JPH11292770A - Matrix formation sthenia inhibitor - Google Patents
Matrix formation sthenia inhibitorInfo
- Publication number
- JPH11292770A JPH11292770A JP11593098A JP11593098A JPH11292770A JP H11292770 A JPH11292770 A JP H11292770A JP 11593098 A JP11593098 A JP 11593098A JP 11593098 A JP11593098 A JP 11593098A JP H11292770 A JPH11292770 A JP H11292770A
- Authority
- JP
- Japan
- Prior art keywords
- activated carbon
- spherical activated
- inhibitor
- spherical
- active ingredient
- 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.)
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Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、マトリックス形成
亢進抑制剤に関する。[0001] The present invention relates to an agent for suppressing matrix formation enhancement.
【０００２】[0002]
【従来の技術】細胞外マトリックス形成亢進及び／又は
線維化の亢進には、トランスフォーミング成長因子−β
（以下、ＴＧＦ−βと称する）等の発現が関与してい
る。ＴＧＦ−βは、心臓、腎臓、又は肝臓等に分布して
おり、内皮細胞又は線維芽細胞等に作用し、細胞外基質
（例えば、プロテオグリカン、フィブロネクチン、又は
コラーゲン等）、すなわち、マトリックスの合成を促進
させる作用がある。また、ＴＧＦ−βは、腫瘍組織にお
いて発現量の高いことが知られている。従って、ＴＧＦ
−βの発現、濃度の亢進、及び／又は過剰産生は、線維
化の亢進に関与し、細胞外マトリックスの異常な増加の
起因となっていることから、様々な内科疾患［例えば、
心疾患（例えば、心肥大又は心筋梗塞など）、肝疾患
（例えば、慢性肝炎、肝線維症、肝硬変、又は肝癌な
ど）、腎疾患（例えば、慢性腎不全、間質性腎炎、腎
炎、又は糖尿病性腎症など）、又は血管性病変（例え
ば、動脈硬化病変、又は糖尿病など）等］の進展に関与
しているといえる。更に、細胞外マトリックスの形成亢
進には、ＴＧＦ−β以外にも、例えば、メタロプロテア
ーゼ組織インヒビター（Ｔｉｓｓｕｅ ｉｎｈｉｂｉｔ
ｏｒ ｏｆｍｅｔａｌｌｏｐｒｏｔｅｉｎａｓｅｓ；以
下、ＴＩＭＰと称する）又はコラーゲン等のｍＲＮＡの
発現の亢進が関与しているといわれている。2. Description of the Related Art Transforming growth factor-β is used for enhancing extracellular matrix formation and / or enhancing fibrosis.
(Hereinafter referred to as TGF-β) and the like. TGF-β is distributed in the heart, kidney, liver, etc., acts on endothelial cells or fibroblasts, etc., and regulates extracellular matrix (eg, proteoglycan, fibronectin, collagen, etc.), that is, synthesis of matrix. It has the effect of promoting. In addition, TGF-β is known to be highly expressed in tumor tissues. Therefore, TGF
Increased expression, concentration, and / or overproduction of -β are involved in enhanced fibrosis and are responsible for an abnormal increase in extracellular matrix.
Heart disease (eg, such as cardiac hypertrophy or myocardial infarction), liver disease (eg, chronic hepatitis, liver fibrosis, cirrhosis, or liver cancer), renal disease (eg, chronic renal failure, interstitial nephritis, nephritis, or diabetes) Etc.) or vascular lesions (eg, arteriosclerotic lesions, diabetes, etc.)]. Furthermore, in order to enhance the formation of extracellular matrix, in addition to TGF-β, for example, a metalloprotease tissue inhibitor (Tissue inhibitor) may be used.
It is said that the enhancement of the expression of mRNA such as collagen or the like is involved.
【０００３】[0003]
【発明が解決しようとする課題】細胞外マトリックスの
形成亢進を抑制させる治療法の一つとして、アンタゴニ
ストが考えられるが、充分に有効な治療法が未だ確立さ
れておらず、副作用も懸念される。従って、特別な副作
用がなく、ＴＧＦ−β、ＴＩＭＰ、及び／又はコラーゲ
ン等の亢進を抑制させ、細胞外マトリックスの形成亢進
及び／又は線維化亢進を抑制させることのできる薬剤が
望まれていた。従って、本発明の課題は、体内において
異常に細胞外マトリックスの形成亢進及び／又は線維化
が亢進している疾患について、副作用等の薬害が少な
く、細胞外マトリックスの形成亢進及び／又は線維化の
亢進を抑制させることのできる医薬製剤を提供すること
にある。本発明者は、前記の課題を解決する目的で、鋭
意研究を重ねたところ、医療用活性炭製剤の経口投与に
より、細胞外マトリックス形成亢進及び／又は線維化の
亢進に関与するＴＧＦ−β、ＴＩＭＰ、及びコラーゲン
の発現が抑制されることを見出した。更に、この点は、
血中における線維化指標であるヒアルロン酸濃度の上昇
及びプロリン水酸化酵素濃度の上昇がそれぞれ抑制され
ることからも確認した。本発明は、こうした知見に基づ
くものである。An antagonist is considered as one of the therapeutic methods for suppressing the increase in extracellular matrix formation, but a sufficiently effective therapeutic method has not yet been established, and there are concerns about side effects. . Therefore, there has been a demand for a drug which has no special side effects and can suppress the increase of TGF-β, TIMP, and / or collagen, and can suppress the formation of extracellular matrix and / or the increase of fibrosis. Therefore, an object of the present invention is to reduce the phytotoxicity such as side effects and reduce the extracellular matrix formation and / or fibrosis in diseases in which extracellular matrix formation and / or fibrosis are abnormally increased in the body. An object of the present invention is to provide a pharmaceutical preparation capable of suppressing hyperactivity. The present inventors have conducted intensive studies for the purpose of solving the above problems, and found that TGF-β, TIMP involved in the promotion of extracellular matrix formation and / or the promotion of fibrosis by oral administration of a medical activated carbon preparation. And the expression of collagen was suppressed. Furthermore, this point
It was also confirmed that the increase in the concentration of hyaluronic acid and the increase in the concentration of proline hydroxylase, which are indicators of fibrosis in blood, were suppressed. The present invention is based on these findings.
【０００４】[0004]
【課題を解決するための手段】本発明は、活性炭を有効
成分とする、マトリックス形成亢進抑制剤に関する。以
下、本明細書において、本発明の「マトリックス形成亢
進抑制剤」、本発明の「線維化亢進抑制剤」、本発明の
「トランスフォーミング成長因子−β（ＴＧＦ−β）発
現抑制剤」、本発明の「メタロプロテアーゼ組織インヒ
ビター（ＴＩＭＰ）発現抑制剤」、本発明の「コラーゲ
ンの発現抑制剤」、及び本発明の「マトリックス形成亢
進の病態を示す疾患の治療又は予防剤」を集合的に、本
発明の「医薬製剤」と称する。Means for Solving the Problems The present invention relates to an agent for suppressing matrix formation, which comprises activated carbon as an active ingredient. Hereinafter, in the present description, the "inhibitor of matrix formation enhancement" of the present invention, the "inhibitor of fibrosis enhancement" of the present invention, the "transforming growth factor-β (TGF-β) expression inhibitor" of the present invention, Collectively, the "metalloprotease tissue inhibitor (TIMP) expression inhibitor" of the present invention, the "collagen expression inhibitor" of the present invention, and the "treatment or prevention agent for a disease exhibiting a pathological condition of enhanced matrix formation" of the present invention, It is referred to as the "pharmaceutical formulation" of the present invention.
【０００５】[0005]
【発明の実施の形態】本発明の医薬製剤の有効成分であ
る活性炭としては、医療用に使用することが可能な活性
炭であれば特に限定されるものではないが、経口投与用
活性炭、すなわち、医療用に内服使用することが可能な
活性炭が好ましい。前記活性炭としては、例えば、粉末
状活性炭又は球形活性炭を用いることができる。粉末状
活性炭としては、従来から解毒剤として医療に用いられ
ている公知の粉末状活性炭を用いることができるが、副
作用として便秘を引き起こす場合があるので、球形活性
炭を用いるのが好ましい。BEST MODE FOR CARRYING OUT THE INVENTION The activated carbon which is an active ingredient of the pharmaceutical preparation of the present invention is not particularly limited as long as it is an activated carbon which can be used for medical purposes. Activated carbon that can be used internally for medical purposes is preferred. As the activated carbon, for example, powdered activated carbon or spherical activated carbon can be used. As the powdered activated carbon, known powdered activated carbon conventionally used in medicine as an antidote can be used, but spherical activated carbon is preferably used because constipation may be caused as a side effect.
【０００６】球形活性炭としては、医療用に内服使用す
ることが可能な球形状の活性炭であれば特に限定されな
い。この球形活性炭は吸着能に優れていることが好まし
い。そのため、前記球形活性炭は、好ましくは直径０．
０５〜２ｍｍ、より好ましくは０．１〜１ｍｍの球形活
性炭である。また、好ましくは比表面積が５００〜２０
００ｍ2 ／ｇ、より好ましくは７００〜１５００ｍ2 ／
ｇの球形活性炭である。また、好ましくは細孔半径１０
０〜７５０００オングストロームの空隙量が０．０１〜
１ｍｌ／ｇ、より好ましくは０．０５〜０．８ｍｌ／ｇ
の球形活性炭である。なお、上記の比表面積は、自動吸
着量測定装置を用いたメタノール吸着法により測定した
値である。空隙量は、水銀圧入ポロシメータにより測定
した値である。前記の球形活性炭は、粉末活性炭に比
べ、服用時に飛散せず、しかも、連続使用しても便秘を
惹起しない点で有利である。直径が０．０５ｍｍ未満の
場合は、便秘などの副作用の除去に充分な効果がなく、
２ｍｍを超える場合は、服用し難いだけでなく、目的と
する薬理効果も迅速に発現されない。球形活性炭の形状
は、重要な因子の１つであり、実質的に球状であること
が重要である。球形活性炭の中では、後述の石油系ピッ
チ由来の球形活性炭が真球に近いため特に好ましい。The spherical activated carbon is not particularly limited as long as it is a spherical activated carbon that can be used internally for medical purposes. This spherical activated carbon preferably has excellent adsorption capacity. Therefore, the spherical activated carbon preferably has a diameter of 0.
It is a spherical activated carbon having a diameter of 0.5 to 2 mm, more preferably 0.1 to 1 mm. Preferably, the specific surface area is 500 to 20.
00m 2 / g, more preferably 700~1500m 2 /
g of spherical activated carbon. Also, preferably, the pore radius is 10
0 to 75000 angstroms void volume is 0.01 to
1 ml / g, more preferably 0.05 to 0.8 ml / g
Is a spherical activated carbon. The above specific surface area is a value measured by a methanol adsorption method using an automatic adsorption amount measuring device. The void amount is a value measured by a mercury intrusion porosimeter. The above-mentioned spherical activated carbon is advantageous in that it does not scatter when taken, and does not cause constipation even when used continuously, as compared with powdered activated carbon. If the diameter is less than 0.05 mm, there is not enough effect to remove side effects such as constipation,
If it exceeds 2 mm, not only is it difficult to take the drug, but also the desired pharmacological effect is not rapidly exhibited. The shape of the spherical activated carbon is one of the important factors, and it is important that the shape is substantially spherical. Among the spherical activated carbons, a spherical activated carbon derived from a petroleum-based pitch described below is particularly preferable because it is close to a true sphere.
【０００７】球形活性炭の製造には、任意の活性炭原
料、例えば、オガ屑、石炭、ヤシ殻、石油系若しくは石
炭系の各種ピッチ類又は有機合成高分子を用いることが
できる。球形活性炭は、例えば、原料を炭化した後に活
性化する方法によって製造することができる。活性化の
方法としては、水蒸気賦活、薬品賦活、空気賦活又は炭
酸ガス賦活などの種々の方法を用いることができるが、
医療に許容される純度を維持することが必要である。For the production of spherical activated carbon, any activated carbon raw material, for example, sawdust, coal, coconut shell, various petroleum-based or coal-based pitches, or organic synthetic polymers can be used. Spherical activated carbon can be produced, for example, by a method of activating carbonized raw materials. As the activation method, various methods such as water vapor activation, chemical activation, air activation or carbon dioxide gas activation can be used,
It is necessary to maintain medically acceptable purity.
【０００８】球形活性炭としては、炭素質粉末からの造
粒活性炭、有機高分子焼成の球形活性炭及び石油系炭化
水素（石油系ピッチ）由来の球形活性炭などがある。炭
素質粉末からの造粒活性炭は、例えば、タール、ピッチ
等のバインダーで炭素質粉末原料を小粒球形に造粒した
後、不活性雰囲気中で６００〜１０００℃の温度に加熱
焼成して炭化し、次いで、賦活することにより得ること
ができる。賦活方法としては、水蒸気賦活、薬品賦活、
空気賦活又は炭酸ガス賦活などの種々の方法を用いるこ
とができる。水蒸気賦活は、例えば、水蒸気雰囲気中、
８００〜１１００℃の温度で行われる。Examples of the spherical activated carbon include granulated activated carbon from carbonaceous powder, spherical activated carbon obtained by firing an organic polymer, and spherical activated carbon derived from petroleum hydrocarbon (petroleum pitch). Granulated activated carbon from carbonaceous powder, for example, after granulating the carbonaceous powder raw material into small spheres with a binder such as tar, pitch, etc., is heated and calcined at a temperature of 600 to 1000 ° C. in an inert atmosphere to carbonize. , Followed by activation. Activation methods include steam activation, chemical activation,
Various methods such as air activation or carbon dioxide activation can be used. Steam activation, for example, in a steam atmosphere,
It is performed at a temperature of 800 to 1100 ° C.
【０００９】有機高分子焼成の球形活性炭は、例えば、
特公昭６１−１３６６号公報に開示されており、次のよ
うにして製造することが可能である。縮合型又は重付加
型の熱硬化性プレポリマーに、硬化剤、硬化触媒、乳化
剤などを混合し、撹拌下で水中に乳化させ、室温又は加
温下に撹拌を続けながら反応させる。反応系は、まず懸
濁状態になり、更に撹拌することにより熱硬化性樹脂球
状物が出現する。これを回収し、不活性雰囲気中で５０
０℃以上の温度に加熱して炭化し、前記の方法により賦
活して有機高分子焼成の球形活性炭を得ることができ
る。石油系ピッチ由来の球形活性炭は、直径が好ましく
は０．０５〜２ｍｍ、より好ましくは０．１〜１ｍｍ、
比表面積が好ましくは５００〜２０００ｍ2 ／ｇ、より
好ましくは７００〜１５００ｍ2 ／ｇ、細孔半径１００
〜７５０００オングストロームの空隙量が好ましくは
０．０１〜１ｍｌ／ｇである。この石油系ピッチ由来の
球形活性炭は、例えば、以下の２種の方法で製造するこ
とができる。[0009] Spherical activated carbon fired by an organic polymer is, for example,
It is disclosed in JP-B-61-1366, and can be manufactured as follows. A curing agent, a curing catalyst, an emulsifier, and the like are mixed with the condensation-type or polyaddition-type thermosetting prepolymer, emulsified in water with stirring, and reacted at room temperature or while heating while stirring. The reaction system is first in a suspended state, and a thermosetting resin spherical substance appears by further stirring. This is collected and placed in an inert atmosphere at 50
It can be heated to a temperature of 0 ° C. or higher for carbonization, and activated by the above-mentioned method to obtain a spherical activated carbon fired by an organic polymer. The spherical activated carbon derived from petroleum-based pitch preferably has a diameter of 0.05 to 2 mm, more preferably 0.1 to 1 mm,
The specific surface area is preferably 500~2000m 2 / g, more preferably 700~1500m 2 / g, pore radius 100
A void volume of ７５75000 Å is preferably 0.01-1 ml / g. This spherical activated carbon derived from petroleum-based pitch can be produced, for example, by the following two methods.
【００１０】第１の方法は、例えば、特公昭５１−７６
号公報（米国特許第３９１７８０６号明細書）及び特開
昭５４−８９０１０号公報（米国特許第４７６１２８４
号明細書）に記載されているように、まず、溶融状態で
小粒球形状としたピッチ類を酸素により不融化した後、
不活性雰囲気中で６００〜１０００℃の温度に加熱焼成
して炭化し、次いで、水蒸気雰囲気中で８５０〜１００
０℃の温度で賦活する方法である。第２の方法は、例え
ば、特公昭５９−１０９３０号公報（米国特許第４４２
０４３３号明細書）に記載されているように、まず、溶
融状態で紐状としたピッチ類を破砕した後、熱水中に投
入して球状化し、次いで、酸素により不融化した後、上
記の第１の方法と同様の条件で炭化、賦活する方法であ
る。The first method is described, for example, in JP-B-51-76.
(US Pat. No. 3,917,806) and JP-A-54-89010 (US Pat. No. 4,761,284).
First, as described in the specification, after the pitches made into small spheres in the molten state are made infusible with oxygen,
Heating and calcining to a temperature of 600 to 1000 ° C. in an inert atmosphere to carbonize, and then in a steam atmosphere to 850 to 100 ° C.
This is a method of activating at a temperature of 0 ° C. The second method is disclosed, for example, in Japanese Patent Publication No. 59-10930 (U.S. Pat. No. 442).
No. 0433), first, crushed string-like pitches in a molten state, then thrown into hot water to make them spherical, and then made infusible with oxygen, This is a method of carbonizing and activating under the same conditions as the first method.
【００１１】本発明において有効成分の球形活性炭とし
ては、（１）アンモニア処理などを施した球形活性炭、
（２）酸化及び／又は還元処理を施した球形活性炭など
も使用することができる。これらの処理を施すことので
きる球形活性炭は、前記の石油系ピッチ由来の球形活性
炭、炭素質粉末の造粒活性炭、有機高分子焼成の球形活
性炭の何れであってもよい。In the present invention, the spherical active carbon as an active ingredient includes (1) spherical activated carbon which has been subjected to ammonia treatment or the like;
(2) Spherical activated carbon subjected to oxidation and / or reduction treatment can also be used. The spherical activated carbon that can be subjected to these treatments may be any of the above-mentioned spherical activated carbon derived from petroleum-based pitch, granulated activated carbon of carbonaceous powder, and spherical activated carbon of organic polymer firing.
【００１２】前記のアンモニア処理とは、例えば、球形
活性炭を、１〜１０００ｐｐｍのアンモニアを含有する
アンモニア水溶液で、アンモニア水溶液と球形活性炭の
容量比を２〜１０として、１０〜５０℃の温度で、０．
５〜５時間処理することからなる。前述の石油系ピッチ
由来の球形活性炭にアンモニア処理を施した活性炭とし
ては、特開昭５６−５３１３号公報（米国特許第４７６
１２８４号明細書）に記載の球形活性炭を挙げることが
できる。例えば、アンモニア処理が施された球形活性炭
としては直径が０．０５〜２ｍｍ、好ましくは０．１〜
１ｍｍ、比表面積が５００〜２０００ｍ2 ／ｇ、好まし
くは７００〜１５００ｍ2 ／ｇ、細孔半径１００〜７５
０００オングストロームの空隙量が０．０１〜１ｍｌ／
ｇ、ｐＨが６〜８の球形活性炭を例示することができ
る。The above-mentioned ammonia treatment means, for example, that spherical activated carbon is an aqueous ammonia solution containing 1 to 1000 ppm of ammonia, the volume ratio of the aqueous ammonia solution to the spherical activated carbon is 2 to 10, and the temperature is 10 to 50 ° C. 0.
Consists of treating for 5 to 5 hours. The activated carbon obtained by subjecting the above-mentioned spherical activated carbon derived from petroleum pitch to ammonia treatment is disclosed in JP-A-56-5313 (US Pat. No. 476).
No. 1284). For example, the spherical activated carbon subjected to the ammonia treatment has a diameter of 0.05 to 2 mm, preferably 0.1 to 2 mm.
1 mm, a specific surface area of 500~2000m 2 / g, preferably 700~1500m 2 / g, pore radius from 100 to 75
000 angstrom void volume of 0.01 to 1 ml /
g and a spherical activated carbon having a pH of 6 to 8 can be exemplified.
【００１３】前記の酸化処理とは、酸素を含む酸化雰囲
気で高温熱処理を行なうことを意味し、酸素源として
は、純粋な酸素、酸化窒素又は空気などを用いることが
できる。また、還元処理とは、炭素に対して不活性な雰
囲気で高温熱処理を行なうことを意味し、炭素に対して
不活性な雰囲気は、窒素、アルゴン若しくはヘリウム又
はそれらの混合ガスを用いて形成することができる。The above-mentioned oxidation means that high-temperature heat treatment is performed in an oxidizing atmosphere containing oxygen, and pure oxygen, nitrogen oxide, air or the like can be used as an oxygen source. In addition, reduction treatment means performing high-temperature heat treatment in an atmosphere inert to carbon, and an atmosphere inert to carbon is formed using nitrogen, argon, helium, or a mixed gas thereof. be able to.
【００１４】前記の酸化処理は、好ましくは酸素含有量
０．５〜２５容量％、より好ましくは酸素含有量３〜１
０容量％の雰囲気中、好ましくは３００〜７００℃、よ
り好ましくは４００〜６００℃の温度で行われる。前記
の還元処理は、好ましくは７００〜１１００℃、より好
ましくは８００〜１０００℃の温度で不活性雰囲気中で
行われる。The above-mentioned oxidation treatment is preferably carried out at an oxygen content of 0.5 to 25% by volume, more preferably at an oxygen content of 3 to 1%.
It is carried out in an atmosphere of 0% by volume, preferably at a temperature of 300 to 700C, more preferably at a temperature of 400 to 600C. The reduction treatment is preferably performed at a temperature of 700 to 1100 ° C, more preferably 800 to 1000 ° C, in an inert atmosphere.
【００１５】前述の石油系ピッチ由来の球形活性炭に酸
化及び／又は還元処理を施した例としては、特公昭６２
−１１６１１号公報（米国特許第４６８１７６４号明細
書）に記載の球形炭素質吸着剤を挙げることができる。
酸化及び／又は還元処理が施された球形活性炭として
は、直径が０．０５〜２ｍｍ、好ましくは０．１〜１ｍ
ｍ、比表面積が５００〜２０００ｍ2 ／ｇ、好ましくは
７００〜１５００ｍ2 ／ｇ、細孔半径１００〜７５００
０オングストロームの空隙量が０．０１〜１ｍｌ／ｇで
ある球形活性炭が好ましい。An example in which the above-mentioned spherical activated carbon derived from petroleum-based pitch is subjected to oxidation and / or reduction treatment is disclosed in
And spherical spherical carbonaceous adsorbents described in U.S. Pat. No. 4,681,764.
The spherical activated carbon subjected to the oxidation and / or reduction treatment has a diameter of 0.05 to 2 mm, preferably 0.1 to 1 m.
m, specific surface area is 500 to 2000 m 2 / g, preferably 700 to 1500 m 2 / g, and pore radius is 100 to 7500.
Spherical activated carbon having a void volume of 0 angstroms of 0.01 to 1 ml / g is preferred.
【００１６】本発明の医薬製剤は、細胞外マトリックス
の形成亢進及び／又は線維化の亢進を抑制することがで
きる。従って、本発明の医薬製剤は、ヒトをはじめとす
る哺乳動物における、細胞外マトリックスの形成亢進及
び／又は線維化の亢進の病態を示す疾患の治療又は予防
に有用である。細胞外マトリックスの形成亢進及び／又
は線維化の亢進の病態を示す疾患としては、例えば、心
疾患（例えば、心肥大又は心筋梗塞など）、肝疾患（例
えば、慢性肝炎、肝線維症、肝硬変、又は肝癌など）、
腎疾患（例えば、慢性腎不全、間質性腎炎、腎炎、又は
糖尿病性腎症など）、又は血管性病変（例えば、動脈硬
化病変、又は糖尿病など）等を挙げることができる。ま
た、本発明の医薬製剤は、細胞外マトリックス形成亢進
及び／又は線維化の亢進に関与するＴＧＦ−β、ＴＩＭ
Ｐ、及びコラーゲンの発現を抑制することができる。本
発明の医薬製剤における細胞外マトリックスの形成亢進
及び／又は線維化亢進の抑制効果は、本発明の医薬製剤
が、血中における線維化指標であるヒアルロン酸濃度及
びプロリン水酸化酵素濃度の上昇を抑制することからも
確認することができる。The pharmaceutical preparation of the present invention can suppress the promotion of extracellular matrix formation and / or the promotion of fibrosis. Therefore, the pharmaceutical preparation of the present invention is useful for treating or preventing a disease showing a pathological condition of enhanced extracellular matrix formation and / or enhanced fibrosis in mammals including humans. Examples of the disease showing a pathological condition of enhanced formation of extracellular matrix and / or enhanced fibrosis include, for example, heart disease (eg, cardiac hypertrophy or myocardial infarction), liver disease (eg, chronic hepatitis, liver fibrosis, cirrhosis, cirrhosis, Or liver cancer),
Examples include kidney disease (eg, chronic renal failure, interstitial nephritis, nephritis, or diabetic nephropathy), or vascular lesion (eg, atherosclerotic lesion, diabetes, etc.). Further, the pharmaceutical preparation of the present invention contains TGF-β, TIM which is involved in promotion of extracellular matrix formation and / or fibrosis.
P and the expression of collagen can be suppressed. In the pharmaceutical preparation of the present invention, the effect of promoting the formation of extracellular matrix and / or suppressing the increase in fibrosis can be confirmed by the fact that the pharmaceutical preparation of the present invention shows an increase in the levels of hyaluronic acid and proline hydroxylase, which are indicators of fibrosis in blood. It can also be confirmed from suppression.
【００１７】本発明の医薬製剤は、好ましくは経口的に
投与される。その投与量は、対象（哺乳動物、特にはヒ
ト）、年齢、個人差、及び／又は病状などに依存する。
例えば、ヒトの場合の１日当たりの投与量は、通常、球
形活性炭量として０．２〜２０ｇであるが、症状によ
り、投与量を適宜増減してもよい。また、投与は１回又
は数回に分けて行なってもよい。球形活性炭は、そのま
ま投与してもよいし、活性炭製剤として投与してもよ
い。球形活性炭をそのまま投与する場合、球形活性炭を
飲料水などに懸濁したスラリーとして投与することもで
きる。The pharmaceutical preparation of the present invention is preferably administered orally. The dose depends on the subject (mammal, especially human), age, individual differences, and / or medical conditions.
For example, the daily dose for humans is usually 0.2 to 20 g as spherical activated carbon, but the dose may be appropriately increased or decreased depending on the symptoms. Further, the administration may be performed once or divided into several times. The spherical activated carbon may be administered as it is, or may be administered as an activated carbon preparation. When the spherical activated carbon is administered as it is, it can be administered as a slurry in which the spherical activated carbon is suspended in drinking water or the like.
【００１８】活性炭製剤における剤形としては、顆粒、
錠剤、糖衣錠、カプセル剤、スティック剤、分包包装体
又は懸濁剤などの任意の剤形を採用することができる。
カプセル剤の場合、通常のゼラチンカプセルの他、必要
に応じ、腸溶性のカプセルを用いることもできる。顆
粒、錠剤又は糖衣錠として用いる場合は、体内で元の微
小粒子に解錠されることが必要である。活性炭製剤中の
球形活性炭の含有量は、通常１〜１００％である。本発
明において、好ましい活性炭製剤は、カプセル剤、ステ
ィック剤又は分包包装体である。これらの製剤の場合、
球形活性炭は、そのまま容器に封入される。[0018] The dosage form in the activated carbon preparation includes granules,
Any dosage form such as tablets, dragees, capsules, sticks, divided packages, or suspensions can be employed.
In the case of capsules, enteric capsules can be used, if necessary, in addition to ordinary gelatin capsules. When used as granules, tablets or sugar-coated tablets, it is necessary to break them down into the original microparticles in the body. The content of the spherical activated carbon in the activated carbon preparation is usually 1 to 100%. In the present invention, a preferred activated carbon preparation is a capsule, a stick or a divided package. For these formulations,
The spherical activated carbon is directly enclosed in a container.
【００１９】[0019]
【実施例】以下、実施例によって本発明を具体的に説明
するが、これらは本発明の範囲を限定するものではな
い。EXAMPLES The present invention will be described below in more detail with reference to examples, but these examples do not limit the scope of the present invention.
【実施例１】《球形活性炭の調製》ナフサ熱分解により
生成した軟化点１８２℃、キノリン不溶分１０重量％、
Ｈ／Ｃ＝０．５３のピッチ７５ｋｇにナフタリン２５ｋ
ｇを、撹拌翼のついた内容積３００リットルの耐圧容器
に導入し、２１０℃に加熱溶融混合し、８０〜９０℃に
冷却して押出紡糸に好適な粘度に調整し、径１．５ｍｍ
の孔を１００個有する下部の口金から５０ｋｇ／ｃｍ2
の圧力下にピッチ混合物を５ｋｇ／ｍｉｎの割合で押出
した。押出した紐状ピッチは、約４０°の傾斜を有する
プラスチック製の樋に沿って１０〜２５℃の冷却槽に流
入する。樋には流速３．０ｍ／ｓｅｃの水を流下するこ
とにより、押出直後の紐状ピッチは連続的に延伸され
る。冷却槽には径５００μｍの紐状ピッチが集積する。
水中に約１分間放置することにより紐状ピッチは固化
し、手で容易に折れる状態のものが得られる。この紐状
ピッチを高速カッターに入れ水を加える。１０〜３０秒
間撹拌すると紐状ピッチの破砕は完了し、棒状ピッチと
なる。顕微鏡で観察すると円柱の長さと直径の比は平均
１．５であった。Example 1 << Preparation of spherical activated carbon >> Softening point generated by naphtha pyrolysis 182 ° C., quinoline insoluble content 10% by weight,
Naphthalene 25k for pitch 75kg with H / C = 0.53
g was introduced into a pressure-resistant container having an internal volume of 300 liters equipped with a stirring blade, heated and mixed at 210 ° C., cooled to 80 to 90 ° C., and adjusted to a viscosity suitable for extrusion spinning.
50 kg / cm 2 from the lower base having 100 holes
The pitch mixture was extruded under a pressure of 5 kg / min. The extruded string pitch flows into a 10-25 ° C. cooling bath along a plastic gutter having a slope of about 40 °. The string pitch immediately after the extrusion is continuously stretched by flowing water having a flow rate of 3.0 m / sec into the gutter. String pitches having a diameter of 500 μm are accumulated in the cooling tank.
By leaving it in water for about 1 minute, the string-shaped pitch is solidified, and a string that can be easily broken by hand is obtained. This string pitch is put into a high-speed cutter and water is added. After stirring for 10 to 30 seconds, the crushing of the string pitch is completed, and the pitch becomes a rod pitch. When observed with a microscope, the ratio of the length to the diameter of the cylinder was 1.5 on average.
【００２０】次にこの棒状ピッチを濾別し、９０℃に加
熱した０．５％ポリビニルアルコール水溶液１ｋｇ中に
棒状物１００ｇを投入し、溶融し、撹拌分散し、冷却し
て球形粒子を形成した。大部分の水を濾別した後、得ら
れた球形粒子を抽出器に入れ、ヘキサンを通液してナフ
タレンを抽出除去し、通風乾燥した。次いで、流動床を
用いて、加熱空気を流通して２５℃／Ｈｒで３００℃ま
で昇温し、更に３００℃に２時間保持して不融化した。
続いて、水蒸気中で９００℃まで昇温し、９００℃で２
時間保持して炭化賦活を行ない、多孔質の球形活性炭を
得た。得られた球形活性炭の直径は０．０５〜１．０ｍ
ｍであり、こうして得られた球形活性炭を流動床を用い
て、６００℃で酸素濃度３％の雰囲気下で３時間処理し
た後、窒素雰囲気下で９５０℃まで昇温し、９５０℃で
３０分間保持して、酸化及び還元処理を施した石油系ピ
ッチ由来の球形活性炭を得た。この球形活性炭の直径は
０．０５〜１ｍｍであった。なお、ラット（Ｃｐｂ：Ｗ
Ｕ：ウイスターランダム）への経口投与による急性毒性
試験では、毒性試験法ガイドライン（薬審第１１８号）
による最大投与量（雌雄ラット５０００ｍｇ／ｋｇ）に
おいても異常は観察されなかった。Next, the rod-shaped pitch was separated by filtration, and 100 g of the rod-shaped material was put into 1 kg of a 0.5% aqueous solution of polyvinyl alcohol heated to 90 ° C., melted, stirred and dispersed, and cooled to form spherical particles. . After filtering out most of the water, the obtained spherical particles were put into an extractor, and phthalic acid was passed through to remove naphthalene, followed by drying with ventilation. Next, using a fluidized bed, heated air was circulated and the temperature was raised to 300 ° C. at 25 ° C./Hr, and the mixture was kept at 300 ° C. for 2 hours to make it infusible.
Subsequently, the temperature is raised to 900 ° C. in steam,
The carbonization was activated by holding for a time to obtain a porous spherical activated carbon. The diameter of the obtained spherical activated carbon is 0.05 to 1.0 m
m, and the spherical activated carbon thus obtained is treated with a fluidized bed at 600 ° C. in an atmosphere having an oxygen concentration of 3% for 3 hours, and then heated to 950 ° C. in a nitrogen atmosphere, and then at 950 ° C. for 30 minutes. The spherical activated carbon derived from petroleum-based pitch subjected to oxidation and reduction treatment was obtained by holding. The diameter of the spherical activated carbon was 0.05 to 1 mm. In addition, rats (Cpb: W
U: Wistar Random) in the toxicity test by oral administration to Toxicity Test Method Guidelines (Yakuzai No. 118)
No abnormalities were observed at the maximum dose (5000 mg / kg for male and female rats).
【００２１】[0021]
【実施例２】《ＴＧＦ−β、ＴＩＭＰ、及びコラーゲン
の発現抑制作用》８週齢のＳｐｒａｇｕｅ−Ｄａｗｌｅ
ｙ系雄ラットから、腎臓を亜全摘出することにより、腎
不全モデルを作製した。腎臓の摘出から６週間経過した
時点において、対照群（５匹）と球形活性炭投与群（５
匹）とに分けた。この際、腎機能を指標として、両群間
に隔たりがないようにした。これ以降１１週間にわた
り、対照群には通常餌を与え、球形活性炭投与群には、
通常餌に加えて、前記実施例１で調製した球形活性炭を
体重１００ｇ当たり０．４ｇ／日の量で経口摂取させ
た。１１週間経過後に、麻酔下において開腹し、腎臓を
摘出した後、所定の方法（Ｔａｋａｓｈｉ Ｍｉｔａｚ
ａｋｉ，Ｍｉｃｈｉｈｉｔｏ Ｉｓｅ，Ｈｉｓａｏ Ｓ
ｅｏ ａｎｄ Ｔｏｓｈｉｍｉｔｓｕ Ｎｉｗａ；Ｋｉ
ｄｎｅｙ Ｉｎｔ．１９９７，Ｖｏｌ．５２，Ｓ１５−
Ｓ２２）により腎臓のＲＮＡを抽出し、ノーザン解析に
よってトランスフォーミング成長因子−β１（ＴＧＦ−
β１）、メタロプロテアーゼ組織インヒビター−１（Ｔ
ＩＭＰ−１）、及びｐｒｏα１（Ｉ）コラーゲンのｍＲ
ＮＡをそれぞれ定量した。また、心重量を測定した。Example 2 << Suppression of TGF-β, TIMP, and Collagen Expression >> Sprague-Dawle at 8 weeks of age
A renal failure model was prepared by removing a subtotal of the kidney from a male y-rat. Six weeks after the removal of the kidney, the control group (5 animals) and the spherical activated carbon administration group (5
). At this time, there was no separation between the two groups using renal function as an index. For the next 11 weeks, the control group was fed a normal diet, and the spherical activated carbon group was
In addition to the normal diet, the spherical activated carbon prepared in Example 1 was orally ingested in an amount of 0.4 g / day per 100 g of body weight. After a lapse of 11 weeks, the abdomen was opened under anesthesia, the kidney was removed, and then a predetermined method (Takashi Mitaz) was performed.
aki, Michihito Ise, Hisao S
eo and Toshimitsu Niwa; Ki
dney Int. 1997, Vol. 52, S15-
S22) to extract kidney RNA, and transforming growth factor-β1 (TGF-
β1), metalloprotease tissue inhibitor-1 (T
IMP-1) and mR of proα1 (I) collagen
NA was quantified respectively. The core weight was measured.
【００２２】その結果、ＴＧＦ−β１のｍＲＮＡの発現
量（平均±ＳＤ）は、 対照群：４．３±１．４、 投与群：２．６±０．８ となり、統計学的に有意差があった（ｐ＜０．０５）。
また、ＴＩＭＰ−１のｍＲＮＡの発現量（平均±ＳＤ）
は、 対照群：２７．３±７．９、 投与群：１６．５±９．４ となり、統計学的に有意差があった（ｐ＜０．０５）。
更に、ｐｒｏα１（Ｉ）コラーゲンのｍＲＮＡの発現量
（平均±ＳＤ）は、 対照群：５．１±１．３、 投与群：２．７±１．０ となり、統計学的に有意差があった（ｐ＜０．０５）。
また、心重量（平均±ＳＤ）は、 対照群：１．６±０．１（ｇ）、 投与群：１．３±０．１（ｇ） となり、統計学的に有意差があった（ｐ＜０．０５）。
すなわち、球形活性炭投与群において、ＴＧＦ−β１、
ＴＩＭＰ−１、及びｐｒｏα１（Ｉ）コラーゲンの遺伝
子発現が、統計学的に有意に抑制され、また、心重量も
抑制されていた。As a result, the expression level (average ± SD) of TGF-β1 mRNA was 4.3 ± 1.4 in the control group and 2.6 ± 0.8 in the administration group, and was statistically significant. (P <0.05).
In addition, the expression level of TIMP-1 mRNA (mean ± SD)
Was as follows: control group: 27.3 ± 7.9, administration group: 16.5 ± 9.4, and there was a statistically significant difference (p <0.05).
Further, the expression level (mean ± SD) of mRNA of proα1 (I) collagen was 5.1 ± 1.3 for the control group and 2.7 ± 1.0 for the administration group, showing a statistically significant difference. (P <0.05).
The heart weight (mean ± SD) was 1.6 ± 0.1 (g) in the control group and 1.3 ± 0.1 (g) in the administration group, and there was a statistically significant difference ( p <0.05).
That is, in the spherical activated carbon administration group, TGF-β1,
Gene expression of TIMP-1 and proα1 (I) collagen was statistically significantly suppressed, and the heart weight was also suppressed.
【００２３】[0023]
【実施例３】《ヒアルロン酸濃度の測定》３２週齢の自
然発症性肝炎ラットを、対照群（７匹）と球形活性炭投
与群（８匹）とに分けた。この際、肝機能を指標とし
て、両群間に隔たりがないようにした。これ以降６週間
にわたり、対照群には通常餌を与え、球形活性炭投与群
には、通常餌に加えて、前記実施例１で調製した球形活
性炭を体重１００ｇ当たり０．４ｇ／日の量で経口摂取
させた。６週間経過後に、血清中のヒアルロン酸濃度を
測定した。その結果、血清中のヒアルロン酸濃度（平均
±ＳＤ）は、 対照群：２５±４ｎｇ／ｍＬ、 投与群：１７±２ｎｇ／ｍＬ となり、統計学的に有意差があった（ｐ＜０．０５）。
すなわち、球形活性炭投与群において、ヒアルロン酸濃
度の上昇が、統計学的に有意に抑制されていた。Example 3 << Measurement of Hyaluronic Acid Concentration >> Spontaneous hepatitis rats at the age of 32 weeks were divided into a control group (7 rats) and a spherical activated carbon administration group (8 rats). At this time, there was no separation between the two groups using liver function as an index. Over the following 6 weeks, the control group was fed the normal diet, and the spherical activated carbon-administered group was administered the spherical activated carbon prepared in Example 1 orally in an amount of 0.4 g / day / 100 g body weight in addition to the normal diet. Ingested. After 6 weeks, the serum hyaluronic acid concentration was measured. As a result, the serum hyaluronic acid concentration (mean ± SD) was 25 ± 4 ng / mL in the control group and 17 ± 2 ng / mL in the administration group, and there was a statistically significant difference (p <0.05). ).
That is, in the spherical activated carbon administration group, the increase in hyaluronic acid concentration was statistically significantly suppressed.
【００２４】[0024]
【実施例４】《プロリン水酸化酵素濃度の測定》８週齢
のＳｐｒａｇｕｅ−Ｄａｗｌｅｙ系雄ラットに、四塩化
炭素をオリーブ油に５０％溶解した溶液を体重１ｋｇ当
たり２ｍＬの量で皮下投与することにより、肝線維症ラ
ットを作製した。なお、前記の皮下投与は、１０週間に
わたって週２回の頻度で行なった。前記皮下投与の終了
から９週間経過後に、対照群（４匹）と球形活性炭投与
群（４匹）とに分けた。この際、肝機能を指標として、
両群間に隔たりがないようにした。これ以降８週間にわ
たり、対照群には通常餌を与え、球形活性炭投与群に
は、通常餌に加えて、前記実施例１で調製した球形活性
炭を体重１００ｇ当たり０．４ｇ／日の量で経口摂取さ
せた。８週間経過後に、血清中のプロリン水酸化酵素の
濃度を測定した。その結果、血清中のプロリン水酸化酵
素濃度（平均±ＳＤ）は、 対照群：３８４±７ｎｇ／ｍＬ、 投与群：３０６±１５ｎｇ／ｍＬ となり、統計学的に有意差があった（ｐ＜０．０５）。
すなわち、球形活性炭投与群において、プロリン水酸化
酵素濃度の上昇が、統計学的に有意に抑制されていた。EXAMPLE 4 << Measurement of Proline Hydroxylase Concentration >> A solution prepared by dissolving 50% of carbon tetrachloride in olive oil at a dose of 2 mL / kg body weight was subcutaneously administered to 8-week-old male Sprague-Dawley rats. Then, liver fibrosis rats were prepared. The subcutaneous administration was performed twice a week for 10 weeks. Nine weeks after the completion of the subcutaneous administration, the animals were divided into a control group (4 animals) and a spherical activated carbon administration group (4 animals). At this time, liver function as an index,
There was no gap between the two groups. Over the following 8 weeks, the control group was fed the normal diet, and the spherical activated carbon-administered group was administered the spherical activated carbon prepared in Example 1 in an amount of 0.4 g / day / 100 g body weight in addition to the normal diet. Ingested. After 8 weeks, the concentration of proline hydroxylase in the serum was measured. As a result, the serum proline hydroxylase concentration (mean ± SD) was 384 ± 7 ng / mL in the control group and 306 ± 15 ng / mL in the administration group, and there was a statistically significant difference (p <0). .05).
That is, in the spherical activated carbon administration group, the increase in proline hydroxylase concentration was statistically significantly suppressed.
【００２５】[0025]
【製剤調製例１】《カプセル剤の調製》前記製造例１で
得た球形活性炭２００ｍｇをゼラチンカプセルに封入し
てカプセル剤を調製した。[Preparation Example 1] << Preparation of capsules >> A capsule was prepared by enclosing 200 mg of the spherical activated carbon obtained in Production Example 1 above in a gelatin capsule.
【００２６】[0026]
【製剤調製例２】《スティック剤の調製》前記製造例１
で得た球形活性炭２ｇを積層フィルム製スティックに充
填した後、ヒートシールしてスティック剤とした。[Preparation Example 2] << Preparation of stick preparation >> Preparation Example 1
After filling 2 g of the spherical activated carbon obtained in the above into a stick made of a laminated film, it was heat-sealed to form a stick.
【００２７】[0027]
【発明の効果】本発明による医薬製剤を、例えば、経口
薬として投与することにより、特別な副作用を起こさず
に、細胞外マトリックスの形成亢進及び／又は線維化の
亢進を抑制することができる。従って、本発明による医
薬製剤は、細胞外マトリックスの形成亢進及び／又は線
維化亢進の病態を示す疾患の治療又は予防に有効であ
る。また、本発明による医薬製剤によれば、細胞外マト
リックス形成亢進及び／又は線維化の亢進に関与するＴ
ＧＦ−β、ＴＩＭＰ、及びコラーゲンの発現を抑制する
ことができる。By administering the pharmaceutical preparation of the present invention, for example, as an oral drug, it is possible to suppress the promotion of extracellular matrix formation and / or the promotion of fibrosis without causing any special side effects. Therefore, the pharmaceutical preparation according to the present invention is effective for treating or preventing a disease showing a pathological condition of enhanced formation of extracellular matrix and / or enhanced fibrosis. Further, according to the pharmaceutical preparation of the present invention, T associated with enhanced extracellular matrix formation and / or enhanced fibrosis
The expression of GF-β, TIMP, and collagen can be suppressed.
Claims (8)
形成亢進抑制剤。1. A matrix formation enhancer comprising activated carbon as an active ingredient.
記載のマトリックス形成亢進抑制剤。2. The matrix formation enhancer according to claim 1, wherein the activated carbon is a spherical activated carbon.
制剤。3. An agent for suppressing fibrosis, comprising activated carbon as an active ingredient.
ーミング成長因子−β（ＴＧＦ−β）の発現抑制剤。4. An agent for suppressing the expression of transforming growth factor-β (TGF-β), comprising activated carbon as an active ingredient.
アーゼ組織インヒビター（ＴＩＭＰ）の発現抑制剤。5. An agent for suppressing the expression of a metalloprotease tissue inhibitor (TIMP), comprising activated carbon as an active ingredient.
発現抑制剤。6. A collagen expression inhibitor comprising activated carbon as an active ingredient.
形成亢進の病態を示す疾患の治療又は予防剤。7. A therapeutic or preventive agent for a disease showing a pathological condition of enhanced matrix formation, comprising activated carbon as an active ingredient.
る疾患である、請求項７に記載の治療又は予防剤。8. The therapeutic or prophylactic agent according to claim 7, wherein the disease is a disease in kidney, heart or liver.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11593098A JPH11292770A (en) | 1998-04-10 | 1998-04-10 | Matrix formation sthenia inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11593098A JPH11292770A (en) | 1998-04-10 | 1998-04-10 | Matrix formation sthenia inhibitor |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2007046278A Division JP2007182448A (en) | 2007-02-26 | 2007-02-26 | Therapeutic or prophylactic agent for vascular lesion |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH11292770A true JPH11292770A (en) | 1999-10-26 |
Family
ID=14674716
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11593098A Pending JPH11292770A (en) | 1998-04-10 | 1998-04-10 | Matrix formation sthenia inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH11292770A (en) |
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