JPS63215642A - Pharmaceutical composition containing natural albumin as carrier and production thereof - Google Patents
Pharmaceutical composition containing natural albumin as carrier and production thereofInfo
- Publication number
- JPS63215642A JPS63215642A JP4913587A JP4913587A JPS63215642A JP S63215642 A JPS63215642 A JP S63215642A JP 4913587 A JP4913587 A JP 4913587A JP 4913587 A JP4913587 A JP 4913587A JP S63215642 A JPS63215642 A JP S63215642A
- Authority
- JP
- Japan
- Prior art keywords
- albumin
- composition
- suspension
- natural albumin
- hydrochloride
- 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.)
- Granted
Links
- 108010088751 Albumins Proteins 0.000 title claims abstract description 39
- 102000009027 Albumins Human genes 0.000 title claims abstract description 39
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 239000003814 drug Substances 0.000 claims abstract description 30
- 229940079593 drug Drugs 0.000 claims abstract description 14
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 230000001747 exhibiting effect Effects 0.000 claims abstract description 4
- 102000004169 proteins and genes Human genes 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- 239000000203 mixture Substances 0.000 abstract description 53
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 abstract description 26
- 229960000210 nalidixic acid Drugs 0.000 abstract description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 17
- 229940092253 ovalbumin Drugs 0.000 abstract description 12
- 239000000725 suspension Substances 0.000 abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- 108010058846 Ovalbumin Proteins 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 8
- 239000003960 organic solvent Substances 0.000 abstract description 7
- 210000002249 digestive system Anatomy 0.000 abstract description 3
- 238000009835 boiling Methods 0.000 abstract description 2
- 230000006378 damage Effects 0.000 abstract description 2
- 208000027418 Wounds and injury Diseases 0.000 abstract 1
- 238000004821 distillation Methods 0.000 abstract 1
- 208000014674 injury Diseases 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 18
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 17
- 229960001597 nifedipine Drugs 0.000 description 17
- 239000000843 powder Substances 0.000 description 16
- 238000000034 method Methods 0.000 description 12
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- 210000002966 serum Anatomy 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
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- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
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- 229920001525 carrageenan Polymers 0.000 description 4
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 229940083542 sodium Drugs 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- GNWUOVJNSFPWDD-XMZRARIVSA-M Cefoxitin sodium Chemical compound [Na+].N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)CC1=CC=CS1 GNWUOVJNSFPWDD-XMZRARIVSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KTNROWWHOBZQGK-UHFFFAOYSA-N Etilefrine hydrochloride (TN) Chemical compound [Cl-].CC[NH2+]CC(O)C1=CC=CC(O)=C1 KTNROWWHOBZQGK-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- MJVAVZPDRWSRRC-UHFFFAOYSA-N Menadione Chemical compound C1=CC=C2C(=O)C(C)=CC(=O)C2=C1 MJVAVZPDRWSRRC-UHFFFAOYSA-N 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 229960003016 cefoxitin sodium Drugs 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229960005172 etilefrine hydrochloride Drugs 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
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- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 238000009775 high-speed stirring Methods 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
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Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明はアルブミンに対し親和性を示す医薬品の一種又
は複数を後述する方法によって高濃度含有させた、アル
ブミンを担体とした医薬組成物に関し、更に詳しくは人
体に好ましくない副作用を軽減し、医薬品の吸収を改善
し、光安定性を向上した医薬組成物に関する。[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a pharmaceutical composition using albumin as a carrier, which contains one or more pharmaceuticals having an affinity for albumin at a high concentration by the method described below. More specifically, the present invention relates to a pharmaceutical composition that reduces undesirable side effects on the human body, improves absorption of pharmaceuticals, and improves photostability.
従来、アルブミンを担体とした医薬組成物として、5−
フルオロウラシル誘導体とアルブミンの複合体(特開昭
54−151988号)、・徐放性アルブミン複合体(
特開昭58−162595号)などが挙げられる。しか
し、この特許公報に記載している方法は、pH6乃至1
)、温度30℃以下において、予め担体アルブミンをハ
ロゲン化シアン又は過ハロゲン酸を用いて結合性を変化
させることを必要とし、更に官能化合物等のスペーサー
を眉い親和性を向上させることを必要とする。Conventionally, as a pharmaceutical composition using albumin as a carrier, 5-
Complex of fluorouracil derivative and albumin (JP-A-54-151988), sustained-release albumin complex (
JP-A No. 58-162595). However, the method described in this patent publication has a pH of 6 to 1.
), at a temperature of 30°C or lower, it is necessary to change the binding properties of the carrier albumin in advance using cyanogen halide or perhalogenated acid, and it is also necessary to add a spacer such as a functional compound to improve the affinity for eyebrows. do.
一方、本発明の天然アルブミンを担体とした医薬組成物
は、以下に記述するようにハロゲン化シアン、過ハロゲ
ン酸又はスペーサーを必要とせず、先の特許公報記載の
ものとは全く相違する。その他のものとしてシクロデキ
ストリンを用いたシクロデキストリン−インドメタシン
包接錯体(特開昭54−62313号、特開昭54−1
)7018号)、また、コラーゲン、ゼラチンなどから
選ばれた生体内分解性担体にインドメタシンを含有させ
たもの(特開昭60−84213号)などが挙げられる
が、これらの従来品は徐放性にはすぐれているが体内の
吸収性が悪く薬効が発現するまでに長時間を要する。On the other hand, the pharmaceutical composition of the present invention using natural albumin as a carrier does not require cyanogen halides, perhalogen acids, or spacers, as described below, and is completely different from those described in the previous patent publications. Other examples include cyclodextrin-indomethacin inclusion complexes using cyclodextrin (JP-A-54-62313, JP-A-54-1
) No. 7018), and products containing indomethacin in a biodegradable carrier selected from collagen, gelatin, etc. (Japanese Patent Application Laid-open No. 84213/1983), but these conventional products are slow-release. However, it is poorly absorbed in the body and takes a long time to develop its medicinal effects.
本発明の目的は医薬品の皮膚及び粘膜、特に消化器系に
対する障害を軽減し、かつ医薬品の吸収性、光に対する
安定性等を改善し得る医薬組成物を提供することにある
。An object of the present invention is to provide a pharmaceutical composition that can reduce the damage caused by pharmaceuticals to the skin and mucous membranes, particularly the digestive system, and improve the absorbability, stability to light, etc. of pharmaceuticals.
本発明は上述の目的を達成するためになされたものであ
り、本発明の医薬組成物はタンパク結合性を示す医薬品
1乃至200部と天然アルブミン100部からなること
を特徴とする。The present invention has been made to achieve the above-mentioned object, and the pharmaceutical composition of the present invention is characterized by comprising 1 to 200 parts of a pharmaceutical exhibiting protein-binding properties and 100 parts of natural albumin.
尚、特開昭58−216126号公報には水不溶性又は
難溶性の薬物を可溶性にするためにヒト血清アルブミン
を用いることが記載されている。しかし、この特許公報
に記載の方法は、従来から知られている医薬品のタンパ
ク結合率測定法を応用したものであり、可溶化し得る医
薬品も血清アルブミンに対して、0.01〜0.8%程
度と極めて低含量であり、この特許公報に示されている
プロスタグランジンの場合のよう・に、臨床上の用量の
極めて低い場合にのみ例外的に有用な技術である。Incidentally, JP-A-58-216126 describes the use of human serum albumin to make water-insoluble or poorly soluble drugs soluble. However, the method described in this patent publication is an application of the conventionally known method for measuring the protein binding rate of pharmaceuticals, and even pharmaceuticals that can be solubilized have a ratio of 0.01 to 0.8 with respect to serum albumin. %, and it is an exceptionally useful technique only when the clinical dose is extremely low, as in the case of prostaglandin shown in this patent publication.
これに対し、本発明の天然アルブミンを担体とした医薬
品組成物は、以下詳述するように、本発明に用いられる
アルブミンとしては、例えば、卵白アルブミン、血清ア
ルブミン、プラクアルブミン、α−ラクトアルブミン、
ロイコシン、ファセリン及びレブメリン等を挙げること
ができるが、特に、卵白アルブミンが好ましい。また、
本発明により得られた組成物を抗原性が問題となる医薬
品の分野に適用するためにはヒト由来のアルブミンを用
いることが好ましい。本発明に利用される医薬品は、そ
のタンパク結合率が10%以上、好ましくは20%以上
であることが好適である。また、その配合量はアルブミ
ン100部に対し少なくとも1部、好ましくは5〜20
0部の割合で使用するのが好ましい。On the other hand, in the pharmaceutical composition of the present invention using natural albumin as a carrier, as described in detail below, the albumin used in the present invention includes, for example, ovalbumin, serum albumin, plaque albumin, α-lactalbumin,
Examples include leucosin, phaselin, and levumelin, and ovalbumin is particularly preferred. Also,
In order to apply the composition obtained according to the present invention to the field of pharmaceuticals where antigenicity is a problem, it is preferable to use human-derived albumin. It is suitable that the drug used in the present invention has a protein binding rate of 10% or more, preferably 20% or more. In addition, the blending amount is at least 1 part, preferably 5 to 20 parts, per 100 parts of albumin.
Preferably, it is used in a proportion of 0 parts.
尚、本発明に用いられる医薬品の具体的な例としては、
解熱、鎮痛、抗炎症剤として、アスピリン、イブプロフ
ェン、アルクロフェナック、インドメタシン、メフェナ
ム酸、フルフェナム酸、スリンダク、ピロキシカム、ジ
クロフェナックナトリウム、チアラミド、トルメチンな
ど;ステロイド性抗炎症剤として、プレドニゾロン、ト
リアムシノロン、デキサメタシン、ベクロメタゾン、ヒ
ドロコルチゾンなど;精神神経用剤として、塩酸クロル
プロマジン、カルバマゼピン、クロナゼパム、フェニト
イン、ハロペリドール、クロルジアゼポキシド、メキサ
ゾラム、塩酸アミトリブチリン、塩酸イミプラミン、フ
ルニトラゼパム、トリアゾラムなど;降圧利尿薬として
、フロセミド、エタクリン酸、ブメタニド、ヒドロクロ
ロチアジド、トリクロロメチアジド、メトラゾン、クロ
ルタリドンなど;高血圧治療薬として、塩酸プラゾシン
、レセルピン、ラペクロール、塩酸クロニジン、塩酸ブ
ナゾシン、カプトプリル、塩酸ヒドララジ・ン、ブドラ
ラジンなど;循環器官作用薬として、テオフィリン、塩
酸エチレフリン、塩酸ドブタミン、硫酸キニジン、リド
カイン、塩酸メキシレチン、ジギトキシン、ジゴキシン
、デスラノシド、ビンポセチン、マレイン酸シネパミド
など;冠血管拡張剤として、塩酸ジルチアゼム、ニフエ
ジピン、塩酸ベラパミル、塩酸ニカルジピン、硝酸イソ
ソルビド、ニトログリセリンなど;交感神経作用薬とし
て、塩酸イソプレナリンなど;抹消性骨格筋弛緩薬とし
て、塩酸エペリゾン、ダントロレン、バタロフェンなど
;虚血性心疾患治療薬として、塩酸ジラゼプ、ジビリタ
モール、ニコランジルなど;β−作作用色して、塩酸エ
チレフリン、塩酸ドプタミンなど;β−遮断薬として、
塩酸アルプレノール、塩酸プロプラノロール、塩酸オフ
スプレロール、ピンドロールなど;鎮痙薬として、アト
ロビン、スコブラミンなど;抗生物質として、セフ1ク
ロル、セファレキシン、フロキサシン、ビベシド酸、ス
ルファメトキサセファゾリンナトリウ゛ム、塩酸セフメ
ツキシム、セフオキシチンナトリウム、セフオキシチナ
トリウム、ラタモキセフナトリウム、アンピシリン、ス
ルペニシリンナトリウム、ベンジルペニシリン力1.1
’7ム、フェノキシメチルペニシリンカリウム、塩酸
クロルテトラサイタリン、塩酸テトラサイクリン、塩酸
ミノサイクリン、塩酸ドキシサイクリン、す7アンビシ
ン、エリスロマイシン、タリンダマイシンなど;抗真菌
剤として、グリセオフルビン、ナイスクチン、アンホテ
リシンB1ミコナゾールなど;化学療法剤として、ナリ
ジクス酸、エノキサシン、オゾールなど;抗ウィルス剤
として、ビダラビンなど;抗悪性腫瘍剤として、メトト
レキサート、硫酸ビンデシン、硫酸ビンクリスチン、塩
酸ダウノルビシンなど;消化性潰瘍治療剤として、塩酸
セトラキサート、シメチジン、ファモチジン、塩酸ピレ
ンゼピン、塩酸ラニチジン、スルピリドなど;抗アレル
ギー剤として、テトラフェン、トラニラスト、アゼラス
チン、マレイン酸クロルフェニラミン、フマル酸りレマ
スチン、メキタジンなど;去痰薬として、塩酸アンプロ
キサールなど;ビタミン類として、カルジトリオール、
酢酸トコフェロール、ニコチン酸トコフェロール、リボ
フラビン、葉酸、メナジオン、フィトナジオンなど:肝
疾患用架として、マロチラート、グリチルリチンなど;
糖尿病治療薬として、アセトへキサミド、クロルプロパ
ミド、トルブタミドなど;ホルモン用剤として、ダナゾ
ール、レボチロキシン、リオチロニン、プロピルチオウ
ラシルなど;尿酸排泄剤として、プロベネシドなど;免
疫抑制剤としてアザチオプリン、シクロスポリンなど;
制吐剤として、トンベリトンなどが挙げられる。In addition, specific examples of pharmaceuticals used in the present invention include:
Antipyretic, analgesic and anti-inflammatory agents such as aspirin, ibuprofen, alclofenac, indomethacin, mefenamic acid, flufenamic acid, sulindac, piroxicam, diclofenac sodium, tialamide, tolmetin; steroidal anti-inflammatory agents such as prednisolone, triamcinolone, dexamethacin, Beclomethasone, hydrocortisone, etc.; as neuropsychiatric agents, chlorpromazine hydrochloride, carbamazepine, clonazepam, phenytoin, haloperidol, chlordiazepoxide, mexazolam, amitributyline hydrochloride, imipramine hydrochloride, flunitrazepam, triazolam, etc.; as antihypertensive diuretics, furosemide, ethacrynic acid, bumetanide, hydrochlorothiazide , trichloromethiazide, metolazone, chlorthalidone, etc.; hypertensive drugs such as prazosin hydrochloride, reserpine, lapeclol, clonidine hydrochloride, bunazosin hydrochloride, captopril, hydralazine hydrochloride, budralazine, etc.; cardiovascular agents such as theophylline, etilefrine hydrochloride, hydrochloric acid Dobutamine, quinidine sulfate, lidocaine, mexiletine hydrochloride, digitoxin, digoxin, deslanoside, vinpocetine, cinepamide maleate, etc.; as coronary vasodilators, diltiazem hydrochloride, nifedipine, verapamil hydrochloride, nicardipine hydrochloride, isosorbide nitrate, nitroglycerin, etc.; sympathetic nerve effects Medications such as isoprenaline hydrochloride; peripheral skeletal muscle relaxants such as eperisone hydrochloride, dantrolene, and batalofen; therapeutic drugs for ischemic heart disease such as dilazep hydrochloride, dibilitamol, and nicorandil; beta-agonist agents such as etilefrine hydrochloride, Doptamine hydrochloride, etc.; as a β-blocker,
Alprenol hydrochloride, propranolol hydrochloride, ofsprerol hydrochloride, pindolol, etc.; antispasmodics such as athrobin, scobramin; antibiotics cef1chlor, cephalexin, floxacin, vibesidic acid, sulfamethoxacecefazolin sodium, cefmetuxime hydrochloride , Cefoxitin Sodium, Cefoxitin Sodium, Latamoxef Sodium, Ampicillin, Sulpenicillin Sodium, Benzylpenicillin Power 1.1
Antifungal agents include griseofulvin, nyscutin, amphotericin B1 miconazole, etc.; Therapeutic agents include nalidixic acid, enoxacin, and ozole; antiviral agents include vidarabine; anti-malignant agents include methotrexate, vindesine sulfate, vincristine sulfate, and daunorubicin hydrochloride; therapeutic agents for peptic ulcers include cetraxate hydrochloride, cimetidine, Famotidine, pirenzepine hydrochloride, ranitidine hydrochloride, sulpiride, etc.; as anti-allergic agents, such as tetrafen, tranilast, azelastine, chlorpheniramine maleate, lemastine fumarate, mequitazine, etc.; as an expectorant, amproxal hydrochloride, etc.; as vitamins , cardiotriol,
Tocopherol acetate, tocopherol nicotinate, riboflavin, folic acid, menadione, phytonadione, etc.; Malotylate, glycyrrhizin, etc. for use in liver diseases;
Antidiabetic agents such as acetohexamide, chlorpropamide, tolbutamide; Hormonal agents such as danazol, levothyroxine, liothyronine, propylthiouracil; Uric acid excretion agents such as probenecid; Immunosuppressants such as azathioprine and cyclosporine;
Antiemetics include tonbelitone and the like.
本発明の医薬品−アルブミン組成物の製法についてナリ
ジクス酸−アルブミン組成物の例を挙げ具体的に説明す
る。The method for producing the pharmaceutical-albumin composition of the present invention will be specifically explained using an example of a nalidixic acid-albumin composition.
まず、卵白アルブミン等の天然アルブミンを水性溶液に
懸濁し、該懸濁液に、沸点が100℃以下の適当な有w
1溶媒に溶解したナリジクス酸を添加し、高速攪拌し均
一層を形成する。このときの温度はアルブミンが変性し
ない範囲であれば特に限定されないが、好ましくは4〜
30℃の範囲で約1〜30時間高速攪拌することが必要
であり、高速攪拌は例えば、バイオミキサーBM−4(
日本精器製作断裂、最大回転数3000Orpm)又は
大型高速ホモジナイザー(日音医理科器械製作所製、最
大回転数2000Orpm)を用いて約5000〜40
00Qrpmの条件下に実施するのが好ましい。この組
成物の製造時のアルブミン懸濁液の濃度は特に限定され
ないが、少なくともIff!L%好ましくは2〜25重
量%の濃度で使用することができる。ナリジクス酸に対
するアルブミンの使用割合は、一般にアルブミン100
部に対しナリジクス酸5〜100部を加えた割合で使用
するのが好ましい。水性溶液としてはアルブミンを変性
させずに溶解するものであればいずれのものをも使用で
きるが水が最も好ましい。しかし、水の一部をメタノー
ル、エタノール、インプロパツール、アセトン等の水溶
性溶剤をもって置換することもできる。また、ナリジク
ス酸を有機溶媒に溶解するときに用いられる有機溶媒と
してはアセトン、クロロホルム、メタノール、エタノー
ル等が挙げられる。ナリジクス酸を溶解するときの濃度
は特に限定されないが、少なくとも0.1重量%、好ま
しくは1〜50重量%の範囲で溶解することが有利であ
る。また、を機溶媒に溶解したナリジクス酸溶液とアル
ブミン懸濁液の混合比は特に限定されないが、好ましく
はアルブミン懸濁液100容に対しナリジクス酸溶液1
〜400容の範囲で混合する。かくして得られた反応液
から用いた有機溶媒を減圧下40℃以下の温度において
留去する。この後、スプレー乾燥又は凍結乾燥等の手段
を用いて水性溶媒を除去することにより目的とする粉末
状のナリジクス酸−アルブミン組成物を得ることができ
る。ここで得られる組成物はナリジクス酸とアルブミン
の両者の割合には無関係にほぼ100%反応し両者の加
える割合によりアルブミンに対しナリジクス酸が約5〜
100%結合した組成物が得られる。First, natural albumin such as ovalbumin is suspended in an aqueous solution, and a suitable solution having a boiling point of 100°C or less is added to the suspension.
1 Add nalidixic acid dissolved in a solvent and stir at high speed to form a uniform layer. The temperature at this time is not particularly limited as long as the albumin is not denatured, but is preferably 4 to 4.
It is necessary to stir at high speed for about 1 to 30 hours at a temperature of 30°C.
Approx.
It is preferable to carry out under the condition of 00Qrpm. The concentration of the albumin suspension during the production of this composition is not particularly limited, but at least Iff! L% can be used preferably at a concentration of 2 to 25% by weight. The ratio of albumin to nalidixic acid is generally 100% albumin
It is preferable to use 5 to 100 parts of nalidixic acid per part of nalidixic acid. Any aqueous solution can be used as long as it dissolves albumin without denaturing it, but water is most preferred. However, a portion of the water can also be replaced with a water-soluble solvent such as methanol, ethanol, impropatol, acetone, etc. Furthermore, examples of the organic solvent used when dissolving nalidixic acid in an organic solvent include acetone, chloroform, methanol, ethanol, and the like. The concentration of nalidixic acid in the solution is not particularly limited, but it is advantageous to dissolve it in a concentration of at least 0.1% by weight, preferably in the range of 1 to 50% by weight. In addition, the mixing ratio of the nalidixic acid solution dissolved in an organic solvent and the albumin suspension is not particularly limited, but preferably 1 volume of the nalidixic acid solution to 100 volumes of the albumin suspension.
Mix in a range of ~400 volumes. The organic solvent used is distilled off from the reaction solution thus obtained at a temperature of 40° C. or lower under reduced pressure. Thereafter, the desired powdered nalidixic acid-albumin composition can be obtained by removing the aqueous solvent using means such as spray drying or freeze drying. The composition obtained here reacts almost 100% regardless of the ratio of both nalidixic acid and albumin, and depending on the ratio of both added, the ratio of nalidixic acid to albumin is about 5 to 100%.
A 100% bound composition is obtained.
以上、ナリジクス酸−アルブミン組成物の製造例につい
て説明したが、その他の医薬品をアルブミンに担持させ
た医薬品−アルブミン組成物も同様の方法で製造できる
。なお、ナリジクス酸−アルブミン組成物に限らず本発
明の医薬品−アルブミン組成物の製造においては、医薬
品及びアルブミンとともに脂肪油及び/又は脂肪酸を使
用することもでき、これにより得られた医薬品−アルブ
ミン組成物の吸収性が一層向上する。Although an example of manufacturing a nalidixic acid-albumin composition has been described above, a pharmaceutical-albumin composition in which other pharmaceuticals are supported on albumin can also be manufactured in a similar manner. In addition to the nalidixic acid-albumin composition, in the production of the pharmaceutical-albumin composition of the present invention, fatty oil and/or fatty acid can be used together with the pharmaceutical and albumin, and the resulting pharmaceutical-albumin composition The absorbency of objects is further improved.
上で得られたナリジクス酸−アルブミン組成物は食後服
用するナリジクス酸の吸収を改善することが以下の実験
から立証される。The following experiment proves that the nalidixic acid-albumin composition obtained above improves the absorption of nalidixic acid taken after meals.
リジクス びす1ジクス −アルブミンナリジクス
8.9% のi ヒ”抵腋
実験動物 ラット、ウィスター系、雄性、(体重的
290 g、三協ラボ)
飽食下のものを用いた。Lysix Bis1 Zix - Albuminarisix
Experimental animals containing 8.9% I" were used: male Wistar rats (weight 290 g, Sankyo Lab) under satiated conditions.
投与及び採血 投与量はナリジクス酸として50mg/
kgとした。経口用胃
ゾンデを用いて、1mlの水に
懸濁した状態で投与した。キャ
ピラリ−(D r ummo n d。Administration and blood collection The dose was 50 mg/day as nalidixic acid.
kg. The drug was administered in a suspended state in 1 ml of water using an oral gastric tube. Capillary (Drummon d.
0、1 m l )にて眼底より約0.2mlを採血、
遠心にて血清を得
た。Approximately 0.2 ml of blood was collected from the fundus at 0.1 ml).
Serum was obtained by centrifugation.
試料処理及び 血清を等容積のメタノールと混定量方法
合して除蛋白した。Sample processing and serum was mixed with an equal volume of methanol to remove protein.
定量は高速液体クロマトグラフ 法により行った。Quantification using high performance liquid chromatography It was done by law.
定量条件 カラム:TOYO3ODA。Quantification conditions Column: TOYO3ODA.
ODS−807M。ODS-807M.
4.6mmX 15 cm 移動相ニアセトニトリル:5 0mMクエン酸溶液 :IM酢酸アンモニ・ ラム−35:64: 流速:0.7ml/min 検出波長:258nm 注入管:10μl カラム温度:室温 検量線は、ブランク血清を用い 既知のナリジクス酸を加えて、 試料と同様の処理をすることに より得られた。4.6mmX 15cm Mobile phase niacetonitrile: 5 0mM citric acid solution :IM ammonium acetate Ram-35:64: Flow rate: 0.7ml/min Detection wavelength: 258nm Injection tube: 10μl Column temperature: room temperature The calibration curve uses blank serum. Adding the known nalidixic acid, I decided to process it in the same way as the sample. Obtained from
結果 結果は第1図に示す。Results The results are shown in Figure 1.
第1図より明らかなように、ナリジクス酸−アルブミン
組成物をナリジクス酸として50mg/kg投与した場
合には、投与後1.5時間内に最高血中濃度に達し、こ
のときの濃度は約25μg / m 1と見積もられた
。一方、ナリジクス酸原末の同容量の投与では投与後3
時間内に最高血中濃度に達し、このときの濃度は約7μ
gと見積もられた。また、両者の血清中濃度一時間曲線
下面i (AUG)0〜8時間値を計算したとき組成物
が108.9μg−hr/ml、原末では34.6μg
−hr/mlであった。これら薬動力学的パラメータの
対比から本発明の組成物の吸収性は原末より優れている
と判断できる。一般に、担体に医薬品を吸着又は結合さ
せた医薬組成物は徐放化され吸収は遅延されるが、本発
明の組成物では原末と比べ、むしろ促進されることが第
1図より判る。As is clear from Figure 1, when the nalidixic acid-albumin composition was administered at 50 mg/kg as nalidixic acid, the maximum blood concentration was reached within 1.5 hours after administration, and the concentration at this time was approximately 25 μg. /m1. On the other hand, when administering the same amount of nalidixic acid bulk powder,
The maximum blood concentration is reached within a certain period of time, and the concentration at this time is approximately 7μ.
It was estimated that g. In addition, when calculating the lower surface i (AUG) of the 0-8 hour serum concentration curve for both, the composition was 108.9 μg-hr/ml, and the bulk powder was 34.6 μg.
-hr/ml. From the comparison of these pharmacodynamic parameters, it can be determined that the absorbability of the composition of the present invention is superior to that of the bulk powder. Generally, pharmaceutical compositions in which a drug is adsorbed or bound to a carrier are released in a sustained manner and absorption is delayed, but it can be seen from FIG. 1 that absorption is accelerated in the composition of the present invention compared to the bulk powder.
次に、本発明の消化管への副作用を軽減した例を説明す
る。非ステロイド性抗炎症剤は炎症局所において強力な
消炎作用を有する一方、消化器系に対し出血や潰瘍を起
こすことが知られている。前述の方法によって製造され
るインドメタシン−アルブミン組成物は非ステロイド性
抗炎症剤であるインドメタシンには潰瘍形成を示さずに
インドメタシンと同等の抗炎症作用を発現する。このこ
とは以下の実験から立証される。Next, an example in which the side effects on the gastrointestinal tract of the present invention are reduced will be explained. Although non-steroidal anti-inflammatory drugs have a strong anti-inflammatory effect on inflamed areas, they are known to cause bleeding and ulcers in the digestive system. The indomethacin-albumin composition produced by the above-described method exhibits an anti-inflammatory effect equivalent to that of indomethacin, which is a non-steroidal anti-inflammatory agent, without causing ulcer formation. This is proven by the following experiment.
試験法
試験は、関部らの方法〔ジャパニーズ ジャーナル オ
ブ ファーマコロジー(J、 J a p。Test method The test was performed using the method of Sekibe et al. [Japanese Journal of Pharmacology (J, J ap.
Pharmacol、)29S670頁(1979)〕
に準じて行った。Pharmacol, ) 29S670 pages (1979)]
I followed the instructions.
即ち、体重180〜200gのウィスター(Wi s
t a r)系ラット(1群8匹)を約18時間絶食後
、試料としてインドメタシン−アルブミン組成物をイン
ドメタシンとして20 m g 7kgとなるよう1%
カルポジキメチルセルロースナトリウム溶液(1%CM
CNaと略す)に懸濁したものをラット100g当り0
.5 m lの割合で経口投与した。また、対照として
インドメタシン原末を20mg/kgとなるように1%
CM CN aに懸濁したものを同様に投与した。That is, Wistar weighing 180 to 200 g.
After fasting rats (8 rats per group) for about 18 hours, an indomethacin-albumin composition was added as a sample to 20 mg of indomethacin at 1% to give 7 kg.
Karpodiki methyl cellulose sodium solution (1% CM
(abbreviated as CNa) per 100g of rat.
.. It was orally administered at a rate of 5 ml. In addition, as a control, indomethacin bulk powder was added at 1% to 20 mg/kg.
A suspension in CM CN a was administered in the same manner.
投与7時間後に全ラットをエーテル致死せしめ1%緩衝
ホルマリン水溶液8 m lを胃に注入後摘出して1%
緩衝ホルマリン水溶液に15分間浸漬した0次に、この
胃を大弯に沿って切開し実体顕微鏡下に胃粘膜部を観察
し、損傷部(潰瘍)を認めた場合はその長径(m m
)を測定した。その合計を潰瘍発生係数とし39mm以
上を+士、10〜30mmを廿、5〜lQmmを+、そ
れ以下は発生が認められないものとした。Seven hours after administration, all rats were sacrificed with ether and 8 ml of a 1% buffered formalin aqueous solution was injected into the stomach, which was then removed and 1% buffered formalin was removed.
The stomach was immersed in a buffered formalin aqueous solution for 15 minutes. Next, the stomach was incised along the greater curvature and the gastric mucosa was observed under a stereomicroscope. If a damaged area (ulcer) was found, its major axis (mm
) was measured. The sum was taken as the ulcer incidence coefficient, and 39 mm or more was defined as +, 10 to 30 mm was 2, 5 to 1Q mm was +, and below that, no ulcer occurrence was observed.
その結果を第1表に示す。The results are shown in Table 1.
第1表からも明らかなように、投与7時間後において、
インドメタシン原末投与群は金側に潰瘍が認められたが
、インドメタシン−アルブミン組成物投与群では8例中
6例までが潰瘍の形成を認めず、わずかに認められた2
例においてもその潰瘍は小さかった。As is clear from Table 1, 7 hours after administration,
Ulcers were observed on the gold side in the indomethacin bulk powder administration group, but up to 6 out of 8 subjects in the indomethacin-albumin composition administration group did not observe ulcer formation, and only a small number of ulcers were observed.
In this case, the ulcer was also small.
また、インドメタシン−アルブミン組成物の抗炎症作用
は以下の実験から立証される。Furthermore, the anti-inflammatory effect of the indomethacin-albumin composition is demonstrated by the following experiment.
インドメタシン−アルブミン の ;亙 カラゲニン足随浮腫法により判定した。Indomethacin-albumin; Judgment was made by the carrageenin foot edema method.
即ち、体重150〜180gのウィスター(Wista
r)系雄性ラット、(1群5匹)を用いて約18時間絶
食後、ラット右後肢足諺の足砿容積をラット足砿浮腫容
積はラット後肢足砿浮腫容積測定装置(夏目製作所、T
K−101型)を用いて測定し投与前値゛とした。試料
としてはインドメタシン−アルブミン組成物をインドメ
タシンとして約5 m g / k gとなるよう1%
CM CN aに懸濁したものとインドメタシン原末を
5 m g / k gとなるよう同様に懸濁したもの
とを用いて、ラット100g当り0.5 m lの割合
で経口投与した。また、対照としては1%CMCNaを
ラット100g当りQ、5m1(7)割合で経口投与し
た。経口投与30分後に1%λ−カラゲニン生理食塩水
溶液0.1 m lをラット右後肢足馳皮下に投与し、
直後に水5mlを経口投与した。1%λ−カラゲニン投
与3時間後の足諺浮腫を測定した。下記式(1)、(2
)よりカラゲニン足砿浮腫抑制率を求めた。That is, Wistar weighing 150 to 180 g.
r) After fasting for about 18 hours using male rats (5 rats per group), the volume of the rat hind limb edema was measured using a rat hind paw edema volume measuring device (Natsume Seisakusho, T
K-101 type) was used to determine the pre-administration value. As a sample, the indomethacin-albumin composition was mixed at 1% to give about 5 mg/kg of indomethacin.
A suspension in CM CN a and a similar suspension of indomethacin bulk powder at a concentration of 5 mg/kg were orally administered at a rate of 0.5 ml per 100 g of rats. As a control, 1% CMCNa was orally administered at a rate of Q, 5 ml (7) per 100 g of rats. 30 minutes after oral administration, 0.1 ml of 1% λ-carrageenan saline solution was subcutaneously administered to the right hind foot of the rat.
Immediately thereafter, 5 ml of water was orally administered. Foot edema was measured 3 hours after administration of 1% λ-carrageenan. The following formulas (1), (2
), the inhibition rate of carrageenan foot edema was determined.
×100 その結果を第2表に示す。×100 The results are shown in Table 2.
第2表から明らかなようにインドメタシン−アルブミン
組成物はインドメタシン原末とほぼ同等の効果を示し優
れた抗炎症作用を示す。As is clear from Table 2, the indomethacin-albumin composition exhibits approximately the same effect as the bulk indomethacin powder and exhibits excellent anti-inflammatory action.
次に、本発明により光安定性の向上された例を示す。前
述の方法により製造したニフェジピン−アルブミン組成
物は光に対する安定性において優れることは以下の実験
により立証される。Next, examples of improved photostability according to the present invention will be shown. The following experiment proves that the nifedipine-albumin composition prepared by the above method has excellent stability against light.
ニフェジピン−アルブミン、 の 生4式ニフェ
ジピンを約0.01g含有するニフェジピン−アルブミ
ン組成物的0.1g及び対照とし゛てニフェジピン約0
.1gとニフェジピンを約0゜001g含有する市販ニ
フェジピン細粒的0.1gを第2図に示すような平板(
50X50cm)上に10cm間隔に2X2cm平方に
広げる。Nifedipine-albumin, 0.1 g of nifedipine-albumin composition containing about 0.01 g of fresh formula 4 nifedipine and about 0.0 g of nifedipine as a control.
.. 1 g and 0.1 g of commercially available nifedipine fine granules containing about 0°001 g of nifedipine were placed in a flat plate as shown in Figure 2 (
50 x 50 cm) and spread it out into a 2 x 2 cm square at 10 cm intervals.
この平板を木製の箱で覆い平板中央に付属の蛍光灯(東
芝製10W)を点灯し24時間放置した。実験開始時の
室温は12℃、相対湿度30%であり、終了時は室温1
9℃、相対湿度25%であった。This flat plate was covered with a wooden box, and an attached fluorescent lamp (10 W manufactured by Toshiba) was turned on in the center of the flat plate and left for 24 hours. The room temperature at the start of the experiment was 12°C and relative humidity 30%, and at the end the room temperature was 12°C.
The temperature was 9°C and relative humidity 25%.
光照射後、検体各々をスポット別に回収し、正確にその
重量をネ^密に秤量し、メタノールIQmlを加え、超
音波洗浄機(高周波出力150W、28kHz)にて3
0分間超音波を照射した。不溶物を濾過して除き漏斗上
の残量をメタノールにて洗浄し、濾液と洗液を合わせた
後、メタノールにて全150m lに定容し検体液とし
た。遮光下に同様に保存したニフェジピン−アルブミン
組成物、ニフェジピン原末及び市販ニフェジピン細粒各
々約100mgを正確に秤量しメタノール19m1を加
え以後同様に操作し対照液とした。但し、ニフェジピン
原末については、対照液、検体液のいずれも更に正確に
10倍容に希釈した。対照液、検体液のいずれもその一
定量を正確に高速液体クロマトグラフィに注入しニフェ
ジピン濃度を定量した。尚、定量は2種類の異なる濃度
既知のニフェジピン標準液を同時に分析し得られた検量
線から算出した。高速液体クロマトグラフィの分析条件
は以下のとおりである。After irradiation with light, each sample was collected spot by spot, weighed accurately, and mixed with IQml of methanol, and washed in an ultrasonic cleaner (high frequency output 150W, 28kHz) for 3 hours.
Ultrasonic waves were applied for 0 minutes. Insoluble matter was filtered off, the remaining amount on the funnel was washed with methanol, the filtrate and washing liquid were combined, and the total volume was made up to 150 ml with methanol to provide a sample solution. Approximately 100 mg each of the nifedipine-albumin composition, nifedipine bulk powder, and commercially available nifedipine fine granules, which had been stored in the same manner under light protection, were accurately weighed, and 19 ml of methanol was added thereto, followed by the same procedure to obtain a control solution. However, for the nifedipine bulk powder, both the control solution and the sample solution were further accurately diluted to 10 times the volume. A fixed amount of both the control solution and the sample solution was accurately injected into a high-performance liquid chromatography system to quantify the concentration of nifedipine. The quantitative determination was calculated from a calibration curve obtained by simultaneously analyzing two different nifedipine standard solutions with known concentrations. The analysis conditions for high performance liquid chromatography are as follows.
カラム :ウオターズ型、ツバパック018移動層 :
55%メタノール
流速 : l m I / m i n検出波長:3
50nm
残存率は以下の式により算出した。Column: Waters type, Tsubapack 018 moving bed:
55% methanol flow rate: l m I/min detection wavelength: 3
The 50 nm residual rate was calculated using the following formula.
その結果を第3表に示す。The results are shown in Table 3.
試 料 残 存 率(平均)ニフェジピ
ン原末 30.2 (同 上)市販ニフェジピ
ン細粒 40.6 (同 上)第3表より明らかな
とおりニフェジピン−アルブミン組成物は、含有するニ
フェジピンの光分解を抑制し、その程度は市販ニフェジ
ピン細粒よりも安定性において優れていた。更にこの安
定性は一般の製剤加工により改善される。Sample residual rate (average) Nifedipine bulk powder 30.2 (Same as above) Commercially available Nifedipine fine granules 40.6 (Same as above) As is clear from Table 3, the nifedipine-albumin composition does not inhibit the photodegradation of the nifedipine it contains. and the degree of stability was superior to that of commercially available nifedipine fine granules. Furthermore, this stability is improved by common formulation processing.
更に本発明の組成物の1種である脂溶性ビタミン〃−α
−トコフェロール−卵白アルブミン組成物が吸収特性に
おいて優れていることは以下の実験により立証される。Furthermore, fat-soluble vitamin ッ-α, which is one of the compositions of the present invention
The following experiments demonstrate that the -tocopherol-ovalbumin composition is superior in absorption properties.
トコフェロール−白アルブミン組J物の〃−α−トコフ
ェロール単品及びa−α−トコフェロール−卵白アルブ
ミン組成物(dl−α。Tocopherol-white albumin combination J -α-tocopherol alone and a-α-tocopherol-ovalbumin composition (dl-α).
−トコフェロールとして100mg相当量)をOO号カ
プセル2個に充填し、イヌに経口投与した。経口投与後
3.6.9.12.24.36時間に肢静脈より採血し
遠心分離後血清を得た。血清0.5 m lにメタノー
ル1ml、ヘキサン5mlを加え10分間振盪し、ヘキ
サン相5mlを蒸発乾固後、ヘキサン300μlを加え
、その25μlを高速液体クロマトグラフィ試料とした
。- an amount equivalent to 100 mg as tocopherol) was filled into two No. OO capsules and orally administered to dogs. Blood was collected from the limb vein at 3.6.9.12.24.36 hours after oral administration, and serum was obtained after centrifugation. 1 ml of methanol and 5 ml of hexane were added to 0.5 ml of serum, and the mixture was shaken for 10 minutes. After 5 ml of hexane phase was evaporated to dryness, 300 μl of hexane was added, and 25 μl of the mixture was used as a high performance liquid chromatography sample.
高速液体クロマトグラフィの条件
カラふ :Lichrosorb 5I−60(74
m、 4mm、 j、d、X 25cm)
移動相 :ヘキサン:イソプロパノール(99,5:0
.5)
流速 =1.0ml/min
検出波長:励起波長295nm
螢光波長330nm
結果は第4図に示すように、R−α−トコフェロール−
卵白アルブミン組成物を投与した場合〃−α−トコフェ
ロールの血清中濃度の上昇が観察された。血清中濃度一
時間曲線下面積(AUC)は卵白アルブミン:8−α−
トコフェロール:ステアリン酸(5: 1 :0.5)
の場合単独投与時の2.8倍、卵白アルブミン:dl−
α−トコフェロール(5:1)の場合1.6倍に上昇し
た。特にステアリン酸を添加した場合、最高血中濃度到
達時間は単独投与時の12時間から6時間に短縮された
。これらの結果は〃−α−トコフェロールー卵白アルブ
ミン組成物が吸収特性において極めて優れていることを
示している。Conditions for high performance liquid chromatography: Lichrosorb 5I-60 (74
m, 4mm, j, d, x 25cm) Mobile phase: hexane:isopropanol (99,5:0
.. 5) Flow rate = 1.0 ml/min Detection wavelength: Excitation wavelength 295 nm Fluorescence wavelength 330 nm The results are as shown in Figure 4, R-α-tocopherol-
When the ovalbumin composition was administered, an increase in the serum concentration of -α-tocopherol was observed. The area under the serum concentration one-hour curve (AUC) is ovalbumin: 8-α-
Tocopherol: stearic acid (5:1:0.5)
2.8 times that of single administration, ovalbumin: dl-
In the case of α-tocopherol (5:1), it increased 1.6 times. In particular, when stearic acid was added, the time to reach the maximum blood concentration was shortened from 12 hours when administered alone to 6 hours. These results indicate that the -α-tocopherol-ovalbumin composition has extremely excellent absorption properties.
かくして、本発明の組成物は薬剤として用いる場合、経
口投与に通した種々の形態に製造することができる0例
えば、本発明の組成物は、この種薬剤に使用される無毒
性の製薬学的に許容し得る担体物質と共に含有する薬剤
として製剤することができる。かかる薬剤はその用途に
応じて、固体形態(例えば、錠剤、カプセル剤、顆粒剤
、散剤、細粒、糖衣丸、トローチ錠など)、半固形形態
(例えば、軟膏、ハップ剤、クリーム、坐剤など)及び
液体形!3(例えば、乳剤、懸濁液、ローン「ン、チン
キ剤、スプレー、シロップなど)のいずれの製剤形態に
も調製することができる。しかして、使用し得る無毒性
の製薬学的に許容し得る担体物質としては、例えば、デ
ンプン、ゼラチン、ブドウ糖、乳糖、果糖、マルトース
、炭酸マグネシウム、タルク、ステアリン酸マグネシウ
ム、メチルセルロース、カルボキシメチルセルロース又
はその塩、アラビアゴム、ポリアルキレングリコール、
p−ヒドロキシ安息香酸アルキルエステル、単シロップ
、エタノール、プロピレングリコール、グリセリン、ワ
セリン、カーボワックス等が挙げられる。該薬剤はまた
、治療学的に有用な他の薬剤、分散剤、酸化防止剤、保
存剤、安定剤、香味剤、結合剤、湯沢剤等を含むことが
できる。Thus, when the composition of the present invention is used as a drug, it can be manufactured into a variety of forms for oral administration. It can be formulated as a drug containing together with a carrier material that is acceptable to the manufacturer. Depending on the intended use, such drugs may be in solid form (e.g., tablets, capsules, granules, powders, granules, dragees, lozenges, etc.) or semi-solid forms (e.g., ointments, poultices, creams, suppositories). ) and liquid form! 3 (e.g., emulsions, suspensions, liquids, tinctures, sprays, syrups, etc.).Therefore, non-toxic, pharmaceutically acceptable formulations that can be used may be prepared. Examples of the carrier material to be obtained include starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, polyalkylene glycol,
Examples include p-hydroxybenzoic acid alkyl ester, simple syrup, ethanol, propylene glycol, glycerin, vaseline, carbowax and the like. The agent may also contain other therapeutically useful agents, dispersants, antioxidants, preservatives, stabilizers, flavoring agents, binders, blanching agents, and the like.
該薬剤中における本発明の組成物の含有量はその形態に
応じて異なるが、一般に固体及び半固体形態の場合には
5〜100重量%の濃度で、そして液体形態の場合には
0.1〜10重量%の濃度で該活性化合物を含有してい
ることが望ましい。The content of the composition of the invention in the medicament varies depending on its form, but generally at a concentration of 5 to 100% by weight for solid and semi-solid forms and 0.1% for liquid forms. It is desirable to contain the active compound in a concentration of ~10% by weight.
以下、実施例を挙げ本発明の詳細な説明する。Hereinafter, the present invention will be described in detail with reference to Examples.
実施例1
卵白アルブミン18gを蒸留水400m1に加え、冷却
しつつバイオライザー(日本精器製作所製BM−4型)
を用いて約1)000Orpで高速攪拌することにより
均一相を得た。ニフェジピン2gをアセトン6 m l
に溶解し先の均一相に加えた。更に冷却しつつ1時間高
速攪拌を続け、得られた均一懸濁液から有機溶媒を減圧
下に留去し、凍結乾燥することにより粉体を得た。この
粉体を100メツシユのふるいを通して均一粒径のニフ
ェジピン−アルブミン組成物を得た。得られたニフェジ
ビンーアルブミン組成物は、第3図の走査型電子顕微鏡
写真に示すように最長粒子径的15μmの板状結晶様の
立体構造を有していた。Example 1 Add 18 g of ovalbumin to 400 ml of distilled water and use a biolyzer (Model BM-4 manufactured by Nippon Seiki Seisakusho) while cooling.
A homogeneous phase was obtained by stirring at a high speed of about 1)000 Orp using a . 2 g of nifedipine in 6 ml of acetone
and added to the homogeneous phase. High-speed stirring was continued for 1 hour while further cooling, and the organic solvent was distilled off under reduced pressure from the resulting homogeneous suspension, followed by freeze-drying to obtain a powder. This powder was passed through a 100 mesh sieve to obtain a nifedipine-albumin composition with uniform particle size. The obtained nifedibine-albumin composition had a plate-like three-dimensional structure with a longest particle diameter of 15 μm, as shown in the scanning electron micrograph of FIG.
実施例2〜22
第4表に示した医薬品及び溶媒を用いた点及び用いられ
た医薬品及び溶媒の種類、物性等に応じて高速攪拌条件
及び乾燥条件を適宜変動させた点を除き実施例1と同様
にして各種医薬品−アルブミン組成物の粉末を得た。Examples 2 to 22 Example 1 except that the pharmaceuticals and solvents shown in Table 4 were used, and the high-speed stirring conditions and drying conditions were appropriately varied according to the types, physical properties, etc. of the pharmaceuticals and solvents used. Powders of various pharmaceutical-albumin compositions were obtained in the same manner as above.
第4表 医薬品及び溶媒並びにこれらの使用量2 アス
ピリン 2 エタノール 203 インドメタシ
2 エタノール 204 ナリジクス酸 2 クロロ
ホルム 605 ピロキシカム 2 アセトン 8
06 スリンダク 2 メタノール 100第4表つ
づき
8 セファクロル 2 蒸留水 1009 セフア
レキシ 2 蒸留水 100ン
12 デキサメサゾ 1 エタノール 100ン
14 ハロベリド−2メタノール 100ル
16 セフアレキシ 1 蒸留水 100ン
20 ケトチフェン 2 メタノール 8021 グ
リチルリチ 2 メタノール 60ン
22 トラニラスト 2 アセトン 200*8−α
−トコフェロール−卵白アルブミン組゛成物(1: 5
)以外に一スf1 ’) 7j!1.8 gをも用いた
a−α−トコフェロール−卵白アルブミン−ステアリン
酸組成物(1: 5 :0.5・)も製造した。Table 4 Pharmaceuticals and solvents and their usage amounts 2 Aspirin 2 Ethanol 203 Indometase
2 Ethanol 204 Nalidixic acid 2 Chloroform 605 Piroxicam 2 Acetone 8
06 Sulindac 2 Methanol 100 Table 4 continued 8 Cefaclor 2 Distilled water 1009 Cefalexi 2 Distilled water 100 12 Dexamethazo 1 Ethanol 100 14 Haloberide-2 Methanol 100 16 Cephalexi 1 Distilled water 100 20 Ketotifen 2 Methanol 8021 Glycyrrhizi 2 methanol 60 N22 Tranilast 2 Acetone 200*8-α
-Tocopherol-ovalbumin composition (1:5
) except one f1') 7j! An a-α-tocopherol-ovalbumin-stearic acid composition (1:5:0.5·) was also prepared using 1.8 g.
本発明の天然アルブミンを担体として医薬組成物は、人
体に好ましくない副作用を軽減する医薬品の吸収を改善
する、光安定性に優れている等の顕著な効果を有する。The pharmaceutical composition of the present invention using natural albumin as a carrier has remarkable effects such as reducing unfavorable side effects on the human body, improving absorption of pharmaceuticals, and having excellent photostability.
第1図はナリジクス酸−アルプミン組成物投与後の血中
濃度の経時変化を示すグラフ、第2図はニフェジピン−
アルブミン組成物等の光安定性試験において各種試料を
配置するために用いた平板を示す図、
vJs図はニフェジピン−アルブミン組成物の走査型電
子顕微鏡写真、
第4図は〃−α−トコフェロールー卵白アルブミン組成
物の投与後の血中濃度の経時変化を六すグラフである。
出願人 株式会社日本ハイボックス
代理人 弁理士 中 村 静 男
A:ニフェジピン−アルブミン組成物
B:ニフェジピン原末
C:ニフェジピン茅A粒
D:アルブミン
図面の浄書
時間(hr)
手続補正書く方式)
%式%
1、事件の表示
昭和62年特許願第49135号
2、発明の名称
天然アルブミンを担体とした
医薬組成物及びその製法
名 称 株式会社 日本ハイボックス力ヤヌマビル
802号
昭和62年5月26日
7、補正の内容
(1)明細書第29頁第18行の「走査形電子顕微鏡写
真」をr結晶のWJ造を示す走査形電子顕微鏡写真1に
訂正する。
(2)図面を別紙の訂正図面(第2図及び第4図)に差
し替える。Figure 1 is a graph showing changes in blood concentration over time after administration of the nalidixic acid-alpmin composition, and Figure 2 is a graph showing changes in blood concentration over time after administration of nalidixic acid-alpmin composition.
Figure 4 shows the flat plate used to arrange various samples in the photostability test of albumin compositions, etc. The vJs diagram is a scanning electron micrograph of the nifedipine-albumin composition, and Figure 4 shows the α-tocopherol albumin. 6 is a graph showing changes over time in blood concentration after administration of an albumin composition. Applicant Japan Highbox Co., Ltd. Agent Patent attorney Shizuka Nakamura Man A: Nifedipine-albumin composition B: Nifedipine bulk powder C: Nifedipine Chia A grains D: Albumin Drawing engraving time (hr) Procedural amendment writing method) % formula % 1. Indication of the incident Patent Application No. 49135 of 1988 2. Name of the invention Pharmaceutical composition using natural albumin as a carrier and its manufacturing method Name Nihon Hibox Yanumavir Co., Ltd. No. 802 May 26, 1988 7 , Details of the amendment (1) "Scanning electron micrograph" on page 29, line 18 of the specification is corrected to scanning electron micrograph 1 showing the WJ structure of r crystal. (2) Replace the drawings with the attached corrected drawings (Figures 2 and 4).
Claims (2)
然アルブミン100部からなる医薬組成物。(1) A pharmaceutical composition comprising 1 to 200 parts of a pharmaceutical exhibiting protein-binding properties and 100 parts of natural albumin.
然アルブミン100部に対し1乃至200部を加え、高
速で攪拌した後溶媒を除去することを特徴とする医薬組
成物の製法。(2) A method for producing a pharmaceutical composition, which comprises suspending natural albumin in an aqueous solution, adding 1 to 200 parts of the drug to 100 parts of natural albumin, stirring at high speed, and then removing the solvent.
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62049135A JP2654445B2 (en) | 1987-03-04 | 1987-03-04 | Pharmaceutical composition using natural albumin as carrier and process for producing the same |
US07/620,394 US5051406A (en) | 1987-03-04 | 1988-03-04 | Pharmaceutical composition using albumin as a carrier and process for producing the same |
EP88902237A EP0326618A1 (en) | 1987-03-04 | 1988-03-04 | Medicinal composition containing albumin as carrier and process for its preparation |
PCT/JP1988/000237 WO1988006457A1 (en) | 1987-03-04 | 1988-03-04 | Medicinal composition containing albumin as carrier and process for its preparation |
DK617088A DK617088D0 (en) | 1987-03-04 | 1988-11-04 | PHARMACEUTICAL PREPARATION CONTAINING ALBUMIN AS A CARRIER AND PROCEDURE FOR ITS PREPARATION |
KR1019880701401A KR890700361A (en) | 1987-03-04 | 1988-11-04 | Pharmaceutical composition using albumin as a carrier and its manufacturing method |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62049135A JP2654445B2 (en) | 1987-03-04 | 1987-03-04 | Pharmaceutical composition using natural albumin as carrier and process for producing the same |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS63215642A true JPS63215642A (en) | 1988-09-08 |
JP2654445B2 JP2654445B2 (en) | 1997-09-17 |
Family
ID=12822624
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP62049135A Expired - Lifetime JP2654445B2 (en) | 1987-03-04 | 1987-03-04 | Pharmaceutical composition using natural albumin as carrier and process for producing the same |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP2654445B2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1132097A2 (en) * | 1993-10-15 | 2001-09-12 | ConjuChem, Inc. | Cellular and serum protein anchors and conjugates |
JP2003534357A (en) * | 2000-05-30 | 2003-11-18 | ソシエテ デ プロデユイ ネツスル ソシエテ アノニム | Primary composition containing a lipophilic bioactive compound |
JP2018524265A (en) * | 2015-05-08 | 2018-08-30 | スペクトラル プラットフォームス インコーポレイテッド | Noncovalent complexes based on albumin and methods of use thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5464626A (en) * | 1977-08-01 | 1979-05-24 | Univ Northwestern | Support for dosing into vessel being present locally by magnetic force and production thereof |
JPS5726615A (en) * | 1980-07-23 | 1982-02-12 | Grelan Pharmaceut Co Ltd | Improving method for absorbability of slightly soluble drug |
JPS62174007A (en) * | 1985-10-11 | 1987-07-30 | Sumitomo Pharmaceut Co Ltd | Slow-releasing preparation containing silicone elastomer |
-
1987
- 1987-03-04 JP JP62049135A patent/JP2654445B2/en not_active Expired - Lifetime
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5464626A (en) * | 1977-08-01 | 1979-05-24 | Univ Northwestern | Support for dosing into vessel being present locally by magnetic force and production thereof |
JPS5726615A (en) * | 1980-07-23 | 1982-02-12 | Grelan Pharmaceut Co Ltd | Improving method for absorbability of slightly soluble drug |
JPS62174007A (en) * | 1985-10-11 | 1987-07-30 | Sumitomo Pharmaceut Co Ltd | Slow-releasing preparation containing silicone elastomer |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1132097A2 (en) * | 1993-10-15 | 2001-09-12 | ConjuChem, Inc. | Cellular and serum protein anchors and conjugates |
JP2003534357A (en) * | 2000-05-30 | 2003-11-18 | ソシエテ デ プロデユイ ネツスル ソシエテ アノニム | Primary composition containing a lipophilic bioactive compound |
JP2018524265A (en) * | 2015-05-08 | 2018-08-30 | スペクトラル プラットフォームス インコーポレイテッド | Noncovalent complexes based on albumin and methods of use thereof |
Also Published As
Publication number | Publication date |
---|---|
JP2654445B2 (en) | 1997-09-17 |
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