WO2010027090A1 - Therapeutic agent for uremia - Google Patents
Therapeutic agent for uremia Download PDFInfo
- Publication number
- WO2010027090A1 WO2010027090A1 PCT/JP2009/065681 JP2009065681W WO2010027090A1 WO 2010027090 A1 WO2010027090 A1 WO 2010027090A1 JP 2009065681 W JP2009065681 W JP 2009065681W WO 2010027090 A1 WO2010027090 A1 WO 2010027090A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carbon
- uremia
- therapeutic agent
- carbon nanotubes
- uremic
- Prior art date
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/44—Elemental carbon, e.g. charcoal, carbon black
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Definitions
- the present invention relates to a therapeutic agent for uremia useful for the treatment of uremia such as chronic renal failure.
- Carbon nanotubes are known to have excellent performance as adsorbents and catalyst carriers, and Patent Document 1 uses carbon nanotubes as active ingredients of pharmaceuticals, particularly oral uremic toxin adsorbents. It is disclosed. And since the uremic toxin is efficiently taken into the pores of the carbon nanotubes and the pores (outer diameter) of the carbon nanotubes can be adjusted, a wide range of uremic toxins can be absorbed. It has been found that this has provided a uremic toxin adsorbent with few side effects that is effective in the treatment or prevention of chronic renal failure. However, there is a need for a practically superior uremic therapeutic agent that can absorb uremic toxins with higher efficiency.
- the present invention when a part of the carbon skeleton constituting the surface layer of the carbon nanotube is deleted and an opening is provided in the surface layer, the ability of the carbon nanotube to absorb uremic toxin is improved and / or the carbon nanotube It was found based on these findings that an organic compound having a specific molecular weight was adsorbed in advance and the absorption selectivity of uremic toxins was improved by using it as an active ingredient of a uremic therapeutic agent. That is, the present invention provides a therapeutic agent for uremia, comprising a carbon nanotube having, on the surface layer, an opening in which a part of the carbon skeleton is deleted. The present invention also provides a therapeutic agent for uremia characterized by containing carbon nanotubes adsorbed with a pharmaceutical organic additive having a molecular weight in the range of 0.1 to 10 million.
- the adsorption rate with respect to the indole acetic acid which is the uremic toxin of the uremic treatment agent of this invention of Example 1 is shown.
- the adsorption rate with respect to the digestive enzyme of the uremic therapeutic agent of this invention of Example 2 is shown.
- the adsorption rate with respect to the uremic toxin indole acetic acid and digestive enzyme of the uremic treatment agent of this invention of Example 2 is shown.
- the carbon nanotube used in the present invention is made of carbon (carbon) and has a diameter of 30 to 150 nanometers (nm), preferably a diameter of 100 nanometers (nm) or less. It is a substance having a tube-shaped void and includes a structure such as “diamond structure”, “graphite structure”, and “amorphous structure”. Specifically, single-walled and multi-walled carbon nanotubes, carbon nanohorns, various fullerenes and the like are included. The description of Patent Document 1 regarding carbon nanotubes is included in the description of this specification. In the present invention, among these carbon nanotubes, carbon nanohorns are preferably used.
- a carbon nanohorn is basically a single-layer graphene structure with a large surface area, and a large number of single-walled nanotubes with a diameter of several nanometers with a closed tip and a length of several tens of nanometers gathered, with a diameter of 30 to 150 nanometers. It has a spherical structure of about a meter, preferably about 80 to 100 nanometers.
- the carbon nanohorn has been developed by NEC Corporation and is manufactured by a laser peeling method.
- the present invention is characterized in that it is used as an active ingredient of a therapeutic agent for carbon nanotube uremic disease having an opening in the surface layer in which a part of the carbon skeleton is deleted.
- the total area of the openings is preferably 10 to 90%, more preferably 20 to 60% with respect to the total surface area of the carbon nanotube surface layer.
- the diameter of the opening when converted into a circle is preferably about 0.3 to 8 nm, and the upper limit is preferably about 5 nm and the lower limit is about 1 nm.
- Such a carbon nanotube having an opening in which a part of the carbon skeleton is deleted in the surface layer can be prepared, for example, by the following method (a) or (b) alone or an opening treatment method combining them.
- the carbon nanotube is treated at 350 to 966 ° C. for 10 to 15 minutes in an atmosphere containing 21 to 100% by volume of oxygen. More specifically, (i) treatment at 570-580 ° C for 15 minutes under oxygen perfusion (Mol Pharmaceutics 2005; vol2,6,475), (ii) local combustion treatment in oxygen at 350-620 ° C for 10 minutes (J Phys Chem B 2005; 109, 8909), (iii) Combustion treatment (350-600 ° C) for 10 minutes in 100% oxygen or air (21% oxygen) (J Phys Chem B 2006; 110, 1587) or (iv) local combustion in 100% oxygen at 623-693K (896-966 ° C) for 10 minutes (Langmulr 2002; 16, 4138), (iv) temperature increase of 1 ° C / min in air It can be performed by heating to 400-550 ° C. at a rate and then
- the carbon nanotubes are heat-treated in hydrogen peroxide solution, nitric acid, sulfuric acid and a mixed solution thereof.
- the carbon nanotubes can be mixed with hydrogen peroxide, sulfuric acid, and nitric acid in an arbitrary ratio, and it is preferable to heat-treat at 30 to 100 ° C. for 10 minutes to 24 hours.
- preferable conditions when using hydrogen peroxide solution, nitric acid or sulfuric acid are shown.
- (b-1) When carbon nanotubes are heat-treated in hydrogen peroxide water, the carbon nanotubes are preferably heated in an aqueous solution having a hydrogen peroxide concentration of 10 to 60% by weight at 30 to 100 ° C. for 30 minutes to 24 hours. To process.
- Xenon lamp irradiation treatment (wavelength 250-2000, intensity 3W, diameter 1cm) at the same time as heating (100 ° C) in 30% H 2 O 2 solution (1-5hr) (ACS Nano 2007; 4, 265) is (ii) treatment at 420 ° C for 10 minutes under oxygen perfusion and then overnight treatment with H 2 O 2 (J Phys Chem B 2003; vol107, 20, 4681) Can be performed.
- nitric acid the carbon nanotubes are preferably heat-treated in an aqueous solution having a nitric acid concentration of 5 to 70% by weight at 30 to 100 ° C. for 30 minutes to 24 hours.
- the carbon nanotubes are heat-treated in sulfuric acid
- the carbon nanotubes are preferably heat-treated at 30 to 100 ° C. for 30 minutes to 24 hours in an aqueous solution having a sulfuric acid concentration of 5 to 98% by weight.
- carbon nanotubes formed by adsorbing organic pharmaceutical additives having a molecular weight in the range of 0.1 to 10 million (weight average molecular weight) can be used as an active ingredient of a therapeutic agent for uremia.
- carbon nanotubes formed by adsorbing organic pharmaceutical additives can be prevented from adsorbing digestive enzymes such as amylase, pepsin and trypsin, and the selective absorption rate of uremic toxins Can be improved.
- the carbon nanotube for adsorbing the organic drug additive in advance the conventional carbon nanotube described in Patent Document 1 can be used.
- the carbon nanotube carbon having an opening in which a part of the carbon skeleton is deleted on the surface layer. The use of nanotubes is preferable because both the absorption rate and selective absorption rate of uremic toxins can be improved.
- the pharmaceutical organic additive having a molecular weight in the range of 0.1 to 10 million is preferably a pharmaceutically acceptable water-soluble polymer and / or a surfactant.
- a pharmaceutically acceptable water-soluble polymer and / or a surfactant selected from the group consisting of polysaccharides, polyacrylic acids, polypeptides, polylactic acids, polyalkylene oxides, polyvinylpyrrolidones, polyvinyl alcohols, polyoxyethylenes and alkylallyl polyethers.
- the molecular weight is preferably 1 to 7 million.
- the ratio of adsorbing the organic drug additive to the carbon nanotubes is preferably 1 to 100 parts by weight, more preferably 10 to 70 parts by weight per 100 parts by weight of the carbon nanotubes.
- Examples of the adsorbing method include a method of stirring and mixing the organic drug additive and the carbon nanotube, and a method of spraying an aqueous solution of the organic drug additive on the carbon nanotube.
- the adsorbing method includes these methods. It is not limited.
- carbon formed by adsorbing carbon nanotubes themselves having an opening in which a part of the carbon skeleton is deleted or a pharmaceutical organic additive having a molecular weight in the range of 0.1 to 10 million is adsorbed.
- the nanotubes themselves may be used as they are as a uremic therapeutic agent and administered to uremic patients, preferably orally.
- the dose volume can be reduced by compression with a tableting machine described in Patent Document 1, and the patient's compliance can be significantly improved.
- the therapeutic agent for uremia of the present invention is usually preferably administered to a patient at a dose of about 1 to 2 g once, and preferably taken three times a day.
- the uremic toxin in the patient's body is preferably adsorbed in the gastrointestinal tract by the carbon nanotube, which is the active ingredient of the present invention, and excreted outside the body together with feces.
- this invention is demonstrated based on an Example.
- Example 1 Indole acetic acid and digestive enzyme adsorption test Carbon nanohorns [manufactured by NEC Corporation: purity 95% (no pore opening treatment or pore opening treatment completed) 3 mg each as test substances having respective characteristics in glass vials After weighing, 2 mL of a 50 mg / dL indoleacetic acid solution or digestive enzyme solution was added, and the mixture was shaken and stirred in a 37 ° C. water bath for 120 minutes (120 times / minute).
- the substance to be tested was removed with a filter, and the absorbance of the filtrate was measured at a wavelength of 280 nm using an ultraviolet-visible spectrophotometer, and the amount of indole acetic acid or digestive enzyme that did not bind to the substance to be tested was measured. From the value, the amount of indole acetic acid or digestive enzyme bound to the test substance was converted.
- FIGS. As can be seen from the results shown in FIGS. 1 and 2, by using carbon nanohorn subjected to pore opening treatment as an active ingredient of a therapeutic agent for uremic disease, the adsorption performance for indoleacetic acid and digestive enzyme, which are uremic toxins, is remarkably increased. .
- the opening process of carbon nanohorn was performed by the following method.
- the carbon nanohorn was heated in a 30% H 2 O 2 solution at 100 ° C. for 3 hours.
- the carbon nanohorn was filtered, washed with sufficient pure water, and then dried in a nitrogen atmosphere at 70 ° C. for 24 hours.
- Example 2 Selective Ureotoxin Adsorption Confirmation Test After weighing 3 mg of the aperture-treated carbon nanohorn used in Example 1 into a glass vial, polyethylene glycol which is an organic pharmaceutical additive and a water-soluble polymer (PEG 7,000,000: molecular weight about 7,000,000) 2 mL of solution (50 mg / dL) was added and stirred and shaken in a water bath for 60 minutes (120 times / min). The supernatant polyethylene glycol solution was removed by centrifugation, and carbon nanotubes were prepared by adsorbing organic pharmaceutical additives (10 to 100 parts by weight of polyethylene glycol (PEG7,000,000) per 100 parts by weight of carbon nanotubes). ).
- the carbon nanohorn which is an active ingredient of the present invention, is obtained by preliminarily adsorbing to a carbon nanotube by shaking and stirring with a high molecular weight polyethylene glycol (PEG 7,000,000). Although the adsorption rate with acetic acid did not decrease, it was confirmed that the adsorption rate with digestive enzyme decreased and the adsorption specificity to uremic toxins increased. As is apparent from the results of Example 1 and Example 2, carbon nanohorn, which is an active ingredient of the therapeutic agent for uremic diseases of the present invention, adsorbs uremic toxins in the digestive tract, thereby uremic from the digestive tract into the body. Is effective in improving uremic symptoms and delaying dialysis in patients with chronic renal failure. The above effect is enormous.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nanotechnology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Urology & Nephrology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Carbon And Carbon Compounds (AREA)
Abstract
Disclosed is a therapeutic agent for uremia that contains carbon nanotubes possessing apertures in the surface layer thereof where portions of the carbon skeleton are missing. The present therapeutic agent for uremia is able to absorb the uremic toxin with high efficiency.
Description
本発明は慢性腎不全などの尿毒症の治療に有用な尿毒症治療剤に関する。
The present invention relates to a therapeutic agent for uremia useful for the treatment of uremia such as chronic renal failure.
カーボンナノチューブは、吸着剤や触媒担体として優れた性能を有することが知られており、特許文献１には、カーボンナノチューブを医薬の有効成分、特に、経口尿毒症毒素吸着剤の有効成分として使用することが開示されている。そして、カーボンナノチューブが有する細孔に、尿毒症毒素が効率的に取り込まれ、また、そのカーボンナノチューブの細孔（外径）を調節することができることから、幅広い範囲の尿毒症毒素を吸収し得ることが見出され、これにより、慢性腎不全の治療もしくは予防に有効である、副作用の少ない、尿毒症毒素吸着剤が提供できたことが記載されている。
しかしながら、さらに高効率で尿毒症毒素を吸収し得る実用的に一層優れた尿毒症治療剤が求められている。 Carbon nanotubes are known to have excellent performance as adsorbents and catalyst carriers, and Patent Document 1 uses carbon nanotubes as active ingredients of pharmaceuticals, particularly oral uremic toxin adsorbents. It is disclosed. And since the uremic toxin is efficiently taken into the pores of the carbon nanotubes and the pores (outer diameter) of the carbon nanotubes can be adjusted, a wide range of uremic toxins can be absorbed. It has been found that this has provided a uremic toxin adsorbent with few side effects that is effective in the treatment or prevention of chronic renal failure.
However, there is a need for a practically superior uremic therapeutic agent that can absorb uremic toxins with higher efficiency.
しかしながら、さらに高効率で尿毒症毒素を吸収し得る実用的に一層優れた尿毒症治療剤が求められている。 Carbon nanotubes are known to have excellent performance as adsorbents and catalyst carriers, and Patent Document 1 uses carbon nanotubes as active ingredients of pharmaceuticals, particularly oral uremic toxin adsorbents. It is disclosed. And since the uremic toxin is efficiently taken into the pores of the carbon nanotubes and the pores (outer diameter) of the carbon nanotubes can be adjusted, a wide range of uremic toxins can be absorbed. It has been found that this has provided a uremic toxin adsorbent with few side effects that is effective in the treatment or prevention of chronic renal failure.
However, there is a need for a practically superior uremic therapeutic agent that can absorb uremic toxins with higher efficiency.
本発明は、高効率で尿毒症毒素を吸収し得る尿毒症治療剤を提供することを目的とする。
本発明は、又、より高い選択率で尿毒症毒素を吸収し得る尿毒症治療剤を提供することを目的とする。 An object of the present invention is to provide a uremic therapeutic agent capable of absorbing uremic toxins with high efficiency.
Another object of the present invention is to provide a uremic therapeutic agent capable of absorbing uremic toxins with higher selectivity.
本発明は、又、より高い選択率で尿毒症毒素を吸収し得る尿毒症治療剤を提供することを目的とする。 An object of the present invention is to provide a uremic therapeutic agent capable of absorbing uremic toxins with high efficiency.
Another object of the present invention is to provide a uremic therapeutic agent capable of absorbing uremic toxins with higher selectivity.
本発明は、カーボンナノチューブの表面層を構成するカーボン骨格の一部を欠失させて、表面層に開口を設けると、カーボンナノチューブの尿毒症毒素吸収能力が向上すること、及び/又はカーボンナノチューブに予め特定の分子量の有機化合物を吸着させ、これを尿毒症治療剤の有効成分として用いると、尿毒症毒素の吸収選択率が向上することを見出し、これらの知見に基づいて完成したものである。
すなわち、本発明は、カーボン骨格の一部が欠失した開口を表層に有するカーボンナノチューブを含有することを特徴とする尿毒症治療剤を提供する。
本発明は、又、分子量が０．１～１０００万の範囲にある医薬用有機添加物が吸着してなるカーボンナノチューブを含有することを特徴とする尿毒症治療剤を提供する。 In the present invention, when a part of the carbon skeleton constituting the surface layer of the carbon nanotube is deleted and an opening is provided in the surface layer, the ability of the carbon nanotube to absorb uremic toxin is improved and / or the carbon nanotube It was found based on these findings that an organic compound having a specific molecular weight was adsorbed in advance and the absorption selectivity of uremic toxins was improved by using it as an active ingredient of a uremic therapeutic agent.
That is, the present invention provides a therapeutic agent for uremia, comprising a carbon nanotube having, on the surface layer, an opening in which a part of the carbon skeleton is deleted.
The present invention also provides a therapeutic agent for uremia characterized by containing carbon nanotubes adsorbed with a pharmaceutical organic additive having a molecular weight in the range of 0.1 to 10 million.
すなわち、本発明は、カーボン骨格の一部が欠失した開口を表層に有するカーボンナノチューブを含有することを特徴とする尿毒症治療剤を提供する。
本発明は、又、分子量が０．１～１０００万の範囲にある医薬用有機添加物が吸着してなるカーボンナノチューブを含有することを特徴とする尿毒症治療剤を提供する。 In the present invention, when a part of the carbon skeleton constituting the surface layer of the carbon nanotube is deleted and an opening is provided in the surface layer, the ability of the carbon nanotube to absorb uremic toxin is improved and / or the carbon nanotube It was found based on these findings that an organic compound having a specific molecular weight was adsorbed in advance and the absorption selectivity of uremic toxins was improved by using it as an active ingredient of a uremic therapeutic agent.
That is, the present invention provides a therapeutic agent for uremia, comprising a carbon nanotube having, on the surface layer, an opening in which a part of the carbon skeleton is deleted.
The present invention also provides a therapeutic agent for uremia characterized by containing carbon nanotubes adsorbed with a pharmaceutical organic additive having a molecular weight in the range of 0.1 to 10 million.
本発明で用いるカーボンナノチューブは、特許文献１に記載されているように、カーボン（炭素）でできた、直径が３０－１５０ナノメートル（ｎｍ）、好ましくは直径が１００ナノメートル（ｎｍ）以下のチューブ筒状の空隙を有する物質であり、「ダイヤモンド構造」、「グラファイト構造」、「非結晶質構造」などの構造のものが含まれる。具体的には、単層や多層カーボンナノチューブ、カーボンナノホーン、各種フラーレンなどが含まれる。カーボンナノチューブについての特許文献１の記載内容は、本明細書の記載に含まれるものとする。
本発明では、これらのカーボンナノチューブのうち、カーボンナノホーンを用いるのが好ましい。カーボンナノホーンは、基本的には広い表面積を持つ単層グラフェンの構造体であり、先端が閉じた直径数ナノ、長さ数１０ナノメートルの単層ナノチューブが多数集った、直径３０～１５０ナノメートル程度、好ましくは８０～１００ナノメートル程度の球状の構造を持つ。カーボンナノホーンは、ＮＥＣ株式会社により開発されており、レーザー剥離法により製造される。 As described in Patent Document 1, the carbon nanotube used in the present invention is made of carbon (carbon) and has a diameter of 30 to 150 nanometers (nm), preferably a diameter of 100 nanometers (nm) or less. It is a substance having a tube-shaped void and includes a structure such as “diamond structure”, “graphite structure”, and “amorphous structure”. Specifically, single-walled and multi-walled carbon nanotubes, carbon nanohorns, various fullerenes and the like are included. The description of Patent Document 1 regarding carbon nanotubes is included in the description of this specification.
In the present invention, among these carbon nanotubes, carbon nanohorns are preferably used. A carbon nanohorn is basically a single-layer graphene structure with a large surface area, and a large number of single-walled nanotubes with a diameter of several nanometers with a closed tip and a length of several tens of nanometers gathered, with a diameter of 30 to 150 nanometers. It has a spherical structure of about a meter, preferably about 80 to 100 nanometers. The carbon nanohorn has been developed by NEC Corporation and is manufactured by a laser peeling method.
本発明では、これらのカーボンナノチューブのうち、カーボンナノホーンを用いるのが好ましい。カーボンナノホーンは、基本的には広い表面積を持つ単層グラフェンの構造体であり、先端が閉じた直径数ナノ、長さ数１０ナノメートルの単層ナノチューブが多数集った、直径３０～１５０ナノメートル程度、好ましくは８０～１００ナノメートル程度の球状の構造を持つ。カーボンナノホーンは、ＮＥＣ株式会社により開発されており、レーザー剥離法により製造される。 As described in Patent Document 1, the carbon nanotube used in the present invention is made of carbon (carbon) and has a diameter of 30 to 150 nanometers (nm), preferably a diameter of 100 nanometers (nm) or less. It is a substance having a tube-shaped void and includes a structure such as “diamond structure”, “graphite structure”, and “amorphous structure”. Specifically, single-walled and multi-walled carbon nanotubes, carbon nanohorns, various fullerenes and the like are included. The description of Patent Document 1 regarding carbon nanotubes is included in the description of this specification.
In the present invention, among these carbon nanotubes, carbon nanohorns are preferably used. A carbon nanohorn is basically a single-layer graphene structure with a large surface area, and a large number of single-walled nanotubes with a diameter of several nanometers with a closed tip and a length of several tens of nanometers gathered, with a diameter of 30 to 150 nanometers. It has a spherical structure of about a meter, preferably about 80 to 100 nanometers. The carbon nanohorn has been developed by NEC Corporation and is manufactured by a laser peeling method.
本発明では、カーボン骨格の一部が欠失した開口を表層に有するカーボンナノチューブ尿毒症治療剤の有効成分として用いることを特徴とする。
本発明では、カーボンナノチューブ表層の全表面積に対して、開口の合計面積量が１０～９０％であるのが好ましく、より好ましくは２０～６０％である。又、開口の大きさは円に換算した時の直径が０．３～８ｎｍ程度であるのが好ましく、さらに上限が５ｎｍ程度や下限が１ｎｍ程度であるのが好ましい。
このようなカーボン骨格の一部が欠失した開口を表層に有するカーボンナノチューブは、例えば、以下の方法(a)又は(b)単独、又はこれらを組み合わせた開口処理方法により調製することができる。 The present invention is characterized in that it is used as an active ingredient of a therapeutic agent for carbon nanotube uremic disease having an opening in the surface layer in which a part of the carbon skeleton is deleted.
In the present invention, the total area of the openings is preferably 10 to 90%, more preferably 20 to 60% with respect to the total surface area of the carbon nanotube surface layer. The diameter of the opening when converted into a circle is preferably about 0.3 to 8 nm, and the upper limit is preferably about 5 nm and the lower limit is about 1 nm.
Such a carbon nanotube having an opening in which a part of the carbon skeleton is deleted in the surface layer can be prepared, for example, by the following method (a) or (b) alone or an opening treatment method combining them.
本発明では、カーボンナノチューブ表層の全表面積に対して、開口の合計面積量が１０～９０％であるのが好ましく、より好ましくは２０～６０％である。又、開口の大きさは円に換算した時の直径が０．３～８ｎｍ程度であるのが好ましく、さらに上限が５ｎｍ程度や下限が１ｎｍ程度であるのが好ましい。
このようなカーボン骨格の一部が欠失した開口を表層に有するカーボンナノチューブは、例えば、以下の方法(a)又は(b)単独、又はこれらを組み合わせた開口処理方法により調製することができる。 The present invention is characterized in that it is used as an active ingredient of a therapeutic agent for carbon nanotube uremic disease having an opening in the surface layer in which a part of the carbon skeleton is deleted.
In the present invention, the total area of the openings is preferably 10 to 90%, more preferably 20 to 60% with respect to the total surface area of the carbon nanotube surface layer. The diameter of the opening when converted into a circle is preferably about 0.3 to 8 nm, and the upper limit is preferably about 5 nm and the lower limit is about 1 nm.
Such a carbon nanotube having an opening in which a part of the carbon skeleton is deleted in the surface layer can be prepared, for example, by the following method (a) or (b) alone or an opening treatment method combining them.
(a)カーボンナノチューブを酸素の存在下、高温で３０分以下の時間処理すること。好ましくは、カーボンナノチューブを酸素２１～１００容量％含有する雰囲気下、３５０～９６６℃で１０～１５分間処理すること。
より具体的には、(i)酸素灌流下で570-580℃、15分間処理すること（Mol Pharmaceutics 2005; vol2,6,475）、(ii)350-620℃の酸素中で10分間局所燃焼処理すること（J Phys Chem B 2005; 109, 8909）、(iii)100% 酸素中或いは空気中（21% 酸素）で10分間燃焼処理（350-600℃）すること（J Phys Chem B 2006; 110, 1587）又は(iv)623-693K（896-966℃）の100% 酸素中で10分間局所燃焼処理すること（Langmulr 2002; 16, 4138）、(iv)空気中で1℃/minの昇温速度で400－550℃まで加熱し、その後放冷すること（Jing Fan et al. J. Phys. Chem. B, 2006, 110 (4), 1587-1591）、により行なうことができる。 (a) Treating carbon nanotubes in the presence of oxygen at a high temperature for 30 minutes or less. Preferably, the carbon nanotube is treated at 350 to 966 ° C. for 10 to 15 minutes in an atmosphere containing 21 to 100% by volume of oxygen.
More specifically, (i) treatment at 570-580 ° C for 15 minutes under oxygen perfusion (Mol Pharmaceutics 2005; vol2,6,475), (ii) local combustion treatment in oxygen at 350-620 ° C for 10 minutes (J Phys Chem B 2005; 109, 8909), (iii) Combustion treatment (350-600 ° C) for 10 minutes in 100% oxygen or air (21% oxygen) (J Phys Chem B 2006; 110, 1587) or (iv) local combustion in 100% oxygen at 623-693K (896-966 ° C) for 10 minutes (Langmulr 2002; 16, 4138), (iv) temperature increase of 1 ° C / min in air It can be performed by heating to 400-550 ° C. at a rate and then allowing to cool (Jing Fan et al. J. Phys. Chem. B, 2006, 110 (4), 1587-1591).
より具体的には、(i)酸素灌流下で570-580℃、15分間処理すること（Mol Pharmaceutics 2005; vol2,6,475）、(ii)350-620℃の酸素中で10分間局所燃焼処理すること（J Phys Chem B 2005; 109, 8909）、(iii)100% 酸素中或いは空気中（21% 酸素）で10分間燃焼処理（350-600℃）すること（J Phys Chem B 2006; 110, 1587）又は(iv)623-693K（896-966℃）の100% 酸素中で10分間局所燃焼処理すること（Langmulr 2002; 16, 4138）、(iv)空気中で1℃/minの昇温速度で400－550℃まで加熱し、その後放冷すること（Jing Fan et al. J. Phys. Chem. B, 2006, 110 (4), 1587-1591）、により行なうことができる。 (a) Treating carbon nanotubes in the presence of oxygen at a high temperature for 30 minutes or less. Preferably, the carbon nanotube is treated at 350 to 966 ° C. for 10 to 15 minutes in an atmosphere containing 21 to 100% by volume of oxygen.
More specifically, (i) treatment at 570-580 ° C for 15 minutes under oxygen perfusion (Mol Pharmaceutics 2005; vol2,6,475), (ii) local combustion treatment in oxygen at 350-620 ° C for 10 minutes (J Phys Chem B 2005; 109, 8909), (iii) Combustion treatment (350-600 ° C) for 10 minutes in 100% oxygen or air (21% oxygen) (J Phys Chem B 2006; 110, 1587) or (iv) local combustion in 100% oxygen at 623-693K (896-966 ° C) for 10 minutes (Langmulr 2002; 16, 4138), (iv) temperature increase of 1 ° C / min in air It can be performed by heating to 400-550 ° C. at a rate and then allowing to cool (Jing Fan et al. J. Phys. Chem. B, 2006, 110 (4), 1587-1591).
(b)カーボンナノチューブを過酸化水素水、硝酸、硫酸及びそれらの混合溶液中で、加熱処理すること。この場合、カーボンナノチューブを過酸化水素、硫酸、硝酸を任意の割合で混合することができ、３０～１００℃で10分～２４時間加熱処理するのがよい。
次に、過酸化水素水、硝酸又は硫酸を用いる場合の好ましい条件を示す。
(b-1)カーボンナノチューブを過酸化水素水中で加熱処理する場合、好ましくは、カーボンナノチューブを過酸化水素濃度１０～６０重量％濃度の水溶液中で、３０～１００℃で３０分～２４時間加熱処理する。
より具体的には、(i)30% H2O2溶液中で加熱（100℃）すると同時にキセノンランプの照射処理（波長 250-2000、強度 3W、直径 1cm、）を行う（1～5hr）こと（ACS Nano 2007; 4, 265）は(ii)酸素灌流下で420℃、10分間処理した後、H2O2で一晩処理すること（J Phys Chem B 2003; vol107, 20, 4681）により行なうことができる。
(b-2)カーボンナノチューブを硝酸中で加熱処理する場合、好ましくは、カーボンナノチューブを硝酸濃度5～7０重量％濃度の水溶液中で、３０～１００℃で３０分～２４時間加熱処理する。
(b-3)カーボンナノチューブを硫酸中で加熱処理する場合、好ましくは、カーボンナノチューブを硫酸濃度5～98重量％濃度の水溶液中で、３０～１００℃で３０分～２４時間加熱処理する。 (b) The carbon nanotubes are heat-treated in hydrogen peroxide solution, nitric acid, sulfuric acid and a mixed solution thereof. In this case, the carbon nanotubes can be mixed with hydrogen peroxide, sulfuric acid, and nitric acid in an arbitrary ratio, and it is preferable to heat-treat at 30 to 100 ° C. for 10 minutes to 24 hours.
Next, preferable conditions when using hydrogen peroxide solution, nitric acid or sulfuric acid are shown.
(b-1) When carbon nanotubes are heat-treated in hydrogen peroxide water, the carbon nanotubes are preferably heated in an aqueous solution having a hydrogen peroxide concentration of 10 to 60% by weight at 30 to 100 ° C. for 30 minutes to 24 hours. To process.
More specifically, (i) Xenon lamp irradiation treatment (wavelength 250-2000, intensity 3W, diameter 1cm) at the same time as heating (100 ° C) in 30% H 2 O 2 solution (1-5hr) (ACS Nano 2007; 4, 265) is (ii) treatment at 420 ° C for 10 minutes under oxygen perfusion and then overnight treatment with H 2 O 2 (J Phys Chem B 2003; vol107, 20, 4681) Can be performed.
(b-2) When carbon nanotubes are heat-treated in nitric acid, the carbon nanotubes are preferably heat-treated in an aqueous solution having a nitric acid concentration of 5 to 70% by weight at 30 to 100 ° C. for 30 minutes to 24 hours.
(b-3) When carbon nanotubes are heat-treated in sulfuric acid, the carbon nanotubes are preferably heat-treated at 30 to 100 ° C. for 30 minutes to 24 hours in an aqueous solution having a sulfuric acid concentration of 5 to 98% by weight.
次に、過酸化水素水、硝酸又は硫酸を用いる場合の好ましい条件を示す。
(b-1)カーボンナノチューブを過酸化水素水中で加熱処理する場合、好ましくは、カーボンナノチューブを過酸化水素濃度１０～６０重量％濃度の水溶液中で、３０～１００℃で３０分～２４時間加熱処理する。
より具体的には、(i)30% H2O2溶液中で加熱（100℃）すると同時にキセノンランプの照射処理（波長 250-2000、強度 3W、直径 1cm、）を行う（1～5hr）こと（ACS Nano 2007; 4, 265）は(ii)酸素灌流下で420℃、10分間処理した後、H2O2で一晩処理すること（J Phys Chem B 2003; vol107, 20, 4681）により行なうことができる。
(b-2)カーボンナノチューブを硝酸中で加熱処理する場合、好ましくは、カーボンナノチューブを硝酸濃度5～7０重量％濃度の水溶液中で、３０～１００℃で３０分～２４時間加熱処理する。
(b-3)カーボンナノチューブを硫酸中で加熱処理する場合、好ましくは、カーボンナノチューブを硫酸濃度5～98重量％濃度の水溶液中で、３０～１００℃で３０分～２４時間加熱処理する。 (b) The carbon nanotubes are heat-treated in hydrogen peroxide solution, nitric acid, sulfuric acid and a mixed solution thereof. In this case, the carbon nanotubes can be mixed with hydrogen peroxide, sulfuric acid, and nitric acid in an arbitrary ratio, and it is preferable to heat-treat at 30 to 100 ° C. for 10 minutes to 24 hours.
Next, preferable conditions when using hydrogen peroxide solution, nitric acid or sulfuric acid are shown.
(b-1) When carbon nanotubes are heat-treated in hydrogen peroxide water, the carbon nanotubes are preferably heated in an aqueous solution having a hydrogen peroxide concentration of 10 to 60% by weight at 30 to 100 ° C. for 30 minutes to 24 hours. To process.
More specifically, (i) Xenon lamp irradiation treatment (wavelength 250-2000, intensity 3W, diameter 1cm) at the same time as heating (100 ° C) in 30% H 2 O 2 solution (1-5hr) (ACS Nano 2007; 4, 265) is (ii) treatment at 420 ° C for 10 minutes under oxygen perfusion and then overnight treatment with H 2 O 2 (J Phys Chem B 2003; vol107, 20, 4681) Can be performed.
(b-2) When carbon nanotubes are heat-treated in nitric acid, the carbon nanotubes are preferably heat-treated in an aqueous solution having a nitric acid concentration of 5 to 70% by weight at 30 to 100 ° C. for 30 minutes to 24 hours.
(b-3) When carbon nanotubes are heat-treated in sulfuric acid, the carbon nanotubes are preferably heat-treated at 30 to 100 ° C. for 30 minutes to 24 hours in an aqueous solution having a sulfuric acid concentration of 5 to 98% by weight.
本発明ではさらに、分子量が０．１～１０００万（重量平均分子量）の範囲にある医薬用有機添加物が吸着してなるカーボンナノチューブを尿毒症治療剤の有効成分として用いることができる。このように、医薬用有機添加物が吸着してなるカーボンナノチューブを用いると、カーボンナノチューブが、アミラーゼ、ペプシン、トリプシンなどの消化酵素を吸着するのを抑えることができ、尿毒症毒素の選択吸収率を向上させることができるので好ましい。
予め医薬用有機添加物を吸着させるカーボンナノチューブとしては、特許文献１に記載の従来のカーボンナノチューブを用いることができるが、カーボンナノチューブとして、カーボン骨格の一部が欠失した開口を表層に有するカーボンナノチューブを用いると、尿毒症毒素の吸収率と選択吸収率の両方を向上させることができるので好ましい。 Furthermore, in the present invention, carbon nanotubes formed by adsorbing organic pharmaceutical additives having a molecular weight in the range of 0.1 to 10 million (weight average molecular weight) can be used as an active ingredient of a therapeutic agent for uremia. Thus, when carbon nanotubes formed by adsorbing organic pharmaceutical additives are used, carbon nanotubes can be prevented from adsorbing digestive enzymes such as amylase, pepsin and trypsin, and the selective absorption rate of uremic toxins Can be improved.
As the carbon nanotube for adsorbing the organic drug additive in advance, the conventional carbon nanotube described in Patent Document 1 can be used. However, as the carbon nanotube, carbon having an opening in which a part of the carbon skeleton is deleted on the surface layer. The use of nanotubes is preferable because both the absorption rate and selective absorption rate of uremic toxins can be improved.
予め医薬用有機添加物を吸着させるカーボンナノチューブとしては、特許文献１に記載の従来のカーボンナノチューブを用いることができるが、カーボンナノチューブとして、カーボン骨格の一部が欠失した開口を表層に有するカーボンナノチューブを用いると、尿毒症毒素の吸収率と選択吸収率の両方を向上させることができるので好ましい。 Furthermore, in the present invention, carbon nanotubes formed by adsorbing organic pharmaceutical additives having a molecular weight in the range of 0.1 to 10 million (weight average molecular weight) can be used as an active ingredient of a therapeutic agent for uremia. Thus, when carbon nanotubes formed by adsorbing organic pharmaceutical additives are used, carbon nanotubes can be prevented from adsorbing digestive enzymes such as amylase, pepsin and trypsin, and the selective absorption rate of uremic toxins Can be improved.
As the carbon nanotube for adsorbing the organic drug additive in advance, the conventional carbon nanotube described in Patent Document 1 can be used. However, as the carbon nanotube, carbon having an opening in which a part of the carbon skeleton is deleted on the surface layer. The use of nanotubes is preferable because both the absorption rate and selective absorption rate of uremic toxins can be improved.
分子量が０．１～１０００万の範囲にある医薬用有機添加物としては、医薬的に許容される水溶性高分子及び/又は界面活性剤であるのが好ましい。これらのうち、特に、多糖類、ポリアクリル酸類、ポリペプチド類、ポリ乳酸類、ポリアルキレンオキシド類、ポリビニルピロリドン類、ポリビニルアルコール類、ポリオキシエチレン類及びアルキルアリルポリエーテル類からなる群から選ばれる医薬用有機添加物であるのが好ましい。さらに、分子量が１～７００万であるのが好ましい。
医薬用有機添加物をカーボンナノチューブに吸着させる割合は、カーボンナノチューブ１００重量部当り、１～１００重量部であるのが好ましく、より好ましくは１０～７０重量部である。
吸着させる方法としては、医薬用有機添加物とカーボンナノチューブを攪拌混合する方法、医薬用有機添加物の水溶液をカーボンナノチューブに噴霧する方法などをあげることができるが、吸着させる方法はこれらの方法に限定されるものではない。 The pharmaceutical organic additive having a molecular weight in the range of 0.1 to 10 million is preferably a pharmaceutically acceptable water-soluble polymer and / or a surfactant. Among these, in particular, selected from the group consisting of polysaccharides, polyacrylic acids, polypeptides, polylactic acids, polyalkylene oxides, polyvinylpyrrolidones, polyvinyl alcohols, polyoxyethylenes and alkylallyl polyethers. Preferably it is a pharmaceutical organic additive. Further, the molecular weight is preferably 1 to 7 million.
The ratio of adsorbing the organic drug additive to the carbon nanotubes is preferably 1 to 100 parts by weight, more preferably 10 to 70 parts by weight per 100 parts by weight of the carbon nanotubes.
Examples of the adsorbing method include a method of stirring and mixing the organic drug additive and the carbon nanotube, and a method of spraying an aqueous solution of the organic drug additive on the carbon nanotube. The adsorbing method includes these methods. It is not limited.
医薬用有機添加物をカーボンナノチューブに吸着させる割合は、カーボンナノチューブ１００重量部当り、１～１００重量部であるのが好ましく、より好ましくは１０～７０重量部である。
吸着させる方法としては、医薬用有機添加物とカーボンナノチューブを攪拌混合する方法、医薬用有機添加物の水溶液をカーボンナノチューブに噴霧する方法などをあげることができるが、吸着させる方法はこれらの方法に限定されるものではない。 The pharmaceutical organic additive having a molecular weight in the range of 0.1 to 10 million is preferably a pharmaceutically acceptable water-soluble polymer and / or a surfactant. Among these, in particular, selected from the group consisting of polysaccharides, polyacrylic acids, polypeptides, polylactic acids, polyalkylene oxides, polyvinylpyrrolidones, polyvinyl alcohols, polyoxyethylenes and alkylallyl polyethers. Preferably it is a pharmaceutical organic additive. Further, the molecular weight is preferably 1 to 7 million.
The ratio of adsorbing the organic drug additive to the carbon nanotubes is preferably 1 to 100 parts by weight, more preferably 10 to 70 parts by weight per 100 parts by weight of the carbon nanotubes.
Examples of the adsorbing method include a method of stirring and mixing the organic drug additive and the carbon nanotube, and a method of spraying an aqueous solution of the organic drug additive on the carbon nanotube. The adsorbing method includes these methods. It is not limited.
本発明の尿毒症治療剤では、カーボン骨格の一部が欠失した開口を表層に有するカーボンナノチューブ自体又は分子量が０．１～１０００万の範囲にある医薬用有機添加物が吸着してなるカーボンナノチューブ自体をそのまま尿毒症治療剤として用い、尿毒症患者に投与、好ましくは経口投与してもよい。又、既知の尿毒症治療剤と同様に賦形剤、甘味剤、着色剤などを配合し、錠剤や顆粒剤などの各種形態のものとしてもよい。
本発明の尿毒症治療剤では、特許文献１に記載の打錠機による圧縮により服用容量を低減することができ、患者のコンプライアンスは格段に向上させることが可能である。
本発明の尿毒症治療剤は、通常１回１～２ｇ程度患者に投与するのが好ましく、１日３回服用するのが好ましい。本発明の尿毒症治療剤を投与すると、患者の体内の尿毒症毒素が本発明の有効成分であるカーボンナノチューブに消化管内で吸着され、便とともに体外に排泄されるので好ましい。
次に実施例に基づいて本発明を説明する。 In the uremic treatment agent of the present invention, carbon formed by adsorbing carbon nanotubes themselves having an opening in which a part of the carbon skeleton is deleted or a pharmaceutical organic additive having a molecular weight in the range of 0.1 to 10 million is adsorbed. The nanotubes themselves may be used as they are as a uremic therapeutic agent and administered to uremic patients, preferably orally. Moreover, it is good also as various forms, such as a tablet and a granule, mix | blending an excipient | filler, a sweetener, a coloring agent, etc. similarly to the known uremic treatment agent.
In the therapeutic agent for uremia of the present invention, the dose volume can be reduced by compression with a tableting machine described in Patent Document 1, and the patient's compliance can be significantly improved.
The therapeutic agent for uremia of the present invention is usually preferably administered to a patient at a dose of about 1 to 2 g once, and preferably taken three times a day. When the therapeutic agent for uremia of the present invention is administered, the uremic toxin in the patient's body is preferably adsorbed in the gastrointestinal tract by the carbon nanotube, which is the active ingredient of the present invention, and excreted outside the body together with feces.
Next, this invention is demonstrated based on an Example.
本発明の尿毒症治療剤では、特許文献１に記載の打錠機による圧縮により服用容量を低減することができ、患者のコンプライアンスは格段に向上させることが可能である。
本発明の尿毒症治療剤は、通常１回１～２ｇ程度患者に投与するのが好ましく、１日３回服用するのが好ましい。本発明の尿毒症治療剤を投与すると、患者の体内の尿毒症毒素が本発明の有効成分であるカーボンナノチューブに消化管内で吸着され、便とともに体外に排泄されるので好ましい。
次に実施例に基づいて本発明を説明する。 In the uremic treatment agent of the present invention, carbon formed by adsorbing carbon nanotubes themselves having an opening in which a part of the carbon skeleton is deleted or a pharmaceutical organic additive having a molecular weight in the range of 0.1 to 10 million is adsorbed. The nanotubes themselves may be used as they are as a uremic therapeutic agent and administered to uremic patients, preferably orally. Moreover, it is good also as various forms, such as a tablet and a granule, mix | blending an excipient | filler, a sweetener, a coloring agent, etc. similarly to the known uremic treatment agent.
In the therapeutic agent for uremia of the present invention, the dose volume can be reduced by compression with a tableting machine described in Patent Document 1, and the patient's compliance can be significantly improved.
The therapeutic agent for uremia of the present invention is usually preferably administered to a patient at a dose of about 1 to 2 g once, and preferably taken three times a day. When the therapeutic agent for uremia of the present invention is administered, the uremic toxin in the patient's body is preferably adsorbed in the gastrointestinal tract by the carbon nanotube, which is the active ingredient of the present invention, and excreted outside the body together with feces.
Next, this invention is demonstrated based on an Example.
実施例１：インドール酢酸および消化酵素吸着試験
ガラスバイアルにそれぞれの特性を有する被試験物質としてカーボンナノホーン［日本電気社製：純度95%（開孔処理なし、又は開孔処理済み）を各3 mg秤量した後、50 mg／dLのインドール酢酸溶液もしくは消化酵素液を2 mLずつ添加し、37 ℃の水槽中で120分間振盪撹拌した（120回／分）。フィルターで被試験物質を除去し、濾液の吸光度について紫外可視分光光度計を用いて波長280 nmで測定し、被試験物質に結合しなかったインドール酢酸量もしくは消化酵素量を測定した。その値から被試験物質に結合したインドール酢酸量もしくは消化酵素量を換算した。結果を図1及び2に示す。
図1及び2に示した結果から判るように、開孔処理を施したカーボンナノホーンを尿毒症治療剤の有効成分とすることにより、尿毒素であるインドール酢酸及び消化酵素に対する吸着性能が著しく上昇する。
尚、カーボンナノホーンの開孔処理は、以下の方法により行なった。
カーボンナノホーンを30%のH2O2溶液中にて100℃で３時間加熱した。カーボンナノホーンを濾過し、充分な純水で洗浄した後、70℃の窒素雰囲気下で24時間乾燥させた。 Example 1: Indole acetic acid and digestive enzyme adsorption test Carbon nanohorns [manufactured by NEC Corporation: purity 95% (no pore opening treatment or pore opening treatment completed) 3 mg each as test substances having respective characteristics in glass vials After weighing, 2 mL of a 50 mg / dL indoleacetic acid solution or digestive enzyme solution was added, and the mixture was shaken and stirred in a 37 ° C. water bath for 120 minutes (120 times / minute). The substance to be tested was removed with a filter, and the absorbance of the filtrate was measured at a wavelength of 280 nm using an ultraviolet-visible spectrophotometer, and the amount of indole acetic acid or digestive enzyme that did not bind to the substance to be tested was measured. From the value, the amount of indole acetic acid or digestive enzyme bound to the test substance was converted. The results are shown in FIGS.
As can be seen from the results shown in FIGS. 1 and 2, by using carbon nanohorn subjected to pore opening treatment as an active ingredient of a therapeutic agent for uremic disease, the adsorption performance for indoleacetic acid and digestive enzyme, which are uremic toxins, is remarkably increased. .
In addition, the opening process of carbon nanohorn was performed by the following method.
The carbon nanohorn was heated in a 30% H 2 O 2 solution at 100 ° C. for 3 hours. The carbon nanohorn was filtered, washed with sufficient pure water, and then dried in a nitrogen atmosphere at 70 ° C. for 24 hours.
ガラスバイアルにそれぞれの特性を有する被試験物質としてカーボンナノホーン［日本電気社製：純度95%（開孔処理なし、又は開孔処理済み）を各3 mg秤量した後、50 mg／dLのインドール酢酸溶液もしくは消化酵素液を2 mLずつ添加し、37 ℃の水槽中で120分間振盪撹拌した（120回／分）。フィルターで被試験物質を除去し、濾液の吸光度について紫外可視分光光度計を用いて波長280 nmで測定し、被試験物質に結合しなかったインドール酢酸量もしくは消化酵素量を測定した。その値から被試験物質に結合したインドール酢酸量もしくは消化酵素量を換算した。結果を図1及び2に示す。
図1及び2に示した結果から判るように、開孔処理を施したカーボンナノホーンを尿毒症治療剤の有効成分とすることにより、尿毒素であるインドール酢酸及び消化酵素に対する吸着性能が著しく上昇する。
尚、カーボンナノホーンの開孔処理は、以下の方法により行なった。
カーボンナノホーンを30%のH2O2溶液中にて100℃で３時間加熱した。カーボンナノホーンを濾過し、充分な純水で洗浄した後、70℃の窒素雰囲気下で24時間乾燥させた。 Example 1: Indole acetic acid and digestive enzyme adsorption test Carbon nanohorns [manufactured by NEC Corporation: purity 95% (no pore opening treatment or pore opening treatment completed) 3 mg each as test substances having respective characteristics in glass vials After weighing, 2 mL of a 50 mg / dL indoleacetic acid solution or digestive enzyme solution was added, and the mixture was shaken and stirred in a 37 ° C. water bath for 120 minutes (120 times / minute). The substance to be tested was removed with a filter, and the absorbance of the filtrate was measured at a wavelength of 280 nm using an ultraviolet-visible spectrophotometer, and the amount of indole acetic acid or digestive enzyme that did not bind to the substance to be tested was measured. From the value, the amount of indole acetic acid or digestive enzyme bound to the test substance was converted. The results are shown in FIGS.
As can be seen from the results shown in FIGS. 1 and 2, by using carbon nanohorn subjected to pore opening treatment as an active ingredient of a therapeutic agent for uremic disease, the adsorption performance for indoleacetic acid and digestive enzyme, which are uremic toxins, is remarkably increased. .
In addition, the opening process of carbon nanohorn was performed by the following method.
The carbon nanohorn was heated in a 30% H 2 O 2 solution at 100 ° C. for 3 hours. The carbon nanohorn was filtered, washed with sufficient pure water, and then dried in a nitrogen atmosphere at 70 ° C. for 24 hours.
実施例２：選択的尿毒素吸着性確認試験
実施例１で用いた開口処理済みのカーボンナノホーンをガラスバイアルに3 mg秤量した後、医薬用有機添加物であって水溶性高分子であるポリエチレングリコール(PEG7,000,000：分子量 約7,000,000)液（50 mg/dL）を２mLずつ添加し、水槽中で60分間振盪撹拌した（120回／分）。遠心分離により上清のポリエチレングリコール液を除去し、医薬用有機添加物が吸着してなるカーボンナノチューブを調製した（カーボンナノチューブ１００重量部当り、ポリエチレングリコール(PEG7,000,000)を１０～１００重量部吸着）。
その後50 mg/dLインドール酢酸溶液もしくは消化酵素液を2 mLずつ添加し振盪攪拌した（120回／分）。フィルターで被験物質を除去し、濾液の吸光度について紫外可視分光光度計を用いて波長280 nmで測定し、被試験物質に結合しなかったインドール酢酸もしくは消化酵素量を測定した。その値から被試験物質に結合したインドール酢酸もしくは消化酵素量を換算した。結果を図3に示す。 Example 2: Selective Ureotoxin Adsorption Confirmation Test After weighing 3 mg of the aperture-treated carbon nanohorn used in Example 1 into a glass vial, polyethylene glycol which is an organic pharmaceutical additive and a water-soluble polymer (PEG 7,000,000: molecular weight about 7,000,000) 2 mL of solution (50 mg / dL) was added and stirred and shaken in a water bath for 60 minutes (120 times / min). The supernatant polyethylene glycol solution was removed by centrifugation, and carbon nanotubes were prepared by adsorbing organic pharmaceutical additives (10 to 100 parts by weight of polyethylene glycol (PEG7,000,000) per 100 parts by weight of carbon nanotubes). ).
Thereafter, 2 mL of 50 mg / dL indole acetic acid solution or digestive enzyme solution was added and stirred with shaking (120 times / min). The test substance was removed with a filter, and the absorbance of the filtrate was measured using a UV-visible spectrophotometer at a wavelength of 280 nm, and the amount of indole acetic acid or digestive enzyme that did not bind to the test substance was measured. The amount of indole acetic acid or digestive enzyme bound to the test substance was converted from the value. The results are shown in Figure 3.
実施例１で用いた開口処理済みのカーボンナノホーンをガラスバイアルに3 mg秤量した後、医薬用有機添加物であって水溶性高分子であるポリエチレングリコール(PEG7,000,000：分子量 約7,000,000)液（50 mg/dL）を２mLずつ添加し、水槽中で60分間振盪撹拌した（120回／分）。遠心分離により上清のポリエチレングリコール液を除去し、医薬用有機添加物が吸着してなるカーボンナノチューブを調製した（カーボンナノチューブ１００重量部当り、ポリエチレングリコール(PEG7,000,000)を１０～１００重量部吸着）。
その後50 mg/dLインドール酢酸溶液もしくは消化酵素液を2 mLずつ添加し振盪攪拌した（120回／分）。フィルターで被験物質を除去し、濾液の吸光度について紫外可視分光光度計を用いて波長280 nmで測定し、被試験物質に結合しなかったインドール酢酸もしくは消化酵素量を測定した。その値から被試験物質に結合したインドール酢酸もしくは消化酵素量を換算した。結果を図3に示す。 Example 2: Selective Ureotoxin Adsorption Confirmation Test After weighing 3 mg of the aperture-treated carbon nanohorn used in Example 1 into a glass vial, polyethylene glycol which is an organic pharmaceutical additive and a water-soluble polymer (PEG 7,000,000: molecular weight about 7,000,000) 2 mL of solution (50 mg / dL) was added and stirred and shaken in a water bath for 60 minutes (120 times / min). The supernatant polyethylene glycol solution was removed by centrifugation, and carbon nanotubes were prepared by adsorbing organic pharmaceutical additives (10 to 100 parts by weight of polyethylene glycol (PEG7,000,000) per 100 parts by weight of carbon nanotubes). ).
Thereafter, 2 mL of 50 mg / dL indole acetic acid solution or digestive enzyme solution was added and stirred with shaking (120 times / min). The test substance was removed with a filter, and the absorbance of the filtrate was measured using a UV-visible spectrophotometer at a wavelength of 280 nm, and the amount of indole acetic acid or digestive enzyme that did not bind to the test substance was measured. The amount of indole acetic acid or digestive enzyme bound to the test substance was converted from the value. The results are shown in Figure 3.
図3に示した結果から判るように、高分子量のポリエチレングリコール(PEG7,000,000)と予め振盪攪拌させてカーボンナノチューブに予め吸着させておくことにより、本発明の有効成分であるカーボンナノホーンは、インドール酢酸との吸着率は低下しないものの、消化酵素との吸着率が低下し、尿毒症毒素に対しての吸着特異性を増すことが確認された。
実施例１および実施例２の結果から明らかなように、本発明の尿毒症治療剤の有効成分であるカーボンナノホーンは、消化管内の尿毒症毒素を吸着することで、消化管から体内への尿毒症毒素の吸収を選択的に阻害し、血中尿毒症毒素濃度の上昇を抑制するものであることから、慢性腎不全患者における尿毒症症状の改善や透析導入の遅延に有効であり、その医療上の効果は多大なものである。 As can be seen from the results shown in FIG. 3, the carbon nanohorn, which is an active ingredient of the present invention, is obtained by preliminarily adsorbing to a carbon nanotube by shaking and stirring with a high molecular weight polyethylene glycol (PEG 7,000,000). Although the adsorption rate with acetic acid did not decrease, it was confirmed that the adsorption rate with digestive enzyme decreased and the adsorption specificity to uremic toxins increased.
As is apparent from the results of Example 1 and Example 2, carbon nanohorn, which is an active ingredient of the therapeutic agent for uremic diseases of the present invention, adsorbs uremic toxins in the digestive tract, thereby uremic from the digestive tract into the body. Is effective in improving uremic symptoms and delaying dialysis in patients with chronic renal failure. The above effect is enormous.
実施例１および実施例２の結果から明らかなように、本発明の尿毒症治療剤の有効成分であるカーボンナノホーンは、消化管内の尿毒症毒素を吸着することで、消化管から体内への尿毒症毒素の吸収を選択的に阻害し、血中尿毒症毒素濃度の上昇を抑制するものであることから、慢性腎不全患者における尿毒症症状の改善や透析導入の遅延に有効であり、その医療上の効果は多大なものである。 As can be seen from the results shown in FIG. 3, the carbon nanohorn, which is an active ingredient of the present invention, is obtained by preliminarily adsorbing to a carbon nanotube by shaking and stirring with a high molecular weight polyethylene glycol (PEG 7,000,000). Although the adsorption rate with acetic acid did not decrease, it was confirmed that the adsorption rate with digestive enzyme decreased and the adsorption specificity to uremic toxins increased.
As is apparent from the results of Example 1 and Example 2, carbon nanohorn, which is an active ingredient of the therapeutic agent for uremic diseases of the present invention, adsorbs uremic toxins in the digestive tract, thereby uremic from the digestive tract into the body. Is effective in improving uremic symptoms and delaying dialysis in patients with chronic renal failure. The above effect is enormous.
Claims (11)
- カーボン骨格の一部が欠失した開口を表層に有するカーボンナノチューブを含有することを特徴とする尿毒症治療剤。 A therapeutic agent for uremia, comprising a carbon nanotube having an opening in the surface layer, in which a part of the carbon skeleton is deleted.
- カーボン骨格の一部が欠失した開口が、カーボンナノチューブを酸素の存在下、昇温速度１℃/minで８時間かけて５００℃まで上げ、そのまま室温まで冷やす、或いは１０℃/minぐらいの速度で昇温し、５００℃になった後１５分キープし室温まで冷却することにより、カーボンナノチューブの表層に形成されたものである請求項１記載の尿毒症治療剤。 The opening lacking a part of the carbon skeleton raises the carbon nanotubes in the presence of oxygen at a heating rate of 1 ° C / min to 500 ° C over 8 hours and then cools to room temperature as it is, or a rate of about 10 ° C / min. The therapeutic agent for uremia according to claim 1, which is formed on the surface layer of the carbon nanotubes by keeping the temperature at 500 ° C, keeping the temperature at 500 ° C for 15 minutes, and cooling to room temperature.
- カーボン骨格の一部が欠失した開口が、カーボンナノチューブを酸素１～１００容量％含有する雰囲気下、３５０～９６６℃で１０～１５分間処理することにより形成されたものである請求項２記載の尿毒症治療剤。 3. The opening in which a part of the carbon skeleton is deleted is formed by treatment at 350 to 966 ° C. for 10 to 15 minutes in an atmosphere containing 1 to 100% by volume of carbon nanotubes. A therapeutic agent for uremia.
- カーボン骨格の一部が欠失した開口が、カーボンナノチューブを酸素２１～１００容量％含有する雰囲気下、３５０～９６６℃で１０～１５分間処理することにより形成されたものである請求項１記載の尿毒症治療剤。 2. The opening in which a part of the carbon skeleton is deleted is formed by treatment at 350 to 966 ° C. for 10 to 15 minutes in an atmosphere containing 21 to 100% by volume of carbon nanotubes. A therapeutic agent for uremia.
- カーボン骨格の一部が欠失した開口が、カーボンナノチューブを過酸化水素水中で、加熱処理することにより、カーボンナノチューブの表層に形成されたものである請求項１記載の尿毒症治療剤。 The uremic treatment agent according to claim 1, wherein the opening from which a part of the carbon skeleton is deleted is formed on the surface of the carbon nanotube by heat-treating the carbon nanotube in hydrogen peroxide water.
- カーボン骨格の一部が欠失した開口が、カーボンナノチューブを過酸化水素濃度１０～６０重量％濃度の水溶液中で、３０～１００℃で３０分～２４時間加熱処理することにより形成されたものである請求項５記載の尿毒症治療剤。 The opening lacking a part of the carbon skeleton is formed by heat-treating carbon nanotubes in an aqueous solution having a hydrogen peroxide concentration of 10 to 60% by weight at 30 to 100 ° C. for 30 minutes to 24 hours. The therapeutic agent for uremia according to claim 5.
- カーボンナノチューブがカーボンナノホーンである請求項１～６のいずれか１項記載の尿毒症治療剤。 The uremic treatment agent according to any one of claims 1 to 6, wherein the carbon nanotube is carbon nanohorn.
- 分子量が０．１～１０００万の範囲にある医薬用有機添加物が吸着してなるカーボンナノチューブを含有することを特徴とする尿毒症治療剤。 A therapeutic agent for uremia characterized by containing carbon nanotubes adsorbed with organic pharmaceutical additives having a molecular weight in the range of 0.1 to 10 million.
- 医薬用有機添加物が、水溶性高分子及び/又は界面活性剤である請求項８記載の尿毒症治療剤。 The uremic treatment agent according to claim 8, wherein the organic pharmaceutical additive is a water-soluble polymer and / or a surfactant.
- 医薬用有機添加物が、多糖類、ポリアクリル酸類、ポリペプチド類、ポリ乳酸類、ポリアルキレンオキシド類、ポリビニルピロリドン類、ポリビニルアルコール類、ポリオキシエチレン類及びアルキルアリルポリエーテル類からなる群から選ばれる請求項９記載の尿毒症治療剤。 The organic pharmaceutical additive is selected from the group consisting of polysaccharides, polyacrylic acids, polypeptides, polylactic acids, polyalkylene oxides, polyvinylpyrrolidones, polyvinyl alcohols, polyoxyethylenes and alkylallyl polyethers. The uremic treatment agent according to claim 9.
- カーボンナノチューブが、請求項１～７のいずれか１項記載のものである請求項８～１０のいずれか１項記載の尿毒症治療剤。 The uremic treatment agent according to any one of claims 8 to 10, wherein the carbon nanotubes are those according to any one of claims 1 to 7.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008-229789 | 2008-09-08 | ||
| JP2008229789 | 2008-09-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2010027090A1 true WO2010027090A1 (en) | 2010-03-11 |
Family
ID=41797252
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2009/065681 WO2010027090A1 (en) | 2008-09-08 | 2009-09-08 | Therapeutic agent for uremia |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2010027090A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002503204A (en) * | 1996-03-06 | 2002-01-29 | ハイピリオン カタリシス インターナショナル インコーポレイテッド | Functionalized nanotubes |
| JP2005343885A (en) * | 2004-05-07 | 2005-12-15 | Japan Science & Technology Agency | Drug carbon nanohorn composite and method for producing the same |
| JP2006008602A (en) * | 2004-06-25 | 2006-01-12 | Ajinomoto Co Inc | Peroral uremic toxin adsorbent |
| JP2007022873A (en) * | 2005-07-20 | 2007-02-01 | National Institute Of Advanced Industrial & Technology | Water-dispersible protein/carbon nanotube composite and its production method and use |
-
2009
- 2009-09-08 WO PCT/JP2009/065681 patent/WO2010027090A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002503204A (en) * | 1996-03-06 | 2002-01-29 | ハイピリオン カタリシス インターナショナル インコーポレイテッド | Functionalized nanotubes |
| JP2005343885A (en) * | 2004-05-07 | 2005-12-15 | Japan Science & Technology Agency | Drug carbon nanohorn composite and method for producing the same |
| JP2006008602A (en) * | 2004-06-25 | 2006-01-12 | Ajinomoto Co Inc | Peroral uremic toxin adsorbent |
| JP2007022873A (en) * | 2005-07-20 | 2007-02-01 | National Institute Of Advanced Industrial & Technology | Water-dispersible protein/carbon nanotube composite and its production method and use |
Non-Patent Citations (5)
| Title |
|---|
| BEKYAROVA, E ET AL.: "Oxiadation and Porosity Evaluation budlike single-wall carbon nanohorn aggregates", LANGMUIR, vol. 18, no. 10, 2002, pages 4138 - 4141 * |
| BEKYAROVA, E ET AL.: "Single-Wall Nanostructured Carbon for Methane Storage", J PHYS CHEM B, vol. 107, no. 20, 2003, pages 4681 - 4684 * |
| SONG, L. ET AL.: "Protein adsorption and PEG modification on the surface of single-walled carbon nanotubes non-woven film", CHINESE JOURNAL OF BIOMEDICAL ENGINEERING, vol. 24, no. 6, 2005, pages 763 - 766 * |
| URITA, K. ET AL.: "Effects of gas adsorption on the electrical conductivity of single-wall carbon nanohorns", NANO LETT, vol. 6, no. 7, 2006, pages 1325 - 8 * |
| YE, C. ET AL.: "Adsorption of uremic toxins on carbon nanotubes", SEPARATION AND PURIFICATION TECHNOLOGY, vol. 58, no. 1, 2007, pages 2 - 6 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5781164B2 (en) | Adsorbent for oral administration | |
| Chen et al. | Adsorption behavior of epirubicin hydrochloride on carboxylated carbon nanotubes | |
| EP1500397B1 (en) | Adsorbents for oral administration, remedies or preventives for kidney diseases and remedies or preventives for liver diseases | |
| JP3522708B2 (en) | Adsorbent for oral administration | |
| ES2402147B1 (en) | PROCEDURE FOR OBTAINING A SUBSTRATE WITH NANOCLUSTERS OF AU FIXED IN THEIR SURFACE, AND SUBSTRATE AND CATALYST OBTAINED THROUGH SUCH PROCEDURE. | |
| CN111773243B (en) | Medicine for inflammatory bowel disease and preparation method and application thereof | |
| WO2012050025A1 (en) | Medical adsorbent and method for producing same | |
| JP4666467B2 (en) | Activated carbon, method for producing the same, and therapeutic agent for renal liver disease | |
| JP2022546892A (en) | Filtration materials and filters for retaining polycyclic aromatic hydrocarbons, carbonyls and other compounds from smoke from tobacco products | |
| US20090181095A1 (en) | Oxidative stress inhibitor | |
| Sui et al. | Incorporation of cisplatin into PEG-wrapped ultrapurified large-inner-diameter MWCNTs for enhanced loading efficiency and release profile | |
| KR100680449B1 (en) | Adsorbents for oral administration | |
| JPH06135841A (en) | Anti-nephrosis syndrome agent | |
| Moazzen et al. | A novel biocompatible drug carrier for oral delivery and controlled release of antibiotic drug: loading and release of clarithromycin as an antibiotic drug model | |
| Poryvaev et al. | Blatter radical-decorated silica as a prospective adsorbent for selective NO capture from air | |
| WO2010027090A1 (en) | Therapeutic agent for uremia | |
| JP4618409B2 (en) | Oral uremic toxin adsorbent | |
| JPH10316578A (en) | Medicine for improving blood lipoprotein lipase activity-lowering disease | |
| JP2006111604A5 (en) | ||
| Zhu et al. | Carbon nanohorns and their biomedical applications | |
| JP2006070047A5 (en) | ||
| JPH08277216A (en) | Powdery agent and control of release rate of medicine | |
| Bobrowska et al. | Endohedral and Exohedral Single‐Layered Fullerenes | |
| JP2016014057A (en) | Production method for sorbent for oral administration medicines | |
| JP2013035781A (en) | Adsorbent for oral administration and medicine using the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09811613 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 09811613 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: JP |