WO2012026336A1 - 肺気腫の治療剤 - Google Patents
肺気腫の治療剤 Download PDFInfo
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- WO2012026336A1 WO2012026336A1 PCT/JP2011/068318 JP2011068318W WO2012026336A1 WO 2012026336 A1 WO2012026336 A1 WO 2012026336A1 JP 2011068318 W JP2011068318 W JP 2011068318W WO 2012026336 A1 WO2012026336 A1 WO 2012026336A1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Definitions
- the present invention relates to a method for treating emphysema.
- the present invention relates to a method for treating pulmonary emphysema by reducing the volume of alveoli or alveolar sac in which abnormal enlargement accompanied by destruction has occurred due to emphysema.
- COPD Chronic obstructive pulmonary disease
- COPD refers to a broad group of pulmonary diseases that interfere with normal breathing, where the lungs are obstructed by the presence of at least one disease selected from asthma, emphysema and chronic bronchitis It is. COPD is often accompanied by these symptoms, and it is difficult to determine which disease is causing the lung obstruction in individual cases. Clinically, COPD is diagnosed by a decrease in exhaled flow from the lung, which is constant over several months and persists for more than 2 consecutive years in cases of chronic bronchitis. The two most serious conditions associated with COPD are chronic bronchitis and emphysema.
- emphysema refers to a condition in which abnormal enlargement accompanied by destruction has occurred in tissues called alveolar parenchyma such as respiratory bronchioles, alveoli, and alveolar sac that serve as a place for gas exchange.
- alveolar parenchyma contracts on expiration, but emphysematous alveolar parenchyma does not return after dilatation by respiration. For this reason, expiration cannot be performed sufficiently.
- the effective area of the alveoli and the vascular bed are reduced, the ventilation capacity of the entire lung is reduced.
- Oxygen therapy is often used in situations where lung function is severely damaged and cannot absorb enough oxygen from the air, but it only relieves symptoms and is not an effective treatment.
- Drug therapy includes, for example, “Jan A. van Noord et al.,” Effects of Tiotropicum With and Without Outformer on Airflow 17 Instruction and RestorationHyperthinth in 19th.
- pneumothorax is a condition in which a hole opens in the visceral pleura that encloses the lung itself, and air leaks into the lung space between the thoracic visceral pleura.
- a drainage method in which the chest wall is incised and a tube is inserted to discharge air between the wall-side pleura and visceral pleura, or a cyst is removed under thoracoscopy.
- the drainage method requires several days or more for healing, and the operation under the thoracoscope is also an operation, and the degree of invasiveness to the patient is high.
- Pneumothorax has a high recurrence rate, and it is desired to reduce the time required for one treatment and to reduce the degree of surgical invasiveness.
- COPD treatment methods include home oxygen therapy, drug therapy, respiratory rehabilitation, non-invasive positive pressure breathing therapy using a nasal mask, and lung volume reduction surgery therapy. It is not useful, and it is difficult to selectively block only in the respiratory region containing a large amount of emphysematous alveolar parenchyma, and as a result, normal air flow is prevented even in the normal respiratory region. Reduces ventilation function. Further, when the emphysema is damaged, air flows between the wall side pleura and the visceral pleura.
- a film forming component of 0.004 to 200 g / procedure per time preferably 0.07 to 20 g / procedure, more preferably 0.5 to 5 g / procedural film forming component.
- a respiratory region volume inhibitor that forms a film in the respiratory region the main component of which is the film-forming component, which is used for administration to emphysematous alveolar parenchyma in a human respiratory region.
- An object is to provide an agent for reducing the volume of a swollen alveoli or alveolar sac.
- FIG. 1A is a schematic cross-sectional view showing a process sequence of the method of the present invention.
- FIG. 1B is a schematic cross-sectional view showing the process sequence of the method of the present invention.
- FIG. 1C is a schematic cross-sectional view showing a process sequence of the method of the present invention.
- FIG. 2A is a schematic cross-sectional view showing the order of steps of a preferred first embodiment of the method of the present invention.
- FIG. 2B is a schematic cross-sectional view showing the order of steps of the first preferred embodiment of the method of the present invention.
- FIG. 2C is a schematic cross-sectional view showing a process sequence of the first preferred embodiment of the method of the present invention.
- FIG. 1A is a schematic cross-sectional view showing a process sequence of the method of the present invention.
- FIG. 1B is a schematic cross-sectional view showing the process sequence of the method of the present invention.
- FIG. 1C is a schematic cross-sectional view showing a
- FIG. 2D is a schematic cross-sectional view showing a process sequence of the first preferred embodiment of the method of the present invention.
- FIG. 2E is a schematic cross-sectional view showing a process sequence of the first preferred embodiment of the method of the present invention.
- FIG. 2F is a schematic cross-sectional view showing the order of steps of the first preferred embodiment of the method of the present invention.
- FIG. 3A is a schematic cross-sectional view showing the order of steps of a second preferred embodiment of the method of the present invention.
- FIG. 3B is a schematic cross-sectional view showing the order of steps of the second preferred embodiment of the method of the present invention.
- FIG. 3C is a schematic cross-sectional view showing the order of steps of the second preferred embodiment of the method of the present invention.
- FIG. 3D is a schematic cross-sectional view showing a process sequence of the second preferred embodiment of the method of the present invention.
- FIG. 3E is a schematic cross-sectional view showing a process sequence of the second preferred embodiment of the method of the present invention.
- FIG. 4A is a schematic cross-sectional view showing the order of steps in a preferred third embodiment of the method of the present invention.
- FIG. 4B is a schematic cross-sectional view showing the order of steps in a preferred third embodiment of the method of the present invention.
- FIG. 4C is a schematic cross-sectional view showing the order of steps in a third preferred embodiment of the method of the present invention.
- FIG. 4D is a schematic cross-sectional view showing the order of steps in a third preferred embodiment of the method of the present invention.
- FIG. 4E is a schematic cross-sectional view showing the order of steps in a preferred third embodiment of the method of the present invention.
- FIG. 4F is a schematic cross-sectional view showing the order of steps in a preferred third embodiment of the method of the present invention.
- FIG. 5A is a schematic cross-sectional view showing a preferred embodiment of step (a) in the method of the present invention.
- FIG. 5B is a schematic cross-sectional view showing a preferred embodiment of step (a) in the method of the present invention.
- the first of the present invention is a film forming component of 0.004 to 200 g / procedure at a time, preferably 0.07 to 20 g / procedure at a time, more preferably 0.5 to 5 g / procedure at a time.
- Respiratory volume control for forming a film in the respirable region which is mainly composed of the film-forming component, wherein the forming component is used for administration to emphysematous alveolar parenchyma in a human respirable region It is an agent.
- the air staying in emphysematous alveoli or alveolar sac (hereinafter also simply referred to as “alveolar parenchyma”) is efficiently removed and this reduced volume due to breathing is maintained. Therefore, it is possible to alleviate / suppress lung overexpansion, which is one cause of debilitating affected individuals due to emphysema or air-bronchial obstruction.
- lung overexpansion which is one cause of debilitating affected individuals due to emphysema or air-bronchial obstruction.
- the size of the emphysema of alveolar parenchyma to be less than the original size, it is possible to suppress / prevent pressure and obstruction of the surrounding bronchi due to the surrounding alveolar parenchyma.
- the treatment method of the present invention does not require a surgical procedure in the treatment using the catheter, the burden on the patient can be reduced.
- a respiratory region volume inhibitor is injected into the respiratory region including the alveoli or alveolar sac, and a film is formed on the inner wall of the respiratory region, so that the pulmonary alveolar parenchyma is formed. It can be a substantially closed system. For this reason, even if collateral channels exist in the emphysematous alveolar parenchyma, there is little or no air leakage during air suction and removal within the emphysematous alveolar parenchyma, ensuring air in the closed system. The volume of alveolar parenchyma can be reduced easily, efficiently and quickly.
- the single use amount (or dose) of the film-forming component according to the present invention depends on the age of the patient, the severity of symptoms, etc., but is 0.004 to 200 g per procedure, preferably 0.07 to It is preferable to use a film forming component of 20 g / procedure, more preferably 0.5 to 5 g / procedure.
- the respiratory region volume inhibitor of the present invention is preferably a composition comprising a film-forming component as a main component, a film-adjusting component, and a solvent, and the film-adjusting with respect to 100 parts by mass of the film-forming component.
- the component is preferably 0.1 to 100 parts by mass
- the solvent is preferably 100 to 5000 parts by mass
- the film adjusting component is 1 to 50 parts by mass
- the solvent is more preferably 500 to 3000 parts by mass
- More preferably, the film adjusting component is 5 to 25 parts by mass
- the solvent is 1000 to 2000 parts by mass.
- the film adjusting component is preferably in the range of 1 to 50 parts by mass with respect to 100 parts by mass of the film forming component, from the viewpoint that the film exhibits sufficient strength while maintaining the injectable viscosity.
- the solvent is preferably in the range of 1000 to 2000 parts by mass with respect to 100 parts by mass of the film-forming component, from the viewpoint of exhibiting sufficient strength while maintaining the injectable viscosity.
- the “dosage” in the present specification means an initial dose that is first performed in one operation for a patient, and the collected amount is not included even when the dose is collected after the administration.
- the respiratory region volume inhibitor according to the present invention is a respiratory region volume inhibitor mainly composed of a film-forming component that forms a film, and the film-forming component is a balloon-like hermetically sealed film formed in response to an external stimulus. It is preferable that the bag body is formed in close contact with the inner surface of the breathing area so as to be along the inner peripheral surface of the breathing area, and the balloon-shaped sealing bag body contracts by reducing the pressure inside the balloon-shaped sealing bag body from outside the breathing area.
- a balloon-like, sealed bag-like coating is formed so as to be in close contact with the inner wall of the alveolar parenchyma, thereby restoring the elasticity of the emphysematous alveolar parenchyma. Can be mitigated / suppressed.
- a stimulus-responsive material that forms a film in response to moisture, divalent metal ions, oxygen, hydrogen, nitrogen, a polymer electrolyte, and the like was used as a film forming component according to the present invention.
- external stimuli such as moisture and calcium on the inner wall surface of the respiratory region, and the film-forming component Reacts and covers the entire inner wall of the breathing area to form a coating, and the coating is closed except for the inlet of the respiratory region volume inhibitor.
- the pouch is formed so as to be in intimate contact with the emphysematous alveolar inner wall.
- the coating in the shape of the balloon-like sealed bag body is hardened depending on the amount and time of external stimulation, so that the balloon-like sealed bag body is shrunk without being broken even under reduced pressure conditions. Therefore, the air inside the balloon-like sealed bag can be reliably removed, and the volume of the alveolar parenchyma can be easily, efficiently and rapidly reduced.
- the balloon-like airtight bag coating solidifies over time, or the coating curing rate is slow, and the coating formation is terminated after contraction, so that the contracted state of the pulmonary alveolar parenchyma is maintained. Can effectively reduce the alveolar parenchymal volume and maintain this reduced volume due to breathing. For this reason, it is considered that lung overexpansion, which contributes to debilitating affected individuals due to emphysema and air-bronchial obstruction, can be alleviated and suppressed.
- the balloon-like sealed bag according to the present invention is formed in close contact with the inner surface of the breathing area along the inner peripheral surface of the breathing area (for example, alveolar parenchyma). It is preferable that the balloon-shaped airtight bag body and the breathing area are contracted together by decompression from the outside. As a result, it is possible to suppress / prevent pressure or blockage of the surrounding bronchus due to surrounding normal alveolar parenchyma.
- the external stimulus according to the present invention refers to a chemical substance or a physical factor that responds to the film-forming component, and is a concept that includes the film-forming component itself.
- the external stimulus itself may be a component derived from the living body, You may have separately in the respiratory region volume inhibitor of this invention.
- the external stimulus according to the present invention preferably includes an external stimulus component, and examples of the component include water, a reactive gas such as divalent metal ion, oxygen, hydrogen, or nitrogen, or a polymer electrolyte. It is done.
- the film-forming component it is preferable to form a balloon-shaped sealed bag composed of a film in response to an external stimulus, and further the balloon-shaped sealed bag and the respiratory region (for example, alveolar parenchyma) A material that can be easily bonded to each other is preferable.
- the film-like balloon-shaped airtight bag body is formed in close contact with the inner surface of the respiratory region, for example, along the inner circumferential surface of the alveolar parenchyma, the alveolar parenchyma and the balloon-shaped airtight bag body are integrated.
- Can shrink The material of the film-forming component is preferably a polymer or a film-forming polymer precursor (monomer), more preferably an adhesive polymer, a film-forming polymer precursor, or a polymer electrolyte.
- the above-mentioned adhesive polymer means a polymer that exhibits adhesiveness (adhesiveness) when applied to a living tissue such as alveolar parenchyma.
- the adhesive polymer is not particularly limited as long as the polymer has adhesiveness to the alveolar parenchyma and can close the collateral channel, and materials normally used in medical applications are used in the same manner. it can.
- starch starch, gum arabic, sodium alginate, propylene glycol alginate, carboxyvinyl polymer, carmellose sodium, xanthan gum, gellan gum, gelatin, hydrolyzed gelatin, polyacrylic acid, polyacrylate, polyacrylic acid
- examples include Japanese, starch polyacrylate, polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol (PVA), methyl cellulose (MC), carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose, and the like.
- the adhesive polymer may be used alone or in the form of a mixture of two or more.
- water-soluble polymers such as carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, methyl cellulose, starch, sodium alginate, gelatin, hydrolyzed gelatin are preferable, starch, sodium alginate Gelatin and hydrolyzed gelatin are more preferred.
- adhesiveness adhesiveness
- gelatin hydrolyzed gelatin
- starch sodium alginate Gelatin and hydrolyzed gelatin
- the concentration of the adhesive polymer in the respiratory region volume inhibitor is not particularly limited, but is preferably 0.5 to 50% by mass. If it is such a density
- the weight average molecular weight of the adhesive polymer according to the present invention is not particularly limited, but is 10,000 to 10,000,000, more preferably 100,000 to 5,000,000, and still more preferably 500,000 to 2,500,000.
- the weight average molecular weight can be measured by a known method, and can be calculated by, for example, light scattering, chromatographic methods such as GPC, viscosity measurement method, TOFMASS, etc.
- the molecular weight is determined by GPC measurement (manufactured by Waters).
- the film-forming polymer precursor according to the present invention starts reaction (curing) with moisture on the surface of a living tissue such as alveolar parenchyma, and, if present, can close the collateral path,
- a cyanoacrylate monomer is preferably used. At this time, when the cyanoacrylate monomer comes into contact with moisture, it is polymerized to polycyanoacrylate.
- alkyl such as methyl ⁇ -cyanoacrylate, ethyl ⁇ -cyanoacrylate, propyl ⁇ -cyanoacrylate, butyl ⁇ -cyanoacrylate, cyclohexyl ⁇ -cyanoacrylate, heptyl ⁇ -cyanoacrylate, octyl ⁇ -cyanoacrylate, and the like Cycloalkyl ⁇ monocyanoacrylate; alkenyl such as allyl ⁇ -cyanoacrylate, methallyl ⁇ -cyanoacrylate, cyclohexenyl ⁇ -cyanoacrylate, and cycloalkenyl ⁇ -cyanoacrylate; alkynyl ⁇ -cyanoacrylate such as propargyl ⁇ -cyanoacrylate; Aryl ⁇ -cyanoacrylates such as phenyl ⁇ -cyanoacrylate and toluyl ⁇ -cyanoacrylate; methoxyethyl ⁇ -cyanoacrylate containing heteroatoms, To
- ⁇ -cyanoacrylates may be used alone or in the form of a mixture of two or more.
- cyclohexyl ⁇ -cyanoacrylate, heptyl ⁇ -cyanoacrylate, octyl ⁇ -cyanoacrylate, ethyl ⁇ -cyanoacrylate, and the like are preferable.
- cyanoacrylate having a long ester side chain length has a soft polymerized cured product (cured layer), so that the emphysematous alveolar parenchyma (alveoli or alveolar sac) can easily contract.
- polymer electrolyte examples include a polymer electrolyte having a negative charge and a polymer electrolyte having a positive charge.
- the negatively charged polymer electrolyte is not particularly limited as long as it has at least one, preferably two or more anionic groups.
- polyamino acids synthetic polypeptides synthesized artificially; polysaccharides such as heparin, hyaluronic acid, chondroitin, pectin, agarose, glycosaminoglycan, cellulose, starch; artificially synthesized polysaccharides, etc. .
- the polymer electrolyte may be used alone or in the form of a mixture of two or more. Of these, heparin, hyaluronic acid, chondroitin, pectin, agarose, and glycosaminoglycan are preferred, and heparin hyaluronic acid is more preferred.
- a negatively charged polymer electrolyte may be obtained by polymerizing a negatively charged monomer.
- the negatively charged monomer is not limited to the following, but is a sulfo group (—SO 3 H), a carboxyl group (—COOH), a phosphonic acid group (—PO 3 H 2 ), etc.
- the monomer having a sulfo group is not particularly limited, and examples thereof include vinyl sulfonic acid (ethylene sulfonic acid), 2-propene sulfonic acid, 3-butene sulfonic acid, 4- Pentenesulfonic acid, sulfomethyl (meth) acrylate, 2-sulfoethyl (meth) acrylate, 3-sulfopropyl (meth) acrylate, 2-methyl-3-sulfopropyl (meth) acrylate, (meth) acrylic acid 4 -Sulfobutyl, N- (2-sulfoethyl) (meth) acrylic acid 4-sulfobutyl, 2- (meth) acrylamide-2-methylpropanesulfonic acid, N- (2-sulfoethyl) (meth) acrylamide, N- (1- Methyl-2-sulfoethyl) (meth) (meth) acrylamide, N- (1
- the monomer having a carboxyl group is not particularly limited, and examples thereof include (meth) acrylic acid, maleic acid, fumaric acid, glutaconic acid, itaconic acid, crotonic acid, sorbic acid, cinnamic acid, N- ( (Meth) acryloylglycine, N- (meth) acryloylaspartic acid, N- (meth) acryloyl-5-aminosalicylic acid, 2- (meth) acryloyloxyethyl hydrogen succinate, 2- (meth) acryloyloxyethyl hydrogen phthalate 2- (meth) acryloyloxyethyl hydrogen maleate, 6- (meth) acryloyloxyethylnaphthalene-1,2,6-tricarboxylic acid, O- (meth) acryloyl tyrosine, N- (meth) acryloyl tyrosine, N- (Meth) acryloylpheny
- the monomer having a phosphonic acid group is not particularly limited, and examples thereof include phosphooxyethyl (meth) acrylate, 3- (meth) acryloxypropyl-3-phosphonopropionate, and 3- (meth) acryloxy.
- the weight average molecular weight of the negatively charged polymer electrolyte according to the present invention is not particularly limited, but is about 10,000 to about 1,000,000, more preferably about 100,000 to about 700,000, Even more preferably from about 200,000 to about 500,000.
- the positively charged polymer electrolyte is not particularly limited as long as it has at least one, preferably two or more cationic groups. Examples thereof include organic compounds having an N, N-dimethylaminoalkyl group in the side chain; polyethyleneimine.
- the polymer electrolyte may be used alone or in the form of a mixture of two or more.
- poly (N, N-dimethylaminopropylacrylamide) having a weight average molecular weight of about 10,000 to about 1,000,000 poly (N, N-dimethylaminopropylacrylamide) having a weight average molecular weight of about 10,000 to about 1,000,000 N, N-dimethylaminoethylacrylamide), polyethyleneimine having a weight average molecular weight of about 10,000 to 1,000,000 is preferred, and poly (N, N--) having a weight average molecular weight of about 10,000 to about 500,000.
- Dimethylaminopropylacrylamide poly (N, N-dimethylaminoethylacrylamide) having a weight average molecular weight of about 10,000 to about 500,000, weight average molecular weight of about 10,000 to 500,000 (particularly about 100,000) ) Is more preferred.
- a positively charged polymer electrolyte may be obtained by polymerizing a positively charged monomer.
- the positively charged monomer is not limited to the following, but is selected from an amino group (—NH 2), an imino group ( ⁇ NH, —NH—), an imidazolyl group, a pyridyl group, and the like. And a monomer having at least one functional group.
- the monomer having an amino group is not particularly limited.
- examples include (meth) acrylate, methylethylaminoethyl (meth) acrylate, dimethylaminopropyl (meth) acrylate, dimethylaminostyrene, diethylaminostyrene, morpholinoethyl (meth) acrylate, and lysine.
- the monomer having an imino group is not particularly limited, but examples thereof include N-methylaminoethyl (meth) acrylate, N-ethylaminoethyl (meth) acrylate, Nt-butylaminoethyl (meth) acrylate, ethylene Examples include imines.
- Examples of the monomer having an imidazolyl group include 4-vinylimidazole, N-vinyl-2-ethylimidazole, N-vinyl-2-methylimidazole, and the like.
- Examples of the monomer having a pyridyl group include 2-vinylpyridine, 4-vinylpyridine, 2-methyl-5-vinylpyridine and the like.
- the above monomers can be used alone or in combination of two or more.
- the weight average molecular weight of the positively charged polymer electrolyte according to the present invention is not particularly limited, but is preferably 10,000 to 1,000,000, and more preferably 100,000 to 500,000.
- the polymer electrolyte according to the present invention may have a structural unit derived from another monomer in addition to the monomer having the negative charge or the positive charge.
- a well-known monomer can be used.
- salt forms such as sodium salt, potassium salt and ammonium salt of monomer having carboxyl group; monovalent metal salt, divalent metal salt and ammonium salt of monomer having sulfo group And organic amine salts; such as triethylene glycol di (meth) acrylate, (poly) ethylene glycol di (meth) acrylate, polypropylene glycol di (meth) acrylate, (poly) ethylene glycol (poly) propylene glycol di (meth) acrylate, etc.
- the amount of the other monomer used may be such that the effect of the positively charged or negatively charged monomer is not impaired. There is no particular limitation.
- the amount of other monomers used is preferably 1 to 10% by mass relative to the total monomers.
- the method for producing the polymer electrolyte according to the present invention is not particularly limited, and a known polymerization method can be used.
- the monomer may be polymerized using a polymerization initiator.
- the polymerization method of the monomer component is not particularly limited, and can be performed by a method such as polymerization in a solvent or bulk polymerization, for example.
- the polymer electrolyte and the adhesive polymer according to the present invention are block copolymers or graft copolymers, for example, living polymerization, polymerization using a macromonomer, a polymer polymerization initiator was used. Although polymerization, polycondensation, etc. can be illustrated, it is not specifically limited.
- the respiratory region volume inhibitor of the present invention is preferably a composition comprising a film-forming component as a main component, a film-adjusting component, and a solvent.
- the solvent may be any solvent as long as it is appropriately selected depending on the film forming component to be used and can dissolve or disperse the film forming component. Specific examples include water; dimethyl sulfoxide, dimethylformamide; glycols such as ethylene glycol, diethylene glycol, propylene glycol, triethylene glycol, polyethylene glycol, and polypropylene glycol; and oils such as olive oil, castor oil, squalane, and lanolin. It is done.
- the said solvent may be used independently or may be used with the form of a 2 or more types of liquid mixture.
- a salt may be appropriately added to obtain a desired pH with respect to water because a buffer solution is used.
- the film adjusting component preferably has an effect of adjusting the viscosity of the respiratory region volume inhibitor of the present invention, an effect of controlling surface tension, and an effect of making the respiratory region volume inhibitor of the present invention foam.
- the film adjusting component include known surfactants, viscosity adjusting agents, known foaming agents, and known antifoaming agents.
- the said film adjustment component may be used independently or may be used with the form of a 2 or more types of mixture.
- the respiratory region volume inhibitor of the present invention is preferably in the form of foam.
- the film adjusting component nitrogen gas, helium gas, argon gas, carbon monoxide, carbon dioxide, carbon dioxide gas, oxygen, etc. May be added to form a foam, or sodium hydrogen carbonate and citric acid may be added to the respiratory region volume inhibitor of the present invention as the film adjusting component. It is particularly preferable to produce a foamy respiratory region volume inhibitor by dispersing in the state. In addition, manufacture of a foamy respiratory region volume inhibitor is not limited to the said method.
- An external stimulus that responds to the film-forming component according to the present invention may be included in the respiratory region volume inhibitor of the present invention as an external stimulus component.
- Examples of the external stimulus include temperature, pH, light, electric field, magnetic field, chemical Examples include substances.
- the external stimulating component according to the present invention is appropriately selected depending on the film forming component to be used, and preferably water, divalent metal ions, reactive gas, or polymer electrolyte is preferable.
- the polymer electrolyte includes the polymer electrolyte of the present invention described above.
- divalent metal ions examples include calcium ions, magnesium ions, barium ions, iron ions, copper ions, etc., and compounds that generate divalent metal ions in solution, such as calcium chloride and hydrogen phosphate.
- examples thereof include a solution in which calcium, calcium dihydrogen phosphate, tricalcium phosphate, calcium sulfate, calcium hydroxide, magnesium chloride, barium chloride and the like are dissolved in water.
- the reactive gas is appropriately selected depending on the stimulus-responsive material to be used and is not particularly limited.
- the introduced polymer electrolyte A gas having a lower viscosity is preferred. Examples thereof include air, oxygen, carbon dioxide, carbon monoxide, nitrogen, helium gas, and argon gas.
- the film-forming component according to the present invention includes an adhesive polymer, and the external stimulating component is preferably a reactive gas.
- the solvent is the above solvent , Water and dimethyl sulfoxide are preferable, and water is more preferable. These are excellent in safety.
- the film forming component according to the present invention preferably contains a polymer electrolyte (A), and the external stimulating component is a polymer electrolyte (B), or a polymer electrolyte (B) and a polymer electrolyte (A).
- the external stimulating component is a polymer electrolyte other than the polymer electrolyte, and is different from the charge of the polymer electrolyte selected as the film forming component.
- a polyelectrolyte the charge of the polymer electrolyte (A) and the charge of the polymer electrolyte (B) are different symbols.
- the polymer electrolytes (A) and (B) may be produced by appropriately selecting the monomers so that the charges of the polymer electrolytes (A) and (B) are different.
- the polymer electrolytes (A) and (B) are selected from the examples of the polymer electrolyte.
- the film forming component is the polymer electrolyte (A) and the external stimulating component is the polymer electrolyte (B) as described above
- the electrolytes associate to form a so-called ion complex coating so as to cover the entire inner wall of the respiratory region, and the ion complex coating is closed except for the inlet of the respiratory region volume inhibitor. Therefore, a balloon-like hermetic bag composed of the coating is formed. Thereby, if the air inside the balloon-shaped sealed bag body is removed, the volume of the alveolar parenchyma can be reduced easily, efficiently and quickly.
- the respiratory region volume inhibitor according to the present invention includes a polymer electrolyte (A) as a film-forming component, a first film-forming component containing a solvent and a film-adjusting component, and a polymer electrolyte as an external stimulation component.
- the external stimulating component including (B), a solvent, and a membrane adjusting component is independently provided, and further, a polymer electrolyte (A) as a film forming component, a solvent, and a membrane adjusting component
- the components are separately provided without mixing.
- composition ratio of the film forming component in the above case is preferably 5 to 25 parts by mass of the film adjusting component and 75 to 95 parts by mass of the solvent with respect to 100 parts by mass of the film forming component. Is preferably 5 to 25 parts by mass of the film adjusting component and 75 to 100 parts by mass of the solvent with respect to 100 parts by mass of the external stimulating component.
- the mixing ratio of the polymer electrolyte (A) and the polymer electrolyte (B) is not particularly limited.
- the mixing ratio (mass ratio) of the polymer electrolyte (A) and the polymer electrolyte (B) is preferably 1: 0.1 to 5, more preferably 1: 0.5 to 2. With such a mixing ratio, the polymer electrolyte (A) and the polymer electrolyte (B) can efficiently react to form an ion complex film over the entire inner wall of the alveolar parenchyma.
- stimulation component are each independently inject
- the polymer electrolyte (A) or polymer electrolyte (B) may be injected as it is into the respiratory region, but is dissolved or dispersed in an appropriate solvent. You may use it in the state.
- the solvent that can be used in the latter case is not particularly limited as long as it can dissolve or disperse the polymer electrolyte (A) or the polymer electrolyte (B), and is safe.
- Examples include water; dimethyl sulfoxide, dimethylformamide; glycols such as ethylene glycol, diethylene glycol, propylene glycol, triethylene glycol, polyethylene glycol, and polypropylene glycol; and oils such as olive oil, castor oil, squalane, and lanolin.
- the said solvent may be used independently or may be used with the form of a 2 or more types of liquid mixture.
- water, dimethyl sulfoxide, and dimethylformamide are preferable, and water is more preferable. These are excellent in safety.
- a film-forming polymer precursor is selected as the film-forming component according to the present invention
- the external stimulus is preferably water
- a tacky polymer is selected as the film-forming component according to the present invention Is preferably a divalent metal ion.
- a material that can form (harden) a film by reacting with a divalent metal ion (stimulus responsive material)
- a divalent metal ion (stimulus responsive material)
- a solution containing divalent metal ions may be previously injected into the respiratory region via a catheter or the like before injection into the respiratory region of the material. Thereby, formation of a film can be promoted.
- the solution having a divalent metal ion is not particularly limited as long as the reaction (curing) with the material starts, and if present, the collateral channel can be closed. It can be appropriately selected depending on the type of material.
- a compound that generates a divalent metal ion in the solution such as alginic acid and calcium ion, magnesium ion, barium ion
- examples include calcium chloride, calcium hydrogen phosphate, calcium dihydrogen phosphate, tricalcium phosphate, calcium sulfate, calcium hydroxide, magnesium chloride, and barium chloride in water.
- a solution in which alginic acid and a compound that generates calcium ions in the solution are dissolved in water is preferable.
- the alginic acid and the calcium compound are gelled by a crosslinking reaction (egg box structure), and a film is efficiently formed on the inner wall of the alveolar parenchyma.
- the film-forming component is a film-forming polymer precursor or an adhesive polymer, further includes a film-adjusting component, and the external stimulus is water or a divalent metal ion. It is preferable that
- the respiratory region volume inhibitor according to the present invention may contain only the above-mentioned film-forming component as an active ingredient, or may contain other components, and examples of the other components include those necessary for pharmaceutical preparations.
- Additives such as pharmaceutically acceptable carriers, buffering agents, preservatives and antioxidants used in the above can be used as appropriate. The content of these additives can be appropriately determined by those skilled in the art.
- the method of using a respiratory region volume inhibitor for pulmonary emphysema comprises: (a) a step of inserting a catheter into the bronchus or bronchiole (a); (b) respiration including alveoli or alveolar sac via the catheter A step (b) of injecting a respiratory region volume inhibitor into the region to form a film on the inner wall of the respiratory region; and (c) a step (c) of contracting the alveoli or alveolar sac.
- the method of using a respiratory region volume inhibitor is to use the drug for the purpose of treating pulmonary emphysema
- treatment refers to pulmonary emphysema, symptoms of pulmonary emphysema, or pulmonary emphysema. It refers to medical practices aimed at curing, alleviating, alleviating, repairing, preventing or ameliorating secondary medical conditions.
- FIG. 1A to 1C are schematic cross-sectional views showing a process sequence of the method of the present invention. That is, according to the method of using the respiratory region volume inhibitor of the present invention, as shown in FIG. 1A and FIG. 1B, the catheter 1 is inserted into the bronchus or bronchiole 2 [step (a)], and the catheter is passed through this catheter.
- the respiratory region volume inhibitor 4 (14, 24, 26) is injected into the respiratory region including the alveoli or alveolar sac 3 to form the coating 5 (16, 27) on the inner wall of the respiratory region [step (B)] and further contracting the alveoli or alveolar sac [step (c)].
- each process is explained in full detail, each process is not limited to the following form.
- Step (a) a catheter is inserted into the bronchi or bronchiole.
- the catheter 1 is referred to as emphysematous alveoli or alveolar sac (hereinafter also simply referred to as “emphysematous alveolar parenchyma”).
- emphysematous alveolar parenchyma Insert into the bronchus or bronchiole 2 leading to the respiratory zone containing 3.
- the catheter is not particularly limited, and is appropriately selected according to the diameter (number of branches) of the bronchi or bronchiole to be introduced.
- a known respiratory system, circulatory system, digestive system catheter or the like used for medical purposes can be used.
- the structure of the catheter is not particularly limited, and may have a balloon or may have no balloon, but considering the ease of transport into the trachea and the sealing property, It is preferable to have a balloon.
- the number of lumens of the catheter is not particularly limited, and is appropriately selected depending on the number of substances used in the steps (b) and (c) described in detail below, the presence or absence of a balloon, and the like.
- FIG. 5A shows a sheath 31 disposed on the more proximal side.
- the structure of the sheath 31 is not particularly limited and may have a balloon or may not have a balloon, but may have a balloon 31a capable of closing the bronchus or bronchiole. preferable.
- FIG. 5B shows a schematic diagram of the structure of the sheath 31 and the catheter 1 that can be suitably used in the present invention.
- the installation positions of the balloon 31a arranged in the sheath 31 and the balloon 1a arranged in the catheter 1 in the bronchus or bronchiole are not particularly limited.
- the balloon 31a arranged in the sheath 31 is installed in the bronchi
- the balloon 1a arranged in the catheter 1 is installed in the bronchus, particularly in the bronchiole, more distally.
- the pressure between the balloons 1a and 31a for example, normal alveolar parenchyma
- the peripheral side for example, emphysema
- the pressure of the alveolar parenchyma can each be easily adjusted.
- the expansion / contraction method of the balloon 31 a is not particularly limited, but can be performed using a three-way cock 34 provided on the proximal end side of the sheath 31.
- the operation on the distal end side from the catheter 1 can be stably performed.
- the bronchus or bronchiole is occluded with the balloon 31 a and the distal portion of the sheath 31 is depressurized, thereby increasing the degree of adhesion of the bronchial wall or bronchiole wall to the balloon 1 a attached to the catheter 1, and collateral Preventing gas inflow from the tract to the distal portion of the catheter 1 facilitates decompression of the distal portion of the catheter.
- the control method of the pressure on the distal end (erasing) side from the sheath 31 and the distal end (erasing) side from the catheter 1 is not particularly limited.
- a seal valve body 32 is provided on the proximal end side of the sheath 31, and the catheter 1 is inserted into the sheath 31 through the seal valve body 32.
- the seal valve body 32 By providing the seal valve body 32 in this manner, the inside of the alveolar parenchyma on the distal side (disappearance) side from the sheath 31 can be made a closed system, so that the pressure control of the part can be easily performed. Further, by providing a three-way stopcock 33 at the proximal end portion of the sheath 31 and introducing or sucking a gas 38 from the three-way stopcock 33, the pressure in the alveolar parenchyma on the distal side (disappearance) side from the sheath 31 can be controlled. it can.
- the method for controlling the pressure on the distal end (disappearance) side from the catheter 1 can also be performed in the same manner. That is, as shown in FIG.
- the seal valve body 35 is provided on the proximal end side of the catheter 1.
- the seal valve element 35 By providing the seal valve element 35 in this way, the inside of the alveolar parenchyma on the distal side (disappearance) side from the catheter 1 can be made a closed system, so that the pressure control of the part can be easily performed.
- a three-way stopcock 36 is provided on the proximal end side of the catheter 1, and the pressure in the alveolar parenchyma on the distal end (disappearance) side from the catheter 1 is controlled by introducing or sucking a gas or liquid 39 from the three-way stopcock 36. be able to.
- the expansion / contraction method of the balloon 1a is not particularly limited, but may be performed using a three-way cock 37 provided on the proximal end side of the catheter 1.
- the catheter 1 may have a lumen for introducing the guide wire 40 for the purpose of facilitating insertion of the catheter 1 into a desired position.
- a catheter 1 including a balloon 1a for occluding a bronchus, which includes an opening on the distal side and the proximal side, and a lumen capable of feeding liquid to the distal side
- An OTW type PTCA catheter used for the treatment of stenosis of the blood vessel lumen in the cardiovascular region.
- a commercially available product may be used as the catheter.
- a microcatheter for example, FINECROSS (registered trademark), Terumo Corporation
- FINECROSS registered trademark
- Terumo Corporation Terumo Corporation
- a PTCA catheter for example, Ryujin Plus OTW (registered trademark), manufactured by Terumo Corporation
- the catheter can be inserted into the bronchus lumen from the working lumen of the bronchoscope, but it is not essential to use the bronchoscope as long as the catheter can be placed at an arbitrary position.
- the outer diameter of the catheter 1 or the balloon 1a at the time of expansion is not particularly limited, and is appropriately selected according to the diameter of the bronchi or bronchiole 2.
- the outer diameter of the balloon 1a when expanded is slightly larger than the inner diameter of the bronchi or bronchiole 2 communicating with any alveolar sac (air sac) or alveolar tissue to be inserted.
- the outer diameter [Y (mm)] of the balloon 1a when expanded is about 1 to 2 times the inner diameter [X (mm)] of the bronchi or bronchiole 2.
- the bronchus or bronchiole formed by the elastic smooth muscle can be crimped to the catheter or balloon part without being excessively damaged.
- a catheter may be introduced into the bronchus or bronchiole 2 by inserting a guide wire into the lumen of the catheter (for example, a lumen for feeding liquid).
- a guide wire for example, a lumen for feeding liquid.
- the distal end of the catheter can be guided near the alveolar sac (air sac) or the alveolar tissue on the peripheral side of the bronchi or bronchiole 2.
- the guide wire a known respiratory system, circulatory system, digestive system guide wire, etc. used for medical applications can be used, and the outer diameter thereof depends on the size of the lumen of the catheter used. Can be selected as appropriate.
- a guide wire used in cardiovascular treatment for example, a guide wire (hereinafter, referred to as GW) of Runthrough (registered trademark) (manufactured by Terumo Corporation, outer diameter: 0.014 inch) can be used.
- GW guide wire
- Runthrough registered trademark
- a contrasting member is disposed at the distal end of the guide wire or the distal end of the catheter.
- the tip position of the guide wire and catheter protruding from the tip of the endoscope is grasped, and the emphysematous alveoli or alveolar sac specified in advance by X-ray fluoroscopy or CT imaging It can be guided to the respiratory region including.
- the guide wire is removed.
- the catheter tip has a structure capable of suppressing and preventing adhering to the inner wall of the respiratory region including the alveoli and alveolar sac, such as having a mesh structure or a plurality of holes.
- Step (b) In this step, a respiratory region volume inhibitor is injected into the respiratory region including the alveoli or alveolar sac via the catheter to form a coating on the inner wall of the respiratory region. Even if there was a collateral path (Appendix 6 in FIG. 1A) in the alveolar parenchyma that became emphyseated by this process, the collateral path of the alveolar parenchyma that was emphysema with the respiratory region volume inhibitor was included. A film which is a balloon-like hermetic bag is formed on the entire inner wall.
- the emphysematous alveolar parenchyma becomes a closed system other than the communication port with the bronchi or bronchiole (FIG. 1B). For this reason, when the alveolar parenchyma is contracted in the next step, there is little or no air leakage from the emphysematous alveolar parenchyma, so the air in the closed system is reliably removed, and the alveolar parenchyma is efficiently removed. The capacity can be reduced. In addition, the formation of such a film restores the elasticity of the alveolar parenchyma that is emphysematous, so that it is possible to mitigate / suppress lung overexpansion.
- the “respiratory zone” is a general term for respiratory organs on the distal side of the bronchus including the bronchial tree and the alveolar zone (two alveoli).
- the respiratory region includes bronchi, bronchioles, terminal bronchioles, respiratory bronchioles, alveolar ducts (alveolar passages), alveoli, alveolar sac, pulmonary veins, pulmonary arteries, respiratory bronchioles, lungs
- it includes the alveolar duct (alveolar passage), alveoli, alveolar sac, and pulmonary veins.
- the respiratory region volume inhibitor is injected through the catheter into the respiratory region including the alveoli or alveolar sac, particularly into the emphysematous alveolar parenchyma, as shown in FIG. 2B. It is preferable to expand the balloon 1a to close the bronchus or bronchiole 2 before injecting the respiratory region volume inhibitor 4 using the catheter 1 having the above. That is, the method of the present invention further comprises that the catheter has a balloon, and in step (b), the balloon is expanded to block the bronchus or bronchiole before injecting the respiratory region volume inhibitor. Is preferred.
- the respiratory region volume inhibitor 4 is suppressed / prevented from flowing back to the trachea (proximal) side of the bronchus or bronchiole 2, and the respiratory region volume inhibitor 4 is efficiently transformed into a desired emphysema.
- the alveolar parenchyma 3 can be contacted.
- the expansion of the balloon 1a of the catheter 1 is not particularly limited, and a known method can be used. For example, a method of expanding the balloon 1a of the catheter 1 using a syringe or an indeflator connected to a balloon expanding lumen disposed at the proximal end of the catheter can be used.
- the filler used for balloon expansion is not particularly limited, and examples thereof include air, a contrast medium, and a physiological saline containing a contrast medium.
- gas particularly carbon dioxide or oxygen. This is because it is safe even if the balloon is damaged and a leak occurs.
- the installation position of the balloon is not particularly limited.
- the balloon may be placed at the distal end of the catheter or tracheal (proximal) from the distal end of the catheter, but if the catheter tip is located in the bronchus
- the balloon is placed on the catheter so that it does not go beyond the proximal branch of the bronchus.
- a respiratory region volume inhibitor after injecting air into the respiratory region via a catheter.
- the respiratory region volume inhibitor when air is injected into the respiratory region, the normal alveolar parenchyma is filled with air, so even if the respiratory region volume inhibitor is injected later, the respiratory region volume inhibitor hardly enters the alveolar parenchyma. .
- the presence of collateral channels is negligible, and the proportion of normal alveolar parenchyma into which the respiratory volume inhibitor is injected is very small. The impact is negligible.
- the emphysematous alveolar parenchyma has pores called collateral channels that connect to the surrounding alveoli. For this reason, even if air is injected into the respiratory region, air leaks from the collateral channel, and therefore, when the respiratory region volume inhibitor is injected, it easily enters into the pulmonary alveolar parenchyma. Therefore, by performing such an operation, it is possible to selectively inject a respiratory region volume inhibitor into an emphysematous alveolar parenchyma having collateral channels.
- the air injection pressure is not particularly limited as long as it does not substantially damage the normal and emphysematous alveolar parenchyma, and the normal alveolar parenchyma is sufficiently filled with air. .
- the air injection pressure measured at the hand side increases. For this reason, air may be injected while measuring the air injection pressure, and the injection speed may be reduced or stopped when the injection pressure increases.
- the air injection pressure and the injection pressure of the respiratory region volume inhibitor when injecting the respiratory region volume inhibitor are the same pressure. Or a different pressure may be sufficient.
- the air injection pressure and the respiratory region volume inhibitor injection pressure are substantially the same.
- the pressure in the normal alveolar parenchyma is substantially the same as the injection pressure of the respiratory region volume inhibitor, so that the respiratory region volume inhibitor is injected into the normal alveolar parenchyma or normal alveoli. Air can be prevented from leaking from the substance.
- the air pressure in the emphysematous alveolar parenchyma is less than the infusion pressure of the respiratory zone volume inhibitor, so that the respiratory zone volume inhibitor is injected into the emphysematous alveolar parenchyma when injected. Enter selectively and efficiently.
- the pressure at this time is preferably smaller than the injection pressure of the catheter 1.
- it can be maintained at continuous positive pressure or at atmospheric pressure release.
- the catheter 1 can be inserted into the target bronchus or the target bronchiole in a state in which the central bronchus or bronchiole with respect to the target bronchus or target bronchiole is closed with a balloon and the pressure is kept constant. .
- the central bronchus site to be occluded may be the central trachea, but more preferably the main bronchus or its peripheral side allows the remaining portion to continue ventilation.
- the sheath 31 is disposed closer to the proximal side than the catheter 1 inserted into the emphysematous alveolar parenchyma 3.
- the bronchial and bronchiolar pressure (pressure 1) between the balloons 1a and 31a is injected into the catheter 1 (pressure 2).
- the respiratory region volume inhibitor 4 is efficiently flowed without flowing back to the trachea (proximal) side of the bronchi or bronchiole 2.
- the desired emphysematous alveolar parenchyma 3 can be contacted.
- the control method of the pressure (pressure 1) of the bronchi and bronchiole between the balloons 1a and 31a (for example, normal alveolar parenchyma) and the injection pressure (pressure 2) of the catheter 1 is not particularly limited.
- pressure 1 ⁇ pressure 2 for example, normal alveolar parenchyma
- a seal valve body 32 is provided on the proximal end side of the sheath 31, and the catheter 1 is inserted into the sheath 31 through the seal valve body 32.
- the seal valve body 32 By providing the seal valve body 32 in this manner, the inside of the alveolar parenchyma on the distal side (disappearance) side from the sheath 31 can be made a closed system, so that the pressure control of the part can be easily performed.
- a three-way stopcock 33 is provided at the proximal end portion of the sheath 31, and a gas 38 is introduced or sucked from the three-way stopcock 33, whereby the bronchi and bronchioles between the balloons 1a and 31a (for example, normal alveolar parenchyma) are separated.
- the pressure (pressure 1) is appropriately adjusted, preferably at a continuous positive pressure or at atmospheric pressure release.
- the injection pressure of the catheter 1 can be adjusted in the same manner. That is, as shown in FIG. 5B, the seal valve body 35 is provided on the proximal end side of the catheter 1. By providing the seal valve body 35 in this way, it is possible to easily and selectively fill the gas into the closed normal alveolar parenchyma.
- the injection pressure (pressure 2) of the catheter 1 can be adjusted as appropriate.
- a film is formed on the inner wall of the respiratory region by injecting a respiratory region volume inhibitor into the respiratory region including the alveoli or alveolar sac, but the method of forming the coating is not particularly limited .
- the following methods (b-1) to (b-3) are preferably used: (B-1) A method of sucking and removing excess respiratory region volume inhibitor after injecting a respiratory region volume inhibitor into the respiratory region via the catheter as the respiratory region volume inhibitor; (B-2) A material capable of curing by reacting with water or divalent metal ions as the respiratory region volume inhibitor is injected into the respiratory region through the catheter, and water or 2 present on the surface of the respiratory region After reacting with a valent metal ion, the material is sucked away; or (b-3) after injecting the first film-forming component containing the polyelectrolyte (A) into the respiratory region via the catheter; Excess polymer electrolyte (A) is removed by suction to form a coating film of the polymer electrolyte (A)
- excess polyelectrolyte (B) is removed by suction. If present, after removing the polymer electrolyte (B) by suction, After injecting the second film-forming component containing the polymer electrolyte (A) into the respiratory region via the catheter, a method of removing the excess polymer electrolyte (A) by suction (in this case, the polymer electrolyte ( The first and second film-forming components containing A) and the external stimulating component containing the polymer electrolyte (B) are used as the respiratory region volume inhibitor).
- Step (b-1) In this step, as shown in FIGS. 2B and 2C, in the respiratory region including the respiratory region volume inhibitor 4 as the respiratory region volume inhibitor via the catheter 1, the bronchi or bronchiole 2 and the alveoli or alveolar sac 3 After injecting (FIG. 2B), excess respiratory region volume inhibitor 4 is removed by suction (FIG. 2C).
- suction When injecting the respiratory region volume inhibitor or sucking and removing the excess respiratory region volume inhibitor, it is preferable to expand the balloon 1a and seal between the catheter 1 and the inner wall of the bronchus or bronchiole 2.
- the injection of the respiratory region volume inhibitor or the suction removal of the respiratory region volume inhibitor that is in excess of the solution can be suctioned and removed more reliably.
- the respiratory region volume inhibitor 4 has adhesiveness, when the solution is sucked and removed, a thin film 5 of the solution is formed on the inner wall of the respiratory region (in the figure, emphysema, alveolar parenchyma) 3. It is formed. Even if the collateral channel 6 exists in the alveolar parenchyma 3 that has become emphysematous, since the collateral channel is usually a small hole, the coating 5 is formed so as to cover the collateral channel 6. The For this reason, the alveolar parenchyma 3 that has become emphysema by this operation forms a closed system other than the communication port with the bronchi (FIG. 2C).
- the injection / suction removal operation of the respiratory region volume inhibitor 4 may be repeated.
- the firmer film 5 can be more reliably formed over the entire inner wall of the alveolar parenchyma.
- the formation of such a coating more reliably restores the elasticity of the emphysematous alveolar parenchyma, so that the lung overexpansion can be further alleviated and suppressed.
- the collateral path can be more reliably blocked.
- the thickness of the coating can be easily controlled by repeating the above steps.
- air may be injected after the excess solution is removed by suction.
- the alveolar parenchyma that has become emphysematous due to the operation of removing and removing the excessive solution shrinks, and the smoothness of the inner wall cannot be ensured sufficiently, and the adhesion between the coating and the inner wall is insufficient.
- the alveolar parenchyma swelled and the inner wall becomes smooth, so that the adhesion between the coating and the inner wall can be improved.
- the amount of the respiratory region volume inhibitor introduced into the emphysematous alveolar parenchyma is not particularly limited as long as it is an amount that fills the emphysematous alveolar parenchyma with the respiratory region volume inhibitor. For example, if an increase in the injection pressure of the respiratory region volume inhibitor is detected, the injection of the respiratory region volume inhibitor may be stopped. Similarly, the amount of suction removal of the excessive respiratory region volume inhibitor after the introduction of the respiratory region volume inhibitor is also an amount that can substantially remove the respiratory region volume inhibitor from within the pulmonary alveolar parenchyma. Well, not particularly limited. For example, if it becomes impossible to suck the respiratory region volume inhibitor, the suction of the respiratory region volume inhibitor may be stopped.
- the introduction and removal of the respiratory region volume inhibitor may be performed with the same lumen of the catheter or through different lumens, but it is preferable to perform with the same lumen in consideration of ease of operation. .
- the retention time of the respiratory region volume inhibitor in the inner wall of the alveolar parenchyma is not particularly limited, but is preferably 1 to 5 minutes. At such a time, the respiratory region volume inhibitor can start to harden and form a film on the inner wall of the alveolar parenchyma where it has become emphysematous.
- the emphysematous alveolar parenchyma is a closed system other than the communication port with the bronchi or bronchiole. For this reason, when the respiratory region volume inhibitor as the respiratory region volume inhibitor is removed by suction, the respiratory region volume inhibitor is removed in a state of being integrated to some extent with the lumen of the alveolar parenchyma 3 that has become emphysematous. For this reason, the alveolar parenchyma 3 can contract with this suction removal.
- Step (b-2) In this step, as shown in FIGS. 3B and 3C, a material 14 that can be cured by reacting with water or divalent metal ions as a respiratory region volume inhibitor is injected into the respiratory region 2 through the catheter 1 ( 3B) After that, it reacts with water or divalent metal ions (for example, calcium ions) 15 existing on the inner wall surface of the respiratory region 3 (in the figure, emphysema alveolar parenchyma). When injecting the material 14, it is preferable to expand the balloon 1a and seal between the catheter 1 and the inner wall of the bronchi or bronchiole 2 (FIG. 3C).
- water or divalent metal ions for example, calcium ions
- the material 14 can be reliably injected into the respiratory region (in the figure, the emphysematous alveolar parenchyma) 3 without backflow.
- hardening of the material 14 is started by the above reaction, and a coating film 16 is formed on the surface of the alveolar parenchyma 3 that has become emphysematous (FIG. 3C).
- the material 14 that does not come into contact with water or divalent metal ions 15 present on the surface of the emphysema alveolar parenchyma 3 is present without being reacted (cured) (see the partially enlarged view of FIG. 3C). ).
- the balloon 1a is preferably expanded to seal between the catheter 1 and the inner wall of the bronchus or bronchiole 2.
- the material 14 can be reliably removed from the alveolar parenchyma 3 which has been emphysematous without flowing out to the bronchus side.
- the collateral channel 6 is usually a small hole, so that a coating 16 is formed to cover the collateral channel 6.
- the alveolar parenchyma 3 that has become emphysema by this operation forms a closed system other than the communication port with the bronchi (FIG. 3D).
- the alveolar parenchyma that has become emphysema in the next step is contracted, air leakage through the collateral channel 6 does not occur, so that the alveolar parenchyma 3 that has become emphysema can be easily, efficiently and quickly Can be shrunk.
- the material 14 that can be cured by reacting with water as a respiratory region volume inhibitor may contain a plasticizer in addition to the cyanoacrylate monomer.
- a plasticizer in order to impart flexibility to the coating, contraction of emphysematous alveolar parenchyma (alveoli or alveolar sac) in the next step (c) can be facilitated.
- injection and suction removal operation of the solution having divalent metal ions can be performed in the same manner as the injection and suction removal operation of the respiratory region volume inhibitor.
- the amount of the material 14 that can be cured by reacting with water or divalent metal ions as a respiratory region volume inhibitor into the emphysematous alveolar parenchyma is an amount that fills the emphysema of the alveolar parenchyma with the material. There is no particular limitation as long as it is. For example, if an increase in the injection pressure of the material 14 is detected, the injection of the material 14 may be stopped.
- the contact time between water or divalent metal ions (for example, calcium ions) on the inner wall of the pulmonary alveolar parenchyma and the material 14 is not particularly limited, but is preferably 1 to 5 minutes. Such a time allows the material 14 to sufficiently react with water or divalent metal ions in the inner wall of the alveolar parenchyma that has become emphysematous.
- a water droplet is dropped so as to contact the respiratory region volume inhibitor 14 to observe the reaction state.
- the water droplet imitates water or divalent metal ions 15 present on the surface of the alveolar parenchyma.
- the emphysematous alveolar parenchyma is a closed system other than the communication port with the bronchi or bronchiole. For this reason, when the respiratory region volume inhibitor 14 is removed by suction, it is removed in a state of being integrated to some extent with the lumen of the alveolar parenchyma 3 that has become emphysematous. For this reason, the alveolar parenchyma 3 can contract with this suction removal.
- Step (b-3) In this method, as shown in FIGS. 4B to 4E, after the film-forming component 24 containing the polymer electrolyte (A) is injected into the respiratory region 2 through the catheter 1 (FIG. 4B), an excess of the polymer electrolyte (A) 24 is removed by suction (FIG. 4C).
- the film-forming component 24 containing the polymer electrolyte (A) is removed by suction, and the film-forming component 24 containing the polymer electrolyte (A) remains on the inner wall of the alveolar parenchyma 3 that has become emphysematous. 25 (FIG. 4C).
- the film-forming component 24 containing the polyelectrolyte (A) can be reliably injected into the respiratory region (in the figure, emphysematous alveolar parenchyma) 3 without backflow, or flows out to the bronchus side. It can be reliably removed from the alveolar parenchyma 3 which is emphysematous.
- an external stimulation component containing a polymer electrolyte (B) having a charge opposite to that of the polymer electrolyte (A) is injected into the respiratory region 2 through the catheter 1 to form a coating film of the polymer electrolyte (A). 25 (FIG. 4D).
- the charge (for example, positive charge) of the polymer electrolyte (B) reacts with the opposite charge (for example, negative charge) of the polymer electrolyte (A) to form the ion complex film 27.
- the ion complex film 27 remains on the inner wall of the alveolar parenchyma 3 that is emphysematous (FIG. 4E). Even when the collateral channel 6 is present in the emphysematous alveolar parenchyma 3, the polymer electrolyte (A) covering the collateral channel 6 as described above is combined with the polymer electrolyte (B). Since this reacts to form the ion complex film 27, the emphysematous alveolar parenchyma 3 forms a closed system other than the communication port with the bronchi (FIG. 4E).
- the external stimulation component 26 containing the polymer electrolyte (B) when injecting or removing the external stimulation component 26 containing the polymer electrolyte (B), it is preferable to expand the balloon 1a and seal between the catheter 1 and the inner wall of the bronchi or bronchiole 2 (FIG. 4E). ).
- the external stimulation component 26 including the polyelectrolyte (B) can be reliably injected into the respiratory region (in the figure, emphysematous alveolar parenchyma) 3 without backflow, or flows out to the bronchus side. It can be reliably removed from the alveolar parenchyma 3 which is emphysematous.
- the injection / suction removal operation of the film forming component containing the polymer electrolyte (A) and the injection / suction removal operation of the external stimulus component containing the polymer electrolyte (B) are alternately performed. You may repeat. For example, after the external stimulus component 26 containing the polymer electrolyte (B) is removed by suction, a film-forming component containing the polymer electrolyte (A) is injected into the respiratory region via a catheter, and then an excess polymer electrolyte ( A) may be removed by suction (not shown).
- the charge (in the above example, negative charge) of the polymer electrolyte (B) of the external stimulating component that was not involved in the formation of the ion complex film 27 is injected into the polymer electrolyte ( It reacts with the charge of A) (positive charge in the above example) to further form a film.
- A positive charge in the above example
- the thickness of the coating can be easily controlled by repeating the above steps.
- the polymer electrolyte (A) and the polymer electrolyte (B) are used as the respiratory region volume inhibitor according to the present invention.
- the polymer electrolyte (A) of the film forming component 24 and the polymer electrolyte (B) of the external stimulating component 26 may be those having opposite charges.
- the polymer electrolyte (A) has a negative charge
- the polymer electrolyte (B) has a positive charge
- the polymer electrolyte (A) has a positive charge
- the polymer electrolyte (B) has a negative charge.
- the concentration of the polyelectrolyte (A) or polyelectrolyte (B) in the solution or dispersion when injecting into the respiratory region in the form of a solution or dispersion is not particularly limited, but is preferably 5 to 50 masses. %. If it is such a density
- concentration of the polymer electrolyte (A) or the polymer electrolyte (B) in the solution or dispersion may be the same or different.
- the amount of the polyelectrolyte (A) or polyelectrolyte (B) introduced into the emphysematous alveolar parenchyma is such that the polyelectrolyte (A) or polyelectrolyte (B) is contained in the emphysematous alveolar parenchyma. There is no particular limitation as long as the amount is satisfied. For example, if an increase in the injection pressure of the polymer electrolyte (A) or the polymer electrolyte (B) is detected, the injection of the polymer electrolyte (A) or the polymer electrolyte (B) may be stopped.
- the amount of the excess polymer electrolyte (A) or polyelectrolyte (B) sucked and removed after the introduction of the polyelectrolyte (A) or the polyelectrolyte (B) is also increased in the pulmonary alveolar parenchyma.
- the amount of the polymer electrolyte (A) or the polymer electrolyte (B) is not particularly limited as long as the amount can be substantially removed. For example, when the polymer electrolyte (A) or the polymer electrolyte (B) cannot be sucked, the suction of the polymer electrolyte (A) or the polymer electrolyte (B) may be stopped.
- the introduction and removal of the polyelectrolyte (A) or the polyelectrolyte (B) may be performed with the same lumen or different lumens of the catheter, respectively. In consideration, it is preferable to carry out the same lumen.
- the introduction and removal of polyelectrolyte (A) or polyelectrolyte (B) may also be performed with the same lumen of the catheter or via different lumens.
- the operation of introducing and removing the film forming component 24 containing the polymer electrolyte (A) and the external stimulating component 26 containing the polymer electrolyte (B) may be performed once, but may be repeated several times. preferable. As a result, the entire inner wall of the alveolar parenchyma where the polyelectrolyte is emphysematous can be covered.
- an appropriate reactive gas may be injected into the alveolar parenchyma.
- the introduced polyelectrolyte can be uniformly coated on the surface of the pulmonary alveolar parenchyma 3.
- the contact time between the polymer electrolyte (A) and the polymer electrolyte (B) in the coating 25 is not particularly limited, but is preferably 1 to 10 minutes. If it is such time, a polymer electrolyte (A) can fully react with a polymer electrolyte (B).
- the external stimulating component 26 containing the polymer electrolyte (B) is removed by suction.
- the emphysematous alveolar parenchyma is a closed system other than the communication port with the bronchi or bronchiole.
- the external stimulating component 26 containing the polymer electrolyte (B) is removed by suction, it is removed in a state of being integrated to some extent with the lumen of the alveolar parenchyma 3 that has become emphysematous. For this reason, the alveolar parenchyma 3 can contract with this suction removal.
- the respiratory region volume inhibitor used in the above steps (b-1) to (b-3) has a slow film formation (curing) rate. Therefore, according to the steps (b-1) to (b-3), since the alveolar parenchyma that has become emphysematous in the next step (c) is contracted and then cured, the contraction can be maintained. preferable.
- Step (c) the emphysematous alveolar parenchyma (alveoli or alveolar sac) in which the film which is a balloon-like hermetic bag is formed on the inner wall in the step (b) is contracted. It is preferable that the alveolar parenchyma that has become emphyseated by this step is quickly contracted integrally with the film that is a balloon-like hermetic bag. For this reason, the air staying in the alveolar parenchyma can be efficiently removed.
- the respiratory region volume inhibitor used in the above steps (b-1) to (b-3) has a slow film formation (curing) rate and finishes the film formation after contraction.
- the methods (a) to (c) of the present invention perform treatment via a catheter and do not require a surgical procedure, so that the burden on the patient can be reduced.
- the contraction method of the emphysematous alveolar parenchyma is not particularly limited.
- the following methods (c-1) to (c-4) are preferably used:
- the respiratory region volume inhibitor is a foam respiratory region volume inhibitor, and after (b) above, the foam of the respiratory region volume inhibitor disappears or the foamed respiratory region volume inhibitor is passed through the catheter.
- C-3) A method of sucking and removing residual air in the alveoli or alveolar sac through a catheter; and
- the step (c-4) overlaps with the suction removal of the respiratory region volume inhibitor in the steps (b-1) to (b-3). Therefore, when the respiratory region volume inhibitor is removed by suction in the steps (b-1) to (b-3), the step (c-4) can be omitted.
- Step (c-1) In this method, as shown in FIGS. 2D-F, reactive gas 7 is injected into the respiratory zone 2 via the catheter 1 and into the alveoli or alveolar sac (emphysematous alveolar parenchyma) 3. Reactive gas 7 is charged. When filling the reactive gas 7, it is preferable to expand the balloon 1a and seal between the catheter 1 and the inner wall of the bronchus or bronchiole 2 (FIG. 2D). Thereby, the reactive gas 7 can be filled more reliably. Next, the bronchi or bronchiole 2 is occluded by means 8 for occluding the bronchi or bronchiole (FIG. 2D).
- a gas absorbent 9 that absorbs reactive gas is injected into the alveoli or alveolar sac (emphysematous alveolar parenchyma) 3 (FIG. 2E). Absorption of reactive gas by the gas absorbent 9 causes the emphysematous alveolar parenchyma to aggregate and the lung volume of the emphysematous alveolar parenchyma to decrease (FIG. 2F).
- the alveolar parenchymal capacity can be efficiently and quickly reduced.
- the gas absorbent 9 may be removed by suction or the like. However, since the contracted alveolar parenchyma does not function as an alveoli or alveolar sac, it is not necessary to remove the gas absorbent 9 as shown in FIG. 2F.
- the reactive gas 7 is not particularly limited, but preferably has reactivity with the respiratory region volume inhibitor 3 in the coating that is the balloon-shaped sealed bag formed in the step (b). In this case, the reactive gas 7 reacts with the respiratory region volume inhibitor 3 of the coating formed in the step (b), and curing begins slowly, and curing occurs after the emphysematous alveolar parenchyma contracts. As a result, reduced lung volume of emphysematous alveolar parenchyma can be maintained.
- the reactive gas that can be used here include oxygen and carbon dioxide.
- the reactive gas may be used alone or in the form of two or more mixed gases. Of the reactive gases, oxygen is preferred. These are gases originally present in the lungs and are safe to be absorbed into the body.
- the amount of reactive gas introduced into the emphysematous alveolar parenchyma is not particularly limited as long as it is an amount that fills the emphysematous alveolar parenchyma with reactive gas. For example, if an increase in the reactive gas injection pressure is detected, the reactive gas injection may be stopped. In addition, the reactive gas may be introduced into the emphysematous alveolar parenchyma using the same catheter lumen as the introduction of the respiratory volume inhibitor, or a catheter different from the introduction of the respiratory volume inhibitor. May be performed in lumen.
- the retention time of the reactive gas in the pulmonary alveolar parenchyma after introduction is not particularly limited, but is preferably 1 to 10 minutes. If it is such time, the reactive gas can fully react with the respiratory region volume inhibitor in a film.
- the means (occluding means) 8 for closing the bronchus or bronchiole is not particularly limited, and may be temporarily closed or permanently blocked.
- the occlusion means in the former case is not particularly limited, and can be achieved, for example, by installing a balloon 1a on the catheter 1 as shown in FIG. 2D.
- the closing means in the latter case is also not particularly limited, and can be achieved, for example, by closing the bronchus or bronchiole 2 with a soft member such as a sponge.
- the installation position of the closing means 8 is not particularly limited.
- the occlusion means may be placed at the distal end of the catheter or at the tracheal (proximal) side from the distal end of the catheter, but the catheter tip is located in the bronchus
- the occluding means is placed on the catheter so that it does not go beyond the proximal branch of the bronchus. Thereby, it is possible to prevent the reactive gas from leaking to the branch side on the proximal side.
- the bronchi or bronchiole 2 may be occluded in advance before the introduction of the reactive gas.
- the reactive gas can be suppressed / prevented from flowing backward to the trachea (proximal) side of the bronchus or bronchiole 2 and the reactive gas can be efficiently introduced into the desired alveolar parenchyma.
- the bronchial or bronchiolar occlusion means that can be used at this time is not particularly limited.
- the occlusion means 8 can be used in the same manner.
- the gas absorbent 9 is not particularly limited as long as it absorbs the reactive gas 7 and can be appropriately selected depending on the type of the reactive gas 7.
- silica, ceramic, porous ceramic, magnesia, titania, calcium silicate, activated carbon pure iron powder, cast iron powder, steel powder, reduced iron powder, sprayed iron powder, sponge iron powder, electrolytic iron powder, iron alloy powder, etc.
- the gas absorbent may be used alone or in the form of a mixture of two or more.
- iron powder, ceramic, and porous ceramic are preferable. These are excellent in safety.
- an oxidation promoting substance when using iron powder, it is preferable to use an oxidation promoting substance.
- the use of an oxidation promoting substance can improve the oxygen absorption function.
- the oxidation-promoting substance is not particularly limited, and examples thereof include alkali metal or alkaline earth metal halides such as NaCl, CaCl 2, and MgCl 2, ion-exchange resin halides, hydrochloric acid, hypochlorite, and the like.
- the amount of the oxidation promoting substance used is preferably 0.01 to 20 parts by weight with respect to 100 parts by weight of iron powder.
- the amount of the gas absorbent introduced into the emphysematous alveolar parenchyma is not particularly limited as long as it can absorb the reactive gas sufficiently to reduce the volume of the alveolar parenchyma. It can be selected appropriately in consideration of the volume of the alveolar parenchyma. Alternatively, when an increase in the gas absorbent injection pressure is detected, the gas absorbent injection may be stopped. In addition, the introduction of the gas absorbent into the emphysematous alveolar parenchyma may be performed with the same catheter lumen as the introduction of the respiratory volume inhibitor or reactive gas, or the respiratory volume inhibitor or reactive It may be performed with a different lumen of the catheter than the introduction of gas.
- the retention time of the gas absorbent in the emphysematous alveolar parenchyma after introduction is not particularly limited, but is preferably 1 to 10 minutes. At such a time, the gas absorbent can sufficiently absorb the reactive gas and reduce the volume of the alveolar parenchyma.
- the respiratory region volume inhibitor is a foamy respiratory region volume inhibitor.
- the volume of the alveolar parenchyma 3 that has become emphysematous by releasing the gas of the foam of the uncured foamed respiratory region volume inhibitor 14 out of the body or absorbing it into the body to disappear the foam. Can be reduced.
- FIG. 3D does not exist and continues from FIG. 3C to FIG. 3E (FIG. 3C ⁇ FIG. 3E).
- the foamed respiratory region volume inhibitor can be cured by reacting with the respiratory region volume inhibitor described in the above step (b), particularly water or a divalent metal ion described in the above step (b-2).
- the material 14 can be manufactured by introducing nitrogen gas, helium gas, argon gas, carbon monoxide, carbon dioxide, carbon dioxide gas, oxygen or the like into a foam.
- the foam of the uncured foamy respiratory region volume inhibitor 14 may disappear naturally or promote the defoaming using an antifoaming agent. Further, it is desirable that the foamed respiratory region volume inhibitor 14 after curing is naturally absorbed and lost by diffusion.
- the antifoaming agent that can be used in the latter is not particularly limited, and an antifoaming agent used in the medical field can be used in the same manner.
- lower alcohols such as methanol, ethanol, isopropanol, butanol
- silicone compounds such as silicone oil
- 2-ethylhexanol diisobutylcarbinol
- amyl alcohol tributyl phosphate
- octyl phosphate sodium metal stearate
- Organic polar compounds such as palmitic acid metal salts, isoamyl stearic acid ester, diglycol lauric acid ester, sorbitan oleic acid triester, polyoxyethylene sorbitan monolauric acid ester, pluronic-type nonionic activator, polyalkylene glycol and its derivatives, etc. Is mentioned.
- the antifoaming agent may be used alone or in the form of a mixture of two or more.
- the antifoaming agents polyalkylene glycol derivatives are preferred. These are excellent in antifoaming properties.
- the amount of antifoam agent introduced into the emphysematous alveolar parenchyma is sufficient to eliminate the uncured foamy respiratory region volume inhibitor to a level sufficient to reduce the amount of emphysematous alveolar parenchyma. If it is the quantity which can be bubbled, it will not be restrict
- the antifoaming agent is preferably about 0.001 to about 5% by mass with respect to the initial amount of the foamed respiratory region volume inhibitor.
- the antifoaming agent may be introduced into the emphysematous alveolar parenchyma using the same lumen of the catheter as the introduction of the respiratory region volume inhibitor, or a different catheter from the introduction of the respiratory region volume inhibitor. May be performed in lumen.
- the volume of the emphysematous alveolar parenchyma 3 may be reduced by sucking and removing the uncured foamy respiratory region volume inhibitor 14 through the catheter 1.
- FIG. 3D is followed by FIG. 3C to FIG. 3E (FIG. 3C ⁇ FIG. 3D ⁇ FIG. 3E).
- the suction removal amount of the foamed respiratory region volume inhibitor 14 may be an amount that can substantially remove the uncured foamed respiratory region volume inhibitor from the alveolar parenchyma, and is particularly limited. Not. For example, if the foamed respiratory region volume inhibitor cannot be sucked, the suction of the foamed respiratory region volume inhibitor may be stopped.
- the suction and removal of the foamed respiratory region volume inhibitor may be performed with the same catheter lumen as the introduction of the respiratory region volume inhibitor, or with a different catheter lumen than the introduction of the respiratory region volume inhibitor. Also good.
- Step (c-3) In this method, residual air in the alveoli or alveolar sac is removed by suction through the catheter (FIG. 4F). Even after the respiratory region volume inhibitor is removed by suction, the emphysematous alveolar parenchyma 3 may be in an expanded state. In such a case, when the residual air in the emphysematous alveolar parenchyma 3 is sucked and removed through the catheter, the emphysematous alveolar parenchyma 3 is a closed system except for the communication port with the bronchi or bronchiole 2. Therefore, the volume of emphysematous alveolar parenchyma can be reduced efficiently and rapidly.
- the suction removal of residual air in the alveolar parenchyma 3 that has become emphysematous may be terminated when the residual air cannot be suctioned.
- Step (c-4) In this method, the respiratory region volume inhibitor is removed by suction from the alveoli or alveolar sac.
- the emphysematous alveolar parenchyma is a closed system other than the communication port with the bronchi or bronchiole. For this reason, the alveolar parenchyma 3 can be contracted with the suction removal of the respiratory region volume inhibitor.
- This method is preferable because it is very simple. If the alveolar parenchyma 3 cannot be sufficiently contracted even after the operation, it is preferable to further perform at least one of the above steps (c-1) to (c-3).
- steps (a), steps (b-1) to (b-3) and steps (c-1) to (c-3) have been described in detail.
- steps (a) and (b-1); steps (a) and (b-2); steps (a) and (b-3); steps (a), (b-1) and (c- Steps (a), (b-1) and (c-3); Steps (a), (b-2) and (c-2); Steps (a), (b-3) and (c) -3) is preferred, and steps (a) and (b-1); steps (a) and (b-2); steps (a) and (b-3); steps (a) and (b-1) And combinations of steps (a), (b-2) and (c-2); steps (a), (b-3) and (c-3) are more preferred.
- the method of the present invention it is possible to efficiently remove air staying in emphysematous alveolar parenchyma and maintain a reduced volume. For this reason, it is possible to alleviate / suppress lung overexpansion, which is one cause of debilitating affected individuals due to emphysema or air-bronchial obstruction.
- lung overexpansion which is one cause of debilitating affected individuals due to emphysema or air-bronchial obstruction.
- the size of the emphysema of alveolar parenchyma to be less than the original size, it is possible to suppress / prevent pressure and obstruction of the surrounding bronchi due to the surrounding alveolar parenchyma.
- the treatment method of the present invention performs the treatment through the catheter and does not require a surgical procedure, the burden on the patient can be reduced.
- a film is formed on the inner wall of the emphysematous alveoli, and the elasticity of the emphysematous alveolar parenchyma is restored. .
- a film can be formed on a cyst causing pneumothorax, and the volume can be reduced.
- a metal needle or the like is percutaneously punctured into the cyst part, or a catheter is inserted into the cyst part via the bronchus (transbronchial), and the retained air is efficiently removed in the same manner as in the above steps and examples. Can be removed and reduced capacity can be maintained.
- Example 1 1 g of gelatin (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 5 cc of 60 ° C. hot water and mixed to prepare a respiratory region volume inhibitor according to the present invention.
- an OTW type PTCA balloon catheter 1 [Ryujin Plus OTW (registered trademark), medical device approval number: 21600BZZ00035, manufactured by Terumo Corporation) used for the treatment of stenosis of the blood vessel lumen in the cardiovascular region.
- a guide wire [Runthrough (registered trademark), Terumo Corporation] (outer diameter: 0.014 inch) was previously inserted into the working lumen of the bronchoscope.
- the tip of the guide wire was advanced to near the desired emphysematous alveolar parenchyma 3 under fluoroscopy.
- the catheter was advanced to near the desired alveolar parenchyma 3 under fluoroscopy through this guide wire, and then the guide wire was removed.
- a syringe was filled with 2% by weight gelatin aqueous solution 4 as the above respiratory region volume inhibitor.
- the balloon 1a was expanded with air using a syringe connected to a balloon expanding lumen disposed at the proximal end of the catheter 1, and the bronchiole 2 was occluded.
- the gelatin aqueous solution was injected from the syringe into the lumen of the alveolar parenchyma 3 through the lumen of the catheter 1.
- the injection pressure of the syringe increased, the injection of the gelatin aqueous solution was stopped.
- a sufficient amount of gelatin aqueous solution was injected into the lumen of alveolar parenchyma 3.
- the balloon 1a of the catheter 1 was expanded with air to close the bronchiole 2, and oxygen was injected as a reactive gas 7 from the inflation lumen. Since the lumen of the alveolar parenchyma 3 was covered with the respiratory region volume inhibitor 4, the reactive gas 7 was efficiently filled into the alveolar parenchyma 3.
- iron powder was sprayed as a gas absorbent 9 into the lumen of the alveolar parenchyma 3 through the lumen through which the catheter 1 can send air.
- the amount of iron powder introduced was about 3.2 mg with respect to 1 ml of the lumen volume of alveolar parenchyma 3.
- the sprayed iron powder absorbed the gas remaining in the emphysematous alveolar parenchyma 3, and as a result, the emphysema of the alveolar parenchyma 3 contracted and its volume decreased (see FIG. 2F). Further, as a result of further progress of gelatin hardening in such a state where the volume was reduced, emphysematous alveolar parenchyma 3 was maintained in a state in which the volume was reduced (FIG. 2F).
- an OTW type PTCA balloon catheter 1 [Ryujin Plus OTW (registered trademark), medical device approval number: 21600BZZ00035, manufactured by Terumo Corporation) used for the treatment of stenosis of the blood vessel lumen in the cardiovascular region.
- a guide wire [Runthrough (registered trademark), Terumo Corporation] (outer diameter: 0.014 inch) was previously inserted into the working lumen of the bronchoscope.
- the tip of the guide wire was advanced to near the desired emphysematous alveolar parenchyma 3 under fluoroscopy.
- the catheter was advanced to near the desired alveolar parenchyma 3 under fluoroscopy through this guide wire, and then the guide wire was removed.
- the foamed respiratory region volume inhibitor 14 prepared above was filled in a syringe.
- the balloon 1a was expanded with air using an indeflator connected to a balloon-expanding lumen disposed at the proximal end of the catheter 1, and the bronchiole 2 was occluded.
- the respiratory region volume inhibitor was injected from the syringe into the lumen of the alveolar parenchyma 3 through the lumen of the catheter 1. When the injection pressure of the syringe increased, the injection of the respiratory region volume inhibitor was stopped.
- ethyl ⁇ -cyanoacrylate which is a component of the respiratory region volume inhibitor, is adsorbed on the surface of emphysema. It reacted with moisture, which was the external stimulus 15 present, and quickly hardened to form a coating 16 on the inner wall of the alveolar parenchyma 3 (FIG. 3C). At the same time, carbon dioxide was generated to form bubbles.
- an OTW type PTCA balloon catheter 1 [Ryujin Plus OTW (registered trademark), medical device approval number: 21600BZZ00035, manufactured by Terumo Corp.] used for the treatment of stenosis of the blood vessel lumen in the cardiovascular region.
- a guide wire [Runthrough (registered trademark), Terumo Corporation] (outer diameter: 0.014 inch) was previously inserted into the working lumen of the bronchoscope.
- the tip of the guide wire was advanced to near the desired emphysematous alveolar parenchyma 3 under fluoroscopy.
- the catheter was advanced to near the desired alveolar parenchyma 3 under fluoroscopy through this guide wire, and then the guide wire was removed.
- a foamy respiratory region volume inhibitor 14 was filled in a syringe.
- the balloon 1a was expanded with air using an indeflator connected to a balloon-expanding lumen disposed at the proximal end of the catheter 1, and the bronchiole 2 was occluded.
- the foamy respiratory region volume inhibitor 14 was injected from the syringe into the lumen of the alveolar parenchyma 3 through the lumen of the catheter 1. When the injection pressure of the syringe increased, the injection of the foamy respiratory region volume inhibitor 14 was stopped.
- the alginic acid of the foamy respiratory region volume inhibitor 14 becomes emphysematous alveolar parenchyma 3 surface. It quickly hardened by reacting with calcium ions 15 present in the film, and a film 16 was formed on the inner wall of the alveolar parenchyma 3 (FIG. 3C).
- the foamed respiratory region volume inhibitor 14 was removed by suction (FIG. 3D).
- the collateral channel 6 was closed by the formation of the film, the foamy respiratory region volume inhibitor 14 containing unreacted alginic acid could be efficiently sucked and removed.
- an OTW type PTCA balloon catheter 1 [Ryujin Plus OTW (registered trademark), medical device approval number: 21600BZZ00035, manufactured by Terumo Corporation) used for the treatment of stenosis of the blood vessel lumen in the cardiovascular region.
- bronchiole 2 was inserted into the lumen of bronchiole 2 from the working lumen (not shown) of the bronchoscope.
- a guide wire [Runthrough (registered trademark), Terumo Corporation] (outer diameter: 0.014 inch) was previously inserted into the working lumen of the bronchoscope.
- the tip of the guide wire was advanced to near the desired emphysematous alveolar parenchyma 3 under fluoroscopy.
- the catheter was advanced to near the desired alveolar parenchyma 3 under fluoroscopy through this guide wire, and then the guide wire was removed.
- a syringe was filled with hyaluronic acid as a polymer electrolyte (A) which is an example of the film forming component 24.
- the balloon 1a was expanded with air using an indeflator connected to a balloon-expanding lumen disposed at the proximal end of the catheter 1, and the bronchiole 2 was occluded.
- Hyaluronic acid was injected through the lumen of catheter 1 from the syringe into the lumen of alveolar parenchyma 3 that had become emphysematous. When the injection pressure of the syringe increased, the injection of hyaluronic acid was stopped.
- hyaluronic acid which is a polymer electrolyte (A) 24, was formed on the surface of the 3 tissues that had become emphysematous (FIG. 4C).
- the balloon 1a is expanded again with air using an indeflator connected to the balloon expanding lumen disposed at the proximal end of the catheter 1, and the bronchiole 2 is Blocked.
- Poly (N, N-dimethylaminopropylacrylamide) was injected from the syringe into the lumen of alveolar parenchyma 3 through a different lumen from the catheter 1 into which hyaluronic acid was injected.
- poly (N, N-dimethylaminopropylacrylamide) When the injection pressure of the syringe increased, the injection of poly (N, N-dimethylaminopropylacrylamide) was stopped. Thus, when poly (N, N-dimethylaminopropylacrylamide) is injected into the lumen of alveolar parenchyma 3, poly (N, N-dimethylaminopropylacrylamide) becomes emphysematous alveolar parenchyma 3 tissue surface. It reacts with the hyaluronic acid constituting the coating film 25 to be formed and reacts quickly and begins to cure (FIG. 4D).
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Abstract
Description
本工程では、カテーテルを、気管支または細気管支に挿入する。詳細には、図1A、図2A、図3Aおよび図4Aに示されるように、カテーテル1を、気腫化した肺胞または肺胞嚢(以下、単に「気腫化した肺胞実質」とも称する)3を含む呼吸域へ通じる気管支または細気管支2に挿入する。
本工程では、カテーテルを介して肺胞または肺胞嚢を含む呼吸域中に呼吸域体積抑制剤を注入して、前記呼吸域の内壁に被膜を形成する。当該工程により、気腫化した肺胞実質に側副路(図1A中の付号6)が存在したとしても、呼吸域体積抑制剤で気腫化した肺胞実質の側副路を含めた内壁全面に風船状密閉袋体である被膜を形成する。すなわち、当該工程により、気腫化した肺胞実質内は気管支または細気管支との連通口以外は閉鎖系となる(図1B)。このため、次工程で肺胞実質を収縮させる際に、気腫化した肺胞実質からの空気の漏れが少ないまたはないため、閉鎖系内の空気を確実に除去し、効率よく肺胞実質の容量を低減することができる。また、このような被膜の形成は、気腫化した肺胞実質の弾性を回復させるため、肺の過膨張を緩和・抑制することができる。なお、本明細書中、「呼吸域」とは、気管支樹(respiratory bronchiole)および肺胞域(two alveoli)を含む気管支より末端側の呼吸器官の総称である。具体的には、呼吸域は、気管支、細気管支、終末細気管支、呼吸細気管支、肺胞管(肺胞道)、肺胞、肺胞嚢、肺静脈、肺動脈を含み、呼吸細気管支、肺胞管(肺胞道)、肺胞、肺胞嚢、肺静脈を含むことが好ましい。
(b-1)前記呼吸域体積抑制剤として呼吸域体積抑制剤を前記カテーテルを介して呼吸域中に注入した後、過剰な呼吸域体積抑制剤を吸引除去する方法;
(b-2)前記呼吸域体積抑制剤として水または2価の金属イオンと反応して硬化できる材料を前記カテーテルを介して呼吸域中に注入し、前記呼吸域の表面に存在する水または2価の金属イオンと反応させた後、前記材料を吸引除去する;または
(b-3)高分子電解質(A)を含む第一被膜形成成分を前記カテーテルを介して呼吸域中に注入した後、過剰な高分子電解質(A)を吸引除去して、高分子電解質(A)の塗膜を呼吸域の内壁に形成した後、前記高分子電解質(A)と反対の電荷を有する高分子電解質(B)を含む外部刺激成分を前記カテーテルを介して呼吸域中に注入して、前記高分子電解質(A)と接触させた後、過剰な高分子電解質(B)を吸引除去し、さらに必要であれば、前記高分子電解質(B)の吸引除去後に、前記高分子電解質(A)を含む第二被膜形成成分を前記カテーテルを介して呼吸域中に注入した後、過剰な高分子電解質(A)を吸引除去する方法(この際、前記高分子電解質(A)を含む第一および第二被膜形成成分および高分子電解質(B)を含む外部刺激成分が前記呼吸域体積抑制剤として使用される)。
本工程では、図2BおよびCに示されるように、呼吸域体積抑制剤として呼吸域体積抑制剤4をカテーテル1を介して気管支または細気管支2および肺胞または肺胞嚢3を含む呼吸域中に注入した(図2B)後、過剰な呼吸域体積抑制剤4を吸引除去する(図2C)。なお、呼吸域体積抑制剤の注入または溶液過剰な呼吸域体積抑制剤の吸引除去に際しては、バルーン1aを拡張し、カテーテル1と気管支または細気管支2の内壁との間をシールすることが好ましい。これにより、呼吸域体積抑制剤の注入または溶液過剰な呼吸域体積抑制剤の吸引除去をより確実に吸引除去することができる。
本工程では、図3B、Cに示されるように、呼吸域体積抑制剤として水または2価の金属イオンと反応して硬化できる材料14を、カテーテル1を介して呼吸域2中に注入した(図3B)後、呼吸域(図中では、気腫化した肺胞実質)3の内壁表面に存在する水または2価の金属イオン(例えば、カルシウムイオン)15と反応させる。なお、材料14の注入に際しては、バルーン1aを拡張し、カテーテル1と気管支または細気管支2の内壁との間をシールすることが好ましい(図3C)。これにより、材料14は逆流せずに確実に呼吸域(図中では、気腫化した肺胞実質)3中に注入できる。ここで、上記反応により、材料14の硬化が開始し、気腫化した肺胞実質3表面に被膜16を形成する(図3C)。なお、気腫化した肺胞実質3表面に存在する水または2価の金属イオン15と接触しない材料14は、反応(硬化)せずにそのままの状態で存在する(図3Cの部分拡大図参照)。このため、次工程(c)で材料14を吸引することによって、未反応(未硬化)の材料14は速やかに除去され、除去後は被膜16が残る(図3D)。なお、材料14の吸引除去に際しては、バルーン1aを拡張し、カテーテル1と気管支または細気管支2の内壁との間をシールすることが好ましい。これにより、材料14は気管支側に流出することなく確実に気腫化した肺胞実質3から除去できる。また、気腫化した肺胞実質3に側副路6が存在している場合であっても、側副路は通常小さな孔であるため、当該側副路6を覆うよう被膜16が形成される。このため、当該操作により、気腫化した肺胞実質3は、気管支との連通口以外は閉鎖系を形成する(図3D)。これにより、次工程で気腫化した肺胞実質を収縮させる際に、側副路6を介した空気漏れが起こらないため、気腫化した肺胞実質3を、容易に、効率よくかつすばやく収縮させることができる。
本方法では、図4B~Eに示されるように、高分子電解質(A)を含む被膜形成成分24をカテーテル1を介して呼吸域2中に注入した(図4B)後、過剰な高分子電解質(A)24を吸引除去する(図4C)。ここで、高分子電解質(A)を含む被膜形成成分24は、吸引除去後、気腫化した肺胞実質3の内壁に当該高分子電解質(A)を含む被膜形成成分24が残り、薄い被膜25となっている(図4C)。また、気腫化した肺胞実質3に側副路6が存在している場合であっても、側副路は通常小さな孔であるため、当該側副路6を覆うように高分子電解質(A)を含む被膜形成成分24の被膜25が形成される。なお、高分子電解質(A)を含む被膜形成成分24の注入または吸引除去に際しては、バルーン1aを拡張し、カテーテル1と気管支または細気管支2の内壁との間をシールすることが好ましい(図4B)。これにより、高分子電解質(A)を含む被膜形成成分24は、逆流せずに確実に呼吸域(図中では、気腫化した肺胞実質)3中に注入できる、または気管支側に流出することなく確実に気腫化した肺胞実質3から除去できる。
本工程では、前記工程(b)で内壁に風船状密閉袋体である被膜が形成された気腫化した肺胞実質(肺胞または肺胞嚢)を収縮させる。当該工程により、気腫化した肺胞実質は、風船状密閉袋体である被膜と一体となってすみやかに収縮することが好ましい。このため、気腫化した肺胞実質内に滞留した空気を効率よく取除くことができる。特に上記工程(b-1)~(b-3)で使用される呼吸域体積抑制剤は、被膜形成(硬化)速度が遅く、収縮後に被膜形成が終了するため、気腫化した肺胞実質の収縮状態を維持でき、効率よく肺胞実質容量を低減し、呼吸によるこの低減された容量を維持できる。このため、肺気腫や給気気管支の閉塞により罹患者を衰弱させる一因である肺の過膨張を緩和・抑制することができる。また、気腫化した肺胞実質の大きさをもとの大きさ以下に小さくすることにより、これらの周りの肺胞実質による周辺の気管支の圧迫や閉塞を抑制・防止できる。上記に加えて、本発明の上記(a)~(c)の方法は、カテーテルを介して治療を行い、外科的な処置を必要としないため、患者にかかる負担を低減できる。
(c-1)反応性ガスをカテーテルを介して肺胞または肺胞嚢中に充填した後、気管支または細気管支を閉塞する手段で気管支または細気管支を閉塞し、前記反応性ガスを吸収するガス吸収剤を肺胞または肺胞嚢中に注入する方法;
(c-2)呼吸域体積抑制剤が泡状呼吸域体積抑制剤であり、上記(b)後、呼吸域体積抑制剤の泡を消失させるもしくは泡状呼吸域体積抑制剤を前記カテーテルを介して吸引除去する方法;
(c-3)肺胞または肺胞嚢内の残気をカテーテルを介して吸引除去する方法;および
(c-4)肺胞または肺胞嚢から、呼吸域体積抑制剤を吸引除去する。
本方法では、図2D~Fに示されるように、反応性ガス7をカテーテル1を介して呼吸域2に注入して、肺胞または肺胞嚢(気腫化した肺胞実質)3中に反応性ガス7を充填する。なお、反応性ガス7の充填に際しては、バルーン1aを拡張し、カテーテル1と気管支または細気管支2の内壁との間をシールすることが好ましい(図2D)。これにより、反応性ガス7をより確実に充填することができる。次に、気管支または細気管支を閉塞する手段8で気管支または細気管支2を閉塞する(図2D)。このように気管支または細気管支2を閉塞することによって、十分量の反応性ガス7が気腫化した肺胞実質3中に導入されるため、被膜5中の呼吸域体積抑制剤3と効率よく反応できる。さらに、反応性ガスを吸収するガス吸収剤9を肺胞または肺胞嚢(気腫化した肺胞実質)3中に注入する(図2E)。ガス吸収剤9による反応性ガスの吸収により、気腫化した肺胞実質が凝集して、気腫化した肺胞実質の肺容量は減少する(図2F)。上記工程(b)で、被膜5を形成して気腫化した肺胞実質中の空気の漏れを抑制・防止しているため、効率よくかつすばやく肺胞実質容量を低減することができる。なお、当該ガス吸収剤9は、吸引などにより除去してもよい。しかし、収縮した肺胞実質は肺胞または肺胞嚢として機能しないため、図2Fに示されるように、ガス吸収剤9を必ずしも除去する必要はない。
本方法では、呼吸域体積抑制剤が泡状呼吸域体積抑制剤である。このため、上記(b)後、未硬化の泡状呼吸域体積抑制剤14の泡のガスを体外に放出もしくは体内に吸収させ泡を消失させることにより、気腫化した肺胞実質3の容量を減少できる。この場合には、図3Dは存在せず、図3Cから図3Eに続く(図3C→図3E)。ここで、泡状呼吸域体積抑制剤は、上記工程(b)で記載した呼吸域体積抑制剤、特に上記工程(b-2)で記載した水または2価の金属イオンと反応して硬化できる材料14に、窒素ガス、ヘリウムガス、アルゴンガス、一酸化炭素、二酸化炭素、炭酸ガス、酸素などを導入して、泡状にすることによって製造できる。
散により自然に吸収消失させることが望ましい。後者で使用できる消泡剤は、特に制限さ
れず、医療分野で使用される消泡剤が同様にして使用できる。具体的には、メタノール、エタノール、イソプロパノール、ブタノール等の低級アルコール;シリコーンオイル等のシリコーン系化合物;2-エチルヘキサノール、ジイソブチルカルビノール、アミルアル
コール、トリブチルフォスフェート、オクチルフォスフェートナトリウム、ステアリン酸金属塩、パルミチン酸金属塩、イソアミルステアリン酸エステル、ジグリコールラウリン酸エステル、ソルビタンオレイン酸トリエステル、ポリオキシエチレンソルビタンモノラウリン酸エステル、プルロニック型非イオン活性剤、ポリアルキレングリコールおよびその誘導体等の有機極性化合物などが挙げられる。上記消泡剤は、単独で使用されてもあるいは2種以上の混合物の形態で使用されてもよい。上記消泡剤のうち、ポリアルキレングリコールの誘導体が好ましい。これらは、消泡性に優れる。また、消泡剤の気腫化した肺胞実質への導入量は、気腫化した肺胞実質の量を減少するのに十分な程度にまで未硬化の泡状呼吸域体積抑制剤を消泡できる量であれば特に制限されない。消泡剤は、泡状呼吸域体積抑制剤の初期導入量に対して、約0.001~約5質量%であることが好ましい。なお、消泡剤の気腫化した肺胞実質中への導入は、呼吸域体積抑制剤の導入と同じカテーテルのルーメンで行われても、または呼吸域体積抑制剤の導入とは異なるカテーテルのルーメンで行われてもよい。
本方法では、肺胞または肺胞嚢内の残気をカテーテルを介して吸引除去する(図4F)。呼吸域体積抑制剤を吸引除去した後であっても、気腫化した肺胞実質3が膨脹した状態であることがある。このような場合には、当該気腫化した肺胞実質3内の残気をカテーテル介して吸引除去すると、気腫化した肺胞実質3は気管支または細気管支2との連通口以外は閉鎖系であるため、気腫化した肺胞実質の容量を効率よくかつ迅速に減少することができる。ここで、気腫化した肺胞実質3内の残気の吸引除去は、残気を吸引できなくなった時点で終了すればよい。
本方法では、肺胞または肺胞嚢から、呼吸域体積抑制剤を吸引除去する。上記したように、気腫化した肺胞実質内は気管支または細気管支との連通口以外は閉鎖系となる。このため、呼吸域体積抑制剤の吸引除去に伴い、肺胞実質3を収縮することができる。当該方法は、非常に簡便であるため好ましい。なお、当該操作を行った後でも、肺胞実質3の収縮が十分出来ない場合には、上記工程(c-1)~(c-3)の少なくとも一をさらに行うことが好ましい。
ゼラチン(和光純薬工業社製)1gを、60℃の湯 5ccに添加し混合して本発明に係る呼吸域体積抑制剤を調製した。
炭酸水素ナトリウム(和光純薬工業社製)1gとクエン酸(和光純薬工業社製)1gとを粉末の状態でエチル-2-シアノアクリレート(東亞合成株式会社製 商品名「アロンアルファ201」)5gに分散させた後、粘度を低下させるための被膜調整剤として、ポリエチレングリコール(日本油脂社製)(Mw=10000)1gを、20℃で添加し混合して本発明に係る呼吸域体積抑制剤14を調製した。
を観察した。被膜が十分形成したことを確認した後、呼吸域体積抑制剤を吸引除去した(図3D)。ここで、前記被膜形成により側副路6が閉鎖されているため、未反応のエチルα-シアノアクリレートを含む呼吸域体積抑制剤を効率よく吸引除去することができた。
アルギン酸(和光純薬工業社製 Mw=200000)5gを、pH6~8の水に40℃で添加し混合してアルギン酸水溶液を調整した後、当該水溶液にさらに炭酸水素ナトリウム(和光純薬工業社製)4.2gを溶かし、希塩酸(和光純薬工業社製)を混ぜることで本発明に係る泡状の呼吸域体積抑制剤(二酸化炭素を導入した10重量%アルギン酸水溶液)を調製した。図3Aに示されるにように、心臓血管領域において血管内腔の狭窄治療に用いられるOTW型のPTCAバルーンカテーテル1[Ryujin Plus OTW(登録商標)、医療機器承認番号:21600BZZ00035、テルモ株式会社製)]を、気管支鏡のワーキングルーメン(図示せず)から細気管支2の内腔へ挿入した。ここで、ガイドワイヤー[Runthrough(登録商標)、テルモ株式会社製](外径:0.014インチ)を予め気管支鏡のワーキングルーメンに挿入した。このガイドワイヤー先端を、X線透視下、所望の気腫化した肺胞実質3近くにまで進めた。次に、このガイドワイヤーを介して、カテーテルをX線透視下、所望の気腫化した肺胞実質3近くにまで進めた後、ガイドワイヤーを抜去した。
高分子電解質(A)を含む被膜形成成分24としてヒアルロン酸1g(生化学工業社製)、高分子電解質(B)を含む外部刺激成分26としてポリ(N,N-ジメチルアミノプロピルアクリルアミド)(重量平均分子量=10,000~500,000)を用意した。図4Aに示されるように、心臓血管領域において血管内腔の狭窄治療に用いられるOTW型のPTCAバルーンカテーテル1[Ryujin Plus OTW(登録商標)、医療機器承認番号:21600BZZ00035、テルモ株式会社製)]を、気管支鏡のワーキングルーメン(図示せず)から細気管支2の内腔へ挿入した。ここで、ガイドワイヤー[Runthrough(登録商標)、テルモ株式会社製](外径:0.014インチ)を予め気管支鏡のワーキングルーメンに挿入した。このガイドワイヤー先端を、X線透視下、所望の気腫化した肺胞実質3近くにまで進めた。次に、このガイドワイヤーを介して、カテーテルをX線透視下、所望の気腫化した肺胞実質3近くにまで進めた後、ガイドワイヤーを抜去した。
2 細気管支
3 肺胞実質
4 呼吸域体積抑制剤
5 被膜
6 側副路
7 反応性ガス
14 泡状の呼吸域体積抑制剤
16 被膜
27 イオンコンプレックス被膜
Claims (6)
- 1回あたり0.004~200gの被膜形成成分が、ヒトの呼吸域内の気腫化した肺胞実質に投与されるように用いられることを特徴とする、前記被膜形成成分を主成分とした呼吸域内に被膜を形成する呼吸域体積抑制剤。
- 前記被膜形成成分は、外部刺激に応答して被膜からなる風船状密閉袋体が呼吸域内周面に沿うよう前記呼吸域内表面と密着して形成され、かつ前記風船状密閉袋体内を呼吸域外部より減圧により前記風船状密閉袋体が収縮する、請求項1に記載の呼吸域体積抑制剤。
- 前記外部刺激は、外部刺激成分を含む、請求項2に記載の呼吸域体積抑制剤。
- 前記被膜形成成分は粘着性高分子を含み、かつ前記外部刺激成分が反応性ガスである、請求項1~3のいずれか1項に記載の呼吸域体積抑制剤。
- 前記被膜形成成分は高分子電解質Aを含み、かつ前記外部刺激成分は高分子電解質Bまたは高分子電解質Bおよび高分子電解質Aである、請求項1~3のいずれか1項に記載の呼吸域体積抑制剤。
- 前記被膜形成成分は、膜形成高分子前駆体、または粘着性高分子であり、膜調整成分をさらに含み、かつ前記外部刺激が水または2価の金属イオンである、請求項1~3のいずれか1項に記載の呼吸域体積抑制剤。
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CN103068411A (zh) | 2013-04-24 |
BR112013004416A2 (pt) | 2016-05-31 |
US9533070B2 (en) | 2017-01-03 |
US20130178426A1 (en) | 2013-07-11 |
EP2609940A4 (en) | 2016-02-10 |
CN103068411B (zh) | 2016-01-20 |
KR20130100112A (ko) | 2013-09-09 |
JP2012045358A (ja) | 2012-03-08 |
US9192693B2 (en) | 2015-11-24 |
EP2609940A1 (en) | 2013-07-03 |
US20120053513A1 (en) | 2012-03-01 |
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