CA2635518A1 - Agent for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease - Google Patents
Agent for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease Download PDFInfo
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- CA2635518A1 CA2635518A1 CA002635518A CA2635518A CA2635518A1 CA 2635518 A1 CA2635518 A1 CA 2635518A1 CA 002635518 A CA002635518 A CA 002635518A CA 2635518 A CA2635518 A CA 2635518A CA 2635518 A1 CA2635518 A1 CA 2635518A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- 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
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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Abstract
Disclosed is a pharmaceutical for use in the prevention and/or treatment of chronic obstructive pulmonary disease, which comprises an aqueous dispersion solution of a transition metal microparticle, preferably a microparticle of a noble metal such as platinum (e.g., a colloidal aqueous platinum dispersion solution having an average particle diameter of 10 nm or smaller).
Description
SPECIFICATION
Agent for Prophylactic and/or Therapeutic Treatment of Chronic Obstructive Pulmonary Disease Field of the Invention [0001]
The present invention relates to an agent for prophylactic and/or therapeutic treatment of chronic obstructive disease.
Background Art [0002]
Continuous inhalation of harmful particles and gases such as those from tobacco causes continuous inflammation in lungs, resulting in almost everyday continuous coughs and expectoration as well as feeling of shortness of breath at the time of exercise. If inflammation continues for a long period of time, symptoms appear, for example, phlegm increases to thin the bronchial tubes, or alveolar walls are broken to lose elasticity. As a result, flow of air to lungs is chronically aggravated, which further results in causing dyspnoea and inducing various disorders in the whole body. This pathological condition is called as "chronic obstructive pulmonary disease" (hereinafter sometimes abbreviated as "COPD" in the specification), and it is understood that the condition includes most of the pathological conditions called as chronic bronchitis or pulmonary emphysema so far to date. COPD is a progressive disease, and if the disease is left without appropriate therapeutic treatments, pulmonary hypofunction progresses with repetitive acute exacerbation, actions and life may be significantly restricted, or disorders appear in the whole body such as heart and digestive organs, which causes respiratory failure, cardiac insufficiency, or critical pneumonia to result in death. It is estimated that there are about 5,300,000 patients in Japan.
Agent for Prophylactic and/or Therapeutic Treatment of Chronic Obstructive Pulmonary Disease Field of the Invention [0001]
The present invention relates to an agent for prophylactic and/or therapeutic treatment of chronic obstructive disease.
Background Art [0002]
Continuous inhalation of harmful particles and gases such as those from tobacco causes continuous inflammation in lungs, resulting in almost everyday continuous coughs and expectoration as well as feeling of shortness of breath at the time of exercise. If inflammation continues for a long period of time, symptoms appear, for example, phlegm increases to thin the bronchial tubes, or alveolar walls are broken to lose elasticity. As a result, flow of air to lungs is chronically aggravated, which further results in causing dyspnoea and inducing various disorders in the whole body. This pathological condition is called as "chronic obstructive pulmonary disease" (hereinafter sometimes abbreviated as "COPD" in the specification), and it is understood that the condition includes most of the pathological conditions called as chronic bronchitis or pulmonary emphysema so far to date. COPD is a progressive disease, and if the disease is left without appropriate therapeutic treatments, pulmonary hypofunction progresses with repetitive acute exacerbation, actions and life may be significantly restricted, or disorders appear in the whole body such as heart and digestive organs, which causes respiratory failure, cardiac insufficiency, or critical pneumonia to result in death. It is estimated that there are about 5,300,000 patients in Japan.
[0003]
Although any curable therapy of COPD has not yet been developed to date, besides non-smoking education from a prophylactic aspect, therapeutic treatments such as pharmacotherapies, rehabilitations, and oxygen therapies have been often applied depending on severity of the conditions. For the pharmacotherapies, bronchodilators have been used which dilate the contracted respiratory tract to relieve respiration, and /3 2 receptor stimulants (fenoterol, salbutamol, tulobuterol, procaterol, salmeterol, and the like), theophylline formulations (theophylline, aminophylline, and the like), expectorants and the like have been sometimes used.
For acute exacerbation, steroids, antibiotics and the like have also been sometimes used for a short term.
Although any curable therapy of COPD has not yet been developed to date, besides non-smoking education from a prophylactic aspect, therapeutic treatments such as pharmacotherapies, rehabilitations, and oxygen therapies have been often applied depending on severity of the conditions. For the pharmacotherapies, bronchodilators have been used which dilate the contracted respiratory tract to relieve respiration, and /3 2 receptor stimulants (fenoterol, salbutamol, tulobuterol, procaterol, salmeterol, and the like), theophylline formulations (theophylline, aminophylline, and the like), expectorants and the like have been sometimes used.
For acute exacerbation, steroids, antibiotics and the like have also been sometimes used for a short term.
[0004]
International Patent Publication W02004/73723 discloses a medicament for prophylactic and/or therapeutic treatment of a neurodegenerative disease such as amyotrophic lateral sclerosis, rheumatic diseases, ischemic heart diseases, stress ulcer, dermatitis, arteriosclerosis, and hyperlipidemia, which comprises fineparticles of a noble metal. However, this publication does not suggest nor teach that the aforementioned medicament is effective to COPD.
Disclosure of the Invention Object to be Achieved by the Invention [0005]
An object of the present invention is to provide a medicament for prophylactic and/or therapeutic treatment of COPD.
Means for Achieving the Object [0006]
The inventors of the present invention conducted various researches to achieve the aforementioned object, and as a result, they found that colloid comprising fineparticles of a transition metal such as platinum could relieve pathological conditions of COPD, and was also effective in prophylaxis of COPD. The present invention was achieved on the basis of the aforementioned finding.
International Patent Publication W02004/73723 discloses a medicament for prophylactic and/or therapeutic treatment of a neurodegenerative disease such as amyotrophic lateral sclerosis, rheumatic diseases, ischemic heart diseases, stress ulcer, dermatitis, arteriosclerosis, and hyperlipidemia, which comprises fineparticles of a noble metal. However, this publication does not suggest nor teach that the aforementioned medicament is effective to COPD.
Disclosure of the Invention Object to be Achieved by the Invention [0005]
An object of the present invention is to provide a medicament for prophylactic and/or therapeutic treatment of COPD.
Means for Achieving the Object [0006]
The inventors of the present invention conducted various researches to achieve the aforementioned object, and as a result, they found that colloid comprising fineparticles of a transition metal such as platinum could relieve pathological conditions of COPD, and was also effective in prophylaxis of COPD. The present invention was achieved on the basis of the aforementioned finding.
[0007]
The present invention thus provides a medicament for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease, which comprises an aqueous dispersion of transition metal fineparticles, preferably noble metal fineparticles. According to preferred embodiments, the present invention provides the aforementioned medicament, which comprises an aqueous dispersion of noble metal fineparticles; the aforementioned medicament, wherein the noble metal consists of one or more kinds of noble metals selected from the group consisting of ruthenium, rhodium, palladium, and platinum; the aforementioned medicament, wherein the noble metal is platinum; and the aforementioned medicament, wherein the fineparticles of a noble metal consist of platinum colloid having a mean particle size of 10 nm or smaller.
The present invention thus provides a medicament for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease, which comprises an aqueous dispersion of transition metal fineparticles, preferably noble metal fineparticles. According to preferred embodiments, the present invention provides the aforementioned medicament, which comprises an aqueous dispersion of noble metal fineparticles; the aforementioned medicament, wherein the noble metal consists of one or more kinds of noble metals selected from the group consisting of ruthenium, rhodium, palladium, and platinum; the aforementioned medicament, wherein the noble metal is platinum; and the aforementioned medicament, wherein the fineparticles of a noble metal consist of platinum colloid having a mean particle size of 10 nm or smaller.
[0008]
From another aspect, the present invention provides use of an aqueous dispersion of transition metal fineparticles, preferably noble metal fineparticles, for manufacture of the aforementioned medicament; and a method for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease, which comprises the step of administering an aqueous dispersion of transition metal fineparticles, preferably noble metal fineparticles, to a patient of the disease.
Brief Description of the Drawing [ooos]
[Fig. 1] Fig. 1 shows the action of the medicament of the present invention to suppress cell death caused by a solution of tobacco concentrate. In the graph, the gray line indicates the results obtained with PAA-Pt, and the black line indicates the results obtained with NAC, which results were obtained at concentrations of 50 M
and 100 u M, respectively.
[Fig. 2] Fig. 2 shows the action of the medicament of the present invention to suppress acute inflammation induced by acute smoking exposure.
Best Mode for Carrying Out the Invention [0010]
The medicament of the present invention is a medicament for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease, and is characterized to comprise an aqueous dispersion of transition metal fineparticles, preferably noble metal fineparticles. The transition metal means a metal having an incomplete d or f sub-shell, or a metal which can give a cation having such a sub-shell, and includes metals of the groups 3A to 7A, 8, and 1B in the periodic table.
Examples include iron, copper, molybdenum, platinum, and the like. Types of the noble metal are not particularly limited, and any of gold, ruthenium, rhodium, palladium, osmium, iridium, and platinum may be used. However, preferred noble metals are ruthenium, rhodium, palladium, and platinum. The fineparticles of a transition metal, preferably a noble metal, may contain two or more kinds of noble metals. Fineparticles of an alloy containing at least one kind of transition metal, preferably noble metal, or a mixture containing fineparticles of one or more kinds of transition metals, preferably noble metals, and fineparticles of one or more kinds of metals other than transition metal, preferably noble metal, can also be used.
For example, an alloy comprising gold and platinum or the like may be used. Among them, platinum or an alloy containing platinum is preferred, and platinum is particularly preferred.
[0011]
As the transition metal fineparticles, preferably noble metal fineparticles, fineparticles that have a large specific surface area and can form a colloidal state of superior surface reactivity are preferred. A particle size of the fineparticles is not particularly limited. Fineparticles having a mean particle size of 50 nm or smaller can be used, and fineparticles having a mean particle size of, preferably 20 nm or smaller, further preferably 10 nm or smaller, most preferably about 1 to 6 nm, can be used. Fineparticles having a smaller particle size can also be used.
[0012]
Various preparation methods for transition metal fineparticles, preferably noble metal fineparticles, are known (for example, Japanese Patent Publication (KOKOKU) Nos. 57-43125, 59-120249, Japanese Patent Unexamined Publication Nos.
From another aspect, the present invention provides use of an aqueous dispersion of transition metal fineparticles, preferably noble metal fineparticles, for manufacture of the aforementioned medicament; and a method for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease, which comprises the step of administering an aqueous dispersion of transition metal fineparticles, preferably noble metal fineparticles, to a patient of the disease.
Brief Description of the Drawing [ooos]
[Fig. 1] Fig. 1 shows the action of the medicament of the present invention to suppress cell death caused by a solution of tobacco concentrate. In the graph, the gray line indicates the results obtained with PAA-Pt, and the black line indicates the results obtained with NAC, which results were obtained at concentrations of 50 M
and 100 u M, respectively.
[Fig. 2] Fig. 2 shows the action of the medicament of the present invention to suppress acute inflammation induced by acute smoking exposure.
Best Mode for Carrying Out the Invention [0010]
The medicament of the present invention is a medicament for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease, and is characterized to comprise an aqueous dispersion of transition metal fineparticles, preferably noble metal fineparticles. The transition metal means a metal having an incomplete d or f sub-shell, or a metal which can give a cation having such a sub-shell, and includes metals of the groups 3A to 7A, 8, and 1B in the periodic table.
Examples include iron, copper, molybdenum, platinum, and the like. Types of the noble metal are not particularly limited, and any of gold, ruthenium, rhodium, palladium, osmium, iridium, and platinum may be used. However, preferred noble metals are ruthenium, rhodium, palladium, and platinum. The fineparticles of a transition metal, preferably a noble metal, may contain two or more kinds of noble metals. Fineparticles of an alloy containing at least one kind of transition metal, preferably noble metal, or a mixture containing fineparticles of one or more kinds of transition metals, preferably noble metals, and fineparticles of one or more kinds of metals other than transition metal, preferably noble metal, can also be used.
For example, an alloy comprising gold and platinum or the like may be used. Among them, platinum or an alloy containing platinum is preferred, and platinum is particularly preferred.
[0011]
As the transition metal fineparticles, preferably noble metal fineparticles, fineparticles that have a large specific surface area and can form a colloidal state of superior surface reactivity are preferred. A particle size of the fineparticles is not particularly limited. Fineparticles having a mean particle size of 50 nm or smaller can be used, and fineparticles having a mean particle size of, preferably 20 nm or smaller, further preferably 10 nm or smaller, most preferably about 1 to 6 nm, can be used. Fineparticles having a smaller particle size can also be used.
[0012]
Various preparation methods for transition metal fineparticles, preferably noble metal fineparticles, are known (for example, Japanese Patent Publication (KOKOKU) Nos. 57-43125, 59-120249, Japanese Patent Unexamined Publication Nos.
9-225317, 10-176207, 2001-79382, 2001-122723 and the like), and those skilled in the art can easily prepare the fineparticles by referring to these methods. For example, as the method for producing noble metal fineparticles, a chemical method called precipitation method or metal salt reduction method, a physical method called combustion method and the like can be used. Fineparticles prepared by any of the methods may be used as the active ingredient of the medicament of the present invention. It is preferable to use fineparticles prepared by the metal salt reduction method from viewpoints of easiness of the production and quality of the fineparticles.
Methods for preparing noble metal fineparticles as a preferred embodiment of the present invention will be described below. However, the scope of the present invention is not limited to use of noble metals.
[0013]
In the metal salt reduction method, for example, an aqueous solution or organic solvent solution of a water-soluble or organic solvent-soluble noble metal salt or noble metal complex is prepared, then a water-soluble polymer is added to the solution and pH of the solution is adjusted to 9 to 11, and the solution can be refluxed by heating in an inert atmosphere to reduce the metal salt or metal complex to obtain metal fineparticles. Types of the water-soluble or organic solvent-soluble noble metal salt are not particularly limited. For example, acetate, chloride, sulfate, nitrate, sulfonate, phosphate and the like can be used, and complexes thereof may also be used.
[0014]
Types of the water-soluble polymer used for the metal salt reduction method are not particularly limited. For example, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, cyclodextrin, amylopectin, methylcellulose and the like can be used, and two or more kinds of these polymers may be used in combination.
Polyvinylpyrrolidone can be preferably used, and poly(1-vinyl-2-pyrrolidone) can be more preferably used. It is also possible to use various kinds of surface active agents such as anionic, nonionic or liposoluble surface active agents instead of the water-soluble polymer or together with the water-soluble polymer. When an alcohol is used to perform the reduction, ethyl alcohol, n-propyl alcohol, n-butyl alcohol, n-amyl alcohol, ethylene glycol or the like is used. However, the methods for preparing noble metal fineparticles are not limited to the methods explained above.
[0015]
As the medicament of the present invention, an aqueous dispersion comprising transition metal fineparticles, preferably noble metal fineparticles, in a colloidal state prepared by the aforementioned methods, per se, may be used.
An aqueous suspension in which the transition metal fineparticles, preferably noble metal fineparticles, associate to form clusters may also be used as the medicament of the present invention. The dispersion medium of the aqueous suspension of the transition metal fineparticles, preferably noble metal fineparticles, consists preferably of substantially water alone. The medium may contain one or more kinds of the aforementioned water-soluble polymers, surface active agents and the like used for the preparation of the fineparticles in a colloidal state. The medium may also contain a small volume of a water-miscible organic solvent such as ethanol and glycerol in such a range that stable dispersion of the transition metal fineparticles, preferably noble metal fineparticles, is not destroyed and the dispersion is acceptable as a medicament.
[0016]
The medicament of the present invention can be used for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease. As for chronic obstructive pulmonary disease, for example, "COPD Information Network"
(http://www.copd-info.net/) and the like can be referred to. COPD is a disease in which ventilation of lungs is chronically aggravated by either one or both of chronic bronchitis and chronic pulmonary emphysema, and the pathological conditions becomes gradually more serious, and the disease encompasses those so far called as chronic bronchitis and chronic pulmonary emphysema. The medicament of the present invention can suppress the onset of bronchitis, or prevent advance of bronchitis, and it also can prevent alveolar destruction and can exhibit prophylactic and/or therapeutic effect for COPD on the basis of these actions. In the specification, the term "prophylactic and/or therapeutic treatment" should be construed in the broadest sense thereof including prophylaxis of onset of the aforementioned disease and treatment of the aforementioned disease after the onset, as well as suppression of progress of the aforementioned disease, improvement or relief of the aforementioned disease, prophylaxis of recurrence of the aforementioned disease, and the like., and the term should not be construed in any limitative way.
[00171 Administration routes of the medicament of the present invention are not particularly limited, and either route of oral administration or parenteral administration may be chosen. As the medicament of the present invention, noble metal dispersion of a colloidal state or noble metal fineparticles in a dried state prepared by the methods explained above may be used without any treatment. The metal fineparticles prepared in water, organic solvent, or mixture of water and organic solvent exist in a colloidal state. The aforementioned noble metal dispersion in a colloidal state, per se, can be used as the medicament of the present invention.
An aqueous suspension in which the noble metal fineparticles associate to form clusters may also be used as the medicament of the present invention.
Furthermore, when it is desirable to remove a solvent, the solvent can be removed by an operation of heating or the like to obtain fineparticles in a dried state, and the dried fineparticles obtained by the above operation can be used as the medicament of the present invention.
[0018]
The medicament of the present invention can also be administered as a pharmaceutical composition for oral or parenteral use that can be produced by a method well known to those skilled in the art. Examples of the pharmaceutical composition suitable for oral administration include, for example, tablets, capsules, powders, subtilized granules, granules, solutions, syrups, and the like, and examples of the pharmaceutical composition suitable for parenteral administration include, for example, injections, drip infusions, suppositories, inhalants, nasal drops, transdermal preparations, transmucosal preparations, and the like. The aforementioned pharmaceutical compositions can be produced by using one or more kinds of pharmaceutical additives together with the noble metal fineparticles as the active ingredient. Examples of the pharmaceutical additives include, for example, excipients, disintegrating agents or disintegrating aids, binders, lubricants, coating agents, dyes, diluents, bases, dissolving agents or dissolving aids, isotonic agents, pH
modifiers, stabilizers, propellants, tackifiers, and the like, and they can be suitably selected by those skilled in the art depending on the dosage form of the pharmaceutical composition.
[0019]
Doses of the medicament of the present invention are not particularly limited, and the dose can be suitably chosen depending on conditions such as a type of disease, a purpose of administration (prophylactic or therapeutic treatment), an age, body weight, symptoms and the like of a patient. The medicament of the present invention can be used by oral administration for adults in an amount in a range of, for example, about 0.001 to 1,000 mg per day on the basis of a weight of the noble metal fineparticles.
Examples [0020]
Hereafter, the present invention will be explained more specifically with reference to the examples. However, the scope of the present invention is not limited to the following examples.
Example 1: Preparation of the medicament of the present invention In a 100-ml 2-neck pear-shaped flask connected with an Allihn condenser and a 3-neck joint, 0.1467 g of poly(1-vinyl-2-pyrrolidone) (Wako Pure Chemical Industries) was placed and dissolved in 23 ml of distilled water. This solution was stirred for 10 minutes, then mixed with 2 ml of 1.66 x 10-2 M chloroplatinic acid solution obtained by dissolving hexachloroplatinic acid (H2PtCl6 = 61120, Wako Pure Chemical Industries) in distilled water, and stirred for additional 30 minutes. The inside atmosphere of the reaction system was replaced with nitrogen gas.
Twenty five ml of special grade ethanol was added to the reaction mixture and the resulting mixture was refluxed at a temperature of 100 C for 2 hours while the nitrogen atmosphere was maintained. An ultraviolet light spectral scanning analysis of the reaction mixture was performed to confirm disappearance of the platinum ion peak and saturation of the peak due to scattering peculiar to metal solid and thereby confirm completion of the reduction reaction. The organic solvent was evaporated under reduced pressure to prepare a platinum colloidal solution containing platinum fineparticles (mean particle size: 2.4 0.7 nm) (PVP-Pt solution). This platinum colloidal solution was diluted to 1 uM with distilled water for injection to prepare the medicament of the present invention.
[0021]
Example 2: Preparation of the medicament of the present invention A platinum colloidal solution (PAA-Pt solution) containing platinum fineparticles having a mean particle size of 2.0 0.4 nm was prepared in the same manner as that in Example 1, except that poly(sodium acrylate) (Aldrich) was used in an amount of 125 times that of Pt in terms of unit weight instead of poly(1-vinyl-2-pyrrolidone). This platinum colloidal solution was diluted to 1 uM with distilled water for injection to prepare the medicament of the present invention.
[0022]
Example 3: Preparation of the medicament of the present invention A platinum colloidal solution (CP-Pt solution) containing platinum fineparticles having a mean particle size of 4 1 nm was prepared in the same manner as that in Example 1, except that pectin (Unitec Foods) was used in an amount of 1 to 4 times that of Pt in terms of unit weight instead of poly(1-vinyl-2=
pyrrolidone). This platinum colloidal solution was diluted to 1 uM with distilled water for injection to prepare the medicament of the present invention.
[0023]
Example 4: Action of the medicament of the present invention One of the highly probable risk factors for the onset of COPD is oxidant stress by smoking or harmful gases. Therefore, effectiveness of platinum colloid on the smoking-induced oxidant stress was evaluated and examined.
<Method 1>
When a 1% tobacco concentrate is applied to cultured human pneumonocytes (A549 cells), they give the change of absorbance in the Alamar blue assay, and it can be estimated as cell death. Cell death in the group in which platinum colloid was applied beforehand and the group in which N-acetylcysteine (NAC, J. Surg.
Res., 2005 Nov; 129(1):38-45," The effect of N-acetylcysteine on pulmonary lipid peroxidation and tissue damage") was applied at the same dose was compared and examined by the extinction method. As a result, the platinum colloids of Examples 2 and 3 significantly suppressed cell death compared with NAC of the same dose. The results obtained with the platinum colloid of Example 2 and NAC are shown in Fig. 1.
[0024]
<Method 2>
Twenty four DBA/2J mice were divided into a smoking group and a non-smoking group, and the mice of the smoking group were exposed to acute smoking of 5 cigarettes per day over 3 days. The platinum colloid of Example 2 (4 y M/kg) or physiological saline of the same volume was administered beforehand by rhinenchysis to the mice every day, and serum and bronchoalveolar lavage fluid (BALF) were compared and examined. As a result, statistically significant difference was observed between the total neutrophil counts of the smoking + physiological saline administration group and the smoking + platinum colloid administration group (ANOVA: p < 0.05, Krushkal Wallis: p < 0.05), and thus acute inflammation was suppressed by the platinum colloid, although definitely significant difference was not observed between the total cell counts in the bronchoalveolar lavage fluids (BALF) of the groups. The results are shown in Fig. 2.
Industrial Applicability [0025]
The medicament of the present invention is effective for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease, and because the medicament can be orally administered, and has reduced side reactions, prophylactic and/or therapeutic treatment can be achieved with high compliance.
Methods for preparing noble metal fineparticles as a preferred embodiment of the present invention will be described below. However, the scope of the present invention is not limited to use of noble metals.
[0013]
In the metal salt reduction method, for example, an aqueous solution or organic solvent solution of a water-soluble or organic solvent-soluble noble metal salt or noble metal complex is prepared, then a water-soluble polymer is added to the solution and pH of the solution is adjusted to 9 to 11, and the solution can be refluxed by heating in an inert atmosphere to reduce the metal salt or metal complex to obtain metal fineparticles. Types of the water-soluble or organic solvent-soluble noble metal salt are not particularly limited. For example, acetate, chloride, sulfate, nitrate, sulfonate, phosphate and the like can be used, and complexes thereof may also be used.
[0014]
Types of the water-soluble polymer used for the metal salt reduction method are not particularly limited. For example, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, cyclodextrin, amylopectin, methylcellulose and the like can be used, and two or more kinds of these polymers may be used in combination.
Polyvinylpyrrolidone can be preferably used, and poly(1-vinyl-2-pyrrolidone) can be more preferably used. It is also possible to use various kinds of surface active agents such as anionic, nonionic or liposoluble surface active agents instead of the water-soluble polymer or together with the water-soluble polymer. When an alcohol is used to perform the reduction, ethyl alcohol, n-propyl alcohol, n-butyl alcohol, n-amyl alcohol, ethylene glycol or the like is used. However, the methods for preparing noble metal fineparticles are not limited to the methods explained above.
[0015]
As the medicament of the present invention, an aqueous dispersion comprising transition metal fineparticles, preferably noble metal fineparticles, in a colloidal state prepared by the aforementioned methods, per se, may be used.
An aqueous suspension in which the transition metal fineparticles, preferably noble metal fineparticles, associate to form clusters may also be used as the medicament of the present invention. The dispersion medium of the aqueous suspension of the transition metal fineparticles, preferably noble metal fineparticles, consists preferably of substantially water alone. The medium may contain one or more kinds of the aforementioned water-soluble polymers, surface active agents and the like used for the preparation of the fineparticles in a colloidal state. The medium may also contain a small volume of a water-miscible organic solvent such as ethanol and glycerol in such a range that stable dispersion of the transition metal fineparticles, preferably noble metal fineparticles, is not destroyed and the dispersion is acceptable as a medicament.
[0016]
The medicament of the present invention can be used for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease. As for chronic obstructive pulmonary disease, for example, "COPD Information Network"
(http://www.copd-info.net/) and the like can be referred to. COPD is a disease in which ventilation of lungs is chronically aggravated by either one or both of chronic bronchitis and chronic pulmonary emphysema, and the pathological conditions becomes gradually more serious, and the disease encompasses those so far called as chronic bronchitis and chronic pulmonary emphysema. The medicament of the present invention can suppress the onset of bronchitis, or prevent advance of bronchitis, and it also can prevent alveolar destruction and can exhibit prophylactic and/or therapeutic effect for COPD on the basis of these actions. In the specification, the term "prophylactic and/or therapeutic treatment" should be construed in the broadest sense thereof including prophylaxis of onset of the aforementioned disease and treatment of the aforementioned disease after the onset, as well as suppression of progress of the aforementioned disease, improvement or relief of the aforementioned disease, prophylaxis of recurrence of the aforementioned disease, and the like., and the term should not be construed in any limitative way.
[00171 Administration routes of the medicament of the present invention are not particularly limited, and either route of oral administration or parenteral administration may be chosen. As the medicament of the present invention, noble metal dispersion of a colloidal state or noble metal fineparticles in a dried state prepared by the methods explained above may be used without any treatment. The metal fineparticles prepared in water, organic solvent, or mixture of water and organic solvent exist in a colloidal state. The aforementioned noble metal dispersion in a colloidal state, per se, can be used as the medicament of the present invention.
An aqueous suspension in which the noble metal fineparticles associate to form clusters may also be used as the medicament of the present invention.
Furthermore, when it is desirable to remove a solvent, the solvent can be removed by an operation of heating or the like to obtain fineparticles in a dried state, and the dried fineparticles obtained by the above operation can be used as the medicament of the present invention.
[0018]
The medicament of the present invention can also be administered as a pharmaceutical composition for oral or parenteral use that can be produced by a method well known to those skilled in the art. Examples of the pharmaceutical composition suitable for oral administration include, for example, tablets, capsules, powders, subtilized granules, granules, solutions, syrups, and the like, and examples of the pharmaceutical composition suitable for parenteral administration include, for example, injections, drip infusions, suppositories, inhalants, nasal drops, transdermal preparations, transmucosal preparations, and the like. The aforementioned pharmaceutical compositions can be produced by using one or more kinds of pharmaceutical additives together with the noble metal fineparticles as the active ingredient. Examples of the pharmaceutical additives include, for example, excipients, disintegrating agents or disintegrating aids, binders, lubricants, coating agents, dyes, diluents, bases, dissolving agents or dissolving aids, isotonic agents, pH
modifiers, stabilizers, propellants, tackifiers, and the like, and they can be suitably selected by those skilled in the art depending on the dosage form of the pharmaceutical composition.
[0019]
Doses of the medicament of the present invention are not particularly limited, and the dose can be suitably chosen depending on conditions such as a type of disease, a purpose of administration (prophylactic or therapeutic treatment), an age, body weight, symptoms and the like of a patient. The medicament of the present invention can be used by oral administration for adults in an amount in a range of, for example, about 0.001 to 1,000 mg per day on the basis of a weight of the noble metal fineparticles.
Examples [0020]
Hereafter, the present invention will be explained more specifically with reference to the examples. However, the scope of the present invention is not limited to the following examples.
Example 1: Preparation of the medicament of the present invention In a 100-ml 2-neck pear-shaped flask connected with an Allihn condenser and a 3-neck joint, 0.1467 g of poly(1-vinyl-2-pyrrolidone) (Wako Pure Chemical Industries) was placed and dissolved in 23 ml of distilled water. This solution was stirred for 10 minutes, then mixed with 2 ml of 1.66 x 10-2 M chloroplatinic acid solution obtained by dissolving hexachloroplatinic acid (H2PtCl6 = 61120, Wako Pure Chemical Industries) in distilled water, and stirred for additional 30 minutes. The inside atmosphere of the reaction system was replaced with nitrogen gas.
Twenty five ml of special grade ethanol was added to the reaction mixture and the resulting mixture was refluxed at a temperature of 100 C for 2 hours while the nitrogen atmosphere was maintained. An ultraviolet light spectral scanning analysis of the reaction mixture was performed to confirm disappearance of the platinum ion peak and saturation of the peak due to scattering peculiar to metal solid and thereby confirm completion of the reduction reaction. The organic solvent was evaporated under reduced pressure to prepare a platinum colloidal solution containing platinum fineparticles (mean particle size: 2.4 0.7 nm) (PVP-Pt solution). This platinum colloidal solution was diluted to 1 uM with distilled water for injection to prepare the medicament of the present invention.
[0021]
Example 2: Preparation of the medicament of the present invention A platinum colloidal solution (PAA-Pt solution) containing platinum fineparticles having a mean particle size of 2.0 0.4 nm was prepared in the same manner as that in Example 1, except that poly(sodium acrylate) (Aldrich) was used in an amount of 125 times that of Pt in terms of unit weight instead of poly(1-vinyl-2-pyrrolidone). This platinum colloidal solution was diluted to 1 uM with distilled water for injection to prepare the medicament of the present invention.
[0022]
Example 3: Preparation of the medicament of the present invention A platinum colloidal solution (CP-Pt solution) containing platinum fineparticles having a mean particle size of 4 1 nm was prepared in the same manner as that in Example 1, except that pectin (Unitec Foods) was used in an amount of 1 to 4 times that of Pt in terms of unit weight instead of poly(1-vinyl-2=
pyrrolidone). This platinum colloidal solution was diluted to 1 uM with distilled water for injection to prepare the medicament of the present invention.
[0023]
Example 4: Action of the medicament of the present invention One of the highly probable risk factors for the onset of COPD is oxidant stress by smoking or harmful gases. Therefore, effectiveness of platinum colloid on the smoking-induced oxidant stress was evaluated and examined.
<Method 1>
When a 1% tobacco concentrate is applied to cultured human pneumonocytes (A549 cells), they give the change of absorbance in the Alamar blue assay, and it can be estimated as cell death. Cell death in the group in which platinum colloid was applied beforehand and the group in which N-acetylcysteine (NAC, J. Surg.
Res., 2005 Nov; 129(1):38-45," The effect of N-acetylcysteine on pulmonary lipid peroxidation and tissue damage") was applied at the same dose was compared and examined by the extinction method. As a result, the platinum colloids of Examples 2 and 3 significantly suppressed cell death compared with NAC of the same dose. The results obtained with the platinum colloid of Example 2 and NAC are shown in Fig. 1.
[0024]
<Method 2>
Twenty four DBA/2J mice were divided into a smoking group and a non-smoking group, and the mice of the smoking group were exposed to acute smoking of 5 cigarettes per day over 3 days. The platinum colloid of Example 2 (4 y M/kg) or physiological saline of the same volume was administered beforehand by rhinenchysis to the mice every day, and serum and bronchoalveolar lavage fluid (BALF) were compared and examined. As a result, statistically significant difference was observed between the total neutrophil counts of the smoking + physiological saline administration group and the smoking + platinum colloid administration group (ANOVA: p < 0.05, Krushkal Wallis: p < 0.05), and thus acute inflammation was suppressed by the platinum colloid, although definitely significant difference was not observed between the total cell counts in the bronchoalveolar lavage fluids (BALF) of the groups. The results are shown in Fig. 2.
Industrial Applicability [0025]
The medicament of the present invention is effective for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease, and because the medicament can be orally administered, and has reduced side reactions, prophylactic and/or therapeutic treatment can be achieved with high compliance.
Claims (4)
- [1] A medicament for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease, which comprises an aqueous dispersion of transition metal fineparticles, preferably noble metal fineparticles.
- [2] The aforementioned medicament, which comprises an aqueous dispersion of noble metal fineparticles, wherein the medicament according to claim 1, wherein the noble metal consists of one or more kinds of noble metals selected from the group consisting of ruthenium, rhodium, palladium, and platinum.
- [3] The medicament according to claim 1 or 2, wherein the noble metal is platinum.
- [4] The medicament according to any one of claims 1 to 3, wherein the noble metal fineparticles consist of platinum colloid having a mean particle size of 10 nm or smaller.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005373893 | 2005-12-27 | ||
| JP2005-373893 | 2005-12-27 | ||
| PCT/JP2006/325706 WO2007074749A1 (en) | 2005-12-27 | 2006-12-25 | Prophylactic and/or therapeutic agent for chronic obstructive pulmonary disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2635518A1 true CA2635518A1 (en) | 2007-07-05 |
Family
ID=38217969
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002635518A Abandoned CA2635518A1 (en) | 2005-12-27 | 2006-12-25 | Agent for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPWO2007074749A1 (en) |
| CA (1) | CA2635518A1 (en) |
| RU (1) | RU2008130883A (en) |
| TW (1) | TW200803875A (en) |
| WO (1) | WO2007074749A1 (en) |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53109878A (en) | 1977-03-09 | 1978-09-26 | Hidefumi Hirai | Manufacture of rare metal colloid |
| JPS59120249A (en) | 1982-12-27 | 1984-07-11 | Agency Of Ind Science & Technol | Preparation of noble metal catalyst |
| JPH09225317A (en) | 1996-02-26 | 1997-09-02 | Kemipuro Kasei Kk | Nickel/noble metal binary metal cluster and catalyst made from the cluster and its preparation |
| JPH10176207A (en) | 1996-12-18 | 1998-06-30 | I Betsukusu:Kk | Highly active noble metal cluster |
| JP3411195B2 (en) * | 1997-08-18 | 2003-05-26 | 栄一 築地 | Active oxygen remover |
| JP2001010954A (en) * | 1999-06-29 | 2001-01-16 | Otsuka Sangyo Kk | Protective for oxidative stress |
| JP4505084B2 (en) | 1999-09-13 | 2010-07-14 | アイノベックス株式会社 | Method for producing metal colloid and metal colloid produced by the method |
| JP2001114671A (en) * | 1999-10-15 | 2001-04-24 | Otsuka Yakuhin Kogyo Kk | Cataplasm |
| JP4926312B2 (en) | 1999-10-27 | 2012-05-09 | アイノベックス株式会社 | Platinum colloid-containing cosmetics |
| AU8791701A (en) * | 2000-09-22 | 2002-04-02 | Mars Uk Ltd | Food supplement |
| JP2003012523A (en) * | 2001-07-05 | 2003-01-15 | Otsuka Yakuhin Kogyo Kk | Qol ameliorant for patient suffering from parkinson's disease |
| JP3569270B2 (en) * | 2002-04-10 | 2004-09-22 | 株式会社日本トリム | Colloid-containing electrolytic reduced water and method for producing the same |
| US20070141173A1 (en) | 2003-02-20 | 2007-06-21 | Shetech Co.. Ltd. | Medicament comprising noble metal fine particles |
-
2006
- 2006-12-25 CA CA002635518A patent/CA2635518A1/en not_active Abandoned
- 2006-12-25 WO PCT/JP2006/325706 patent/WO2007074749A1/en active Application Filing
- 2006-12-25 RU RU2008130883/15A patent/RU2008130883A/en not_active Application Discontinuation
- 2006-12-25 JP JP2007551943A patent/JPWO2007074749A1/en active Pending
- 2006-12-26 TW TW095149040A patent/TW200803875A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007074749A1 (en) | 2007-07-05 |
| JPWO2007074749A1 (en) | 2009-06-04 |
| TW200803875A (en) | 2008-01-16 |
| RU2008130883A (en) | 2010-02-10 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |