simply observed as the sum of both components, but in the case of clathrate compounds, the peaks of each component disappear and a new peak is created, as shown in Figure 4. The appearance showed different diffraction patterns. Moreover, the peak of the clathrate compound is broadened compared to that of the physical mixture, indicating that it has undergone amorphization. Other molar ratios (1:3, 1:
5, 1:10) shows similar properties.
次に各種モル比で調製したビタミンK2−ジメ
チル−β−シクロデキストリン包接化合物の25℃
における溶解挙動を粉末法により測定した結果を
第５図に示す。各包接化合物は２〜３分で溶解平
衡に達するすぐれた溶解性を示し、包接化合物中
のジメチル−β−シクロデキストリン含量が多い
ほど、過飽和濃度が増大する傾向が認められた。 Next, vitamin K 2 -dimethyl-β-cyclodextrin clathrates prepared at various molar ratios were prepared at 25°C.
FIG. 5 shows the results of measuring the dissolution behavior of the sample using the powder method. Each clathrate exhibited excellent solubility, reaching solubility equilibrium in 2 to 3 minutes, and it was observed that the higher the dimethyl-β-cyclodextrin content in the clathrate, the higher the supersaturation concentration.
以上の様に包接化合物の溶解速度はモル比１：
５付近で一定に達する傾向を示したがモル比１：
１に於ても溶解性の改善が充分認められるのでビ
ーグル犬を用いて経口投与した所、血中濃度が著
しく増大し、生物に対する有効性の向上がみら
れ、又光に対する安定性についても光分解が大巾
に抑制された。 As mentioned above, the dissolution rate of the clathrate compound is at a molar ratio of 1:
It showed a tendency to reach a certain level around 5, but when the molar ratio was 1:
1 also showed a sufficient improvement in solubility, and when administered orally to beagle dogs, the blood concentration increased markedly, and the effectiveness against living organisms was improved, and the stability against light was also improved. Decomposition was greatly suppressed.
本発明のビタミンK2−ジメチル−β−シクロ
デキストリン包接化合物は生理学的にも理化学的
にも優れた特徴を有し例えば水への溶解性の向上
はビタミンK2の注射剤の改善、シロツプ剤への
適用を可能としまた経口投与での吸収性の改善に
よつてもたらせる血中濃度の増大は効果の増強又
は投与量の減少を可能とし、光安定性は経口剤と
して錠剤、カプセル剤、ドライシロツプ剤、顆粒
剤、細粒剤等剤形の多様化を可能とした。 The vitamin K 2 -dimethyl- β -cyclodextrin clathrate compound of the present invention has excellent characteristics both physiologically and physicochemically. In addition, the increase in blood concentration brought about by improving the absorption during oral administration makes it possible to enhance the effect or reduce the dosage, and the photostability of the tablets and capsules as oral preparations. It has made it possible to diversify dosage forms such as tablets, dry syrups, granules, and fine granules.
次に本発明の実施例を示す。 Next, examples of the present invention will be shown.
実施例 １
メナテトレノン0.76gとジメチル−β−シクロ
デキストリン2.24gを乳鉢に入れ蒸溜水を適量加
えてゾル状とし、約30分間混練しメナテトレノン
のジメチル−β−シクロデキストリン包接化合物
を得た。このものを３日間減圧乾燥したのち100
メツシユの篩を通過したものを製剤用とした。Example 1 0.76 g of menatetrenone and 2.24 g of dimethyl-β-cyclodextrin were placed in a mortar, an appropriate amount of distilled water was added to form a sol, and the mixture was kneaded for about 30 minutes to obtain a dimethyl-β-cyclodextrin clathrate of menatetrenone. After drying this product under reduced pressure for 3 days,
The material that passed through the mesh sieve was used for pharmaceutical preparations.
以下にその製剤例を示す。 Examples of the formulation are shown below.
製剤例 １ （錠剤）
ビタミンK2−ジメチル−β−シクロデキスト
リン包接化合物（ビタミンK2として10mg）3.99mg
結晶セルロース 36.0
乳糖 76.2
トウモロコシデンプン 18.0
カルボキシメチルセルロースカルシウム 9.0
ステアリン酸マグネシウム 0.9
180.0mg
包接化合物に賦形剤、崩壊剤、結合剤、滑沢剤
を加えて均等に混和した后、打錠機で圧縮成型す
る。Formulation example 1 (tablet) Vitamin K 2 -dimethyl-β-cyclodextrin clathrate compound (10 mg as vitamin K 2 ) 3.99 mg Crystalline cellulose 36.0 Lactose 76.2 Corn starch 18.0 Carboxymethyl cellulose calcium 9.0 Magnesium stearate 0.9 180.0 mg Inclusion compound After adding excipients, disintegrants, binders, and lubricants and mixing them evenly, the mixture is compressed using a tablet machine.
製剤例 ２ （カプセル剤）
ビタミンK2−ジメチル−β−シクロデキスト
リン包接化合物（ビタミンK2として10mg）39.9mg
トウモロコシデンプン 50.0
乳糖 21.7
ヒドロキシプロピルセルロース 6.0
ステアリン酸マグネシウム 2.4
120.0mg
トウモロコシデンプンと乳糖を均等に混和した
后、ヒドロキシプロピルセルロース水溶液を結合
剤として顆粒状とし、これに包接化合物、ステア
リン酸マグネシウムを加えて硬質カプセルに充填
する。Formulation example 2 (capsule) Vitamin K 2 -dimethyl-β-cyclodextrin clathrate compound (10 mg as vitamin K 2 ) 39.9 mg Corn starch 50.0 Lactose 21.7 Hydroxypropyl cellulose 6.0 Magnesium stearate 2.4 120.0 mg Corn starch and lactose are equalized After mixing, the mixture is made into granules using an aqueous hydroxypropylcellulose solution as a binder, and the clathrate compound and magnesium stearate are added to the granules, which are then filled into hard capsules.
製剤例 ３ （顆粒剤）
ビタミンK2−ジメチル−β−シクロデキスト
リン包接化合物（ビタミンK2として10mg）39.9mg
トウモロコシデンプン 300.0
乳糖 135.1
ポリビニルピロリドン 25.0
500.0mg
包接化合物に賦形剤、崩壊剤、結合剤を加えて
均等に混和した后、造粒機で造粒后、乾燥、篩過
し顆粒を製する。Formulation example 3 (granules) Vitamin K 2 -dimethyl-β-cyclodextrin clathrate compound (10 mg as vitamin K 2 ) 39.9 mg Corn starch 300.0 Lactose 135.1 Polyvinylpyrrolidone 25.0 500.0 mg Excipient, disintegrant, disintegrant, After adding a binder and mixing evenly, the mixture is granulated using a granulator, dried, and sieved to produce granules.
製造例 ４ （ドライシロツプ剤）
ビタミンK2−ジメチル−β−シクロデキスト
リン包接化合物（ビタミンK2として10mg）39.9mg
粉糖 910.1
ヒドロキシプロピルセルロース 50.0
1000.0mg
包接化合物に賦形剤、結合剤を加えて均等に混
和した后、造粒機で細粒状としドライシロツプを
得る。Production example 4 (dry syrup) Vitamin K 2 -dimethyl-β-cyclodextrin clathrate compound (10 mg as vitamin K 2 ) 39.9 mg Powdered sugar 910.1 Hydroxypropyl cellulose 50.0 1000.0 mg Add excipients and binders to the clathrate compound After evenly mixing the mixture using a granulator, it is pulverized into fine particles to obtain a dry syrup.
第１図は本発明の包接化合物の溶解度相図であ
り、第２図は示差熱分析曲線図であり、第３図お
よび第４図はＸ線回折のパターンを示す図であ
り、第５図は溶解挙動を示す図である。
FIG. 1 is a solubility phase diagram of the clathrate compound of the present invention, FIG. 2 is a differential thermal analysis curve diagram, FIGS. 3 and 4 are diagrams showing X-ray diffraction patterns, and FIG. The figure shows the dissolution behavior.
Claims (1)
トリン包接化合物。1 Dimethyl-β-cyclodextrin clathrate of vitamin K2 .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4243285A JPS61200942A (en) | 1985-03-04 | 1985-03-04 | Vitamin k2-dimethyl-beta-cyclodextrin clathrate compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4243285A JPS61200942A (en) | 1985-03-04 | 1985-03-04 | Vitamin k2-dimethyl-beta-cyclodextrin clathrate compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61200942A JPS61200942A (en) | 1986-09-05 |
| JPH053864B2 true JPH053864B2 (en) | 1993-01-18 |
Family
ID=12635903
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4243285A Granted JPS61200942A (en) | 1985-03-04 | 1985-03-04 | Vitamin k2-dimethyl-beta-cyclodextrin clathrate compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61200942A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005035477A1 (en) * | 2003-10-08 | 2005-04-21 | Kaneka Corporation | Method of stabilizing compound having quinone skeleton and stabilized composition |
| GB0710439D0 (en) * | 2007-05-31 | 2007-07-11 | Uni I Oslo | Oral dosage form |
| CN108057019A (en) * | 2016-11-09 | 2018-05-22 | 西宝生物科技（上海）股份有限公司 | A kind of micro- micella of menaquinone, its preparation method, the oral formulations containing micro- micella and its application |
| CN106511276A (en) * | 2016-12-13 | 2017-03-22 | 云南师范大学 | Water-soluble coagulant drug vitamin k2 solid-state complex and preparation method thereof |
| CN111840632A (en) * | 2019-04-25 | 2020-10-30 | 广东泰宝医疗科技股份有限公司 | Liquid dressing containing hemostatic microcapsule and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58124733A (en) * | 1982-01-20 | 1983-07-25 | Nippon Iyakuhin Kogyo Kk | Preparation of stable aqueous solution of vitamin k |
| JPS58206540A (en) * | 1982-05-26 | 1983-12-01 | Fujisawa Pharmaceut Co Ltd | Beta-cyclodextrin inclusion compound of ubidecarenone and its preparation |
-
1985
- 1985-03-04 JP JP4243285A patent/JPS61200942A/en active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58124733A (en) * | 1982-01-20 | 1983-07-25 | Nippon Iyakuhin Kogyo Kk | Preparation of stable aqueous solution of vitamin k |
| JPS58206540A (en) * | 1982-05-26 | 1983-12-01 | Fujisawa Pharmaceut Co Ltd | Beta-cyclodextrin inclusion compound of ubidecarenone and its preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61200942A (en) | 1986-09-05 |
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