JP2893140B2 - Stable vitamin D preparation - Google Patents
Stable vitamin D preparationInfo
- Publication number
- JP2893140B2 JP2893140B2 JP2335724A JP33572490A JP2893140B2 JP 2893140 B2 JP2893140 B2 JP 2893140B2 JP 2335724 A JP2335724 A JP 2335724A JP 33572490 A JP33572490 A JP 33572490A JP 2893140 B2 JP2893140 B2 JP 2893140B2
- Authority
- JP
- Japan
- Prior art keywords
- vitamin
- ethanol
- powder
- dissolved
- added
- 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
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、安定なビタミンＤ製剤に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a stable vitamin D preparation.
ビタミンＤは、くる病、骨軟化症等の骨疾患に優れた
治療薬として知られている。しかしビタミンＤは、熱及
び光に対して非常に不安定な物質で室温においても分解
し、製剤化しても長期保存が不可能であった。Vitamin D is known as an excellent therapeutic agent for bone diseases such as rickets and osteomalacia. However, vitamin D is a substance that is very unstable to heat and light and decomposes even at room temperature.
従来、これを安定化する方法としては、シクロデキス
トリンにより包接化する方法（特開昭52−130904号）、
２−ｔ−ブチル−４−ヒドロキシ−アニソール等を添加
する方法（特公昭34−2199号）などが知られている。し
かし、これらの方法は必ずしも満足し得るものではな
く、更に優れたビタミンＤの安定化法が望まれていた。Conventionally, as a method for stabilizing this, a method of clathrate with cyclodextrin (JP-A-52-130904),
A method of adding 2-t-butyl-4-hydroxy-anisole and the like (Japanese Patent Publication No. 34-2199) is known. However, these methods are not always satisfactory, and a more excellent method of stabilizing vitamin D has been desired.
斯かる実状において、本発明者は、ビタミンＤを含有
する安定な製剤を製造すべく、種々検討した結果、アミ
ノアルキルメタアクリレートコポリマーＥがビタミンＤ
に対して優れた安定効果を有することを見出し、本発明
を完成した。Under such circumstances, the present inventors have conducted various studies to produce a stable preparation containing vitamin D. As a result, the aminoalkyl methacrylate copolymer E was found to contain vitamin D
Have been found to have an excellent stabilizing effect on the present invention, and have completed the present invention.
すなわち、本発明は、ビタミンＤとアミノアルキルメ
タアクリレートコポリマーＥを含有することを特徴とす
る安定なビタミンＤ製剤を提供するものである。That is, the present invention provides a stable vitamin D preparation containing vitamin D and aminoalkyl methacrylate copolymer E.
本発明において、ビタミンＤとしては、例えばビタミ
ンD2（エルゴカルシフェロール）、ビタミンD3（コレカ
ルシフェロール）、活性型ビタミンD3（１α−ヒドロキ
シビタミンD3［１α−OH−D3］などの１α位に水酸基を
有するもの、24−ヒドロキシビタミンD3［24−OH−D3］
などの１α位に水酸基を有しないもの）などが挙げられ
る。In the present invention, examples of the vitamin D include vitamin D 2 (ergocalciferol), vitamin D 3 (cholecalciferol), and active vitamin D 3 (1α-hydroxyvitamin D 3 [1α-OH-D 3 ]). Having a hydroxyl group at the 1α-position, 24-hydroxyvitamin D 3 [24-OH-D 3 ]
Having no hydroxyl group at the 1α-position).
アミノアルキルメタアクリレートコポリマーＥはオイ
ドラギットＥの商品名で市販されているもので、その配
合量はビタミンＤに対し１重量倍以上、特に10〜10,000
重量倍が好ましい。Aminoalkyl methacrylate copolymer E is commercially available under the trade name of Eudragit E, and its compounding amount is at least 1 time by weight to vitamin D, especially 10 to 10,000.
Weight times are preferred.
本発明の安定なビタミンＤ製剤は、ビタミンＤとアミ
ノアルキルメタアクリレートコポリマーＥを均一に混合
することにより製造される。具体的には、アミノアルキ
ルメタアクリレートコポリマーＥを、これを溶解する溶
媒、例えばエタノール、メタノール、イソプロパノー
ル、塩化メチレン等に溶解し、これにビタミンＤを添加
し、更に必要に応じて、通常医薬品の製造に使用される
添加剤を加えて、常法により散剤、顆粒剤、打錠用顆粒
等を製造すればよい。添加剤としては、例えば賦形剤
（乳糖、コーンスターチ、ショ糖、結晶セルロース、マ
ンニトール、炭酸マグネシウム、炭酸カルシウム等）、
崩壊剤（カルボキシメチルセルロースカルシウム、デン
プン類等）、結合剤（ヒドロキシプロピルセルロース、
ポリビニルヒロリドン、メチルセルロース、ヒドロキシ
プロピルメチルセルロース等）などが挙げられる。尚、
製剤化にあたっては、上記成分のほかに、更に一般に使
用される製剤化のための補助剤及び他の有効成分を配合
することができる。The stable vitamin D preparation of the present invention is produced by uniformly mixing vitamin D and aminoalkyl methacrylate copolymer E. Specifically, aminoalkyl methacrylate copolymer E is dissolved in a solvent in which it is dissolved, for example, ethanol, methanol, isopropanol, methylene chloride, and the like, and vitamin D is added thereto. Powders, granules, granules for tableting and the like may be produced by a conventional method by adding additives used in the production. Examples of additives include excipients (lactose, corn starch, sucrose, crystalline cellulose, mannitol, magnesium carbonate, calcium carbonate, etc.),
Disintegrant (calcium carboxymethylcellulose, starches, etc.), binder (hydroxypropylcellulose,
Polyvinyl hololidone, methylcellulose, hydroxypropylmethylcellulose, etc.). still,
In formulating, in addition to the above-mentioned components, further commonly used adjuvants for formulation and other active ingredients can be blended.
本発明によれば、本発明の製剤中のビタミンＤの安定
性は著しく向上されており、長期間保存しても活性は殆
ど失われない。According to the present invention, the stability of vitamin D in the preparation of the present invention is remarkably improved, and almost no activity is lost even after long-term storage.
次に本発明を実施例により更に詳細に説明する。 Next, the present invention will be described in more detail by way of examples.
実施例１ ビタミンD30.25g、オイドラギットE100 12.5gをエタ
ノール17.5gに溶解し、バーチカルグラニューレーター
（FM−VG−10、富士産業（株））で、沈降炭酸カルシウ
ム967.25gに添加し、更にヒドロキシプロピルセルロー
ス20gをエタノール130gに溶解した液を添加して造粒し
た後、30℃で乾燥し、30号篩を通過する粉末Ａを得た。Example 1 Vitamin D 3 0.25 g, Eudragit E100 12.5 g was dissolved in ethanol 17.5 g, with vertical granulator (FM-VG-10, Fujisangyo Co.) was added to the precipitated calcium carbonate 967.25G, further hydroxy A solution obtained by dissolving 20 g of propylcellulose in 130 g of ethanol was added, and the mixture was granulated, and dried at 30 ° C. to obtain a powder A passing through No. 30 sieve.
実施例２ ビタミンD30.25g、オイドラギットE100 25gをエタノ
ール30gに溶解し、実施例１と同様にして粉末Ｂを得
た。Example 2 0.25 g of vitamin D 3 and 25 g of Eudragit E100 were dissolved in 30 g of ethanol, and a powder B was obtained in the same manner as in Example 1.
実施例３ ビタミンD30.25g、オイドラギットE100 100gをエタノ
ール105gに溶解し、実施例１と同様にして粉末Ｃを得
た。Example 3 0.25 g of vitamin D 3 and 100 g of Eudragit E100 were dissolved in 105 g of ethanol, and powder C was obtained in the same manner as in Example 1.
実施例４ ビタミンD30.25g、AEA50gをエタノール55gに溶解し、
実施例１同様にして粉末Ｄを得た。Example 4 0.25 g of vitamin D 3 and 50 g of AEA were dissolved in 55 g of ethanol,
Powder D was obtained in the same manner as in Example 1.
実施例５ オイドラギットE100 100gをエタノール900gに溶解
し、これにエタノール10gに溶解したビタミンD310mgを
添加し攪はんした後、結晶セルロース（アビセルPH10
1）300gを添加し攪はんした。これを減圧乾燥し30号篩
を通過する粉末Ｅを得た。Example 5 100 g of Eudragit E100 was dissolved in 900 g of ethanol, 10 mg of vitamin D 3 dissolved in 10 g of ethanol was added thereto, and the mixture was stirred.
1) 300g was added and stirred. This was dried under reduced pressure to obtain Powder E which passed through No. 30 sieve.
実施例６ ビタミンD3を100mgにする以外は実施例５と同様にし
て粉末Ｆを得た。Except that the Example 6 Vitamin D 3 to 100mg obtain a powder F in the same manner as in Example 5.
実施例７ 沈降炭酸カルシウム1500g、塩酸リジン100g、アミノ
エチルスルホン酸100g、Ｄ−マンニット1790gをバーチ
カルグラニュレーターで均一に混合し、ヒドロキシプロ
ピルセルロース70gをエタノール467gに溶解した液を添
加して造粒した後、30℃で乾燥し、30号篩を通過する粉
末Ｇを得た。この粉末G3560gと、実施例１〜４で得た粉
末Ａ〜D 40gをそれぞれ均一に混合して散剤Ａ〜Ｄを得
た。Example 7 1500 g of precipitated calcium carbonate, 100 g of lysine hydrochloride, 100 g of aminoethylsulfonic acid, and 1790 g of D-mannitol were uniformly mixed with a vertical granulator, and a solution prepared by dissolving 70 g of hydroxypropyl cellulose in 467 g of ethanol was added and granulated. After drying at 30 ° C., powder G passing through No. 30 sieve was obtained. Powders A to D were obtained by uniformly mixing 3560 g of this powder G and 40 g of the powders A to D obtained in Examples 1 to 4, respectively.
実施例８ 沈降炭酸カルシウム1500g、塩酸リジン100g、アミノ
エチルスルホン酸100g、Ｄ−マンニット1436gをバーチ
カルグラニュレーターで均一に混合し、ヒドロキシプロ
ピルセルロース64gをエタノール427gに溶解した液を添
加して造粒した後、30℃で乾燥し、30号篩を通過する粉
末Ｈを得た。この粉末H3200gと、実施例５、６で得た粉
末Ｅ、F400gをそれぞれ均一に混合して散剤Ｅ、Ｆを得
た。Example 8 1500 g of precipitated calcium carbonate, 100 g of lysine hydrochloride, 100 g of aminoethylsulfonic acid, and 1436 g of D-mannitol were uniformly mixed with a vertical granulator, and a solution prepared by dissolving 64 g of hydroxypropylcellulose in 427 g of ethanol was added and granulated. After that, the powder was dried at 30 ° C. to obtain a powder H passing through a No. 30 sieve. Powder H3200g and powders E and F400g obtained in Examples 5 and 6 were uniformly mixed to obtain powders E and F, respectively.
実施例９ ビタミンD310mg、オイドラギットE100 2gをエタノー
ル10gに溶解し、バーチカルグラニュレーターで、沈降
炭酸カルシウム1500g、塩酸リジン100g、Ｄ−マンニッ
ト1925.99gに添加し、更にヒドロキシプロピルセルロー
ス72gをエタノール480gに溶解した液を添加した後、0.5
mm押出し造粒機（ファインリュウザーEXR60、不二パウ
ダル（株））にて造粒し、30℃で乾燥し、20号篩を通過
させ顆粒剤Ｉを得た。Example 9 10 mg of vitamin D 3 and 2 g of Eudragit E100 were dissolved in 10 g of ethanol, and 1500 g of precipitated calcium carbonate, 100 g of lysine hydrochloride, and 1925.99 g of D-mannitol were added to a vertical granulator. After adding the solution dissolved in
The mixture was granulated with a mm extrusion granulator (FINE LUZER EXR60, Fuji Paudal Co., Ltd.), dried at 30 ° C., and passed through a No. 20 sieve to obtain Granule I.
実施例10 ビタミンD310mg、オイドラギットE100 2gをエタノー
ル10gに溶解し、バーチカルグラニュレーターで、沈降
炭酸カルシウム1500g、塩酸リジン100g、Ｄ−マンニッ
ト1925.99gに添加し、更にヒドロキシプロピルセルロー
ス72gをエタノール480gに溶解した液を添加して造粒し
た後、30℃で乾燥し、20号篩を通過させた。これをロー
タリー型打錠機（RT−S15−T35、菊水製作所（株））を
用いて打錠し、直径9mm重さ300mgの錠剤Ｊを得た。Example 10 10 mg of vitamin D 3 and 2 g of Eudragit E100 were dissolved in 10 g of ethanol, and using a vertical granulator, 1500 g of precipitated calcium carbonate, 100 g of lysine hydrochloride, and 1925.99 g of D-mannitol were added. Was added, and the mixture was granulated, dried at 30 ° C., and passed through a No. 20 sieve. This was tableted using a rotary tableting machine (RT-S15-T35, Kikusui Seisakusho Co., Ltd.) to obtain a tablet J having a diameter of 9 mm and a weight of 300 mg.
実施例11 オイドラギットE100 10gをエタノール90gに溶解し、
これにエタノール60gに溶解した１−α−ヒドロキシビ
タミンD31mgを添加し攪はんした後、無水乳糖30gを添加
し攪はんした。これを減圧乾燥し粉末Ｍを得た。Example 11 Eudragit E100 10 g was dissolved in ethanol 90 g,
After addition was攪solder the 1-alpha-hydroxyvitamin D 3 1 mg to thereto was dissolved in ethanol 60 g, was攪solder anhydride was added lactose 30g. This was dried under reduced pressure to obtain powder M.
対照例１ ビタミンD30.25gをエタノール200gに溶解し、沈降炭
酸カルシウム999.75gに添加して造粒した後、30℃で乾
燥し、30号篩を通過する粉末Ｋを得た。Comparative Example 1 0.25 g of vitamin D 3 was dissolved in 200 g of ethanol, added to 999.75 g of precipitated calcium carbonate, granulated, and dried at 30 ° C. to obtain Powder K which passed through No. 30 sieve.
対照例２ ビタミンD30.25g、ブチルヒドロキシトルエン（BHT）
2.5gをエタノール200gに溶解し、沈降炭酸カルシウム99
7.25gに添加して造粒した後、30℃で乾燥し、30号篩を
通過する粉末Ｌを得た。Comparative Example 2 Vitamin D 3 0.25 g, butylhydroxytoluene (BHT)
2.5 g was dissolved in 200 g of ethanol, and precipitated calcium carbonate 99
The mixture was added to 7.25 g, granulated, and dried at 30 ° C. to obtain a powder L passing through No. 30 sieve.
対照例３ 実施例７で得た粉末G3560gと、対照例１、２で得た粉
末Ｋ、L40gをそれぞれ均一に混合して散剤Ｋ、Ｌを得
た。Control Example 3 Powder G and L were obtained by uniformly mixing 3560 g of the powder G obtained in Example 7 and 40 g of the powders K and L obtained in Control Examples 1 and 2, respectively.
対照例４ １−α−ヒドロキシビタミンD31mgをエタノール60gに
溶解した後、無水乳糖30gを添加し攪はんした。これを
減圧乾燥し粉末Ｎを得た。Comparative Example 4 1 mg of 1-α-hydroxyvitamin D 3 was dissolved in 60 g of ethanol, and then 30 g of anhydrous lactose was added and stirred. This was dried under reduced pressure to obtain powder N.
試験例１ 実施例１〜６、対照例１、２で得た粉末を50℃に保存
し、30日後のビタミンD3の残存率を測定した。結果を表
−１に示した。Test Example 1 The powders obtained in Examples 1 to 6 and Control Examples 1 and 2 were stored at 50 ° C., and the residual ratio of vitamin D 3 after 30 days was measured. The results are shown in Table 1.
試験例２ 実施例７〜10、対照例３で得た散剤、顆粒剤、錠剤を
50℃に保存し、30日後のビタミンD3の残存率を測定し
た。結果を表−２に記載した。 Test Example 2 The powders, granules and tablets obtained in Examples 7 to 10 and Control Example 3 were used.
After storage at 50 ° C., the residual ratio of vitamin D 3 after 30 days was measured. The results are shown in Table-2.
試験例３ 実施例11、対照例４で得た粉末を50℃に保存し、30日
後の活性型ビタミンD3の残存率を測定した。結果を表−
３に記載した。 Test Example 3 The powders obtained in Example 11 and Control Example 4 were stored at 50 ° C., and the residual ratio of active vitamin D 3 after 30 days was measured. Table-Results
No. 3.
フロントページの続き (58)調査した分野(Int.Cl.6，ＤＢ名) A61K 31/59 A61K 47/32 A61K 47/38 ＣＡ（ＳＴＮ)Continued on the front page (58) Fields surveyed (Int. Cl. 6 , DB name) A61K 31/59 A61K 47/32 A61K 47/38 CA (STN)
Claims (2)
ートコポリマーＥを含有することを特徴とする安定なビ
タミンＤ製剤。1. A stable vitamin D preparation containing vitamin D and aminoalkyl methacrylate copolymer E.
ーＥの量が、ビタミンＤの１重量倍以上である請求項１
記載の安定なビタミンＤ製剤。2. The method according to claim 1, wherein the amount of the aminoalkyl methacrylate copolymer E is at least 1 time by weight of the vitamin D.
A stable vitamin D preparation as described.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2335724A JP2893140B2 (en) | 1990-11-30 | 1990-11-30 | Stable vitamin D preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2335724A JP2893140B2 (en) | 1990-11-30 | 1990-11-30 | Stable vitamin D preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04208225A JPH04208225A (en) | 1992-07-29 |
| JP2893140B2 true JP2893140B2 (en) | 1999-05-17 |
Family
ID=18291763
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2335724A Expired - Fee Related JP2893140B2 (en) | 1990-11-30 | 1990-11-30 | Stable vitamin D preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2893140B2 (en) |
Cited By (1)
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|---|---|---|---|---|
| EP2968172B1 (en) | 2013-03-15 | 2020-07-22 | EirGen Pharma Ltd. | Stabilized modified release vitamin d formulation and method of administring same |
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|---|---|---|---|---|
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| ES2593047T3 (en) | 2006-02-03 | 2016-12-05 | Opko Renal, Llc | Treatment of vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 |
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| SG11201604805XA (en) * | 2013-12-16 | 2016-07-28 | Massachusetts Inst Technology | Fortified micronutrient salt formulations |
| SG10201911274TA (en) | 2014-08-07 | 2020-02-27 | Opko Ireland Global Holdings Ltd | Adjunctive therapy with 25-hydroxyvitamin d |
| JP6851868B2 (en) * | 2016-03-23 | 2021-03-31 | 株式会社ファンケル | Vitamin D3 stabilizing composition |
| TWI747893B (en) | 2016-03-28 | 2021-12-01 | 愛爾蘭商歐科愛爾蘭全球控股股份有限公司 | Methods of vitamin d treatment |
| JP7085105B2 (en) * | 2016-11-10 | 2022-06-16 | 日産化学株式会社 | Vitamin D3 derivative formulation |
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1990
- 1990-11-30 JP JP2335724A patent/JP2893140B2/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2968172B1 (en) | 2013-03-15 | 2020-07-22 | EirGen Pharma Ltd. | Stabilized modified release vitamin d formulation and method of administring same |
| EP3332773B1 (en) | 2013-03-15 | 2020-08-26 | OPKO Ireland Global Holdings, Limited | Stabilized modified release vitamin d formulation and method of administering same |
| EP3650016B1 (en) | 2013-03-15 | 2021-05-05 | EirGen Pharma Ltd. | Stabilized modified release vitamin d formulation and method of administering same |
| US11253528B2 (en) | 2013-03-15 | 2022-02-22 | Eirgen Pharma Ltd. | Stabilized modified release Vitamin D formulation and method of administering same |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04208225A (en) | 1992-07-29 |
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