JPH0624991A - Long acting preparation of ursodeoxycholic acid - Google Patents
Long acting preparation of ursodeoxycholic acidInfo
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- JPH0624991A JPH0624991A JP3148404A JP14840491A JPH0624991A JP H0624991 A JPH0624991 A JP H0624991A JP 3148404 A JP3148404 A JP 3148404A JP 14840491 A JP14840491 A JP 14840491A JP H0624991 A JPH0624991 A JP H0624991A
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- release
- sustained
- granule
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Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、ウルソデスオキシコー
ル酸（化学名； 3α,7β-dihydroxy-5β-cholan-24-oic
acid)を薬効成分として含有する持続性製剤に関する。The present invention relates to ursodesoxycholic acid (chemical name: 3α, 7β-dihydroxy-5β-cholan-24-oic
acid) as a medicinal component.
【０００２】[0002]
【従来の技術】下記の式で表されるウルソデスオキシコ
ール酸は、各種胆道系疾患、慢性肝疾患における肝機能
改善及びコレステロール系胆石溶解治療剤として通常の
錠剤、顆粒剤等が市販され、長年に亘り使用されその有
用性が認められている。2. Description of the Related Art Ursodesoxycholic acid represented by the following formula is an ordinary tablet, a granule, etc., which is commercially available as a therapeutic agent for improving biliary tract diseases, hepatic function improvement in chronic liver diseases and cholesterol gallstone dissolution, It has been used for many years and its usefulness has been recognized.
【０００３】[0003]
【化１】 [Chemical 1]
【０００４】例えば、イタリアのGi pharmex社より「Ｄ
ＥＵＲＳＩＬ ＲＲ」の商品名で、コレステロール系胆
石溶解剤として、１日１回就寝前服用のウルソデスオキ
シコール酸徐放性製剤が市販されている。For example, "D from Gi pharmex, Italy
Under the trade name of "EURSIL RR", a sustained release preparation of ursodesoxycholic acid for once-a-day administration before bedtime is marketed as a cholesterol-based gallstone dissolving agent.
【０００５】これは、ｐＨ依存型反復徐放性製剤で、０
０号サイズのカプセル中に径７φの３種の異なる錠剤を
含有し、各々の錠剤は特定のｐＨにより皮膜が溶解し放
出するよう設計されている。This is a pH-dependent repetitive sustained-release preparation,
No. 0 size capsules contain 3 different tablets with a diameter of 7φ, and each tablet is designed to dissolve and release the film at a specific pH.
【０００６】このカプセル剤はサイズが大きく、物理的
にも服用しにくい。又、３種の錠剤のうち一つは胃部で
皮膜が溶けて崩壊するが、他の二つは腸溶性基剤で被覆
されているため胃内では崩壊しない。このため、錠剤の
胃内排出時間、消化管移動速度が個体内及び個体間で変
動しやすく、かつｐＨ変化の影響も受け易い。This capsule has a large size and is hard to take physically. In addition, one of the three types of tablets is disintegrated by dissolving the film in the stomach, but the other two are not disintegrated in the stomach because they are coated with the enteric base. Therefore, the gastric emptying time of tablets and the moving speed of the digestive tract are likely to vary within and between individuals, and are also susceptible to pH changes.
【０００７】従って、この徐放化システムでは、血中動
態に山と谷のピークを生じ、又、山と谷との間が常に一
定とならず、一定量を持続的に長時間に亙り吸収させる
ことは困難である。Therefore, in this sustained-release system, peaks of peaks and valleys occur in the blood dynamics, and the peaks and valleys are not always constant, and a constant amount is absorbed over a long period of time. It is difficult to get it done.
【０００８】[0008]
【発明が解決しようとする課題】コレステロール系胆石
溶解治療に対するウルソデスオキシコール酸通常製剤の
用法用量は、例えばウルソサン錠（東京田辺製薬株式会
社；商品名）５０mgの場合、１日食後３回、１回４錠で
１日１２錠も服用しなければならず、繁雑でコンプライ
アンスを履行しにくい。[Problems to be Solved by the Invention] The usual dosage of ursodesoxycholic acid for the treatment of cholesterol-based gallstone dissolution is, for example, 50 mg of ursososan tablets (Tokyo Tanabe Seiyaku Co., Ltd .; trade name), 3 times a day after meal, It is necessary to take 4 tablets at a time and 12 tablets a day, which is complicated and difficult to fulfill compliance.
【０００９】元来胆石症は慢性化しやすく、又しばしば
再発を伴い、長期間の治療に及ぶことが多いことから、
患者に対して服用が簡便でコンプライアンスを高めるこ
とが可能な１日１回服用の持続型製剤が治療上からも重
要で望まれていた。Since gallstone disease originally tends to become chronic and often accompanies recurrence, and often extends to long-term treatment,
A sustained-release preparation which can be taken once a day and is easy to take for patients and which can enhance compliance has been important and therapeutically desired.
【００１０】コレステロール系胆石の成因の一つとし
て、肝臓から分泌される胆汁組成のバランスがくずれ、
コレステロール量に比してこれをミセル化するに必要な
胆汁酸と燐脂質との量が相対的に低いためと考えられて
いる。元来、夜間は胆汁分泌が少なく、絶食状態にある
ため、食事摂取に伴う胆嚢からの胆汁排泄がなく、胆嚢
中にプールされたままである。このため、胆嚢壁から水
分や塩類が吸収されて胆汁が濃縮し、ミセル化能が低下
してコレステロール過飽和を起こし、結石を生じること
が容易に推察される。As one of the causes of cholesterol gallstones, the bile composition secreted from the liver is out of balance,
It is considered that the amount of bile acid and phospholipid required for micelle formation of cholesterol is relatively low compared to the amount of cholesterol. Originally, since bile secretion is low at night and is in a fasting state, there is no bile excretion from the gallbladder associated with food intake, and the gall bladder remains pooled. Therefore, it is easily inferred that water and salts are absorbed from the wall of the gallbladder, the bile is concentrated, the micellization ability is reduced, cholesterol oversaturation is caused, and stones are generated.
【００１１】従って、本発明は、コレステロール系胆石
症の治療剤として、１日１回就寝前服用により、夜間に
亙り一定量が持続的に長時間放出されるウルソデスオキ
シコール酸持続性製剤を提供することにある。Therefore, the present invention provides a sustained-release preparation of ursodesoxycholic acid, which is a therapeutic agent for cholesterol gallstone disease, which is taken once a day before bedtime and a constant amount is continuously released over a long period of time at night. To provide.
【００１２】[0012]
【課題を解決するための手段】本発明者らは上記の要件
に鑑み種々の製剤的工夫により鋭意研究したところ、新
規組成の速放性粒状剤と徐放性粒状剤とを適当な比率に
組み合わせた複合粒状剤とすることにより、生体におけ
る各種変動要因に左右されにくく、一定量を持続的に長
時間放出するウルソデスオキシコール酸持続性製剤を見
い出し本発明を完成するに至った。[Means for Solving the Problems] The inventors of the present invention have made extensive studies in view of the above-mentioned requirements by devising various pharmaceutical preparations, and found that an immediate release granular agent having a novel composition and a sustained release granular agent are mixed in an appropriate ratio. The present invention has been completed by finding a sustained-release preparation of ursodesoxycholic acid that is not affected by various variable factors in the living body and releases a fixed amount continuously for a long time by using the combined granular agent in combination.
【００１３】すなわち本発明は、薬効成分としてウルソ
デスオキシコール酸を含有する速放性粒状剤と徐放性粒
状剤との組み合わせよりなる複合粒状剤であるウルソデ
スオキシコール酸の持続性製剤を提供するものである。That is, the present invention provides a sustained-release preparation of ursodesoxycholic acid which is a composite granule comprising a combination of an immediate release granule containing ursodesoxycholic acid as a medicinal component and a sustained release granule. It is provided.
【００１４】本発明に使用される速放性粒状剤は、ウル
ソデスオキシコール酸に、例えばトウモロコシデンプ
ン、バレイショデンプン、部分アルファー化デンプン等
のデンプン類、乳糖、ブドウ糖、マンニット等の糖類、
微結晶セルロース等のセルロース類から選ばれた一種以
上の賦形剤と、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、ポリビニルピロリドン
等から選ばれた一種以上の結合剤と、カルボキシメチル
セルロース、カルボキシメチルセルロースカルシウム、
低置換度ヒドロキシプロピルセルロース、ヒドロキシプ
ロピルスターチ、架橋カルボキシメチルセルロースナト
リウム等から選ばれた一種以上の崩壊剤とを加え、常法
により粒状剤としたものであり、必要によりヒドロキシ
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、ポリビニルアセタールジエチルアミノアセテー
ト、アミノアルキルメタアクリレートコポリマーＥ等の
胃溶性コーティング基剤を用いて皮膜を施すことができ
る。The rapid-release granules used in the present invention include ursodesoxycholic acid, starches such as corn starch, potato starch and partially pregelatinized starch, sugars such as lactose, glucose and mannitol,
One or more excipients selected from celluloses such as microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, one or more binders selected from polyvinylpyrrolidone and the like, carboxymethylcellulose, carboxymethylcellulose calcium,
Low-substituted hydroxypropyl cellulose, hydroxypropyl starch, and one or more disintegrating agents selected from cross-linked sodium carboxymethyl cellulose and the like, which are granulated by a conventional method. If necessary, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, The coating can be applied using a gastric soluble coating base such as polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer E and the like.
【００１５】又、これらのフィルム基剤にタール系色素
及びそのレーキ又は天然色素類を配合して着色被覆粒状
剤とすることもできる。Further, a tar-based dye and its lake or natural dyes may be blended with these film bases to form a colored coated granule.
【００１６】本発明に使用される徐放性粒状剤は、速放
性粒状剤による速やかな放出後、絶えることなく更に一
定の放出量を持続化すべく組み合わされたもので、速放
性粒状剤１重量部に対して徐放性粒状剤の配合量が１〜
１１重量部、好ましくは１〜６重量部組み合わせてなる
粒状剤である。The sustained-release granules used in the present invention are those which are combined in such a manner that the rapid-release granules are rapidly released and then continuously maintained at a constant release amount. The blending amount of the sustained-release granule is 1 to 1 part by weight.
It is 11 parts by weight, preferably 1 to 6 parts by weight, which is a granular agent.
【００１７】この徐放性粒状剤は、薬効成分であるウル
ソデスオキシコール酸の溶解度のｐＨ依存性がきわめて
高いことから、消化管移動に伴うｐＨ変化に対応して一
定量を持続的に長時間放出するために、ｐＨ6.５〜７で
一定に放出するように調節された徐放部Ｉと、ｐＨ7.５
〜８で一定に放出するように調節された徐放部IIとを適
当な比率に組み合わせた複合粒状剤としたものである。This sustained-release granule has a very high pH dependence of the solubility of ursodesoxycholic acid, which is a medicinal component, and therefore, a certain amount of the sustained-release granule can be sustained for a long time in response to the pH change accompanying the movement of the digestive tract. In order to release it over time, a sustained release part I adjusted to release constantly at pH 6.5 to 7 and pH 7.5
It is a composite granule obtained by combining the sustained-release part II, which is adjusted so as to be released at a constant rate of ~ 8, in an appropriate ratio.
【００１８】徐放部Ｉの放出制御基剤としては、親水性
高分子、疎水性高分子、腸溶性物質より選ばれた一種又
は二種以上が挙げられる。又、徐放部IIの放出制御基剤
としては、疎水性高分子、ワックス類、ロウ類及び高級
脂肪酸又はその金属塩より選ばれた一種又は二種以上が
挙げられる。Examples of the release controlling base for the sustained release part I include one or more selected from hydrophilic polymers, hydrophobic polymers and enteric substances. Examples of the release controlling base for the sustained release part II include one or more selected from hydrophobic polymers, waxes, waxes and higher fatty acids or metal salts thereof.
【００１９】尚、徐放部Ｉ及び徐放部IIの徐放性粒状剤
は、必要により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、ポリビニルアセタール
ジエチルアミノアセテート、アミノアルキルメタアクリ
レートコポリマーＥ等の胃溶性コーティング基剤を用い
て皮膜を施すことができる。If desired, the sustained-release granules of the sustained-release part I and the sustained-release part II are gastric-soluble coating bases such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetal diethylaminoacetate and aminoalkyl methacrylate copolymer E. Can be used to apply the coating.
【００２０】又、これらのフィルム基剤にタール系色素
及びそのレーキ又は天然色素類を配合して着色被覆粒状
剤とすることもできる。Further, a tar-based dye and its lake or natural dyes may be blended with these film bases to prepare a colored coated granule.
【００２１】次に、本発明に使用される放出制御基剤に
ついてさらに詳しく説明する。Next, the controlled-release base used in the present invention will be described in more detail.
【００２２】まず、徐放部Ｉの親水性高分子としては、
メチルセルロース、ポリビニルアルコール、カルボキシ
ビニルポリマー、カルボキシメチルセルロースナトリウ
ム、プルラン、アルギン酸ナトリウム等が挙げられる。
疎水性高分子としては、エチルセルロース、アミノアル
キルメタクリレートコポリマー等が挙げられる。腸溶性
物質としては、ヒドロキシプロピルメチルセルロースフ
タレート、ヒドロキシプロピルメチルセルロースアセテ
ートサクシネート、メタアクリル酸コポリマーＳ、Ｌ、
ＬＤ、カルボキシメチルエチルセルロースが挙げられ
る。First, as the hydrophilic polymer of the sustained release part I,
Examples include methyl cellulose, polyvinyl alcohol, carboxyvinyl polymer, sodium carboxymethyl cellulose, pullulan, sodium alginate and the like.
Examples of the hydrophobic polymer include ethyl cellulose and aminoalkyl methacrylate copolymer. Enteric substances include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymers S and L,
LD and carboxymethyl ethyl cellulose are mentioned.
【００２３】又、徐放部IIの疎水性高分子としては、エ
チルセルロース、アミノアルキルメタアクリレートコポ
リマー等が挙げられる。ワックス類としては、パラフィ
ンワックス、ライスワックス、カルナバロウワックス等
が挙げられる。ロウ類としては、ミツロウ、カルナバロ
ウ、ゲイロウ等が挙げられる。高級脂肪酸又はその金属
塩としては、ステアリン酸、パルミチン酸、ミリスチン
酸あるいはそれらのナトリウム、カルシウム、マグネシ
ウム塩等が挙げられる。Examples of the hydrophobic polymer of the sustained release part II include ethyl cellulose and aminoalkyl methacrylate copolymer. Examples of waxes include paraffin wax, rice wax, and carnauba wax. Examples of waxes include beeswax, carnauba wax, and gallows. Examples of higher fatty acids or metal salts thereof include stearic acid, palmitic acid, myristic acid, or their sodium, calcium, magnesium salts and the like.
【００２４】そして、これらをそれぞれ単独ないしは二
種以上の組み合わせで配合し、混末として又は水若しく
は含エタノール水に分散、溶解させた結合液として練合
造粒法により、あるいは含エタノール水又は有機溶媒に
分散、溶解させ、噴霧乾燥造粒法により、それぞれマト
リックス粒状物、コーティング粒状物が調製される。These are blended individually or in a combination of two or more kinds and mixed by a kneading granulation method as a powder mixture or as a binding solution dispersed and dissolved in water or ethanol-containing water, or ethanol-containing water or organic. Matrix granules and coating granules are prepared by dispersing and dissolving in a solvent and spray-drying granulation method, respectively.
【００２５】又、放出制御基剤に高融点のロウ類、ワッ
クス類を用いる場合は、加熱造粒法で調製される。ここ
でいうマトリックス粒状物とは、マトリックス細粒、顆
粒又は粒状組成物で、コーティング粒状物とは、コーテ
ィング細粒、顆粒又は粒状組成物である。When waxes and waxes having a high melting point are used as the release controlling base, they are prepared by a heat granulation method. The matrix granules referred to herein are matrix fine particles, granules or granular compositions, and the coating granules are coating fine particles, granules or granular compositions.
【００２６】徐放部Ｉの放出制御基剤は、製剤全重量に
対し５〜４０重量％、好ましくは１０〜３０重量％に配
合される。又、徐放部IIの放出制御基剤は、製剤全重量
に対し２〜５０重量％、好ましくは５〜４０重量％に配
合される。The controlled release base of the sustained release part I is incorporated in an amount of 5 to 40% by weight, preferably 10 to 30% by weight, based on the total weight of the preparation. The controlled release base of the sustained release part II is added in an amount of 2 to 50% by weight, preferably 5 to 40% by weight, based on the total weight of the preparation.
【００２７】これらの各種放出制御基剤は、その種類、
組み合わせ又は薬効成分との配合比により、ｐＨ6.５〜
７で任意に一定量放出するように調節された徐放部Ｉ及
びｐＨ7.５〜８で任意に一定量放出するように調節され
た徐放部IIが得られる。These various controlled release bases are
Depending on the combination or the compounding ratio with the medicinal component, pH 6.5
A sustained release part I adjusted to release a certain amount at 7 and a sustained release part II adjusted to release a certain amount at pH 7.5 to 8 are obtained.
【００２８】又、同一放出制御基剤であっても、薬効成
分との配合比あるいは結合液種、液量、乾燥温度等の製
造条件によっては、徐放部Ｉないし徐放部IIの徐放性粒
状剤として用いることが可能で、更に上記要因により、
細粒、顆粒、粒状組成物等所望の剤型が調製される。Further, even with the same controlled release base, depending on the compounding ratio with the medicinal component or the production conditions such as the type of binding solution, the amount of liquid, the drying temperature, etc., the sustained release part I or the sustained release part II may be released. It can be used as a granular agent, and due to the above factors,
A desired dosage form such as fine granules, granules and granular composition is prepared.
【００２９】尚、徐放部Ｉ及び徐放部IIよりなる徐放性
粒状剤は、徐放部Ｉ１重量部に対して徐放部IIを0.５〜
４重量部、好ましくは１〜2.５重量部組み合わせてなる
ことが、生体における消化管移動に伴うｐＨ変化及び薬
効成分自身が有するｐＨ依存性に対応して長時間一定の
放出量を持続する上で好ましい。The sustained-release granule comprising the sustained-release part I and the sustained-release part II is 0.5 parts of the sustained-release part II with respect to 1 part by weight of the sustained-release part I.
A combination of 4 parts by weight, preferably 1 to 2.5 parts by weight, maintains a constant release amount for a long time in response to the pH change associated with the movement of the digestive tract in the living body and the pH dependence of the medicinal component itself. It is preferable above.
【００３０】又、本発明のウルソデスオキシコール酸持
続性製剤は、薬効成分であるウルソデスオキシコール酸
が製剤全重量中速放性粒状剤に対し５０〜９０重量％、
徐放性粒状剤徐放部Ｉに対し４０〜８０重量％、徐放性
粒状剤徐放部IIに対し４０〜７０重量％含有してなる複
合粒状剤である。剤型としては、粒状剤すなわち細粒、
顆粒又は粒状組成物である。本製剤は、速放性粒状剤と
徐放性粒状剤とを適当な比率で組み合わせてなる複合粒
状剤で、一製剤投与単位が多数個に分割された形態であ
り、個体間の胃内排出速度及び消化管移動速度、それに
伴うｐＨ変化に対する変動を小さくすることが可能であ
る。Further, in the ursodesoxycholic acid sustained-release preparation of the present invention, ursodesoxycholic acid as a medicinal component is contained in an amount of 50 to 90% by weight based on the total weight of the preparation, which is a medium-speed release granular agent.
It is a composite granule containing 40 to 80% by weight of the sustained release granule sustained release part I and 40 to 70% by weight of the sustained release granule sustained release part II. As the dosage form, granules, that is, fine particles,
It is a granular or granular composition. This preparation is a composite granule consisting of an immediate release granule and a sustained release granule combined in an appropriate ratio, and is a form in which one dosage unit of the preparation is divided into multiple parts, and it is gastric emptying between individuals. It is possible to reduce fluctuations in the speed and the gastrointestinal tract migration speed, and accompanying changes in pH.
【００３１】コレステロール系胆石溶解治療を目的とす
る就寝前１日１回投与の本製剤は、薬効成分であるウル
ソデスオキシコール酸１投与単位として３００〜８００
mg含有し、１製剤単位重量が簡便に服用可能な量である
0.５〜1.８ｇに設定され、ストリップパッケージ（ＳＰ
包装）、スティック包装などの分包単位として提供され
る。The present preparation, which is administered once a day before bedtime for the purpose of treating cholesterol-based gallstones, contains 300 to 800 as one dosage unit of ursodesoxycholic acid, which is a medicinal component.
Containing mg, the unit weight of one preparation can be easily taken.
Set to 0.5-1.8g, strip package (SP
Packaging), stick packaging, etc.
【００３２】以上、本発明の持続性製剤及びその配合組
成は、文献末記載の新規知見であり、本発明者らの鋭意
研究の結果見い出されたものである。As described above, the sustained-release preparation of the present invention and the composition thereof are new findings described in the end of the literature, and have been found as a result of intensive studies by the present inventors.
【００３３】[0033]
【作用】本発明持続性製剤の溶出試験及び胆管瘻ラット
モデルにおけるインビボ(In vivo) 試験の徐放性につい
て示す。[Effect] The sustained release properties of the sustained release preparation of the present invention are shown in the dissolution test and in vivo test in a rat model of biliary fistula.
【００３４】〔溶出試験〕第十一改正日本薬局法溶出試
験法第２法（パドル法）に準じ、本発明持続性製剤の速
放性粒状剤及び徐放性粒状剤徐放部Ｉ、IIについて、そ
れぞれ試験液としてｐＨ6.５、７、８の0.０５Ｍリン酸
緩衝液（Clark-Lubs；KH2PO4-NaOH)９００ml、パドル回
転数１００ｒｐｍ、液温３７±１℃の条件で、各試料
（ウルソデスオキシコール酸として５０mg相当量）を試
験液に投入し、経時的に、0.４５μｍのメンブランフィ
ルターを通過してくる溶出液５mlを分取し、総胆汁酸測
定用キットを用いて酵素比色法によりウルソデスオキシ
コール酸量を測定した。又、本発明持続性製剤及び従来
製剤（ウルソサン錠５０mg）について、試験液のｐＨを
経時的に変化させた方法により、同じく溶出試験を行っ
た。結果を図１〜図４に示す。[Dissolution test] According to the eleventh revised Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method), the immediate-release granules and sustained-release granules sustained-release parts I and II of the sustained-release preparation of the present invention About 0.05 M phosphate buffer (Clark-Lubs; KH 2 PO 4 -NaOH) of pH 6.5, 7, 8 as 900 ml, paddle rotation speed 100 rpm, liquid temperature 37 ± 1 ° C. Each sample (50 mg equivalent of ursodesoxycholic acid) was added to the test solution, and 5 ml of the eluate that passed through the 0.45 μm membrane filter was collected over time to prepare a total bile acid measurement kit. The amount of ursodesoxycholic acid was measured by the enzyme colorimetric method. In addition, the sustained-release preparation of the present invention and the conventional preparation (ursosan tablet 50 mg) were similarly subjected to the dissolution test by a method in which the pH of the test solution was changed with time. The results are shown in FIGS.
【００３５】以上の結果から明らかなように、速放性粒
状剤は、ｐＨ6.５の試験液で比較的速やかな溶出挙動を
示し、徐放性粒状剤の徐放部ＩはｐＨ7.０の試験液で、
徐放性粒状剤の徐放部IIはｐＨ8.０の試験液でそれぞれ
０次放出に近似した徐放性を示した。又、これらの各部
を適切な比率で組み合わせた本発明の持続性製剤は、生
体内を考慮したｐＨ変化法による溶出試験において、い
ずれも従来製剤と比べ顕著な徐放性を示し、約７〜８時
間に亙り一定量の放出が維持された。As is clear from the above results, the immediate release granules show a relatively rapid dissolution behavior in the test solution having a pH of 6.5, and the sustained release part I of the sustained release granules has a pH of 7.0. With the test solution,
The sustained-release part II of the sustained-release granules showed a sustained-release property similar to the 0th-order release with the test solution of pH 8.0. Further, the sustained-release preparations of the present invention in which these respective parts are combined in an appropriate ratio all show remarkable sustained-release properties in comparison with the conventional preparations in the dissolution test by the pH change method considering the in vivo, and about 7 to 7 A constant release was maintained over 8 hours.
【００３６】〔胆管瘻ラットモデルによるIn vivo 試
験〕体重２００〜２５０ｇのウィスター系雄性ラットを
用いて１群３匹とし、胆管瘻ラットを作製した後、本発
明の持続性製剤及びメノウ乳鉢で粉砕した従来製剤（ウ
ルソサン錠５０mg）を0.５％ＣＭＣ−Ｎａ溶液に加えて
懸濁液とし、ウルソデスオキシコール酸２００mg／3.７
５ml／kg相当量を経口用ゾンデを用いて強制投与した。[In vivo test using cholangiostomy rat model] Male Wistar rats having a body weight of 200 to 250 g were used as one group, and three cholangiostomy rats were prepared, and then crushed with the sustained-release preparation of the present invention and an agate mortar. The conventional formulation (Ursosan tablet 50 mg) was added to 0.5% CMC-Na solution to give a suspension, and ursodesoxycholic acid 200 mg / 3.7
An amount equivalent to 5 ml / kg was forcibly administered using an oral probe.
【００３７】胆管カニューレ先端より常時流出してくる
胆汁を一定時間ごとに0.１ml分取し、エタノール２mlを
加えて希釈混合後、遠心分離し、上澄液を試料溶液と
し、液体クロマトグラフ法によりウルソデスオキシコー
ル酸及びその抱合体の経時的な排泄量を測定した。結果
を図５〜図７に示す。0.1 ml of bile constantly flowing out from the tip of the bile duct cannula was collected at regular intervals, diluted with 2 ml of ethanol, mixed and centrifuged, and the supernatant was used as a sample solution for liquid chromatography. The time-dependent excretion of ursodesoxycholic acid and its conjugate was measured by. The results are shown in FIGS.
【００３８】以上の結果から明らかなように、本発明持
続性製剤は、従来製剤と比べ、初期の吸収が制御され、
胆汁中へのウルソデスオキシコール酸抱合体が一定量徐
々に排泄され、持続性が認められた。As is clear from the above results, the sustained release preparation of the present invention has a controlled initial absorption compared with the conventional preparations,
A constant amount of ursodesoxycholic acid conjugate was excreted into the bile, and persistence was observed.
【００３９】次に、本発明の持続性製剤の製造例を実施
例をもって示すが、これらが本発明を限定するものでは
ない。Next, production examples of the sustained-release preparation of the present invention will be shown with examples, but these do not limit the present invention.
【００４０】[0040]
【実施例１】 −速放性粒状剤− ウルソデスオキシコール酸１５０ｇ、トウモロコシデン
プン１０５ｇ、カルボキシメチルセルロースカルシウム
３０ｇ及びヒドロキシプロピルセルロース（日本曹達Ｈ
ＰＣ−Ｌ；商品名）１５ｇを加えて混合後、３０％(W/
W）エタノール水溶液１２０ｇを徐々に加えて２分間撹
拌練合した。この練合物をイクストルーダ（φ1.０mm）
を用いて造粒し、５５〜６０℃で３時間乾燥させた後、
１２〜３２メッシュに整粒し、速放性顆粒剤２４０ｇを
得た。Example 1-Rapid release granular agent-Ursodesoxycholic acid 150 g, corn starch 105 g, carboxymethyl cellulose calcium 30 g and hydroxypropyl cellulose (Nippon Soda H
After adding 15 g of PC-L (trade name) and mixing, 30% (W /
W) 120 g of ethanol aqueous solution was gradually added, and the mixture was stirred and kneaded for 2 minutes. This kneaded mixture is extruded (φ1.0 mm)
After granulating with and drying at 55-60 ° C. for 3 hours,
The particles were sized to 12 to 32 mesh to obtain 240 g of immediate release granules.
【００４１】−徐放性粒状剤徐放部Ｉ− ウルソデスオキシコール酸３００ｇ、乳糖５０ｇ、カル
ボキシメチルセルロースナトリウム１００ｇ及びヒドロ
キシプロピルメチルセルロース（信越化学、メトローズ
９０ＳＨ；商品名）５０ｇを加えて混合後、水２５０ｇ
を徐々に加えて３分間撹拌練合した。この練合物をイク
ストルーダ（φ1.０mm）を用いて造粒し、５５〜６０℃
で３時間乾燥させた後１２〜３２メッシュに整粒し、徐
放性顆粒剤徐放部Ｉ４００ｇを得た。-Sustained release granules Slow release part I- 300 g of ursodesoxycholic acid, 50 g of lactose, 100 g of sodium carboxymethyl cellulose and 50 g of hydroxypropylmethyl cellulose (Shin-Etsu Chemical Co., Ltd., METOLOSE 90SH; trade name) were added and mixed with water 250 g
Was gradually added and kneaded with stirring for 3 minutes. This kneaded product is granulated using an extruder (φ1.0 mm), and the temperature is 55 to 60 ° C.
After being dried for 3 hours, the particles were sized to 12 to 32 mesh to obtain 400 g of sustained release granule sustained release part I.
【００４２】−徐放性粒状剤徐放部II− ウルソデスオキシコール酸２００ｇ、乳糖１７５ｇ、カ
ルボキシメチルセルロースナトリウム７５ｇ及びエチル
セルロース（日商岩井、エトセルＥＣ−Ｎ７；商品名）
５０ｇを加えて混合後、局方エタノール１５０ｇを徐々
に撹拌しながら加えて練合した。この練合物をイクスト
ルーダ（φ1.０mm）を用いて造粒し、５５〜６０℃で３
時間乾燥させた後、１２〜３２メッシュに整粒し、徐放
性顆粒剤徐放部II４００ｇを得た。-Slow-release granular agent sustained-release part II- Ursodesoxycholic acid 200 g, lactose 175 g, sodium carboxymethyl cellulose 75 g and ethyl cellulose (Nissho Iwai, Etocel EC-N7; trade name)
After 50 g was added and mixed, 150 g of pharmacopoeia ethanol was gradually added with stirring and kneaded. This kneaded product was granulated using an extruder (φ1.0 mm), and the mixture was kneaded at 55-60 ° C for 3 hours.
After drying for an hour, the particles were sized to 12 to 32 mesh to obtain 400 g of sustained release granule sustained release part II.
【００４３】次に、これらの速放性顆粒剤、徐放性顆粒
剤徐放部Ｉ及び徐放部IIをそれぞれ１重量部、2.５重量
部、2.５重量部の割合で混合し、速放性粒状剤１重量部
に対し、徐放性粒状剤が５重量部組み合わせてなる複合
粒状剤とした。これを１製剤投与単位1.２ｇ（ウルソデ
スオキシコール酸６００mg含有）としてストリップパッ
ケージ（ＳＰ包装）に充填して持続性製剤を得た。Next, these rapid-release granules, sustained-release granules sustained-release part I and sustained-release part II were mixed at a ratio of 1 part by weight, 2.5 parts by weight and 2.5 parts by weight, respectively. Then, 5 parts by weight of the sustained-release granule was combined with 1 part by weight of the immediate-release granule to give a composite granule. This was filled in a strip package (SP packaging) as a preparation dosage unit of 1.2 g (containing 600 mg of ursodesoxycholic acid) to obtain a sustained-release preparation.
【００４４】[0044]
【実施例２】 −速放性粒状剤− ウルソデスオキシコール酸２５０ｇ、部分アルファー化
デンプン１２０ｇ、微結晶セルロース７０ｇ、低置換度
ヒドロキシプロピルセルロース５０ｇ及びポリビニルピ
ロリドン１０ｇを加えて混合した後、３０％(W/W）エタ
ノール含有水溶液２５０ｇを徐々に加えて２分間撹拌練
合した。この練合物をイクストルーダ（φ0.５mm）を用
いて造粒し、次いで５５〜６０℃で３時間乾燥させた
後、４２〜８０メッシュに整粒し、速放性細粒剤３５０
ｇを得た。Example 2 Rapid Release Granular Agent 250 g of ursodesoxycholic acid, 120 g of partially pregelatinized starch, 70 g of microcrystalline cellulose, 50 g of low-substituted hydroxypropyl cellulose and 10 g of polyvinylpyrrolidone were added and mixed, and then 30%. 250 g of (W / W) ethanol-containing aqueous solution was gradually added, and the mixture was stirred and kneaded for 2 minutes. This kneaded product was granulated using an extruder (φ0.5 mm), then dried at 55-60 ° C. for 3 hours, and then sized to 42-80 mesh to give a quick release fine granule 350.
g was obtained.
【００４５】−徐放性粒状剤徐放部Ｉ− ウルソデスオキシコール酸１５０ｇ、乳糖９7.５ｇ、ヒ
ドロキシプロピルセルロース２2.５ｇ及びカルボキシビ
ニルポリマー１５ｇを加えて混合した後、これにメタア
クリル酸コポリマーＳ（樋口商会、オイドラギットＳ−
１００；商品名）１５ｇに局方エタノール２５０ｇを加
えて溶解した液を徐々に加えて３分間撹拌練合した。こ
の練合物をイクストルーダ（φ0.５mm）を用いて造粒
し、５５〜６０℃で３時間乾燥後、４２〜８０メッシュ
に整粒して徐放性細粒剤徐放部Ｉ２２０ｇを得た。-Slow-release granular agent Slow-release part I- 150 g of ursodesoxycholic acid, 97.5 g of lactose, 22.5 g of hydroxypropylcellulose and 15 g of carboxyvinyl polymer were added and mixed, and then a methacrylic acid copolymer was added thereto. S (Higuchi Shokai, Eudragit S-
250 g of pharmacopoeia ethanol was added to 15 g of 100; trade name), and a solution obtained by dissolving was gradually added and kneaded with stirring for 3 minutes. This kneaded product was granulated using an extruder (φ0.5 mm), dried at 55-60 ° C. for 3 hours, and then sized to 42-80 mesh to obtain 220 g of sustained-release fine granule sustained-release part I. .
【００４６】−徐放性粒状剤徐放部II− ウルソデスオキシコール酸１５０ｇ、乳糖９６ｇ、カル
ボキシメチルセルロースナトリウム３０ｇ、エチルセル
ロース１５ｇ、アミノアルキルメタアクリレートコポリ
マー（樋口商会、オイドラギットＲＳ；商品名）９ｇを
加えて混合した後、局方エタノール１６０ｇを徐々に加
えて５分間撹拌練合した。この練合物をイクストルーダ
（φ0.５mm）を用いて造粒し、５５〜６０℃で３時間乾
燥させた後、４２〜８０メッシュに整粒して徐放性細粒
剤徐放部II２４０ｇを得た。-Sustained release granular agent sustained release portion II- Add 150 g of ursodesoxycholic acid, lactose 96 g, sodium carboxymethyl cellulose 30 g, ethyl cellulose 15 g, aminoalkyl methacrylate copolymer (Higuchi Shokai, Eudragit RS; trade name) 9 g. After mixing, 160 g of pharmacopoeia ethanol was gradually added, and the mixture was stirred and kneaded for 5 minutes. This kneaded product was granulated using an extruder (φ0.5 mm), dried at 55-60 ° C. for 3 hours, and then sized to 42-80 mesh to give 240 g of sustained-release fine granule sustained-release part II. Obtained.
【００４７】次に、これらの速放性細粒剤、徐放性細粒
剤徐放部Ｉ及び徐放部IIをそれぞれ３重量部、1.５重量
部、1.５重量部の割合で混合し、速放性粒状剤１重量部
に対し、徐放性粒状剤が１重量部組み合わせてなる複合
粒状剤とした。これを１製剤投与単位0.６ｇ（ウルソデ
スオキシコール酸３００mg含有）としてストリップパッ
ケージ（ＳＰ包装）に充填して持続性製剤を得た。Next, these rapid-release fine granules, sustained-release fine granules sustained-release part I and sustained-release part II were respectively added in proportions of 3 parts by weight, 1.5 parts by weight and 1.5 parts by weight, respectively. The mixture was mixed to obtain a composite granule comprising 1 part by weight of the immediate release granule and 1 part by weight of the sustained release granule. This was filled in a strip package (SP package) as a dosage unit of 0.6 g (containing 300 mg of ursodesoxycholic acid) to obtain a sustained-release preparation.
【００４８】[0048]
【実施例３】 −速放性粒状剤− ウルソデスオキシコール酸３２０ｇ、乳糖４８ｇ、微結
晶セルロース２０ｇ及びヒドロキシプロピルスターチ１
２ｇを加えて混合した後、１５％(W/W) エタノール含有
水溶液１６０ｇを徐々に加えて２分間撹拌練合した。こ
の練合物をスピードミル（２mm巾ヘリンボン）を用いて
造粒し、次いで５５〜６０℃で３時間乾燥させた後、６
０〜１２０メッシュに整粒し、速放性細粒剤３００ｇを
得た。Example 3 -Immediate release granular agent- 320 g of ursodesoxycholic acid, 48 g of lactose, 20 g of microcrystalline cellulose and hydroxypropyl starch 1
After adding 2 g and mixing, 160 g of a 15% (W / W) ethanol-containing aqueous solution was gradually added, and the mixture was stirred and kneaded for 2 minutes. This kneaded product was granulated using a speed mill (2 mm width herringbone), and then dried at 55-60 ° C. for 3 hours, and then 6
The particle size was adjusted to 0 to 120 mesh to obtain 300 g of an immediate release fine granule.
【００４９】−徐放性粒状剤徐放部Ｉ− エチルセルロース９０ｇをジクロルメタン１５００ｇに
加えて超音波処理して溶解した液にウルソデスオキシコ
ール酸２１０ｇを加えて撹拌しながら均一な懸濁液を調
製し、噴霧乾燥造粒装置を用いて常法に従って造粒し、
８０〜１５０メッシュに整粒して徐放性細粒剤徐放部Ｉ
２５０ｇを得た。-Slow-release granular agent, slow-release part I- To 90 g of ethyl cellulose was added to 1500 g of dichloromethane and ultrasonically treated, 210 g of ursodesoxycholic acid was added to a dissolved solution to prepare a uniform suspension. Then, using a spray drying granulator, granulate according to a conventional method,
Controlled-release fine granule sustained-release part I by sizing to 80-150 mesh
250 g was obtained.
【００５０】−徐放性粒状剤徐放部II− エチルセルロース９０ｇ、アミノアルキルメタアクリレ
ートコポリマー３０ｇをジクロルメタン１５００ｇに加
えて超音波処理して溶解した液にウルソデスオキシコー
ル酸１８０ｇを加えて撹拌しながら均一な懸濁液を調製
し、噴霧乾燥造粒装置を用いて常法に従って造粒し、８
０〜１５０メッシュに整粒して徐放性細粒剤徐放部II２
６０ｇを得た。-Sustained release granular agent sustained release part II- 90 g of ethyl cellulose and 30 g of aminoalkyl methacrylate copolymer were added to 1500 g of dichloromethane and ultrasonically treated to dissolve 180 g of ursodesoxycholic acid while stirring. A uniform suspension was prepared and granulated according to a conventional method using a spray-drying granulator.
Granules controlled to 0-150 mesh, sustained release fine granule sustained release part II2
60 g was obtained.
【００５１】次に、これらの速放性細粒剤、徐放性細粒
剤徐放部Ｉ及び徐放部IIをそれぞれ１重量部、２重量
部、３重量部の割合で混合し、速放性粒状剤１重量部に
対し、徐放性粒状剤が５重量部組み合わせてなる複合粒
状剤とした。これを１製剤投与単位0.９ｇ（ウルソデス
オキシコール酸６００mg含有）としてストリップパッケ
ージ（ＳＰ包装）に充填して持続性製剤を得た。Next, these rapid-release fine granules, sustained-release fine granules sustained-release part I and sustained-release part II were mixed in the proportions of 1 part by weight, 2 parts by weight and 3 parts by weight, respectively, and mixed immediately. 5 parts by weight of the sustained-release granules were combined with 1 part by weight of the release granules to give a composite granule. This was filled in a strip package (SP package) as a dosage unit of 0.9 g (containing 600 mg of ursodesoxycholic acid) to obtain a continuous preparation.
【００５２】[0052]
【実施例４】 −速放性粒状剤− ウルソデスオキシコール酸２１０ｇ、乳糖２４ｇ、トウ
モロコシデンプン４５ｇ、架橋カルボキシメチルセルロ
ースナトリウム１２ｇ及びヒドロキシプロピルメチルセ
ルロース９ｇを加えて混合した後、３０％(W/W) エタノ
ール含有水溶液１１０ｇを徐々に加えて２分間撹拌練合
した。この練合物をスピードミル（２mm巾ヘリンボン）
を用いて造粒し、次いで５５〜６０℃で３時間乾燥させ
た後、６０〜１５０メッシュに整粒し、速放性細粒剤２
２０ｇを得た。Example 4 -Immediate release granular agent- 210 g of ursodesoxycholic acid, 24 g of lactose, 45 g of corn starch, 12 g of crosslinked sodium carboxymethyl cellulose and 9 g of hydroxypropylmethyl cellulose were added and mixed, and then 30% (W / W). 110 g of an ethanol-containing aqueous solution was gradually added, and the mixture was stirred and kneaded for 2 minutes. This kneaded product is speed mill (2 mm width herringbone)
Granules, then dried at 55-60 ° C. for 3 hours, and then sized to 60-150 mesh to give an immediate release fine granule 2
20 g was obtained.
【００５３】−徐放性粒状剤徐放部Ｉ− ヒドロキシプロピルメチルセルロースアセテートサクシ
ネート（信越化学、ＡＱＯＡＴ〔ＨＦ〕；商品名）９０
ｇ、メチルセルロース３０ｇを３０％(W/W) エタノール
含有水溶液１２００ｇに加えて超音波処理して溶解した
液にウルソデスオキシコール酸１８０ｇを加えて撹拌し
ながら均一な懸濁液を調製した後、噴霧乾燥造粒装置を
用いて常法に従って造粒し、８０〜１５０メッシュに整
粒して徐放性粒状組成物徐放部Ｉ２３０ｇを得た。-Sustained release granular agent Slow release part I-Hydroxypropyl methylcellulose acetate succinate (Shin-Etsu Chemical, AQOAT [HF]; trade name) 90
g, 30 g of methylcellulose was added to 1200 g of a 30% (W / W) ethanol-containing aqueous solution and ultrasonically treated to dissolve the solution, and 180 g of ursodesoxycholic acid was added to the solution to prepare a uniform suspension while stirring. Using a spray-drying granulator, granulation was performed according to a conventional method, and the granules were sized to 80 to 150 mesh to obtain 230 g of sustained-release granular composition I.
【００５４】−徐放性粒状剤徐放部II− アミノアルキルメタアクリレートコポリマー１０５ｇを
ジクロルメタン２０００ｇに加えて超音波処理して溶解
した液にステアリン酸マグネシウム１５ｇ、ウルソデス
オキシコール酸１８０ｇを加えて撹拌しながら均一な懸
濁液を調製した後、噴霧乾燥造粒装置を用いて常法に従
って造粒し、８０〜１５０メッシュに整粒して徐放性粒
状組成物徐放部II２１０ｇを得た。-Slow-release granular agent, slow-release part II- 105 g of aminoalkyl methacrylate copolymer was added to 2000 g of dichloromethane, ultrasonically treated and dissolved, and 15 g of magnesium stearate and 180 g of ursodesoxycholic acid were added and stirred. While preparing a uniform suspension, the mixture was granulated by a conventional method using a spray-drying granulator and sized to 80-150 mesh to obtain 210 g of sustained-release granular composition II.
【００５５】次に、これらの速放性細粒剤、徐放性粒状
組成物徐放部Ｉ及び徐放部IIをそれぞれ1.５重量部、３
重量部、1.５重量部の割合で混合し、速放性粒状剤１重
量部に対し、徐放性粒状剤が３重量部組み合わせてなる
複合粒状剤とした。これを１製剤投与単位0.８ｇ（ウル
ソデスオキシコール酸５００mg含有）としてストリップ
パッケージ（ＳＰ包装）に充填して持続性製剤を得た。Next, 1.5 parts by weight of each of these immediate release fine granules, sustained release granular composition sustained release part I and sustained release part II were added.
Part by weight and 1.5 parts by weight were mixed to obtain a composite granular agent in which 3 parts by weight of the sustained-release granular agent was combined with 1 part by weight of the immediate-release granular agent. This was filled in a strip package (SP packaging) as a dosage unit of 0.8 g (containing 500 mg of ursodesoxycholic acid) to obtain a continuous preparation.
【００５６】[0056]
【実施例５】 −速放性粒状剤− ウルソデスオキシコール酸２７０ｇ、部分アルファー化
デンプン１５ｇ、架橋カルボキシメチルセルロース６ｇ
及びヒドロキシプロピルセルロース９ｇを加えて混合し
た後、３０％(W/W) エタノール含有水溶液１２０ｇを徐
々に加えて２分間撹拌練合した。この練合物をスピード
ミル（２mm巾ヘリンボン）を用いて造粒し、次いで５５
〜６０℃で３時間乾燥させた後、４８〜１２０メッシュ
に整粒し、速放性細粒剤２４５ｇを得た。Example 5 -Immediate release granular agent- 270 g of ursodesoxycholic acid, 15 g of partially pregelatinized starch, 6 g of crosslinked carboxymethyl cellulose
After adding and mixing 9 g of hydroxypropyl cellulose, 120 g of an aqueous solution containing 30% (W / W) ethanol was gradually added, and the mixture was stirred and kneaded for 2 minutes. The kneaded product was granulated using a speed mill (2 mm width herringbone), and then 55
After drying at -60 ° C for 3 hours, the particles were sized to 48-120 mesh to obtain 245 g of an immediate release fine granule.
【００５７】−徐放性粒状剤徐放部Ｉ− ウルソデスオキシコール酸２００ｇ、乳糖１４０ｇ、ポ
リビニルアルコール２０ｇ及びプルラン（林原商事、プ
ルランＰＩ−２０；商品名）４０ｇを加えて混合後、水
２３０ｇを徐々に加えて５分間撹拌練合した。この練合
物をイクストルーダ（φ0.５mm）を用いて造粒し、５５
〜６０℃で３時間乾燥させた後、４８〜１００メッシュ
に整粒し、徐放性細粒剤徐放部Ｉ２８０ｇを得た。-Sustained release granular agent sustained release part I- 200 g of ursodesoxycholic acid, 140 g of lactose, 20 g of polyvinyl alcohol and 40 g of pullulan (Pullulan PI-20, trade name) (Hayashibara Shoji Co., Ltd.), and after mixing 230 g of water Was gradually added and kneaded with stirring for 5 minutes. This kneaded product was granulated using an extruder (φ0.5 mm), and 55
After drying at -60 ° C for 3 hours, the particles were sized to 48-100 mesh to obtain 280 g of sustained-release fine granule sustained-release part I.
【００５８】−徐放性粒状剤徐放部II− パラフィンワックス８０ｇ、ステアリン酸２０ｇを加え
て８０〜９０℃に加熱溶融した後、これにウルソデスオ
キシコール酸１６０ｇ、乳糖１４０ｇを加えて３分間撹
拌練合した。次いで撹拌しながら室温まで冷却して固化
した後、スピードミル（１６＃スクリーン）で粉砕し、
４８〜１００メッシュに整粒して徐放性粒状剤組成物徐
放部II３２０ｇを得た。-Sustained release granular agent sustained release part II- After adding 80 g of paraffin wax and 20 g of stearic acid and heating and melting at 80 to 90 ° C, 160 g of ursodesoxycholic acid and 140 g of lactose were added to this and 3 minutes Stir kneaded. Then cool to room temperature with stirring and solidify, then crush with a speed mill (16 # screen),
The granule size was adjusted to 48 to 100 mesh to obtain 320 g of sustained release granule composition sustained release part II.
【００５９】次に、これらの速放性細粒剤、徐放性細粒
剤徐放部Ｉ及び粒状組成物徐放部IIをそれぞれ１重量
部、１重量部、４重量部の割合で混合し、速放性粒状剤
１重量部に対し、徐放性粒状剤が５重量部組み合わせて
なる複合粒状剤とした。これを１製剤投与単位1.２ｇ
（ウルソデスオキシコール酸６００mg含有）としてスト
リップパッケージ（ＳＰ包装）に充填して持続性製剤を
得た。Next, 1 part by weight, 1 part by weight and 4 parts by weight of these rapid release fine granules, sustained release fine granules sustained release part I and granular composition sustained release part II were mixed respectively. Then, 5 parts by weight of the sustained-release granule was combined with 1 part by weight of the immediate-release granule to give a composite granule. 1.2g of this is 1 dosage unit
(Containing 600 mg of ursodesoxycholic acid) was filled in a strip package (SP packaging) to obtain a sustained-release preparation.
【００６０】[0060]
【実施例６】 −速放性粒状剤− ウルソデスオキシコール酸１８０ｇ、マンニット６９
ｇ、微結晶セルロース１５ｇ、カルボキシメチルセルロ
ースカルシウム２2.５ｇ及びヒドロキシプロピルセルロ
ース１3.５ｇを加えて混合後、１５％(W/W) エタノール
含有水溶液１５０ｇを徐々に加えて３分間撹拌練合し
た。この練合物をイクストルーダ（φ1.０mm）を用いて
造粒し、５５〜６０℃で３時間乾燥させた後、１６〜４
８メッシュに整粒し、速放性顆粒剤２５０ｇを得た。Example 6-Immediate release granular agent-Ursodesoxycholic acid 180 g, Mannit 69
g, 15 g of microcrystalline cellulose, 22.5 g of carboxymethyl cellulose calcium and 13.5 g of hydroxypropyl cellulose were added and mixed, then 150 g of a 15% (W / W) ethanol-containing aqueous solution was gradually added, and the mixture was stirred and kneaded for 3 minutes. This kneaded product was granulated using an extruder (φ1.0 mm), dried at 55 to 60 ° C. for 3 hours, and then 16 to 4
The particles were sized to 8 mesh to obtain 250 g of immediate release granules.
【００６１】−徐放性粒状剤徐放部Ｉ− ウルソデスオキシコール酸２００ｇ、乳糖１７５ｇ、ヒ
ドロキシプロピルメチルセルロースフタレート（信越化
学、ＨＰＭＣＰ〔ＨＰ−５５〕；商品名）７５ｇ及びア
ルギン酸ナトリウム５０ｇを加えて混合後、水２４０ｇ
を徐々に加えて３分間撹拌練合した。この練合物をイク
ストルーダ（φ1.０mm）を用いて造粒し、５５〜６０℃
で３時間乾燥させた後、１６〜４８メッシュに整粒し、
徐放性顆粒剤徐放部Ｉ４２０ｇを得た。-Sustained release granular agent I-Ursodesoxycholic acid 200 g, lactose 175 g, hydroxypropylmethyl cellulose phthalate (Shin-Etsu Chemical, HPMCP [HP-55]; trade name) 75 g and sodium alginate 50 g were added. 240g of water after mixing
Was gradually added and kneaded with stirring for 3 minutes. This kneaded product is granulated using an extruder (φ1.0 mm), and the temperature is 55 to 60 ° C.
After drying for 3 hours, size is adjusted to 16-48 mesh,
420 g of sustained-release granule sustained-release part I was obtained.
【００６２】−徐放性粒状剤徐放部II− ライスワックス１００ｇ、カルナバロウ５０ｇを加えて
８０〜９０℃に加熱溶融した後、これにウルソデスオキ
シコール酸３５０ｇを加えて３分間撹拌練合した。次い
で撹拌しながら室温まで冷却して固化した後、スピード
ミル（１２＃スクリーン）で粉砕し、１６〜４８メッシ
ュに整粒して徐放性顆粒剤徐放部II４００ｇを得た。-Sustained release granular agent sustained release part II- After adding 100 g of rice wax and 50 g of carnauba wax and heating and melting at 80 to 90 ° C., 350 g of ursodesoxycholic acid was added thereto and kneaded for 3 minutes with stirring. . Then, the mixture was cooled to room temperature with stirring and solidified, then pulverized with a speed mill (12 # screen) and sized to 16 to 48 mesh to obtain 400 g of sustained release granule sustained release part II.
【００６３】次に、これらの速放性顆粒剤、徐放性顆粒
剤徐放部Ｉ及び徐放部IIをそれぞれ1.５重量部、2.５重
量部、２重量部の割合で混合し、速放性粒状剤１重量部
に対し、徐放性粒状剤が３重量部組み合わせてなる複合
粒状剤とした。これを１製剤投与単位1.０ｇ（ウルソデ
スオキシコール酸５５０mg含有）としてストリップパッ
ケージ（ＳＰ包装）に充填して持続性製剤を得た。Next, these rapid-release granules, sustained-release granules sustained-release part I and sustained-release part II were mixed at a ratio of 1.5 parts by weight, 2.5 parts by weight and 2 parts by weight, respectively. Then, 3 parts by weight of the sustained-release granules were combined with 1 part by weight of the immediate-release granules to give a composite granule. This was filled in a strip package (SP packaging) as 1.0 g of one preparation dosage unit (containing 550 mg of ursodesoxycholic acid) to obtain a sustained-release preparation.
【００６４】[0064]
【実施例７】 −速放性粒状剤− ウルソデスオキシコール酸１５０ｇ、トウモロコシデン
プン１０５ｇ、微結晶セルロース１５ｇ、カルボキシメ
チルセルロース２１ｇ及びポリビニルピロリドン９ｇを
加えて混合した後、１５％(W/W) エタノール含有水溶液
１５０ｇを徐々に加えて２分間撹拌練合した。この練合
物をスピードミル（３mm巾ヘリンボン）を用いて造粒
し、次いで５５〜６０℃で３時間乾燥させた後、１２〜
４８メッシュに整粒し、速放性顆粒剤２５０ｇを得た。Example 7-Immediate release granular agent-Ursodesoxycholic acid 150 g, corn starch 105 g, microcrystalline cellulose 15 g, carboxymethyl cellulose 21 g and polyvinylpyrrolidone 9 g were added and mixed, and then 15% (W / W) ethanol was added. 150 g of the contained aqueous solution was gradually added, and the mixture was stirred and kneaded for 2 minutes. This kneaded product was granulated using a speed mill (3 mm width herringbone), then dried at 55-60 ° C. for 3 hours, and then 12-
The particles were sized to 48 mesh to obtain 250 g of immediate release granules.
【００６５】−徐放性粒状剤徐放部Ｉ− ウルソデスオキシコール酸３２０ｇ、カルボキシメチル
セルロースナトリウム４０ｇ及びアミノアルキルメタア
クリレートコポリマー１０ｇを加えて混合した後、これ
にヒドロキシプロピルメチルセルロース（信越化学、Ｔ
Ｃ−５Ｒ；商品名）３０ｇに水３５０ｇ加えて溶解した
液を徐々に加えて３分間撹拌練合した。-Sustained release granular agent sustained release portion I- 320 g of ursodesoxycholic acid, 40 g of sodium carboxymethyl cellulose and 10 g of aminoalkyl methacrylate copolymer were added and mixed, and then hydroxypropylmethyl cellulose (Shin-Etsu Chemical, T.
350 g of water was added to 30 g of C-5R (trade name), and a solution obtained by dissolving the mixture was gradually added and kneaded with stirring for 3 minutes.
【００６６】この練合物をイクストルーダ（φ1.０mm）
を用いて造粒し、５５〜６０℃で３時間乾燥後、１２〜
４８メッシュに整粒して徐放性顆粒剤徐放部Ｉ３３０ｇ
を得た。This kneaded product was mixed with an extruder (φ1.0 mm)
Granulate, dry at 55-60 ° C. for 3 hours, then 12-
Granules are sized to 48 mesh and sustained-release granules sustained-release part I 330 g
Got
【００６７】−徐放性粒状剤徐放部II− カルナバロウワックス８０ｇ、パルミチン酸１０ｇを加
えて８０〜９０℃に加熱溶融した後、これにウルソデス
オキシコール酸２１０ｇを加えて３分間撹拌練合した。
次いで撹拌しながら室温まで冷却して固化した後、スピ
ードミル（１２＃スクリーン）で粉砕し、１２〜４８メ
ッシュに整粒して徐放性顆粒剤徐放部II２４０ｇを得
た。-Slow-release granular agent sustained-release part II- After adding 80 g of carnauba wax and 10 g of palmitic acid and heating and melting at 80 to 90 ° C, 210 g of ursodesoxycholic acid was added thereto and kneaded for 3 minutes with stirring. did.
Then, the mixture was cooled to room temperature with stirring and solidified, then pulverized with a speed mill (12 # screen) and sized to 12 to 48 mesh to obtain 240 g of sustained release granule sustained release part II.
【００６８】次に、これらの速放性顆粒剤、徐放性顆粒
剤徐放部Ｉ及び徐放部IIをそれぞれ0.５重量部、2.５重
量部、3.５重量部の割合で混合し、速放性粒状剤１重量
部に対し、徐放性粒状剤が１１重量部組み合わせてなる
複合粒状剤とした。これを１製剤投与単位1.２ｇ（ウル
ソデスオキシコール酸８００mg含有）としてストリップ
パッケージ（ＳＰ包装）に充填して持続性製剤を得た。Next, 0.5 parts by weight, 2.5 parts by weight and 3.5 parts by weight of these rapid-release granules, sustained-release granules sustained-release part I and sustained-release part II, respectively, were used. The mixture was mixed to give a composite granule comprising 1 part by weight of the immediate release granule and 11 parts by weight of the sustained release granule. This was filled in a strip package (SP packaging) as a preparation dosage unit of 1.2 g (containing 800 mg of ursodesoxycholic acid) to obtain a sustained-release preparation.
【００６９】[0069]
【実施例８】 −速放性粒状剤− ウルソデスオキシコール酸１５０ｇ、マンニット９０
ｇ、トウモロコシデンプン３０ｇ、ヒドロキシプロピル
スターチ２１ｇ及びヒドロキシプロピルセルロース９ｇ
を加えて混合した後、１５％(W/W) エタノール含有水溶
液１７０ｇを徐々に加えて２分間撹拌練合した。この練
合物をスピードミル（２mm巾ヘリンボン）を用いて造粒
し、次いで５５〜６０℃で３時間乾燥させた後、３２〜
１００メッシュに整粒し、速放性細粒剤２４０ｇを得
た。[Example 8] -Immediate release granular agent-Ursodesoxycholic acid 150 g, Mannitol 90
g, corn starch 30 g, hydroxypropyl starch 21 g and hydroxypropyl cellulose 9 g
After adding and mixing, 170 g of a 15% (W / W) ethanol-containing aqueous solution was gradually added, and the mixture was stirred and kneaded for 2 minutes. This kneaded product was granulated by using a speed mill (2 mm width herringbone), and then dried at 55-60 ° C. for 3 hours, and then 32-
The particle size was adjusted to 100 mesh to obtain 240 g of an immediate release fine granule.
【００７０】−徐放性粒状剤徐放部Ｉ− ウルソデスオキシコール酸１６０ｇ、乳糖１００ｇ、カ
ルボキシメチルセルロースナトリウム８０ｇ及びプルラ
ン４０ｇを加えて混合した後、これにエチルセルロース
２０ｇに局方エタノール２５０ｇを加えて溶解した液を
徐々に加えて３分間撹拌練合した。この練合物をスピー
ドミル（２mm巾ヘリンボン）を用いて造粒し、５５〜６
０℃で３時間乾燥させた後、３２〜１００メッシュに整
粒し、徐放性細粒剤徐放部Ｉ３１０ｇを得た。-Sustained release granular agent sustained release part I- 160 g of ursodesoxycholic acid, 100 g of lactose, 80 g of sodium carboxymethyl cellulose and 40 g of pullulan were added and mixed, and then 20 g of ethyl cellulose and 250 g of pharmacological ethanol were added thereto. The dissolved liquid was gradually added, and the mixture was stirred and kneaded for 3 minutes. This kneaded product was granulated by using a speed mill (2 mm width herringbone), and then 55 to 6
After drying at 0 ° C for 3 hours, the particles were sized to 32 to 100 mesh to obtain sustained release fine granule sustained release portion I310g.
【００７１】−徐放性粒状剤徐放部II− エチルセルロース８０ｇ、アミノアルキルメタアクリレ
ートコポリマー２０ｇをエタノール：ジクロルメタン
（１：１）混液１８００ｇに加えて超音波処理して溶解
した液にウルソデスオキシコール酸１６０ｇ、ダイラク
トース１２０ｇ及びステアリン酸マグネシウム２０ｇを
加えて撹拌しながら均一な懸濁液を調製し、噴霧乾燥造
粒装置を用いて常法に従って造粒し、６０〜１２０メッ
シュに整粒して徐放性細粒剤徐放部II２８０ｇを得た。-Sustained release granular agent sustained release part II- 80 g of ethyl cellulose and 20 g of aminoalkyl methacrylate copolymer were added to 1800 g of a mixed solution of ethanol: dichloromethane (1: 1) and ultrasonically treated to dissolve ursodesoxychol. 160 g of acid, 120 g of dilactose and 20 g of magnesium stearate were added to prepare a uniform suspension while stirring, granulated according to a conventional method using a spray-drying granulator, and sized to 60 to 120 mesh. 280 g of sustained release fine granule sustained release part II was obtained.
【００７２】次に、これらの速放性細粒剤、徐放性細粒
剤徐放部Ｉ及び徐放部IIをそれぞれ１重量部、３重量
部、２重量部の割合で混合し、速放性粒状剤１重量部に
対し、徐放性粒状剤が５重量部組み合わせてなる複合粒
状剤とした。これを１製剤投与単位1.８ｇ（ウルソデス
オキシコール酸７５０mg含有）としてストリップパッケ
ージ（ＳＰ包装）に充填して持続性製剤を得た。Next, these rapid-release fine granules, sustained-release fine granules sustained-release part I and sustained-release part II were mixed in the proportions of 1 part by weight, 3 parts by weight and 2 parts by weight, respectively, and mixed immediately. 5 parts by weight of the sustained-release granules were combined with 1 part by weight of the release granules to give a composite granule. This was filled in a strip package (SP packaging) as a dosage unit of 1.8 g (containing 750 mg of ursodesoxycholic acid) to obtain a sustained-release preparation.
【００７３】[0073]
【発明の効果】本発明の持続性製剤は、生体内の消化管
を考慮したｐＨ変化法による溶出試験において、従来製
剤と比べ長時間一定量の放出を維持し、又、胆管瘻ラッ
トモデルにおいても、初期の吸収は制御され、胆汁中へ
持続的にウルソデスオキシコール酸抱合体が排泄され、
明らかな徐放性が認められた。INDUSTRIAL APPLICABILITY The sustained-release preparation of the present invention maintains a constant amount of release for a longer period of time in a dissolution test by a pH change method considering the digestive tract in a living body, and in a rat model of biliary fistula. However, the initial absorption was controlled, and the ursodesoxycholic acid conjugate was continuously excreted into the bile,
A clear sustained release was observed.
【００７４】よって、本製剤は、胆汁酸分泌の少ない就
寝前１日１回の服用で夜間に亙り持続的にウルソデスオ
キシコール酸が供給されることにより確実に治療効果を
高め、かつ大幅なコンプライアンスの改善が期待できる
もので、その有用性は大である。Therefore, the preparation of the present invention can be administered once daily at bedtime with a low secretion of bile acids, and the ursodesoxycholic acid can be continuously supplied throughout the night to surely enhance the therapeutic effect. It can be expected to improve compliance, and its usefulness is great.
【図１】本発明の実施例１、３、５の速放性粒状剤のｐ
Ｈ6.５における溶出試験結果を示すグラフ図である。FIG. 1 shows the p of the immediate release granules of Examples 1, 3, and 5 of the present invention.
It is a graph which shows the elution test result in H6.5.
【図２】本発明の実施例１、３、５の徐放性粒状剤徐放
部ＩのｐＨ7.０における溶出試験結果を示すグラフ図で
ある。FIG. 2 is a graph showing the results of a dissolution test of the sustained release granular agent sustained release part I of Examples 1, 3, and 5 of the present invention at pH 7.0.
【図３】本発明の実施例１、３、５の徐放性粒状剤徐放
部IIのｐＨ8.０における溶出試験結果を示すグラフ図で
ある。FIG. 3 is a graph showing the results of dissolution tests of the sustained release granular agent sustained release part II of Examples 1, 3, and 5 of the present invention at pH 8.0.
【図４】本発明の実施例１、３、５の持続性製剤及び市
販製剤（ウルソサン錠５０mg）のｐＨ変化法による溶出
試験結果を示すグラフ図である。FIG. 4 is a graph showing the results of a dissolution test of the sustained-release preparations and commercial preparations (ursosan tablets 50 mg) of Examples 1 to 3 and 5 of the present invention by the pH change method.
【図５】従来製剤を胆管瘻ラットに経口投与した時の胆
管カニューレより経時的に排出してくる胆汁中のウルソ
デスオキシコール酸（抱合体）量の測定結果を示すグラ
フ図である。FIG. 5 is a graph showing the measurement results of the amount of ursodesoxycholic acid (conjugate) in bile expelled with time from a bile duct cannula when a conventional preparation is orally administered to a cholangiostomy rat.
【図６】実施例１の持続性製剤を胆管瘻ラットに経口投
与した時の胆管カニューレより経時的に排出してくる胆
汁中のウルソデスオキシコール酸（抱合体）量の測定結
果を示すグラフ図である。FIG. 6 is a graph showing the measurement results of the amount of ursodesoxycholic acid (conjugate) in the bile discharged over time from the bile duct cannula when the sustained-release preparation of Example 1 was orally administered to a cholangiostomy rat. It is a figure.
【図７】実施例５の持続性製剤を胆管瘻ラットに経口投
与した時の胆管カニューレより経時的に排出してくる胆
汁中のウルソデスオキシコール酸（抱合体）量の測定結
果を示すグラフ図である。FIG. 7 is a graph showing the measurement results of the amount of ursodesoxycholic acid (conjugate) in the bile that is discharged from the bile duct cannula over time when the sustained-release preparation of Example 5 was orally administered to cholangiofistula rats. It is a figure.
フロントページの続き (72)発明者 小口 真奈美 埼玉県浦和市田島４丁目24番３号 アート パレス浦和Ｎｏ．２ 203号Front Page Continuation (72) Inventor Manami Oguchi 4-24-3 Tajima, Urawa City, Saitama Art Palace Urawa No. 4 2 No. 203
Claims (11)
酸を含有する速放性粒状剤と徐放性粒状剤との組み合わ
せよりなる複合粒状剤であるウルソデスオキシコール酸
持続性製剤。1. A sustained release preparation of ursodesoxycholic acid, which is a composite granule comprising a combination of an immediate release granule containing ursodesoxycholic acid as a medicinal component and a sustained release granule.
酸、デンプン類若しくは糖類若しくはセルロース類から
選ばれた一種又は二種以上の賦形剤、崩壊剤及び結合剤
を配合してなる複合粒状剤であることを特徴とする請求
項１記載のウルソデスオキシコール酸持続性製剤。2. A composite granule in which an immediate release granule is blended with one or more kinds of excipients selected from ursodesoxycholic acid, starches or sugars or celluloses, a disintegrating agent and a binder. The ursodesoxycholic acid sustained-release preparation according to claim 1, which is an agent.
酸及び親水性高分子、疎水性高分子若しくは腸溶性物質
から選ばれた一種又は二種以上の放出制御基剤とを配合
してなる徐放部Ｉ並びに疎水性高分子、ワックス類、ロ
ウ類又は高級脂肪酸若しくはその金属塩から選ばれた一
種又は二種以上の放出制御基剤を配合してなる徐放部II
を組み合わせた複合粒状剤であることを特徴とする請求
項１記載のウルソデスオキシコール酸持続性製剤。3. A sustained-release granule comprising ursodesoxycholic acid and one or more release-controlling bases selected from hydrophilic polymers, hydrophobic polymers or enteric substances. Sustained release part I and sustained release part II containing one or more release controlling bases selected from hydrophobic polymers, waxes, waxes, higher fatty acids or metal salts thereof
The sustained-release preparation for ursodesoxycholic acid according to claim 1, which is a composite granular agent in which
酸が製剤全重量中、速放性粒状剤に対し５０〜９０重量
％、徐放性粒状剤徐放部Ｉに対し４０〜８０重量％、徐
放性粒状剤徐放部IIに対し４０〜７０重量％配合してな
る複合粒状剤であることを特徴とする請求項１記載のウ
ルソデスオキシコール酸持続性製剤。4. Ursodesoxycholic acid as a medicinal component is contained in the total weight of the preparation in an amount of 50 to 90% by weight with respect to the immediate release granular agent, and 40 to 80% by weight with respect to the sustained release granular agent I. Sustained-release granular agent The sustained-release preparation of ursodesoxycholic acid according to claim 1, which is a composite granular agent in which 40 to 70% by weight is mixed with the sustained-release part II.
製剤全重量に対し５〜４０重量％配合され、徐放部IIの
放出制御基剤が製剤全重量に対し２〜５０重量％配合さ
れてなることを特徴とする請求項３記載のウルソデスオ
キシコール酸持続性製剤。5. The controlled release base for sustained release granular agent sustained release part I is blended in an amount of 5 to 40% by weight based on the total weight of the preparation, and the controlled release base for sustained release part II is 2 to the total weight of the preparation. The sustained-release preparation for ursodesoxycholic acid according to claim 3, which is contained in an amount of 50% by weight.
出するように調節された徐放部ＩとｐＨ7.５〜８で一定
に放出するように調節された徐放部IIとの組み合わせよ
りなることを特徴とする請求項３又は５記載のウルソデ
スオキシコール酸持続性製剤。6. A sustained-release part I in which the sustained-release granule is adjusted to have a constant release at pH 6.5 to 7 and a sustained-release part II to have a constant release in pH 7.5 to 8. 6. The sustained-release preparation for ursodesoxycholic acid according to claim 3, which is a combination with
重量部に対し１〜１１重量部となるように組み合わされ
た複合粒状剤であることを特徴とする請求項１、２、３
又は４記載のウルソデスオキシコール酸持続性製剤。7. A controlled release granule 1 containing a controlled release granule.
It is a composite granular agent combined so as to be 1 to 11 parts by weight with respect to parts by weight.
Alternatively, the ursodesoxycholic acid sustained-release preparation according to 4 above.
Ｉ１重量部に対し0.５〜４重量部となるように組み合わ
された複合粒状剤であることを特徴とする請求項３、
５、６又は７記載のウルソデスオキシコール酸持続性製
剤。8. A composite granule which is combined so that the blending amount of the sustained-release part II is 0.5 to 4 parts by weight with respect to 1 part by weight of the sustained-release part I. Claim 3,
The sustained-release preparation of ursodesoxycholic acid according to 5, 6, or 7.
成物、顆粒組成物又は粒状組成物であることを特徴とす
る請求項１〜８のいずれか１記載のウルソデスオキシコ
ール酸持続性製剤。9. The ursodesoxy according to any one of claims 1 to 8, wherein the immediate-release granular agent and the sustained-release granular agent are a fine-grain composition, a granular composition or a granular composition. Cholic acid sustained release formulation.
トリックス顆粒、マトリックス粒状組成物、コーティン
グ細粒、コーティング顆粒又はコーティング粒状組成物
であることを特徴とする請求項１、３〜８又は９記載の
ウルソデスオキシコール酸持続性製剤。10. The sustained release granule is a matrix fine granule, a matrix granule, a matrix granule composition, a coated granule, a coated granule or a coated granule composition, wherein the granule is a granule. The ursodesoxycholic acid sustained-release preparation described.
ル酸が１投与単位として３００〜８００mg含有され、１
製剤単位重量が0.５〜1.８ｇであることを特徴とする請
求項１記載のウルソデスオキシコール酸持続性製剤。11. A medicinal ingredient, ursodesoxycholic acid, is contained in an amount of 300 to 800 mg as one dosage unit, and 1
The sustained-release preparation of ursodesoxycholic acid according to claim 1, wherein the preparation unit weight is 0.5 to 1.8 g.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3148404A JPH0624991A (en) | 1991-06-20 | 1991-06-20 | Long acting preparation of ursodeoxycholic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3148404A JPH0624991A (en) | 1991-06-20 | 1991-06-20 | Long acting preparation of ursodeoxycholic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0624991A true JPH0624991A (en) | 1994-02-01 |
Family
ID=15452028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3148404A Pending JPH0624991A (en) | 1991-06-20 | 1991-06-20 | Long acting preparation of ursodeoxycholic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0624991A (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002087549A1 (en) * | 2001-04-25 | 2002-11-07 | Taisho Pharmaceutical Co., Ltd. | Multiple unit type sustained-release tablets |
| WO2006057637A1 (en) * | 2004-11-24 | 2006-06-01 | Seo Hong Yoo | Dried forms of aqueous solubilized bile acid dosage formulation: preparation and uses thereof |
| WO2008130234A1 (en) * | 2007-04-19 | 2008-10-30 | Disphar International B.V. | High dose composition of ursodeoxycholic acid |
| WO2009051022A2 (en) | 2007-10-19 | 2009-04-23 | Otsuka Pharmaceutical Co., Ltd. | Matrix-type pharmaceutical solid preparation |
| US7772220B2 (en) | 2004-10-15 | 2010-08-10 | Seo Hong Yoo | Methods and compositions for reducing toxicity of a pharmaceutical compound |
| US7932243B2 (en) | 1998-07-24 | 2011-04-26 | Seo Hong Yoo | Bile preparations for gastrointestinal disorders |
| US8173627B2 (en) | 2004-08-30 | 2012-05-08 | Seo Hong Yoo | Neuroprotective effect of solubilized UDCA in focal ischemic model |
| US9907789B2 (en) | 2011-10-21 | 2018-03-06 | Takeda Pharmaceutical Company Limited | Sustained-release preparation |
| JP2018527371A (en) * | 2015-09-16 | 2018-09-20 | ラボラトワ シー．ティー．アール．エス． | Pediatric preparations containing bile acids |
| CN110478304A (en) * | 2019-08-20 | 2019-11-22 | 广州市金熊大健康科技有限公司 | A kind of toothpaste containing bear gall microcapsules |
| CN114515268A (en) * | 2022-02-21 | 2022-05-20 | 上海宣泰医药科技股份有限公司 | Ursodeoxycholic acid medicine composition, its preparation method and medicinal preparation |
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Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7932243B2 (en) | 1998-07-24 | 2011-04-26 | Seo Hong Yoo | Bile preparations for gastrointestinal disorders |
| WO2002087549A1 (en) * | 2001-04-25 | 2002-11-07 | Taisho Pharmaceutical Co., Ltd. | Multiple unit type sustained-release tablets |
| US8173627B2 (en) | 2004-08-30 | 2012-05-08 | Seo Hong Yoo | Neuroprotective effect of solubilized UDCA in focal ischemic model |
| US7772220B2 (en) | 2004-10-15 | 2010-08-10 | Seo Hong Yoo | Methods and compositions for reducing toxicity of a pharmaceutical compound |
| WO2006057637A1 (en) * | 2004-11-24 | 2006-06-01 | Seo Hong Yoo | Dried forms of aqueous solubilized bile acid dosage formulation: preparation and uses thereof |
| JP2008521800A (en) * | 2004-11-24 | 2008-06-26 | セオ ホン ユー | Dry form of water-solubilized bile acid dosage formulation, production method and use thereof |
| WO2008130234A1 (en) * | 2007-04-19 | 2008-10-30 | Disphar International B.V. | High dose composition of ursodeoxycholic acid |
| JP2010524926A (en) * | 2007-04-19 | 2010-07-22 | ディスパル・インターナショナル・ビー．ブイ． | High dose composition of ursodeoxycholic acid |
| WO2009051022A2 (en) | 2007-10-19 | 2009-04-23 | Otsuka Pharmaceutical Co., Ltd. | Matrix-type pharmaceutical solid preparation |
| KR20100087011A (en) | 2007-10-19 | 2010-08-02 | 오츠카 세이야쿠 가부시키가이샤 | Matrix-type pharmaceutical solid preparation |
| US9072670B2 (en) | 2007-10-19 | 2015-07-07 | Otsuka Pharmaceutical Co., Ltd. | Matrix-type pharmaceutical solid preparation |
| US9289389B2 (en) | 2007-10-19 | 2016-03-22 | Otsuka Pharmaceutical Co., Ltd. | Method for producing matrix-type pharmaceutical solid preparation |
| US9907789B2 (en) | 2011-10-21 | 2018-03-06 | Takeda Pharmaceutical Company Limited | Sustained-release preparation |
| JP2018527371A (en) * | 2015-09-16 | 2018-09-20 | ラボラトワ シー．ティー．アール．エス． | Pediatric preparations containing bile acids |
| CN110478304A (en) * | 2019-08-20 | 2019-11-22 | 广州市金熊大健康科技有限公司 | A kind of toothpaste containing bear gall microcapsules |
| CN110478304B (en) * | 2019-08-20 | 2022-07-05 | 广州市金熊大健康科技有限公司 | Toothpaste containing bear gall microcapsule |
| CN114515268A (en) * | 2022-02-21 | 2022-05-20 | 上海宣泰医药科技股份有限公司 | Ursodeoxycholic acid medicine composition, its preparation method and medicinal preparation |
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