JP2000356632A - Testing method - Google Patents
Testing methodInfo
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- JP2000356632A JP2000356632A JP2000111808A JP2000111808A JP2000356632A JP 2000356632 A JP2000356632 A JP 2000356632A JP 2000111808 A JP2000111808 A JP 2000111808A JP 2000111808 A JP2000111808 A JP 2000111808A JP 2000356632 A JP2000356632 A JP 2000356632A
- Authority
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- Prior art keywords
- preparation
- elution
- solid preparation
- active ingredient
- ultraviolet
- Prior art date
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- Investigating Or Analysing Materials By Optical Means (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、生物学的製剤や生薬製
剤等の動植物を起源とする分画又は抽出製剤において、
錠剤等の固形製剤からの有効成分の溶出を確認する試験
方法、該試験方法を特徴とする固形製剤の製造方法、並
びに該試験方法により品質を担保された医薬品製剤に関
する。The present invention relates to a fractionation or extraction preparation originating from animals and plants such as biological preparations and crude drug preparations,
The present invention relates to a test method for confirming dissolution of an active ingredient from a solid preparation such as a tablet, a method for producing a solid preparation characterized by the test method, and a pharmaceutical preparation whose quality is ensured by the test method.
【０００２】[0002]
【従来の技術】溶出試験法とは、日本薬局方解説書・第
十三改正の一般試験法の項に説明されている通り、内用
固形製剤（錠剤、散剤、カプセル剤、ドライシロップ剤
など）からの主成分の溶出を試験する方法であって、内
用固形製剤の品質を一定水準に確保し、併せて著しい生
物学的非同等性を防ぐことを目的とするものである。2. Description of the Related Art The dissolution test method is a solid preparation for internal use (tablets, powders, capsules, dry syrups, etc.), as described in the Japanese Pharmacopoeia Manual, 13th Revised General Test Methods. This is a method for testing the elution of the main component from a solid preparation, which aims to ensure the quality of a solid preparation for internal use to a certain level and also to prevent significant biological non-equivalence.
【０００３】有機化学的に合成され有効成分が明確であ
る薬剤については、サンプリングした溶出試験液中の有
効成分量を、高速液体クロマトグラフィー（ＨＰＬＣ）
等を用いた分析試験や特異的反応試薬等を用いた定量分
析によって、固形製剤から水溶液中への有効成分の溶出
状態を定量的に検出して確認することができる。[0003] For a drug which is synthesized organically and has a clear active ingredient, the amount of the active ingredient in the sampled dissolution test solution is determined by high performance liquid chromatography (HPLC).
The elution state of the active ingredient from the solid preparation into the aqueous solution can be quantitatively detected and confirmed by an analytical test using the above or a quantitative analysis using a specific reaction reagent or the like.
【０００４】[0004]
【発明が解決しようとする課題】しかし、生物学的製剤
や生薬製剤のように動物や植物の組織からの抽出製剤で
ある場合、その有効成分としては種々の組織成分が含ま
れており、これらの多種成分が総合的に作用して薬効を
奏するため、このような薬剤の溶出試験は非常に困難で
ある。従ってワクシニアウイルス接種家兎炎症皮膚抽出
物等の有効成分未詳の抽出物製剤につき、それを有効成
分として含有する経口用固形製剤の定量的且つ簡便な溶
出試験方法の確立が望まれていた。However, in the case of extract preparations from animal or plant tissues, such as biological preparations and crude drug preparations, various tissue components are contained as active ingredients. The dissolution test of such a drug is very difficult because the various components described above act comprehensively to exert a drug effect. Therefore, it has been desired to establish a quantitative and simple dissolution test method for an oral solid preparation containing an active ingredient such as vaccinia virus-inoculated rabbit inflamed rabbit extract whose active ingredient is unknown.
【０００５】[0005]
【課題を解決するための手段】本発明の目的は、有効成
分の溶出を正確に反映し且つ簡便に測定可能な生物学的
製剤や生薬製剤等の固形製剤からの溶出試験方法、該試
験方法を特徴とする固形製剤の製造方法、並びに該試験
方法により品質を担保された医薬品製剤を提供すること
にある。DISCLOSURE OF THE INVENTION An object of the present invention is to provide a method for testing dissolution from solid preparations such as biological preparations and crude drug preparations which accurately reflects the dissolution of an active ingredient and can be easily measured. It is an object of the present invention to provide a method for producing a solid preparation characterized by the following, and a pharmaceutical preparation whose quality is ensured by the test method.
【０００６】[0006]
【発明の実施の形態】本発明は、動植物起源の分画又は
抽出製剤の固形製剤から水溶液中への有効成分の溶出を
紫外部吸光度又は紫外部吸収物質を測定して確認するこ
とを特徴とする試験方法、該試験方法を特徴とする固形
製剤の製造方法、並びに該試験方法により品質を担保さ
れた医薬品製剤である。BEST MODE FOR CARRYING OUT THE INVENTION The present invention is characterized in that the elution of an active ingredient from a solid preparation of a fraction or an extract preparation of animal or plant origin into an aqueous solution is confirmed by measuring an ultraviolet absorbance or an ultraviolet absorbing substance. A test method, a method for producing a solid preparation characterized by the test method, and a pharmaceutical preparation whose quality is ensured by the test method.
【０００７】さらに具体的には、ワクシニアウイルス接
種家兎炎症皮膚抽出物を有効成分とする固形製剤から水
溶液中への有効成分の溶出を紫外部吸光度又は紫外部吸
収物質を測定して確認することを特徴とする錠剤等の固
形製剤の溶出試験方法、該溶出試験方法を特徴とする固
形製剤の製造方法、並びに該溶出試験方法により品質を
担保された医薬品製剤である。More specifically, the elution of the active ingredient from a solid preparation containing the vaccinia virus-inoculated rabbit inflamed skin extract as an active ingredient into an aqueous solution is confirmed by measuring the ultraviolet absorbance or the ultraviolet absorbing substance. And a method for producing a solid preparation characterized by the dissolution test method, and a pharmaceutical preparation whose quality is ensured by the dissolution test method.
【０００８】生体はウイルス等の外界からの侵襲や内的
な病態状態の進行に対して、過剰反応に対する抑制作用
と機能低下に対する増強作用という二相性をもってその
恒常性を維持し、生体機能を調整し正常化するために種
々の生体機能調整物質を産生することが知られている。
例えばワクシニアウイルスを接種した炎症組織において
産生される生体機能調整物質、該物質を病態組織から抽
出する製造方法並びにそれらの薬理活性については種々
報告されている（特公昭63-39572号公報、特公昭63-256
00号公報、特公平3-43279号公報、特許第2594222号公報
など）。[0008] The living body maintains its homeostasis with respect to the invasion of the virus and the like from the outside and the progression of the internal pathological condition, and maintains its homeostasis with a duality of an inhibitory action against an overreaction and an enhancement action against a functional decline, and regulates the biological function. It is known to produce various biological function regulating substances for normalization.
For example, there have been various reports on a biological function regulating substance produced in inflamed tissue inoculated with vaccinia virus, a production method for extracting the substance from diseased tissue, and pharmacological activities thereof (Japanese Patent Publication No. 63-39572, Japanese Patent Publication No. Sho 63-39572). 63-256
No. 00, Japanese Patent Publication No. 3-43279, Japanese Patent No. 2594222, etc.).
【０００９】実際の医薬品としてはワクシニアウイルス
接種家兎炎症皮膚抽出物製剤（商品名：ノイロトロピ
ン）がある。この製剤は例えば医療薬日本医薬品集（19
98-99年、第22版、日本医薬情報センター編、薬業時報
社発行）の1925及び1926頁に記載されているように、ワ
クシニアウイルスを接種した家兎の炎症皮膚組織から抽
出分離した非蛋白性の活性物質を含有する薬剤であり、
腰痛症、頸肩腕症候群、肩関節周囲炎、変形性関節症、
症候性神経痛、皮膚疾患（湿疹、皮膚炎、じんま疹）に
伴う掻痒、アレルギー性鼻炎、スモン後遺症状の冷感、
痛み、異常知覚等に対する適応が認められており、皮
下、筋注、静注用の注射剤並びに錠剤が医療用医薬品と
して製造承認を受けて市販されている。本発明の目的の
一つは、具体的にはこのワクシニアウイルス接種家兎炎
症皮膚抽出物製剤の錠剤の溶出試験方法、該溶出試験方
法を特徴とするワクシニアウイルス接種家兎炎症皮膚抽
出物製剤の錠剤の製造方法、並びに該溶出試験方法によ
り品質を担保されたワクシニアウイルス接種家兎炎症皮
膚抽出物製剤の錠剤である。As an actual drug, there is a vaccinia virus-inoculated rabbit inflamed skin extract preparation (trade name: neurotropin). This formulation can be used, for example, in the Japanese Pharmaceutical Collection (19
98-99, 22nd edition, edited by The Japan Pharmaceutical Information Center, published by Pharmaceutical Times Co., Ltd.), pages 1925 and 1926). A drug containing a proteinaceous active substance,
Low back pain, neck and shoulder arm syndrome, shoulder periarthritis, osteoarthritis,
Symptomatic neuralgia, pruritus associated with skin diseases (eczema, dermatitis, urticaria), allergic rhinitis, coldness of SMON sequelae,
Indications for pain, abnormal sensation, etc. have been recognized, and injections and tablets for subcutaneous, intramuscular and intravenous injections have been approved as manufacturing pharmaceuticals and are commercially available. One of the objects of the present invention is specifically a dissolution test method for tablets of this vaccinia virus-inoculated rabbit inflamed skin extract preparation, and a vaccinia virus-inoculated rabbit inflamed skin extract preparation characterized by the dissolution test method. It is a tablet of a vaccinia virus-inoculated rabbit inflamed skin extract preparation, the quality of which is ensured by the tablet production method and the dissolution test method.
【００１０】上記ワクシニアウイルス接種炎症組織抽出
物の有効成分は未詳であるため、重量ではなく鎮痛効力
（力価）によって有効成分量が規定される場合がある。
例えば市販製剤（ノイロトロピン錠）には、１錠中ワク
シニアウイルス接種家兎炎症皮膚抽出液4.0ノイロトロ
ピン単位（ＮＵ）が含有されている。鎮痛効力試験は、
痛覚過敏状態にある病態モデル動物（詳しくは後述）を
用いて行われる。従って、錠剤からの溶出試験もこの鎮
痛効力試験を用いてワクシニアウイルス接種家兎炎症皮
膚抽出物の溶出量を定量して確認するのが基本と考えら
れる。しかし、通常のＨＰＬＣや特異的反応試薬等を用
いた定量分析の場合とは異なって、前記実験動物を用い
て溶出試験を実施する方法は、 前記病態モデル動物の作成に日数とコストがかかる、 製造ロット毎に実施する溶出試験法としては煩雑であ
る、 動物を用いた効力試験は一般的に感度が鋭敏ではな
く、多量の被験試料（錠剤）を必要とする、 等の日常的に繰り返し実施する溶出試験方法として経済
性、簡便性などの面で必ずしも好ましい方法とは言えな
い。[0010] Since the active ingredient of the vaccinia virus-inoculated inflamed tissue extract is not known, the amount of the active ingredient may be determined not by weight but by analgesic potency (titer).
For example, a commercially available formulation (neurotropin tablet) contains 4.0 neurotropin units (NU) in vaccinia virus-inoculated rabbit inflamed skin extract in one tablet. The analgesic efficacy test is
It is performed using a disease model animal in a hyperalgesic state (to be described in detail later). Therefore, it is considered that a dissolution test from a tablet is basically performed by quantifying the dissolution amount of a vaccinia virus-inoculated rabbit inflamed skin extract using this analgesic effect test. However, unlike the case of ordinary quantitative analysis using HPLC or a specific reaction reagent, etc., a method of performing a dissolution test using the experimental animal requires days and costs to create the disease state model animal, It is a complicated dissolution test method for each production lot. Efficacy tests using animals are generally not sensitive and require a large amount of test samples (tablets). This is not necessarily a preferable dissolution test method in terms of economy, simplicity, and the like.
【００１１】そこで、上記の力価に基づく定量試験の測
定値と良い相関性のある代替試験法を種々検討した結
果、溶出液の紫外部吸光度又は紫外部吸収物質を測定す
ることによって、操作が簡便で且つ有効成分の溶出を正
確に反映し得ることを明らかにし、本発明を完成した。Therefore, as a result of studying various alternative test methods having a good correlation with the measured values of the quantitative test based on the above-mentioned titer, the operation was determined by measuring the ultraviolet absorbance or the ultraviolet absorbing substance of the eluate. The inventors have clarified that the method is simple and can accurately reflect the elution of the active ingredient, and completed the present invention.
【００１２】以下に本発明の好ましい態様を示す。 （１）動植物起源の分画又は抽出製剤の固形製剤から水
溶液中への有効成分の溶出を紫外部吸光度又は紫外部吸
収物質を測定して確認することを特徴とする試験方法。 （２）ワクシニアウイルス接種家兎炎症皮膚抽出物を有
効成分とする固形製剤から水溶液中への有効成分の溶出
を紫外部吸光度又は紫外部吸収物質を測定して確認する
ことを特徴とする試験方法。 （３）固形製剤から水溶液中への有効成分の溶出を紫外
部吸光度を測定して確認する上記（１）又は（２）記載
の溶出試験方法。 （４）固形製剤から水溶液中への有効成分の溶出を紫外
部吸収物質を測定して確認する上記（１）又は（２）記
載の溶出試験方法。 （５）紫外部吸収物質がウロカニン酸、ウラシル、ヒポ
キサンチン、キサンチン及び／又はチミンである上記
（４）記載の溶出試験方法。 （６）固形製剤が錠剤である上記（１）乃至（５）のい
ずれか一つに記載の溶出試験方法。Hereinafter, preferred embodiments of the present invention will be described. (1) A test method characterized in that elution of an active ingredient from a solid preparation of a fraction or an extract preparation derived from animals and plants into an aqueous solution is confirmed by measuring an ultraviolet absorbance or an ultraviolet absorbing substance. (2) A test method characterized by confirming the elution of an active ingredient from a solid preparation containing a vaccinia virus-inoculated rabbit inflamed skin extract as an active ingredient into an aqueous solution by measuring an ultraviolet absorbance or an ultraviolet absorbing substance. . (3) The dissolution test method according to the above (1) or (2), wherein the elution of the active ingredient from the solid preparation into the aqueous solution is confirmed by measuring the ultraviolet absorbance. (4) The dissolution test method according to the above (1) or (2), wherein the elution of the active ingredient from the solid preparation into the aqueous solution is confirmed by measuring an ultraviolet absorbing substance. (5) The dissolution test method according to the above (4), wherein the ultraviolet absorbing substance is urocanic acid, uracil, hypoxanthine, xanthine and / or thymine. (6) The dissolution test method according to any one of (1) to (5) above, wherein the solid preparation is a tablet.
【００１３】（７）動植物起源の分画又は抽出製剤の固
形製剤を製造する方法において、該固形製剤から水溶液
中への有効成分の溶出を紫外部吸光度又は紫外部吸収物
質を測定して確認することを特徴とする固形製剤の製造
方法。 （８）ワクシニアウイルス接種家兎炎症皮膚抽出物を有
効成分とする固形製剤を製造する方法において、該固形
製剤から水溶液中への有効成分の溶出を紫外部吸光度又
は紫外部吸収物質を測定して確認することを特徴とする
固形製剤の製造方法。 （９）ワクシニアウイルスを接種した動物の炎症組織を
原料として有効成分を抽出し、該有効成分を含有する固
形製剤を製造する方法において、消化管にて該固形製剤
から必要量の有効成分が放出されることを確認するた
め、紫外部吸光度又は紫外部吸収物質を測定して該固形
製剤から水溶液中への有効成分の溶出を確認することを
特徴とする固形製剤の製造方法。 （１０）動物の炎症組織がウサギの皮膚組織である上記
（９）記載の製造方法。 （１１）固形製剤から水溶液中への有効成分の溶出を紫
外部吸光度を測定して確認する上記（７）乃至（１０）
のいずれか一つに記載の固形製剤の製造方法。 （１２）固形製剤から水溶液中への有効成分の溶出を紫
外部吸収物質を測定して確認する上記（７）乃至（１
０）のいずれか一つに記載の固形製剤の製造方法。 （１３）紫外部吸収物質がウロカニン酸、ウラシル、ヒ
ポキサンチン、キサンチン及び／又はチミンである上記
（１２）記載の溶出試験方法。 （１４）固形製剤が錠剤である上記（７）乃至（１３）
のいずれか一つに記載の製造方法。(7) In a method for producing a solid preparation of a fraction or an extract preparation of animal or plant origin, the elution of the active ingredient from the solid preparation into an aqueous solution is confirmed by measuring an ultraviolet absorbance or an ultraviolet absorbing substance. A method for producing a solid preparation, comprising: (8) In a method for producing a solid preparation containing a vaccinia virus-inoculated rabbit inflamed skin extract as an active ingredient, the elution of the active ingredient from the solid preparation into an aqueous solution is measured by measuring an ultraviolet absorbance or an ultraviolet absorbing substance. A method for producing a solid preparation, characterized in that it is confirmed. (9) In a method for extracting an active ingredient from an inflamed tissue of an animal inoculated with vaccinia virus as a raw material to produce a solid preparation containing the active ingredient, a required amount of the active ingredient is released from the solid preparation in the digestive tract. A method for producing a solid preparation, comprising measuring an ultraviolet absorbance or an ultraviolet absorbing substance in order to confirm that the active ingredient is eluted from the solid preparation into an aqueous solution. (10) The method according to (9), wherein the inflamed tissue of the animal is rabbit skin tissue. (11) The elution of the active ingredient from the solid preparation into the aqueous solution is confirmed by measuring ultraviolet absorbance (7) to (10).
The method for producing a solid preparation according to any one of the above. (12) The above (7) to (1) in which the elution of the active ingredient from the solid preparation into the aqueous solution is confirmed by measuring the ultraviolet absorbing substance.
0) The method for producing a solid preparation according to any one of the above. (13) The dissolution test method according to the above (12), wherein the ultraviolet absorbing substance is urocanic acid, uracil, hypoxanthine, xanthine and / or thymine. (14) The above (7) to (13), wherein the solid preparation is a tablet.
The production method according to any one of the above.
【００１４】（１５）動植物起源の分画又は抽出製剤の
固形製剤から水溶液中への有効成分の溶出を紫外部吸光
度又は紫外部吸収物質を測定して確認することにより品
質を担保された医薬品製剤。 （１６）ワクシニアウイルス接種家兎炎症皮膚抽出物を
有効成分とする固形製剤から水溶液中への有効成分の溶
出を紫外部吸光度又は紫外部吸収物質を測定して確認す
ることにより品質を担保された医薬品製剤。 （１７）ワクシニアウイルスを接種した動物の炎症組織
を原料として有効成分を抽出し、該有効成分を含有する
固形製剤を製造する方法において、消化管にて該固形製
剤から必要量の有効成分が放出されることを確認するた
め、紫外部吸光度又は紫外部吸収物質を測定して該固形
製剤から水溶液中への有効成分の溶出を確認することに
より品質を担保された医薬品製剤。 （１８）固形製剤から水溶液中への有効成分の溶出を、
紫外部吸光度を測定して確認することにより品質を担保
された上記（１５）乃至（１７）のいずれか一つに記載
の医薬品製剤。 （１９）固形製剤から水溶液中への有効成分の溶出を、
紫外部吸収物質を測定して確認することにより品質を担
保された上記（１５）乃至（１７）のいずれか一つに記
載の医薬品製剤。 （２０）紫外部吸収物質がウロカニン酸、ウラシル、ヒ
ポキサンチン、キサンチン及び／又はチミンである上記
（１９）記載の医薬品製剤。 （２１）固形製剤が錠剤である上記（１５）乃至（２
０）のいずれか一つに記載の医薬品製剤。(15) Pharmaceutical preparations whose quality is ensured by confirming the elution of the active ingredient from a solid preparation of a fraction or an extract preparation of animal or plant origin into an aqueous solution by measuring the ultraviolet absorbance or the ultraviolet absorbing substance . (16) The quality was secured by confirming the elution of the active ingredient from the solid preparation containing the vaccinia virus-inoculated rabbit inflamed skin extract as an active ingredient into an aqueous solution by measuring the ultraviolet absorbance or the ultraviolet absorbing substance. Pharmaceutical formulations. (17) In a method for extracting an active ingredient from an inflamed tissue of an animal inoculated with vaccinia virus as a raw material to produce a solid preparation containing the active ingredient, a required amount of the active ingredient is released from the solid preparation in the digestive tract. A pharmaceutical preparation whose quality is ensured by measuring the ultraviolet absorbance or ultraviolet absorbing substance to confirm that the active ingredient is eluted from the solid preparation into an aqueous solution. (18) Dissolution of the active ingredient from the solid preparation into the aqueous solution,
The pharmaceutical preparation according to any one of the above (15) to (17), whose quality is ensured by measuring and confirming ultraviolet absorbance. (19) Dissolution of the active ingredient from the solid preparation into the aqueous solution,
The pharmaceutical preparation according to any one of the above (15) to (17), wherein the quality is ensured by measuring and confirming the ultraviolet absorbing substance. (20) The pharmaceutical preparation according to the above (19), wherein the ultraviolet absorbing substance is urocanic acid, uracil, hypoxanthine, xanthine and / or thymine. (21) The above (15) to (2) wherein the solid preparation is a tablet.
0) The pharmaceutical preparation according to any one of the above.
【００１５】錠剤の溶出試験の操作は通常行われている
方法、例えば日本薬局方の一般試験法に記載されている
溶出試験法に従って行うことができる。ワクシニアウイ
ルス接種家兎炎症皮膚抽出液の市販されている錠剤は、
フィルムコーティングされた錠剤であるため、日本薬局
方の一般試験法・溶出試験法の第２法（パドル法）で溶
出試験を行うこととされているが、固形製剤の種類によ
って下記ガイドライン等に従って適切な方法を選択すれ
ばよい。The operation of the tablet dissolution test can be carried out according to a commonly used method, for example, a dissolution test method described in General Test Methods of the Japanese Pharmacopoeia. Vaccinia virus inoculated rabbit inflamed skin extract commercially available tablets,
Because the tablet is a film-coated tablet, the dissolution test is to be performed according to the Japanese Pharmacopoeia's general test method / dissolution test method 2 (paddle method). What is necessary is just to choose a method.
【００１６】溶出液の種類は紫外部吸光度の測定や紫外
部吸収物質の定量に影響を与えない溶液、即ち測定波長
付近に吸収のない溶液（溶媒自体及び添加される緩衝剤
等の試薬に測定波長付近の吸収がないもの）などが好ま
しく、例えば日本薬局方の一般試験法・崩壊試験法記載
の試験液などを用いることができる。厚生省が指導して
いる溶出試験の方法は、例えば平成9年12月22日付医薬
審第487号のガイドラインに詳述されており、試験条件
としては、試験液の量は900ｍL、試験液の温度は37℃と
してパドル法で行うこととされ、中性又は塩基性薬物を
含む製剤やコーティング製剤については、日本薬局方の
一般試験法・崩壊試験法記載の第１液（pH1.2）、
同第２液（pH6.8）、McIlvaine緩衝液（pH3.0〜5.0）
及び水で溶出試験を行うことが示されている。The type of the eluate is a solution that does not affect the measurement of ultraviolet absorbance or the quantification of an ultraviolet absorbing substance, that is, a solution that does not absorb near the measurement wavelength (measured by the solvent itself and the reagents such as buffer added). And those having no absorption near the wavelength) are preferable. For example, a test solution described in the general test method / disintegration test method of the Japanese Pharmacopoeia can be used. The method of the dissolution test instructed by the Ministry of Health and Welfare is described in detail, for example, in the guidelines of the Pharmaceutical Affairs Commission No. 487 on December 22, 1997, and the test conditions are as follows. Is performed by the paddle method at 37 ° C. For preparations containing neutral or basic drugs and coating preparations, the first liquid (pH 1.2) described in the general test method / disintegration test method of the Japanese Pharmacopoeia,
Second liquid (pH6.8), McIlvaine buffer (pH3.0-5.0)
And water to perform a dissolution test.
【００１７】本発明において、ワクシニアウイルス接種
家兎炎症皮膚抽出物の錠剤等の固形製剤から水溶液中へ
の溶出を確認するために測定する紫外部吸光度の波長は
適宜設定可能であるが、ワクシニアウイルス接種家兎炎
症皮膚抽出物の紫外部スペクトルは255乃至275nmの範囲
内に吸収の極大値があるため、245乃至285nmの範囲内の
波長を設定するのが好ましいが、前記範囲外でも充分吸
光度を測定できる波長ならば測定可能なので、これは特
に限定されるものではない。In the present invention, the wavelength of ultraviolet absorbance measured to confirm the elution of a vaccinia virus-inoculated rabbit inflamed skin extract from a solid preparation such as a tablet into an aqueous solution can be appropriately set. The ultraviolet spectrum of the inoculated rabbit inflamed skin extract has a maximum absorption in the range of 255 to 275 nm, so it is preferable to set the wavelength in the range of 245 to 285 nm, but sufficient absorbance even outside the above range. This is not particularly limited, as it can be measured if it can be measured.
【００１８】また本発明において、紫外部吸光度と同様
にワクシニアウイルス接種家兎炎症皮膚抽出物の溶出試
験の指標と成り得る紫外部吸収物質としては、該抽出物
に含まれるウロカニン酸、ウラシル、ヒポキサンチン、
キサンチン、チミン等が好ましい物質として挙げること
ができる。これらの定量試験方法としては、繁用されて
いるＨＰＬＣ（高速液体クロマトグラフィー）が利用し
やすい。ＨＰＬＣにおける測定条件は、測定対象物質や
溶出液の種類によって常法に従って適宜設定すればよ
い。当分野で常識であるように、事前に測定対象物質の
標準試薬等を用いて、各対象物質が適切に分離できる条
件を設定し、その条件下での対象物質の保持時間を確認
しておき、それを指標に被験溶液中の各物質の濃度を定
量することができる。測定条件によっては、チャージす
る被験溶液（溶出液）のｐＨによりウロカニン酸とウラ
シルが完全に分離できずにピークが重なることなどがあ
り、その場合は両物質の総和を測定値として求めてもよ
い。上記の紫外部吸収物質の測定においては、ＨＰＬＣ
が一般的に用いられているが、当然ながらその他の測定
方法、例えば測定対象物質に特異的な呈色反応を用いる
定量試験法等を利用して本発明を実施してもよい。又、
本発明方法が、錠剤以外の内用固形製剤の溶出試験にも
適用できることは言うまでもない。以下の実施例によっ
て、本発明をさらに詳細に説明する。Further, in the present invention, the ultraviolet absorbing substance which can serve as an index for the dissolution test of rabbit inflamed skin extract inoculated with vaccinia virus in the same manner as the ultraviolet absorbance includes urocanic acid, uracil and hypopox contained in the extract. Xanthine,
Xanthine, thymine and the like can be mentioned as preferred substances. As these quantitative test methods, HPLC (high performance liquid chromatography), which is widely used, is easily used. The measurement conditions in HPLC may be appropriately set according to a conventional method depending on the type of the substance to be measured and the type of eluate. As is common knowledge in the field, using conditions such as standard reagents for the substances to be measured, set in advance the conditions under which each substance can be appropriately separated, and confirm the retention time of the substances under those conditions. The concentration of each substance in the test solution can be quantified using the index as an index. Depending on the measurement conditions, depending on the pH of the test solution (eluate) to be charged, urocanic acid and uracil may not be completely separated and the peaks may overlap.In such a case, the sum of both substances may be obtained as the measured value . In the above measurement of the ultraviolet absorbing substance, HPLC
Is generally used, but it goes without saying that the present invention may be carried out using other measurement methods, for example, a quantitative test method using a color reaction specific to the substance to be measured. or,
It goes without saying that the method of the present invention can also be applied to dissolution tests of solid preparations for internal use other than tablets. The following examples illustrate the invention in more detail.
【００１９】[0019]
【実施例】（１）溶出試験 日本薬局方解説書・第十三改正の一般試験法・溶出試験
法の第２法（パドル法）に準じて行った。即ち、錠剤試
料を試験液（水900mL、液温37±0.5℃）に入れ、パドル
の回転数を50rpmとして溶出試験を行った。採取した試
験液は孔径0.45μmのディスクフィルターで加圧濾過
し、紫外部吸収測定用の試料溶液とした。また鎮痛効力
試験用の試料溶液も同様に溶出試験を行い、濃縮して調
製した。即ち、採取した溶出試験液を同様に孔径0.45μ
mのディスクフィルターで加圧濾過し、最初の濾液100mL
は除いて、次の濾液（約700mL）をとり、45℃以下で減
圧下に濃縮乾固し正確に5mLとして鎮痛効力試験に供し
た。[Examples] (1) Dissolution test The dissolution test was carried out in accordance with the Japanese Pharmacopoeia Manual, 13th Revised General Test Method and Dissolution Test Method 2 (paddle method). That is, a tablet sample was placed in a test solution (water 900 mL, liquid temperature 37 ± 0.5 ° C.), and a dissolution test was performed at a paddle rotation speed of 50 rpm. The collected test solution was filtered under pressure with a disk filter having a pore size of 0.45 μm to obtain a sample solution for ultraviolet absorption measurement. In addition, a sample solution for an analgesic effect test was similarly subjected to a dissolution test, and concentrated and prepared. In other words, the collected dissolution test solution was similarly prepared with a pore size of 0.45 μm.
pressure filtration with a 100-m disc filter and the first filtrate 100 mL
Then, the following filtrate (about 700 mL) was taken and concentrated to dryness under reduced pressure at 45 ° C. or lower to make exactly 5 mL and subjected to an analgesic efficacy test.
【００２０】（２）紫外部吸収測定 錠剤試料として、上記ワクシニアウイルス接種家兎炎症
皮膚抽出液4.0ノイロトロピン単位を含有する錠剤を4錠
用いて（１）の溶出試験を行い、試料溶液の波長270nm
における吸光度を経時的に測定した。(2) Measurement of Ultraviolet Absorption As a tablet sample, the dissolution test of (1) was carried out using four tablets containing 4.0 neurotropin units of the vaccinia virus-inoculated rabbit inflamed skin extract, and the wavelength of the sample solution was 270 nm.
Was measured over time.
【００２１】（３）鎮痛効力試験 鎮痛効力試験には、ＳＡＲＴストレスマウスという慢性
的な痛覚過敏状態を呈する病態モデル動物を用いた。Ｓ
ＡＲＴ（Specific Alternation of Rhythm inTemperatu
re）ストレス、即ち反復寒冷ストレスの負荷は、喜多ら
の方法に（日薬理誌、71巻、195-210頁、1975年）に準
じて行った。飼育用恒温槽を用い、ddY系雄性マウスの
飼育環境温度を午前10時から午後5時までは1時間毎に4
℃と24℃に交互に変更し、次いで午後5時から翌朝の午
前10時の間は4℃に維持し、水及び飼料は自由に摂取さ
せ4日間飼育して反復寒冷ストレスを負荷した後、実験
に供した。被験薬の投与前および投与30分後にRandall-
Selitto変法（尾圧法：日薬理誌、72巻、573-584頁、19
76年）により痛覚閾値を測定した。即ち、圧力子をマウ
ス尾部用に改変したRandall-Selitto式鎮痛効果測定装
置を用い、マウス尾根部より先端側へ1.5cmの部位に圧
刺激を16g/secの速度で加え、逃避或いは啼鳴反応を示
す加圧重量を測定し、「被験薬投与後の加圧重量(g)」
を「被験薬投与前の加圧重量(g)」で除して鎮痛係数を
算出した。従って、被験薬に全く効果の無い場合は鎮痛
係数が1.0となり、効果が強くなるにつれて、1.1、1.
2、1.3と鎮痛係数の値は増加してゆく。ワクシニアウイ
ルス接種家兎炎症皮膚抽出液16.0ノイロトロピン単位を
含有する錠剤を4錠用いて上記（１）の溶出試験を行
い、濃縮して調製した試料溶液を被験薬として用いマウ
ス体重1kgあたり20mLを腹腔内に投与して、その鎮痛効
力を測定した。(3) Analgesic Efficacy Test In the analgesic efficacy test, a SART stress mouse, a disease model animal exhibiting chronic hyperalgesia, was used. S
ART (Specific Alternation of Rhythm in Temperatu
re) Stress, that is, loading of repetitive cold stress, was performed according to the method of Kita et al. (Nihon Pharmaceutical Journal, Vol. 71, pp. 195-210, 1975). Using a breeding thermostat, raise the breeding environment temperature of the ddY male mice from 10 am to 5 pm every hour.
Alternately to ℃ and 24 ℃, then maintained at 4 ℃ from 5:00 pm to 10:00 am the next morning, water and feed were allowed free access, bred for 4 days and subjected to repeated cold stress, before the experiment Provided. Randall- before and 30 minutes after administration of study drug
Modified Selitto method (tail pressure method: Nihon Pharmacology Journal, 72, 573-584, 19)
76 years). In other words, using a Randall-Selitto-type analgesic effect measuring device in which the indenter is modified for the mouse tail, a pressure stimulus is applied at a rate of 16 g / sec to the site 1.5 cm from the mouse ridge to the tip side, and the escape or squeal reaction is performed. Measure the pressurized weight indicating, `` pressurized weight after test drug administration (g) ''
Was divided by “the weight under pressure (g) before administration of the test drug” to calculate the analgesic coefficient. Therefore, when the test drug has no effect, the analgesic coefficient is 1.0, and as the effect becomes stronger, 1.1, 1.
The value of the analgesic index increases to 2, 1.3. Vaccinia virus inoculated rabbit inflamed skin extract 16.0 The dissolution test of (1) above was carried out using 4 tablets containing neurotropin units, and a sample solution prepared by concentration was used as a test drug. And its analgesic efficacy was measured.
【００２２】上記（２）の紫外部吸収測定および（３）
鎮痛効力試験につき、溶出液の紫外部吸光度と鎮痛係数
を経時的に測定した結果の一例を図１に示す。The ultraviolet absorption measurement of (2) and (3)
FIG. 1 shows an example of the results obtained by measuring the ultraviolet absorbance and the analgesic coefficient of the eluate over time in the analgesic efficacy test.
【００２３】（４）紫外部吸収物質測定 上記紫外部吸収測定で用いた試料溶液につき、オクタデ
シルシリル化シルカゲルカラム（NUCLEOSIL 5C18、ケム
コ社製、4.0mm I.D.×250mm、5μm）によるＨＰＬＣを
行った結果を図２に示した。ウロカニン酸、ウラシル、
ヒポキサンチン、キサンチン、チミン等の紫外部吸収物
質の溶出挙動は、溶出液の270nmにおける吸光度測定値
の変化と良い一致を示した。また水以外の溶出液、即ち
コーティング製剤について溶出試験を行うことが指導さ
れている日本薬局方の一般試験法・崩壊試験法記載の第
１液（pH1.2）、同第2液（pH6.8）及びMcIlvaine緩衝液
（pH3.0〜5.0）を用いた場合も、同様に各紫外部吸収物
質の溶出濃度と吸光度測定値とは相関することが認めら
れた。(4) Measurement of Ultraviolet Absorbing Substance The sample solution used in the above ultraviolet absorption measurement was subjected to HPLC using an octadecylsilylated silkagel column (NUCLEOSIL 5C18, manufactured by Chemco, 4.0 mm ID × 250 mm, 5 μm). The results are shown in FIG. Urocanic acid, uracil,
The elution behavior of ultraviolet absorbing substances such as hypoxanthine, xanthine and thymine showed good agreement with the change in the measured absorbance at 270 nm of the eluate. In addition, the first solution (pH 1.2) and the second solution (pH 6.2) described in the general test method and disintegration test method of the Japanese Pharmacopoeia, which are instructed to perform dissolution tests on eluates other than water, that is, coating formulations. Also in the case of using 8) and McIlvaine buffer solution (pH 3.0 to 5.0), it was recognized that the elution concentration of each ultraviolet absorbing substance and the measured absorbance were similarly correlated.
【００２４】上記（４）の紫外部吸収物質測定につき、
溶出液中の紫外部吸収物質の濃度および紫外部吸光度を
経時的に測定した結果の一例を図２に示す。In the measurement of the ultraviolet absorbing substance in the above (4),
FIG. 2 shows an example of the results of measuring the concentration of the ultraviolet absorbing substance and the ultraviolet absorbance in the eluate over time.
【００２５】[0025]
【発明の効果】図１に示した結果より明らかなように、
ワクシニアウイルス接種家兎炎症皮膚抽出物の錠剤から
水溶液中への溶出において、溶出液の紫外部吸光度と鎮
痛係数の経時的増加は良い相関関係を示した。上記試験
に用いた錠剤の場合は、紫外部吸光度および鎮痛係数は
共に20分後にはプラトーに達することから、ワクシニア
ウイルス接種家兎炎症皮膚抽出物を含有する上記錠剤は
水中では約20分程で有効成分の溶出が完了していること
が確認できた。また図２に示した通り、溶出液における
紫外部吸光度とウロカニン酸、ウラシル、ヒポキサンチ
ン、キサンチン、チミン等の紫外部吸収物質の溶出液中
濃度の両変化は良い相関性を示し、ワクシニアウイルス
接種家兎炎症皮膚抽出物の錠剤から水溶液中への溶出
は、吸光度測定だけでなく各紫外部吸収物質を指標とし
ても確認できることが明らかになった。As is clear from the results shown in FIG.
When the vaccinia virus-inoculated rabbit inflamed skin extract was eluted from the tablet into an aqueous solution, the UV absorbance of the eluate and the time-dependent increase in the analgesic coefficient showed a good correlation. In the case of the tablets used in the above test, since both the ultraviolet absorbance and the analgesic coefficient reach a plateau after 20 minutes, the tablets containing the vaccinia virus-inoculated rabbit inflamed skin extract can be treated in water for about 20 minutes. It was confirmed that the elution of the active ingredient was completed. In addition, as shown in FIG. 2, both changes in the ultraviolet absorbance in the eluate and the concentrations in the eluate of ultraviolet absorbing substances such as urocanic acid, uracil, hypoxanthine, xanthine, and thymine show a good correlation. It was revealed that the elution of the rabbit inflamed skin extract from the tablet into the aqueous solution can be confirmed not only by measuring the absorbance but also by using each ultraviolet absorbing substance as an index.
【００２６】ワクシニアウイルス接種家兎炎症皮膚抽出
物の有効成分量が力価（鎮痛効力など）によって規定さ
れている場合、溶出液中の有効成分量を測定するために
は動物を用いなければならず、更には動物に投与可能な
試料とするための濃縮等の煩雑な操作が必要とされる。
これに対して、紫外部吸光度やウロカニン酸、ウラシ
ル、ヒポキサンチン、キサンチン、チミン等の紫外部吸
収物質を測定する本発明試験方法の操作は、溶出液の少
量を分取して分光光度計又はＨＰＬＣを用いて測定する
だけの極めて簡便且つ短時間で実施可能なものである。
このように本発明は、ワクシニアウイルス接種家兎炎症
皮膚抽出物の錠剤等の内用固形製剤に関して、有効成分
の溶出を正確に反映し且つ簡便に測定可能な溶出試験方
法を提供するものであり、本発明方法は、動物を必要と
し操作が煩雑な力価に基づく定量試験に代わり得る新規
且つ有用性の高いものである。When the amount of the active ingredient in the vaccinia virus-inoculated rabbit inflamed skin extract is defined by the titer (such as analgesic effect), an animal must be used to measure the amount of the active ingredient in the eluate. In addition, complicated operations such as concentration for obtaining a sample that can be administered to animals are required.
On the other hand, the operation of the test method of the present invention for measuring an ultraviolet absorbing substance such as ultraviolet absorbance or urocanic acid, uracil, hypoxanthine, xanthine, and thymine is performed by separating a small amount of the eluate and using a spectrophotometer or It is very simple and can be carried out in a short time only by measuring using HPLC.
As described above, the present invention provides a dissolution test method that can accurately reflect the dissolution of an active ingredient and can be easily measured with respect to an internal solid preparation such as a tablet of a vaccinia virus-inoculated rabbit inflamed skin extract. The method of the present invention is novel and highly useful, which can replace a quantitative test based on a titer which requires an animal and requires complicated operation.
【図１】図１は、ワクシニアウイルス接種家兎炎症皮膚
抽出物を有効成分として含有する錠剤の溶出試験におい
て、溶出液の紫外部吸光度および鎮痛係数を経時的に測
定した結果を示すものである。FIG. 1 shows the results of measuring the ultraviolet absorbance and the analgesic coefficient of an eluate with time in a dissolution test of a tablet containing a vaccinia virus-inoculated rabbit inflamed skin extract as an active ingredient. .
【図２】図２は、ワクシニアウイルス接種家兎炎症皮膚
抽出物を有効成分として含有する錠剤の溶出試験におい
て、溶出液中の紫外部吸収物質の濃度および紫外部吸光
度を経時的に測定した結果を示すものである。[Fig. 2] Fig. 2 shows the results of a time-dependent measurement of the concentration of an ultraviolet absorbing substance and the ultraviolet absorbance in an eluate in a dissolution test of a tablet containing a vaccinia virus-inoculated rabbit inflamed skin extract as an active ingredient. It shows.
Claims (3)
剤から水溶液中への有効成分の溶出を紫外部吸光度又は
紫外部吸収物質を測定して確認することを特徴とする試
験方法。1. A test method characterized in that elution of an active ingredient from a solid preparation of a fraction or an extract preparation derived from animals and plants into an aqueous solution is confirmed by measuring an ultraviolet absorbance or an ultraviolet absorbing substance.
剤を製造する方法において、該固形製剤から水溶液中へ
の有効成分の溶出を紫外部吸光度又は紫外部吸収物質を
測定して確認することを特徴とする固形製剤の製造方
法。2. A method for producing a solid preparation of a fraction or an extract preparation of animal or plant origin, wherein the elution of the active ingredient from the solid preparation into an aqueous solution is confirmed by measuring ultraviolet absorbance or an ultraviolet absorbing substance. A method for producing a solid preparation, characterized in that:
剤から水溶液中への有効成分の溶出を紫外部吸光度又は
紫外部吸収物質を測定して確認することにより品質を担
保された医薬品製剤。3. A pharmaceutical preparation whose quality is ensured by confirming the elution of an active ingredient from a solid preparation of a fraction or an extract preparation derived from animals and plants into an aqueous solution by measuring ultraviolet absorbance or an ultraviolet absorbing substance.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000111808A JP3649989B2 (en) | 1999-04-16 | 2000-04-13 | Test method |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11-108826 | 1999-04-16 | ||
| JP10882699 | 1999-04-16 | ||
| JP2000111808A JP3649989B2 (en) | 1999-04-16 | 2000-04-13 | Test method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2000356632A true JP2000356632A (en) | 2000-12-26 |
| JP3649989B2 JP3649989B2 (en) | 2005-05-18 |
Family
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| Application Number | Title | Priority Date | Filing Date |
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| JP2000111808A Expired - Fee Related JP3649989B2 (en) | 1999-04-16 | 2000-04-13 | Test method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5275502B1 (en) * | 2012-10-10 | 2013-08-28 | 日本臓器製薬株式会社 | Extracts and formulations |
| CN108226353A (en) * | 2016-12-14 | 2018-06-29 | 北京满格医药科技有限公司 | A kind of assay method of calcium hydrophenyl sulfonate capsule stripping curve |
-
2000
- 2000-04-13 JP JP2000111808A patent/JP3649989B2/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5275502B1 (en) * | 2012-10-10 | 2013-08-28 | 日本臓器製薬株式会社 | Extracts and formulations |
| CN108226353A (en) * | 2016-12-14 | 2018-06-29 | 北京满格医药科技有限公司 | A kind of assay method of calcium hydrophenyl sulfonate capsule stripping curve |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3649989B2 (en) | 2005-05-18 |
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