JPS5959610A - Propranolol preparation - Google Patents
Propranolol preparationInfo
- Publication number
- JPS5959610A JPS5959610A JP17199582A JP17199582A JPS5959610A JP S5959610 A JPS5959610 A JP S5959610A JP 17199582 A JP17199582 A JP 17199582A JP 17199582 A JP17199582 A JP 17199582A JP S5959610 A JPS5959610 A JP S5959610A
- Authority
- JP
- Japan
- Prior art keywords
- preparation
- propranolol
- administration
- bioavailability
- buccogingival
- 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.)
- Pending
Links
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
【発明の詳細な説明】
本発明はプロプフッロー／Ｉ／（一般名）またはその塩
の上部瞳頬移行部投与用製剤に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a formulation of Propfluoro/I/ (common name) or a salt thereof for administration at the upper pupil-buccal junction.
プロプフッロー／ｌ’またはその塩はβ−アドレナリン
遮断作用を有し主として高血圧症、および狭心症、不整
脈、その他の心臓疾患、偏頭痛の治療又は予防に広く使
用されている。Propfluoro/l' or a salt thereof has a β-adrenergic blocking effect and is widely used mainly for the treatment or prevention of hypertension, angina pectoris, arrhythmia, other heart diseases, and migraine.
しかしながら、この薬物は経口投与すると血中への吸収
の程度が低く且つ一定しない。However, when this drug is administered orally, the degree of absorption into the blood is low and inconsistent.
例えばシャント（５ｈａｎｄ ）らの報告〔クリ二カμ
・ファーマコｐシイ−・アンド・テフビューティツクス
（Ｃ１１ｎ−ＰｈａｒｍａＣＯＬ Ｔｈｅｒａｐ、 、
１１１１１２（１９７０））によればヒトにプロプフ
ッロールを８ＯＭｆ１人の投与量で経口投与した場合、
５人の被検者における最高血漿中濃度は７倍も異り、さ
らに有効利用率〔パイオアペイフビリテイ（ｂｉｏ−ａ
ｖａ、１ｌａｂｉｌｉｔｙ ）］も１６％と低い値であ
る。For example, a report by Shant (5hand) et al.
・PharmaCOL Therapy (C11n-PharmaCOL Therapy)
111112 (1970)), when propfluorol is orally administered to humans at a dose of 8OMf per person,
The peak plasma concentrations in the five subjects differed by a factor of seven, and the bioavailability
va, lability)] is also a low value of 16%.
本発明者等は、このような点を克服すべく検討したとこ
ろ、プロプフッロー／Ｌ／−４だはその塩に徐放化助剤
を混合して製造された製剤を上部醸頬移行部に投与する
と有効利用率〔パイオアベイフビリテイ（ｂｉｏａｖａ
ｉｌａｂｉｌｉｔ、ｙ ） ）がほぼ１００％近くに
なシ、しかも、そのバラツキが顕著に減少することを知
見し、さらに鋭意研究を続けた結果、本発明を完成した
。The present inventors investigated to overcome these problems and found that a preparation prepared by mixing Propfluoro/L/-4 or its salt with a sustained release aid was administered to the upper cheek-cheek transition area. Then, the effective utilization rate [bioava
It was discovered that the ilabilit, y)) was almost 100%, and the variation was significantly reduced, and as a result of further intensive research, the present invention was completed.
即ち、本発明はプロプラノロー）ｖまたはその塩および
徐放化助剤を含有することを特徴とする上部晴頬移行部
投与用製剤に関する。That is, the present invention relates to a preparation for administration at the upper buccal transition area, which is characterized by containing propranolol)v or a salt thereof and a sustained release aid.
本発明のプロプラノロール、即ちｌ−（イソプロピルア
ミノ）−３−（１−ナフチルオキシ）−２−プロパツー
ルは、構迫式
により表わされる。The propranolol of the present invention, ie 1-(isopropylamino)-3-(1-naphthyloxy)-2-propatol, is represented by the formula.
本発明の１０プラノローρの塩としては、例えば塩酸、
臭化水素酸等の無機酸や例えば、ステアリン酸、バルミ
チン酸等の有機酸との塩が用いられる。Examples of the 10-planorho salt of the present invention include hydrochloric acid,
Salts with inorganic acids such as hydrobromic acid and organic acids such as stearic acid and valmitic acid are used.
プロプラノロールは分子内に１個の不斉度素を有し、（
２Ｒ）又は（２８）−１−（イソ１０ピルアミノ）−３
−（１−ナフチルオキシ）−２−グロパノールの両光学
異性体が存在する。本発明製剤は通常光学不活性なプロ
プラノロール即ちラセミ体が用いられるが、上記（２Ｒ
）−又は（２Ｓ）−異性体又はそれらの任意の混合物を
用いることもできる。Propranolol has one asymmetric element in the molecule, (
2R) or (28)-1-(iso10pylamino)-3
Both optical isomers of -(1-naphthyloxy)-2-gropanol exist. The preparation of the present invention usually uses optically inactive propranolol, that is, racemic form, but the above (2R
)- or (2S)-isomers or any mixtures thereof can also be used.
本発明製剤中のプロプラノロールまたはその塩の含量は
約１〜５０重量％、好ましくは約５〜３０重量％である
。The content of propranolol or its salt in the formulation of the present invention is about 1 to 50% by weight, preferably about 5 to 30% by weight.
本発明製剤で用いられる徐放化助剤としては、例ｔばヒ
ドロキシエチルセルロース、ヒドロキシプロピルセルロ
ース、ヒドロキシグロビルメチルセルロース、力μボキ
シメチルセルロースなどの七μロース誘導体、ゼラチン
、アラビアゴム、アミロペクチンスターチ、０，５％水
溶液の粘度を測定するときｐＨ６，０〜７．０で１０３
〜１０５０ＰＳを示す範囲のアクリル酸重合体（例えば
市販品にあるアクリル酸とアリμ庶糖、アクリル酸メチ
ル、メタアクリル酸、メタアクリル酸メチル。Examples of sustained release aids used in the formulation of the present invention include hydroxyethylcellulose, hydroxypropylcellulose, hydroxyglobil methylcellulose, 7μlose derivatives such as hydroxylboxymethylcellulose, gelatin, gum arabic, amylopectin starch, , 103 at pH 6.0 to 7.0 when measuring the viscosity of a 5% aqueous solution.
Acrylic acid polymers in the range of ~1050PS (for example, commercially available acrylic acid and sucrose, methyl acrylate, methacrylic acid, methyl methacrylate).
ヒドロキシエチルメタアクリレート、スチレンあるいは
メチルビニルエーテルのようなどニ／Ｌ［工〔例えばウ
イテプゾ／Ｌ’ Ｗ−３１（商品名、ダイナミツトノ
ーベル社製（西ドイツ）〕、〕及０−→壬チ出→９興ｉ
ｂ−匹−ＪＪ、−合渡４−ｏ−ｏ−ｏ〜１−ｏｏｏｏ：
、＋−←←等が用いられる。このうち好ま
しくは、ヒドロキシプロピルセルロース、上記アクリル
酸重合体、アミロペクチンスターチ、融点３０〜４０℃
のグリセライド等である。Such as hydroxyethyl methacrylate, styrene or methyl vinyl ether, etc. Xing i
b-fish-JJ, -Awado 4-o-o-o~1-oooo:
, +-←←, etc. are used. Among these, hydroxypropyl cellulose, the above acrylic acid polymer, amylopectin starch, melting point 30-40°C
glycerides, etc.
上記徐放化助剤は、本発明製剤巾約２〜２を重量％、好
ましくは約゛１０〜・７０重Ｍ％添加される。The above-mentioned sustained release aid is added in an amount of about 2 to 2% by weight, preferably about 10 to 70% by weight.
本発明の製剤は、その剤型および大きさに制限はなく、
上部躍頬移行部に用いうる剤型であれば、常温で固状ま
たは半固状の錠剤、丸剤、トローチ剤、バッカル剤、軟
膏剤等いかなる剤型でもよく、これらは通常の方法によ
って製造することができる。従って、上記徐放化助剤の
他通常の賦形剤、たとえばコーンスターチ、小麦でんぷ
ん、バレイショでんぷんなどのでんぷん類、乳糖、シ３
糖。The formulation of the present invention is not limited in its dosage form or size,
Any dosage form that can be used for the supra-buccal transition area may be used, such as tablets, pills, troches, buccal preparations, and ointments that are solid or semi-solid at room temperature, and these can be manufactured by conventional methods. can do. Therefore, in addition to the above-mentioned sustained-release aids, conventional excipients such as cornstarch, wheat starch, potato starch, lactose, sugar, etc.
sugar.
ブドウ糖、マンニド−μなどの糖類、硫酸カルシウム、
リン酸カルシウム、沈降度酸ナトリウム。Glucose, sugars such as mannide-μ, calcium sulfate,
Calcium phosphate, sodium precipitate.
塩化ナトリウム、ホウ酸などの無機物質；通常の結合剤
、たとえばでんぷん類、糖類、デキストリン、アラビア
ゴム、トラガント、アルギン酸ナトリウム、グルテンな
どの天然物質、メチルセルロース、工ｆｌＶセルロース
などのセルロース［４体、ポリビニルピロリドン、ポリ
ビニルアルコール）ポリビニルアセテートなどの合成高
分子化合物の他、上記徐放化助剤が結合剤としても使用
される；通常の滑沢剤、たとえばステアリン酸マグネシ
ウム、タルク、合成ケイ酸アルミニウム、微粒子性酸化
ケイ素、高級脂肪酸、高級アルコール、マクロゴール、
水素添加植物油、シリコン油、ポリオキシエチレングリ
コール脂肪酸エステル、パフフィン類など纂通常の吸着
剤、たとえば微粒子性酸化ケイ素、活性炭など；通常の
矯味剤、たとえばシミ糖、ブドウ糖、果糖、ソルビトー
ルなどの天然甘味料、サッカリンなどの人工甘味料、ク
エン酸、コハク酸、酒石酸などの有機酸、ｅ−メントー
μなどのフレーバーなどを用いて、常法に従って製造す
ることができる。上記賦形剤、結合剤、滑沢剤、吸着剤
の含有割合はプロプラノロールる。本発明製剤はβ−ア
ドレナリン遮断作用を有し、高血圧症、狭心症、不整脈
および偏頭痛の治療に有効である。Inorganic substances such as sodium chloride, boric acid; common binders such as starches, sugars, dextrins, gum arabic, tragacanth, sodium alginate, natural substances such as gluten, cellulose such as methyl cellulose, engineered flV cellulose, polyvinyl In addition to synthetic polymeric compounds such as pyrrolidone, polyvinyl alcohol) polyvinyl acetate, the above sustained release aids are also used as binders; common lubricants such as magnesium stearate, talc, synthetic aluminum silicates, fine particles silicon oxide, higher fatty acids, higher alcohols, macrogol,
Hydrogenated vegetable oils, silicone oils, polyoxyethylene glycol fatty acid esters, puffins, etc.Common adsorbents, such as particulate silicon oxide, activated carbon, etc.; common flavoring agents, such as natural sweeteners such as cimiculose, glucose, fructose, sorbitol, etc. It can be produced according to a conventional method using artificial sweeteners such as saccharin, organic acids such as citric acid, succinic acid, and tartaric acid, and flavors such as e-menthol μ. The content of the excipient, binder, lubricant, and adsorbent is propranolol. The preparation of the present invention has a β-adrenergic blocking effect and is effective in treating hypertension, angina pectoris, arrhythmia and migraine.
本発明の製剤においてはプロプラノロールまたはその塩
を成人１人あたシ５〜１ｏｏｑ、好ましくは１０〜５０
哩、１日２〜４回にわけて投与する勿が、症状に広し適
宜増量することもできる。In the formulation of the present invention, propranolol or its salt is administered at a dose of 5 to 1 ooq, preferably 10 to 50 ooq, per adult.
Of course, the dose may be divided into 2 to 4 doses per day, but the dose may be increased as appropriate depending on the symptoms.
本発明製剤投与部位は通常は上部際頬移行部（上顎歯肉
部と***の間の空隙）である。The administration site of the preparation of the present invention is usually the upper buccal transition area (the space between the maxillary gingival area and the lips).
この部位に投与した場合、違和感もなく、特別の接着性
物質を加えることなく長時間保持され、食事をとること
も可能である。When administered to this area, there is no discomfort, the drug is retained for a long time without the addition of special adhesive substances, and it is possible to take a meal.
現在までにこの上部暖頬移行部への投与に関して若干報
告されているが（日本薬学会第１０２年会講演要旨集：
１９８２年、第６０１頁３Ｗ ４−５）、口腔内局
所治療剤に関してのみで、しかも口腔からは吸収せずに
消化管で吸収する薬物で、本発明のように、この部位に
投与し口腔からの吸収がその主たる吸収部位で全身的治
療を目的とした報告は未だなく、本発明の特長の１つで
ある。To date, there have been some reports regarding administration to this upper warm cheek transition area (collection of abstracts from the 102nd Annual Meeting of the Pharmaceutical Society of Japan).
1982, p. 601, 3W 4-5), it is only a topical therapeutic agent for the oral cavity, and it is a drug that is not absorbed from the oral cavity but is absorbed in the gastrointestinal tract, and as in the present invention, it is administered to this site and administered from the oral cavity. As yet, there has been no report on the absorption of the drug as a main absorption site for the purpose of systemic treatment, which is one of the features of the present invention.
この部位へ適用する場合に製剤の大きさに特に制限はな
いが、官能検査で調べると錠剤の場合、直径１２ｍｍ以
下で厚み１．５ｍｍ以下であれば通常の成人では食事中
でも何の抵抗もなく挿入していることが可能であった。There are no particular restrictions on the size of the preparation when applied to this area, but according to sensory tests, if the tablet is 12 mm or less in diameter and 1.5 mm or less in thickness, a normal adult will not experience any resistance even during meals. It was possible to insert it.
さらに本発明の投与方法によれば、他の投与ルートに比
べ投与が簡便で、製剤の製造も特殊な操作を必要とせず
平易にできるという利点がある。Furthermore, the administration method of the present invention has the advantage that administration is simpler than other administration routes, and the preparation can be easily produced without requiring any special operations.
以下に実験例、実施例を示し本発明をさらに詳述する。The present invention will be further explained in detail by showing experimental examples and examples below.
実施例
実施例１記戦の方法に従って製造されたプロプラノロー
／Ｉ／２０ｑを含有する錠剤をピーグル大に上部離頬移
行部または経口投与する。それぞれのピーグル犬から経
時的に採血し、血漿中のプロプフッロールの濃度を逆相
系液体クロマトグラフィー〔カラム充てん剤；マイクロ
ボンＦＶりＣ−１８（商品名）ウオータズ社製（アメリ
カ）、溶出液；アセトニトリ／’：１．５％酢酸水＝１
： ２）で定量する。さらにプロプフッロール塩酸塩
２０Ｒｆをパイロジエンを除去した水溶液１ ｗｅに溶
解し、これをピーグル大に静脈内投与した後、経時的に
採血し、血漿中のプロプフッロールの濃度を上記と同様
にして測定する。EXAMPLES A peagle-sized tablet containing Propranolor/I/20q prepared according to the method described in Example 1 is administered at the upper distal junction or orally. Blood was collected over time from each pegle dog, and the concentration of propfluorol in the plasma was measured by reversed-phase liquid chromatography [column packing material: Microbon FV Ri C-18 (trade name) manufactured by Waters Inc. (USA), elution Liquid; acetonitrile/': 1.5% acetic acid water = 1
: Quantify in 2). Further, propfluorol hydrochloride 20Rf was dissolved in an aqueous solution 1we from which pyrogen was removed, and this was administered intravenously to a Peagle-sized animal. Blood was collected over time, and the concentration of propfluorol in plasma was determined in the same manner as above. Measure.
得られた結果から、トラベゾイタリレ ルールに、従っ
て血漿中濃度一時間曲線下面債（ＡＵＣ）を計算した。From the results obtained, the plasma concentration one-hour curve under the curve (AUC) was calculated according to the Travezoitariler rule.
さらに、有効利用率〔バイオアベイラビリティ（ｂｉｏ
ａｖａｉｌａｂｉｌｉｔｙ ） ）は下式に従って求め
た。Furthermore, the effective utilization rate [bioavailability (bioavailability)
availability )) was determined according to the following formula.
中Ｓ、 Ｅ、 、スタンダード エラーＣ標準誤差）表
１から明らかなように、経口投与におけるプロプフッロ
ールのバイオアベイラビリティ（ｂｉｏ−ａＶａｉｌａ
ｂｉｌｉｔｙ ）は平均でわずか１４．２％であシ、そ
のパフツキも大きく３．８％から２５．０％と約７倍の
変動がみられた。As is clear from Table 1, the bioavailability of propfluorol in oral administration (bio-a Vaila
The average value (bility) was only 14.2%, and its puffiness varied greatly, from 3.8% to 25.0%, about 7 times as much.
一方、上部暖頬移行部投与においてはそのバイオアベイ
ラビリティ（ｂｉｏａｖａｉｌａｂｉｌｉｔｙ ）は平
均で９３．８％と大きく、バラツキも８１．６％から１
１２％と１．４倍の変動しかみられなかった。On the other hand, when administered to the upper warm cheek transition area, the bioavailability was as high as 93.8% on average, and the variation ranged from 81.6% to 1.
The change was only 12%, or 1.4 times.
実施例／
プロプラノロー／Ｉ／１ｇ、乳糖７Ｑ、ヒドロキシグロ
ピｐセルロース２ｇをよく混合し、常法によって湿式造
粒した後、乾燥して得られる顆粒にステアリン酸マグネ
シウム０．０５９を混合した後、直径９−５＋ｎｍ、厚
み１．５＋ｎｍの錠剤で１錠あたり２ｏｍｙの鍜頬移行
部投与用錠剤として約１５００ｋｇ／ｃｍ” （圧力）
で打錠する。Example / Propranolor/I/1 g, lactose 7Q, and hydroxyglopi p-cellulose 2 g were thoroughly mixed, wet granulated by a conventional method, and 0.059 g of magnesium stearate was mixed into the granules obtained by drying. Approximately 1500 kg/cm" (pressure) as a tablet with a diameter of 9-5+ nm and a thickness of 1.5+ nm, each tablet having a weight of 2 omy for administration at the buccal junction.
Press into tablets.
実施例λ
プロプラノロー）Ｖ塩酸塩１す、ウイテプゾ／Ｌ’Ｗ−
３１（商品名、グイナミットノーベＡ４製（西ドイツ）
〕９ｇを３０〜５０℃に加温下でよく練合した後、成型
機に入れ冷却し、縦５ｍｍ、ｆｆ４１１關、厚み３ｍｍ
の直方体で１個１５０１１Ｆの油性半固型の際頬移行部
投与用製剤とする。Example λ
31 (product name, made by Guinamit Nobe A4 (West Germany)
] After kneading 9g well under heating at 30-50℃, put it in a molding machine and cool it to make a 5mm long, FF411 size, and 3mm thick.
One 15011F oil-based semi-solid rectangular parallelepiped preparation for administration at the buccal transition area.
実施例３
プロプラノロールステアリン酸＠１ｇ、乳糖７ｑ、ヒド
ロキシプロピルセルロース２ｇを湿式造粒後、乾燥して
得られる顆粒にステアリン酸マグネシウム０．０５９を
混合した後、１錠あたシプロデフノロー＃２０’ｆを含
有する顛頬移行部投与用錠剤として約１５００ｋｇ／ｃ
ｎ＋２（圧力）で打錠する。Example 3 After wet granulating propranolol stearic acid @ 1 g, lactose 7 q, and hydroxypropyl cellulose 2 g, 0.059 of magnesium stearate was mixed with the granules obtained by drying, and Ciprodefnol #20'f was mixed per tablet. Approximately 1500 kg/c as a tablet for administration at the buccal junction containing
Compress at n+2 (pressure).
Claims (1)
することを特徴とする上部鍜頬移行部投与用製剤。1. A preparation for administration at the upper buccal junction, comprising propranolol or a salt thereof and a sustained release aid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17199582A JPS5959610A (en) | 1982-09-29 | 1982-09-29 | Propranolol preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17199582A JPS5959610A (en) | 1982-09-29 | 1982-09-29 | Propranolol preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS5959610A true JPS5959610A (en) | 1984-04-05 |
Family
ID=15933570
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17199582A Pending JPS5959610A (en) | 1982-09-29 | 1982-09-29 | Propranolol preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5959610A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59181218A (en) * | 1983-03-29 | 1984-10-15 | Dai Ichi Seiyaku Co Ltd | Pharmaceutical for administration to interior of oral cavity |
| JPS63502187A (en) * | 1986-01-22 | 1988-08-25 | キ−・ファ−マシュ−ティカルス・インコ−ポレ−テッド | buccal agent |
| WO1998006379A1 (en) * | 1996-08-08 | 1998-02-19 | R.P. Scherer Limited | Pharmaceutical compositions |
-
1982
- 1982-09-29 JP JP17199582A patent/JPS5959610A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59181218A (en) * | 1983-03-29 | 1984-10-15 | Dai Ichi Seiyaku Co Ltd | Pharmaceutical for administration to interior of oral cavity |
| JPS63502187A (en) * | 1986-01-22 | 1988-08-25 | キ−・ファ−マシュ−ティカルス・インコ−ポレ−テッド | buccal agent |
| WO1998006379A1 (en) * | 1996-08-08 | 1998-02-19 | R.P. Scherer Limited | Pharmaceutical compositions |
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