JPH0437803B2 - - Google Patents
Info
- Publication number
- JPH0437803B2 JPH0437803B2 JP59198084A JP19808484A JPH0437803B2 JP H0437803 B2 JPH0437803 B2 JP H0437803B2 JP 59198084 A JP59198084 A JP 59198084A JP 19808484 A JP19808484 A JP 19808484A JP H0437803 B2 JPH0437803 B2 JP H0437803B2
- Authority
- JP
- Japan
- Prior art keywords
- capsules
- present
- composition
- tocopherol
- formula
- 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 - Lifetime
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
〔産業上の利用分野〕
本発明は、安定化された活性型ビタミンD3類
を主薬とするカプセル剤用組成物に関する。
〔従来の技術〕
式〔〕で示されるビタミンD3誘導体は、主
として肝臓で、先ずその25位が水酸化されて25−
ヒドロキシコレカルシフエロールとなり、ついで
腎臓で１位が水酸化されて1α−25−ジヒドロキ
シコレカルシフエロールとなつて生理活性を発現
するといわれている。
また、その類似化合物としてジヒドロタテステ
ロール、1α−ヒドロキシドロールカルシフエロ
ール、1α−24−ジヒドロキシコレカルシフエロ
ール等があり、いづれも、腎不全や副甲状腺機能
低下等、腎における1α−ヒドロキシラーゼの阻
害または欠損に基づく低カルシウム血症や骨疾
患、あるいは骨粗鬆症等の予防または治療に用い
られる医薬である。
〔式中、R1、R2、およびR3は同一または異なつ
て水素原子またはヒドロキシ基をあらわす。但
し、R1、R2およびR3のうち少なくとも１つはヒ
ドロキシ基である〕
上記ビタミンD3類は卓越した薬効を有するが、
熱や光に対して不安定であり、酸化されやすいと
いう製剤上の難点がある。この対策として、1α
−ヒドロキシビタミンD3類を油性基剤に溶解し、
ついでソルビン酸類を含む剤皮で軟カプセル剤化
する方法（特開昭52−128210号公報）、あるいは
紫外線吸収剤を含有する剤皮で被覆した軟カプセ
ル剤を使用する方法（特公昭57−45415号公報）
等が提案されている。しかし、軟カプセル製剤化
の困難性や紫外線吸収剤の毒性等の問題が残る。
〔発明が解決しようとする課題〕
本発明は、上記従来の製剤の欠点を伴わずに活
性型ビタミンD3誘導体の安定性を高めることを
目的としている。
本発明者等はこの目的を達成すべく鋭意研究を
進め、中鎖直鎖状飽和脂肪酸トリグリセライド
が、活性型ビタミンD3誘導体の熱安定性、酸化
防止にある程度有効であること、しかしながら光
安定性の点で問題があること、医薬品として提供
するには長期安定性の点で不満足なものであるこ
とから、さらに研究を続けた結果、トコフエロー
ルエステル類が、長期間の熱安定性、酸化防止能
を示すと共に、光安定性の点で特に有効であるこ
とを見出し、本発明を完成するに到つた。
〔課題を解決するための手段および作用〕
本発明の組成物は、前記〔〕式で示される活
性型ビタミンD3誘導体の１種もしくは２種以上
を主薬とし、これにトコフエロールエステル類お
よび油性基剤を配合して成る液状組成物である。
トコフエロールエステル類が配合された本発明
の組成物における主薬である活性型ビタミンD3
誘導体は、熱や光に対する安定性にすぐれてお
り、これをカプセル剤とする場合、前記のような
特別の軟カプセルを必要とせず、一般的な軟カプ
セルまたは硬カプセルに充填してカプセル剤とす
ることにより、長期にわたり当初のすぐれた薬効
が保持される。
本発明組成物を構成するトコフエロールエステ
ル類および油性基剤は、特に限定されず種々のも
のが適宜使用される。トコフエロールエステル類
の例としては、ニコチン酸トコフエロール、酢酸
トコフエロール類等が挙げられる。これらは、空
気による酸化をうけず、抗酸化力をもたないもの
である。また、油性基剤としては、中鎖の直鎖状
飽和脂肪酸のトリグセライド等が挙げられる。
本発明組成物におけるトコフエロールエステル
類の配合量は、主薬であるビタミンD3誘導体の
１重量部に対し、１重量部以上であることが望ま
しい。
本発明の液状組成物は、これをカプセルに充填
し、経口投与用カプセル剤として使用される。硬
カプセル剤として製剤する場合、カプセルのキヤ
ツプとボデイとの嵌合部からの液漏れを防止する
方法としては、嵌合部外周にゼラチン粘稠液を塗
布してシールする方法、またはボデイとキヤツプ
の嵌合せ部分にロツク機構としてノツチを設ける
方法などを適用すればよい。ノツチを設ける方法
は、ゼラチン粘稠液によるシール法のような煩瑣
なシール工程や特別の装置を必要としない点で有
利である。この場合、嵌合部のノツチは通常２個
所設けられるが、嵌合部に円周方向にわたつてほ
ぼ等間隔に６個所設けることによりほぼ完全に液
洩れを防止することができる。
〔実施例〕
実施例 １
1α−ヒドロキシコレカルシフエロールを油状
基材：トリグリセライドに溶解し（濃度1μg／
200mg）、これに酢酸トコフエロール20μｇ／200
mgを添加して試料を調製し、これを硬カプセルに
充填して硬カプセル剤を得た。
対照として、酢酸トコフエロールを添加しない
点を除き、上記と同一条件で試料を調製し、硬カ
プセル剤を得た。
上記各カプセル剤を、別々に透明ガラス瓶に入
れ、室内散乱光（700Lux）照射下に保存し、1α
−ヒドロキシコレカルシフエロール残存率の経時
変化を測定した。その結果を第１表に示す。
[Industrial Application Field] The present invention relates to a composition for capsules containing stabilized active vitamin D 3 as a main ingredient. [Prior Art] The vitamin D3 derivative represented by the formula [] is first hydroxylated at the 25th position to form the 25-
It is said that it becomes hydroxycholecalciferol, which is then hydroxylated at the 1st position in the kidney to become 1α-25-dihydroxycholecalciferol, which exhibits physiological activity. In addition, its similar compounds include dihydrotatesterol, 1α-hydroxydololcalciferol, and 1α-24-dihydroxycholecalciferol, all of which are used to inhibit 1α-hydroxylase in the kidney, such as renal failure and hypoparathyroid function. It is a drug used for the prevention or treatment of hypocalcemia, bone diseases, osteoporosis, etc. due to inhibition or deficiency. [In the formula, R 1 , R 2 and R 3 are the same or different and represent a hydrogen atom or a hydroxy group. However, at least one of R 1 , R 2 and R 3 is a hydroxy group] The above vitamin D 3 types have outstanding medicinal efficacy,
It has the disadvantage of being unstable to heat and light, and easily oxidized. As a countermeasure, 1α
-Dissolve 3 types of hydroxyvitamin D in an oily base,
Then, a method of forming soft capsules with a shell containing sorbic acids (Japanese Patent Publication No. 52-128210) or a method of using a soft capsule coated with a shell containing an ultraviolet absorber (Japanese Patent Publication No. 57-45415) Publication No.)
etc. have been proposed. However, problems remain, such as the difficulty in forming soft capsule formulations and the toxicity of ultraviolet absorbers. [Problems to be Solved by the Invention] The present invention aims to increase the stability of active vitamin D 3 derivatives without the above-mentioned drawbacks of conventional formulations. The present inventors have carried out intensive research to achieve this objective, and have found that medium-chain linear saturated fatty acid triglycerides are effective to some extent in the thermal stability and oxidation prevention of active vitamin D 3 derivatives. As a result of further research, we found that tocopherol esters have long-term thermal stability and oxidation prevention. The present inventors have discovered that the present invention is particularly effective in terms of photostability and has completed the present invention. [Means and effects for solving the problems] The composition of the present invention contains one or more active vitamin D 3 derivatives represented by the above formula [] as a main ingredient, and tocopherol esters and oil-based It is a liquid composition containing a base. Active vitamin D 3 , which is the main drug in the composition of the present invention containing tocopherol esters
Derivatives have excellent stability against heat and light, and when used as capsules, there is no need for special soft capsules as mentioned above, and they can be filled into general soft or hard capsules and used as capsules. By doing so, the original excellent medicinal efficacy is maintained over a long period of time. The tocopherol esters and oily base constituting the composition of the present invention are not particularly limited, and various types may be used as appropriate. Examples of tocopherol esters include tocopherol nicotinate, tocopherol acetate, and the like. These substances are not oxidized by air and have no antioxidant power. Examples of the oily base include triglycerides of medium-chain linear saturated fatty acids. The amount of tocopherol esters in the composition of the present invention is desirably 1 part by weight or more per 1 part by weight of the vitamin D 3 derivative as the main drug. The liquid composition of the present invention is filled into capsules and used as capsules for oral administration. When formulated as a hard capsule, there are two ways to prevent liquid leakage from the joint between the cap and body of the capsule: apply a gelatin viscous liquid to the outer periphery of the joint to seal it, or seal the joint between the body and the cap. A method such as providing a notch as a locking mechanism in the fitting portion may be applied. The method of providing a notch is advantageous in that it does not require a complicated sealing process or special equipment, such as the sealing method using a gelatin viscous liquid. In this case, the fitting portion is normally provided with two notches, but by providing the fitting portion with six notches at approximately equal intervals in the circumferential direction, liquid leakage can be almost completely prevented. [Example] Example 1 1α-hydroxycholecalciferol was dissolved in an oily base: triglyceride (concentration 1 μg/
200mg), plus tocopherol acetate 20μg/200
mg was added to prepare a sample, which was filled into hard capsules to obtain hard capsules. As a control, a sample was prepared under the same conditions as above, except that tocopherol acetate was not added, and hard capsules were obtained. Each of the above capsules was placed separately in a transparent glass bottle and stored under indoor scattered light (700 Lux) irradiation.
- Changes in the residual rate of hydroxycholecalciferol over time were measured. The results are shown in Table 1.
【表】
実施例 ２
1α−ヒドロキシコレカルシフエロールをトリ
グリセライドに溶解し（濃度1μｇ／200mg）、こ
れにニコチン酸トコフエロール20μｇ／200mgを
添加して試料を調製し、これを硬カプセルに充填
して硬カプセル剤を得た。
対照として、ニコチン酸トコフエロールを添加
しない点を除き、上記と同じ条件で試料を調製
し、硬カプセル剤を得た。
上記各カプセル剤につき、実施例１と同一の保
存条件下に1α−ヒドロキシコレカルシフエロー
ル残存率の経時変化を測定し第２表に示す結果を
得た。[Table] Example 2 A sample was prepared by dissolving 1α-hydroxycholecalciferol in triglyceride (concentration 1 μg/200 mg) and adding tocopherol nicotinate 20 μg/200 mg, which was then filled into hard capsules. Hard capsules were obtained. As a control, a sample was prepared under the same conditions as above, except that tocopherol nicotinate was not added, and hard capsules were obtained. For each of the above capsules, changes over time in the residual rate of 1α-hydroxycholecalciferol were measured under the same storage conditions as in Example 1, and the results shown in Table 2 were obtained.
本発明の組成物は、主薬である活性型ビタミン
D3の安定性にすぐれており、長期にわたり当初
の薬効が保たれる。
また、本発明組成物は、カプセル剤として製剤
する場合にも、従来のような酸化等の変質防止の
ための特殊なカプセルやカプセル剤化工程を必要
としない。
The composition of the present invention contains active vitamins as the main drug.
D3 has excellent stability and maintains its original efficacy over a long period of time. Further, even when the composition of the present invention is formulated as a capsule, it does not require special capsules or encapsulation steps to prevent deterioration such as oxidation as in the past.
Claims (1)
て水素原子またはヒドロキシ基をあらわす。但
し、R1、R2およびR3のうち少なくとも１つはヒ
ドロキシ基である〕 で示される活性型ビタミンD3誘導体の少なくと
も１種とトコフエロールエステル類の少くとも１
種および油性基剤とから成る安定性にすぐれた活
性型ビタミンD3誘導体のカプセル剤用組成物。[Claims] 1 Formula: [In the formula, R 1 , R 2 and R 3 are the same or different and represent a hydrogen atom or a hydroxy group. However, at least one of R 1 , R 2 and R 3 is a hydroxy group] and at least one of the tocopherol esters.
A composition for capsules of an active vitamin D 3 derivative with excellent stability, comprising seeds and an oily base.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19808484A JPS6176416A (en) | 1984-09-20 | 1984-09-20 | Activated type vitamin d3 derivative composition for encapsulation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19808484A JPS6176416A (en) | 1984-09-20 | 1984-09-20 | Activated type vitamin d3 derivative composition for encapsulation |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3361432A Division JPH0774149B2 (en) | 1991-12-27 | 1991-12-27 | Hard gelatin capsule |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6176416A JPS6176416A (en) | 1986-04-18 |
| JPH0437803B2 true JPH0437803B2 (en) | 1992-06-22 |
Family
ID=16385243
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19808484A Granted JPS6176416A (en) | 1984-09-20 | 1984-09-20 | Activated type vitamin d3 derivative composition for encapsulation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6176416A (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE58468B1 (en) * | 1984-10-25 | 1993-09-22 | Warner Lambert Co | Method for sealing capsules and capsule |
| US4797405A (en) * | 1987-10-26 | 1989-01-10 | Eli Lilly And Company | Stabilized pergolide compositions |
| AU2004264958B2 (en) | 2003-08-13 | 2010-04-15 | Biocon, Ltd | Micro-particle fatty acid salt solid dosage formulations for therapeutic agents |
| JP6127295B2 (en) * | 2015-03-10 | 2017-05-17 | 杏林製薬株式会社 | Imidafenacin-containing intraoral rapidly disintegrating tablets |
| JP6212588B2 (en) * | 2016-03-24 | 2017-10-11 | 杏林製薬株式会社 | Imidafenacin-containing intraoral rapidly disintegrating tablets |
| JP6303037B2 (en) * | 2017-02-14 | 2018-03-28 | 杏林製薬株式会社 | Imidafenacin-containing intraoral rapidly disintegrating tablets |
| JP6303038B2 (en) * | 2017-02-14 | 2018-03-28 | 杏林製薬株式会社 | Imidafenacin-containing intraoral rapidly disintegrating tablets |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5312414A (en) * | 1976-07-21 | 1978-02-03 | Chugai Pharmaceut Co Ltd | Production of preparation containing stable 1alpha-hydroxyvitamines d |
| JPS5740415A (en) * | 1980-08-25 | 1982-03-06 | Teijin Ltd | Novel active type vitamin d3 derivative composition |
| JPS5740414A (en) * | 1980-08-25 | 1982-03-06 | Teijin Ltd | Novel active type vitamin d3 derivative composition |
| JPS5740461A (en) * | 1980-08-25 | 1982-03-06 | Teijin Ltd | Novel activated vitamin d3 derivative composition |
-
1984
- 1984-09-20 JP JP19808484A patent/JPS6176416A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6176416A (en) | 1986-04-18 |
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