WO2009116257A1 - 肺線維症処置剤 - Google Patents
肺線維症処置剤 Download PDFInfo
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- WO2009116257A1 WO2009116257A1 PCT/JP2009/001148 JP2009001148W WO2009116257A1 WO 2009116257 A1 WO2009116257 A1 WO 2009116257A1 JP 2009001148 W JP2009001148 W JP 2009001148W WO 2009116257 A1 WO2009116257 A1 WO 2009116257A1
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K31/7088—Compounds having three or more nucleosides or nucleotides
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- C12N15/09—Recombinant DNA-technology
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- C12N15/111—General methods applicable to biologically active non-coding nucleic acids
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- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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- C12N2320/32—Special delivery means, e.g. tissue-specific
Definitions
- the present invention relates to a substance delivery carrier targeting extracellular matrix-producing cells in the lung, a pulmonary fibrosis treatment agent and a pulmonary fibrosis treatment method using the same.
- Pulmonary fibrosis is a disease characterized by diffuse fiber growth in the alveolar wall, with dry cough and dyspnea during exertion as main symptoms. In the narrow sense, it refers to the end condition of interstitial pneumonia, but in the broad sense, it means a coexisting state of strict fibrosis and interstitial pneumonia. Any interstitial pneumonia can cause pulmonary fibrosis. Interstitial pneumonia is a general term for diseases that cause inflammation in the lung stroma (including alveolar septum in the narrow sense, lobular stroma, in the broad sense, near the pleura, etc.), infection, collagen disease, radiation, drugs, dust And the like, and idiopathic interstitial pneumonia whose cause is unknown.
- Idiopathic interstitial pneumonia is based on idiopathic pulmonary fibrosis (IPF), nonspecific stroma based on thoracoscopic lung biopsy (VATS) and high-resolution computed tomography (HRCT) findings.
- IPF idiopathic pulmonary fibrosis
- VATS thoracoscopic lung biopsy
- HRCT high-resolution computed tomography
- Interstitial pneumonia whose cause can be identified, is often cured by removing the cause or administering an anti-inflammatory agent such as a steroid, but currently there is no radical treatment for idiopathic interstitial pneumonia.
- an anti-inflammatory agent such as a steroid
- steroid fibrosis, azathioprine, cyclophosphamide, etc. at the time of symptom exacerbation, oxygen therapy at the onset of hypoxemia, etc. are given, and pulmonary fibrosis progresses to death .
- the average survival time after confirmation of diagnosis is as short as 2.5 to 5 years, and it is designated as a specific disease in Japan.
- JP-A-8-268906 International Publication No. 00/57913 Pamphlet JP 2002-371006 A JP 2003-119138 A JP 2005-513031 Gazette JP-T-2005-53628 Special Table 2006-502153 International Publication No. 2006/068232 Pamphlet Ann Intern Med. 2001; 134 (2): 136-51
- An object of the present invention is to provide a carrier capable of specifically delivering a substance such as a drug to extracellular matrix-producing cells in the lung, a pulmonary fibrosis treatment agent and a pulmonary fibrosis treatment method using the carrier.
- pulmonary fibrosis can be effectively treated by administering a composition in which an extracellular matrix production inhibitor is supported on a carrier containing retinoid.
- the headline and the present invention were completed. It has been known that carriers containing vitamin A deliver drugs to stellate cells that store vitamin A (see Patent Document 8), but the relationship with pulmonary fibrosis has never been known.
- the present invention relates to the following.
- a carrier for substance delivery to an extracellular matrix-producing cell in the lung comprising a retinoid as a targeting agent.
- a composition for treating pulmonary fibrosis comprising the carrier according to any one of (1) to (4) above and a drug that controls the activity or proliferation of extracellular matrix-producing cells in the lung.
- the composition according to (5) above which is selected from the group consisting of chimeric polynucleotides and vectors expressing them.
- composition according to (6) above wherein the molecule involved in the production or secretion of an extracellular matrix constituent molecule is HSP47.
- 9 including one or more containers containing drugs, retinoids, and optionally carrier constituents other than retinoids, alone or in combination, that control the activity or proliferation of extracellular matrix-producing cells in the lung
- retinoids are targeted to extracellular matrix-producing cells in the lung such as fibroblasts and myofibroblasts. It is considered that an anti-pulmonary fibrosis effect is exerted by delivering an active ingredient, for example, a drug that controls the activity or proliferation of extracellular matrix-producing cells in the lung, to the cells. Accordingly, since the active ingredient can be efficiently delivered to the site of action and further to the target cells by the carrier of the present invention, pulmonary fibrosis, particularly idiopathic interstitial pneumonia, which has been difficult to treat, can be cured and progressed.
- an active ingredient for example, a drug that controls the activity or proliferation of extracellular matrix-producing cells in the lung
- the carrier of the present invention can be combined with an arbitrary drug (for example, an existing pulmonary fibrosis therapeutic drug) to increase its action efficiency, it has a wide range of pharmaceutical applications and produces an effective therapeutic agent. There is also an advantage that it can be performed easily.
- an arbitrary drug for example, an existing pulmonary fibrosis therapeutic drug
- FIG. 1 is a schematic diagram showing pulmonary fibrosis induction and drug administration schedule in rats.
- FIG. 2 is a graph showing the total number of cells in the BAL fluid on the 21st day after bleomycin administration. Normal controls are normal rats that have not been administered bleomycin.
- FIG. 3 is a graph showing the amount of lung hydroxyproline (HP) on the 21st day after bleomycin administration. Normal controls are normal rats that have not been administered bleomycin.
- FIG. 4 is a photograph showing a HE-stained image of lung tissue 21 days after bleomycin administration.
- FIG. 5 is a photograph showing an Azan staining image of lung tissue 21 days after bleomycin administration.
- FIG. 6 is a photograph showing the distribution of ⁇ SMA positive cells in lung tissue on the 21st day after bleomycin administration.
- the extracellular matrix-producing cells in the lung are not particularly limited as long as they are cells having an extracellular matrix-producing ability present in the lung, and include, for example, fibroblasts and myofibroblasts present in the lungs.
- fibroblasts present in the lung include vascular outer membrane fibroblasts and bronchiole outer membrane fibroblasts.
- the myofibroblasts present in the lung are not only derived from fibroblasts present in the lung, but also derived from fibroblasts in the circulating blood, and are converted from endothelial cells by endothelial mesenchymal transdifferentiation. May also be included.
- Myofibroblasts are characterized by the expression of ⁇ -SMA ( ⁇ smooth muscle actin).
- the myofibroblasts in the present invention are identified by immunostaining using a detectably labeled anti- ⁇ -SMA antibody.
- fibroblasts express vimentin characteristic of mesenchymal cells but do not express ⁇ -SMA, and thus can be identified by double staining of vimentin and ⁇ -SMA.
- the retinoid in the present invention is not particularly limited as long as it promotes substance delivery to the extracellular matrix-producing cells in the lung.
- retinol vitamin A
- etretinate tretinoin
- isotretinoin adapalene
- acitretin tazarotene
- palmiticin Retinoid derivatives such as acid retinol
- vitamin A analogs such as fenretinide (4-HPR) and bexarotene
- the retinoid in the present invention promotes specific substance delivery to extracellular matrix-producing cells in the lung.
- retinoids specifically bound to RBP (retinol binding protein) is located on the cell surface of extracellular matrix-producing cells in the lung. It is thought that it is taken up into the same cell through the receptor of a seed
- RBP retinol binding protein
- Retinoids are a member of a group of compounds with a skeleton in which four isoprenoid units are linked in a head-to-tail manner (GP Moss, “Biochemical Nomenclature and Related Documents,” 2nd Ed. Portland Press, pp. 247 -251 (1992)), vitamin A is a general descriptor of retinoids that qualitatively shows the biological activity of retinol.
- the retinoid that can be used in the present invention is not particularly limited, for example, retinol, retinal, retinoic acid, ester of retinol and fatty acid, ester of aliphatic alcohol and retinoic acid, etretinate, tretinoin, isotretinoin, adapalene, Mention may be made of retinoid derivatives such as acitretin, tazarotene, retinol palmitate, and vitamin A analogues such as fenretinide (4-HPR), bexarotene.
- retinoid derivatives such as acitretin, tazarotene, retinol palmitate, and vitamin A analogues such as fenretinide (4-HPR), bexarotene.
- retinol, retinal, retinoic acid, esters of retinol with fatty acids (eg retinyl acetate, retinyl palmitate, retinyl stearate, and retinyl laurate) and esters of fatty alcohols with retinoic acid (Eg, ethyl retinoate) is preferred in terms of the efficiency of delivery of specific substances to extracellular matrix-producing cells in the lung. All isomers, including cis-trans of retinoids, are within the scope of the present invention.
- the retinoid may also be substituted with one or more substituents.
- the retinoid in the present invention includes not only an isolated state but also a retinoid in a state of being dissolved or mixed in a medium capable of dissolving or holding the same.
- the carrier of the present invention may be constituted by these retinoids themselves, or may be constituted by binding or including a retinoid in another carrier component. Therefore, the carrier of the present invention may contain carrier components other than retinoids. Such components are not particularly limited, and any of those known in the pharmaceutical and pharmaceutical fields can be used, but those that can include or bind to retinoids are preferred. Examples of such components include lipids, phospholipids such as glycerophospholipid, sphingolipids such as sphingomyelin, sterols such as cholesterol, vegetable oils such as soybean oil and poppy oil, lecithins such as mineral oil and egg yolk lecithin, and the like. However, it is not limited to these.
- liposomes for example, natural phospholipids such as lecithin, semisynthetic phospholipids such as dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), and dioleylphosphatidylethanol Amine (DOPE), dilauroyl phosphatidylcholine (DLPC), cholesterol and the like are preferable.
- natural phospholipids such as lecithin
- semisynthetic phospholipids such as dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), and dioleylphosphatidylethanol Amine (DOPE), dilauroyl phosphatidylcholine (DLPC), cholesterol and the like are preferable.
- DMPC dimyristoylphosphatidy
- Particularly preferred components include components that can avoid capture by the reticuloendothelial system, such as N- ( ⁇ -trimethylammonioacetyl) -didodecyl-D-glutamate chloride (TMAG), N, N ′, N ′′, N ′ ′′-tetramethyl-N, N ′, N ′′, N ′ ′′-tetrapalmitylspermine (TMTPS), 2,3-dioleyloxy-N- [2 (sperminecarboxamido) ethyl] -N , N-dimethyl-1-propanaminium trifluoroacetate (DOSPA), N- [1- (2,3-dioleyloxy) propyl] -N, N, N-trimethylammonium chloride (DOTMA), dioctadecyldimethyl Ammonium chloride (DODAC), didodecyl ammonium bromide (DDAB), 1,2-dioleyloxy-3 Trimethyl
- the binding or inclusion of the retinoid to the carrier of the present invention can also be achieved by binding or including the retinoid to other components of the carrier by chemical and / or physical methods.
- the retinoid can be bound or included in the carrier of the present invention by mixing the retinoid and other carrier components at the time of producing the carrier.
- the amount of retinoid bound to or included in the carrier of the present invention is 0.01% to 100%, preferably 0.2% to 20%, more preferably 1 to 5% by weight in the carrier component. Is possible.
- the binding or inclusion of the retinoid to the carrier may be performed before the drug is loaded on the carrier, or may be performed by mixing the carrier, the retinoid derivative, etc. and the drug simultaneously, or the drug Etc.
- the present invention also provides a step of binding a retinoid to any existing drug-binding carrier or drug-encapsulating carrier, for example, a liposome preparation such as DaunoXome (registered trademark), Doxil, Caelix (registered trademark), Myocet (registered trademark). And a method for producing a preparation specific for extracellular matrix-producing cells in the lung.
- a liposome preparation such as DaunoXome (registered trademark), Doxil, Caelix (registered trademark), Myocet (registered trademark).
- the form of the carrier of the present invention may be any form as long as a desired substance or substance can be delivered to the extracellular matrix-producing cells in the target lung, for example, but not limited to, polymeric micelles, liposomes, emulsions , Microspheres, nanospheres, and the like.
- a desired substance or substance can be delivered to the extracellular matrix-producing cells in the target lung
- polymeric micelles, liposomes, emulsions , Microspheres, nanospheres, and the like for example, but not limited to, polymeric micelles, liposomes, emulsions , Microspheres, nanospheres, and the like.
- the form of liposomes is preferred, and among these, cationic liposomes containing cationic lipids are particularly preferred.
- the molar ratio of the retinoid to the other liposome-constituting lipid is preferably 8: 1 to 1: 4, considering the efficiency of binding or inclusion of the retinoid to the carrier.
- the ratio is preferably 4: 1 to 1: 2, more preferably 3: 1 to 1: 1, particularly 2: 1.
- the retinoid contained therein may contain a transported material inside, or may be attached to the outside of the transported material, It may be mixed with a transported item.
- functioning as a targeting agent means that a carrier containing a retinoid reaches and / or takes up extracellular matrix-producing cells in the lung, which is a target cell, more rapidly and / or in a larger amount than a carrier containing no retinoid. This can be easily confirmed, for example, by adding a carrier with a label or containing a label to a culture of target cells and analyzing the site of the label after a predetermined time. .
- the above requirement can be satisfied if the retinoid is at least partially exposed to the outside of the preparation containing the carrier before reaching the target cell at the latest. Whether or not the retinoid is exposed to the outside of the preparation is evaluated by contacting the preparation with a substance that specifically binds to the retinoid, for example, retinol binding protein (RBP) and investigating the binding to the preparation. be able to.
- a substance that specifically binds to the retinoid for example, retinol binding protein (RBP) and investigating the binding to the preparation.
- the substance or object to be delivered by the carrier is not particularly limited, but is preferably sized so that it can be physically moved from the administration site to the lesion site where the target cells are present. Therefore, the carrier of the present invention carries not only substances such as atoms, molecules, compounds, proteins, and nucleic acids but also objects such as vectors, virus particles, cells, drug release systems composed of one or more elements, and micromachines. be able to.
- the substance or object preferably has a property that has some influence on the target cell, such as one that labels the target cell or one that controls (eg, enhances or suppresses) the activity or proliferation of the target cell. including.
- the substance delivered by the carrier is a “drug that controls the activity or proliferation of extracellular matrix-producing cells in the lung”.
- the activity of extracellular matrix-producing cells in the lung refers to various activities such as secretion, uptake, and migration that are exhibited by the extracellular matrix-producing cells in the lung. In particular, it means an activity involved in the onset, progression and / or recurrence of pulmonary fibrosis.
- Such activities include, but are not limited to, gelatinase A and B (MMP2 and 9 respectively), physiologically active substances such as angiotensinogen, collagen, proteoglycan, tenastin, fibronectin, thrombospondin, osteopontin, osteonectin, elastin Production and secretion of extracellular matrix components such as
- drugs that control the activity or proliferation of extracellular matrix-producing cells in the lung include physical, chemical, and / or physiological effects of the cells related to the onset, progression, and / or recurrence of pulmonary fibrosis, etc.
- Dominant negative effects such as antibodies and antibody fragments, substances such as siRNA, ribozyme, antisense nucleic acid (including RNA, DNA, PNA, or a complex thereof) that suppress the expression of the physiologically active substance, or dominant negative mutants
- the “drug that regulates the activity or proliferation of extracellular matrix-producing cells in the lung” in the present invention refers to extracellular matrix production in the lung that is directly or indirectly related to suppression of the onset, progression, and / or recurrence of pulmonary fibrosis. Any drug that directly or indirectly promotes the physical, chemical and / or physiological actions of cells may be used.
- the delivery of the carrier of the present invention is not limited, and drugs other than those mentioned above that suppress the onset, progression and / or recurrence of pulmonary fibrosis, such as, but not limited to, colchicine, D-penicillamine, pirfenidone ( 5-methyl-1-phenyl-2- [1H] -pyridone), interferon ⁇ 1a, relaxin, N-acetylcysteine, keratinocyte growth factor, captopril, hepatocyte growth factor, Rho kinase inhibitor, thrombomodulin-like protein, bilirubin, PPAR ⁇ Activators, imatinib, interferon ⁇ , TGF ⁇ receptor kinase inhibitors and the like can be mentioned.
- drugs other than those mentioned above that suppress the onset, progression and / or recurrence of pulmonary fibrosis such as, but not limited to, colchicine, D-penicillamine, pirfenidone ( 5-
- the substance or object delivered by the carrier of the present invention may or may not be labeled. Labeling makes it possible to monitor the success or failure of transportation and the increase / decrease of target cells, and is particularly useful at the test / research level.
- the label is selected from any known to those skilled in the art, for example, any radioisotope, magnetic substance, substance that binds to the labeling substance (eg, antibody), fluorescent substance, fluorophore, chemiluminescent substance, enzyme, and the like can do.
- “for extracellular matrix-producing cells in the lung” or “for delivering extracellular matrix-producing cells in the lung” means that the extracellular matrix-producing cells in the lung are suitable for use as target cells.
- the carrier of the present invention is an extracellular matrix-producing cell in the lung that is 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.5 times or more, 2 times or more as compared with other cells.
- the substance can be delivered at a rate and / or efficiency that is three times or more.
- the present invention also includes the carrier and a drug that controls the activity or proliferation of extracellular matrix-producing cells in the lung, or for controlling the activity or proliferation of extracellular matrix-producing cells in the lung, or lung fibrosis As well as the use of said carriers for the production of these compositions.
- pulmonary fibrosis includes not only pulmonary fibrosis in a narrow sense but also pulmonary fibrosis in a broad sense including coexistence with interstitial pneumonia.
- pulmonary fibrosis refers to any interstitial pneumonia such as viral pneumonia, fungal pneumonia, infectious interstitial pneumonia accompanying mycoplasma pneumonia, rheumatoid arthritis, systemic scleroderma, dermatomyositis, multiple Interstitial pneumonia associated with collagen disease such as hereditary myositis, mixed connective tissue disease (MCTD), interstitial pneumonia associated with radiation exposure, anticancer agents such as bleomycin, Chinese medicine such as Shosaikoto, interferon, antibiotics, paraquat, etc.
- interstitial pneumonia such as viral pneumonia, fungal pneumonia, infectious interstitial pneumonia accompanying mycoplasma pneumonia, rheumatoid arthritis, systemic scleroderma, dermatomyositis, multiple Interstitial pneumonia associated with collagen disease such as hereditary myositis, mixed connective tissue disease (MCTD), interstitial pneumonia associated with radiation exposure, anticancer agents such as bleomycin, Chinese medicine such as Shosaikoto, interferon
- Drug-induced interstitial pneumonia idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, idiopathic organizing pneumonia, respiratory bronchiolitis-related interstitial lung disease, exfoliative interstitium Pneumonia, idiopathic interstitial pneumonia such as lymphocytic interstitial pneumonia and the like, and thus include those in which these interstitial pneumonia has become chronic.
- the pulmonary fibrosis in the present invention preferably includes a chronic form of drug-induced interstitial pneumonia and idiopathic interstitial pneumonia.
- the carrier may contain the delivery product inside or be attached to the outside of the delivery product. It may also be mixed with a delivery product.
- the composition may be coated with a suitable material, such as an enteric coating or a time-disintegrating material, and a suitable drug release system. It may be incorporated.
- the compositions of the present invention may be used in a variety of routes including both oral and parenteral, including, but not limited to, oral, intravenous, intramuscular, subcutaneous, topical, intrapulmonary, intratracheal, intratracheal, intrabronchial.
- dosage forms suitable for oral administration include, but are not limited to, powders, granules, tablets, capsules, solutions, suspensions, emulsions, gels, syrups, etc.
- Suitable dosage forms include injections such as solution injections, suspension injections, emulsion injections, and injections prepared at the time of use.
- Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile solutions or suspensions.
- the carrier or composition of the present invention may be supplied in any form, but from the viewpoint of storage stability, it is preferably in a form ready for use, for example, at or near the medical site and / or It is provided in a form that can be prepared by a pharmacist, nurse, or other paramedical.
- the carrier or composition of the present invention is provided as one or more containers comprising at least one of the essential components thereof, and is used before use, for example, within 24 hours, preferably 3 Prepared within an hour and more preferably immediately before use.
- reagents, solvents, dispensing devices and the like that are usually available at the place of preparation can be appropriately used.
- the present invention also provides a kit for preparing a carrier or composition comprising one or more containers containing retinoids and / or deliverables and / or carrier constituents other than retinoids, alone or in combination, It also relates to the necessary components of the carrier or composition provided in the form of such a kit.
- the kit of the present invention may contain instructions on how to prepare and administer the carrier and composition of the present invention, and electronic recording media such as CD and DVD.
- the kit of the present invention may contain all of the components for completing the carrier or composition of the present invention, but may not necessarily contain all of the components. Therefore, the kit of the present invention may not contain reagents and solvents that are usually available at medical sites, experimental facilities, etc., such as sterile water, physiological saline, and glucose solution.
- the present invention further includes administering an effective amount of the composition to a subject in need thereof, for controlling the activity or proliferation of extracellular matrix-producing cells in the lung, or treating pulmonary fibrosis Related to the method.
- the effective amount is, for example, the amount that suppresses the onset or recurrence of pulmonary fibrosis, reduces the symptoms, or delays or stops the progression of the latter, preferably the onset of pulmonary fibrosis and An amount that prevents or cures recurrence.
- an amount that does not cause adverse effects exceeding the benefits of administration is preferred.
- Such an amount can be appropriately determined by an in vitro test using cultured cells or the like and a test in a model animal such as a mouse, rat, dog or pig, and such a test method is well known to those skilled in the art. .
- the doses of retinoid contained in the carrier and the drug used in the method of the present invention are known to those skilled in the art or can be appropriately determined by the above-described tests and the like.
- the specific dose of the composition to be administered in the methods of the present invention can vary depending on various conditions related to the subject in need of treatment, such as severity of symptoms, general health of the subject, age, weight, subject sex, diet, administration It may be determined in consideration of the timing and frequency of the drug, the medicine used in combination, the response to the treatment, the compliance with the treatment, and the like.
- Administration routes include various routes including both oral and parenteral, such as oral, intravenous, intramuscular, subcutaneous, topical, intrapulmonary, intratracheal, intratracheal, intrabronchial, nasal, rectal, Includes routes such as intraarterial, intraportal, intraventricular, intramedullary, intralymphatic, intralymphatic, intracerebral, intrathecal, intraventricular, transmucosal, transdermal, intranasal, intraperitoneal, and intrauterine. It is.
- the frequency of administration varies depending on the properties of the composition used and the conditions of the subject as described above.
- the term “subject” means any living individual, preferably an animal, more preferably a mammal, more preferably a human individual.
- a subject may be healthy or afflicted with some disease, but when treatment of pulmonary fibrosis is contemplated, typically interstitial pneumonia or lung fibrosis Means a subject suffering from or at risk of being affected.
- interstitial pneumonia particularly idiopathic interstitial pneumonia, without limitation.
- treatment is also intended to encompass all types of medically acceptable prophylactic and / or therapeutic interventions intended to cure, temporarily ameliorate or prevent disease.
- the term “treatment” includes medically acceptable interventions for various purposes, including delaying or stopping the progression of pulmonary fibrosis, regression or disappearance of lesions, preventing or preventing the onset of pulmonary fibrosis, etc. Is included.
- the present invention also relates to a method for delivering a drug to extracellular matrix-producing cells in the lung using the carrier.
- This method is not limited, and includes, for example, a step of carrying a delivery product on the carrier, and administering or adding the carrier carrying the delivery product to an organism or medium containing extracellular matrix-producing cells in the lung, such as a culture medium. Including the step of. These steps can be appropriately achieved according to any known method or the method described in the present specification.
- the delivery method can also be combined with other delivery methods, such as other delivery methods targeting the lung.
- the method includes an embodiment performed in vitro and an embodiment targeting extracellular matrix-producing cells in the lungs of the body.
- siRNA targeting gp46 GenBank Accession No. M69246
- a rat Homologue of human HSP47 a rat Homologue of human HSP47
- control random siRNA purchased from Hokkaido System Science.
- Each siRNA consists of 27 bases having an overhang on the 3 ′ side, and the sequence is as follows.
- Sequence A 5′-GUUCCCACCAUAAGUGUGGUACACAAGAG-3 ′ (sense, SEQ ID NO: 1) 5′-GUUGGUCUACUCAUCUAUUGUGGAGAAU-3 ′ (antisense, SEQ ID NO: 2)
- Sequence B 5′-CCACAAGUUUAUAUUCCAAUCUAGCAG-3 ′ (sense, SEQ ID NO: 3) 5′-GCUAGAUUGGAUAUAAAACUUGUGGAU-3 ′ (antisense, SEQ ID NO: 4)
- Sequence C 5′-CUAGAGCCAUUACAAUUACAAUGACAAG-3 ′ (sense, SEQ ID NO: 5) 5′-UGUCAAUGUUAAUGUAAUGGCUCUAGAU-3 ′ (antisense, SEQ ID NO: 6) random siRNA: 5'-CGAUUCCGCUAGACCGGCUUCAUUGCAG-3 '(sense, SEQ ID NO: 7) 5′-GCAAUGAGGCCGGUCUAGCGAAUCG
- Example 2 Production of siRNA-containing VA-bound liposomes As liposomes, cationic liposomes (Lipotrust, Hokkaido System Science) containing DC-6-14, cholesterol and DOPE in a molar ratio of 4: 3: 3 were used. In a 1.5 ml tube, 10 nmol of liposome and 20 nmol of vitamin A (VA: all-trans retinol, Sigma) were mixed in DMSO, dissolved in chloroform, once evaporated, and suspended in PBS. Thereafter, siRNA (10 ⁇ g / ml) obtained in Example 1 and the liposome suspension were mixed at a ratio of 1: 1 (w / w).
- VVA all-trans retinol
- VA-lip-siRNA siRNA-containing VA-bound liposomes
- Example 3 Anti-pulmonary fibrosis activity of siRNA-containing VA-bound liposomes in vivo (1) Induction of pulmonary fibrosis and administration of drugs SD male rats (6 rats per group, 4 weeks old, Charles River) , Bleomycin (BLM) 0.5 mg dissolved in 0.5 cc physiological saline was cannulated into the trachea under anesthesia and administered intrapulmonary once into the lung. Produced. This method usually causes significant fibrosis in the lungs in about 3 weeks.
- VA-lip-siRNA prepared in Example 2 (0.75 mg / kg as siRNA amount, 1 ml / kg as volume, ie 200 ⁇ l in 200 g rat) or PBS (volume of 1 ml / kg) was administered on the day of bleomycin administration From the tail vein at a frequency of 3 times / week. On day 21 after bleomycin administration, the animals were euthanized, and bronchoalveolar lavage (BAL) fluid analysis, pulmonary hydroxyproline quantification, and histological examination of lung tissue were performed (see FIG. 1). Note that Student's t-test was used to evaluate statistical significance.
- BAL bronchoalveolar lavage
- BAL liquid BAL was performed as follows. That is, the animals were given a lethal dose of pentobarbital sodium intraperitoneally and then thoracotomy was performed to expose the trachea and a cannula was inserted into the trachea. Thereafter, 7 ml of physiological saline was injected into the lung through the tracheal cannula, and the lavage fluid was collected. This injection and recovery operation was repeated 5 times, and the recovered washings were combined and centrifuged at 250 ⁇ g for 10 minutes. The total number of cells was counted using a hemocytometer, and the cell fraction was counted on smears by cell centrifugation stained with May Giemsa.
Abstract
Description
ビタミンAを含む担体が、ビタミンAを貯蔵する星細胞に薬物を送達することは知られていたが(特許文献8参照)、肺線維症との関係についてはこれまで全く知られていなかった。
(1)レチノイドを標的化剤として含む、肺における細胞外マトリックス産生細胞への物質送達用担体。
(2)レチノイド誘導体がレチノールを含む上記(1)の担体。
(3)レチノイドの含有量が担体全体の0.2~20重量%である上記(1)または(2)の担体。
(4)リポソームの形態を有し、レチノイドと、リポソームに含まれる脂質とのモル比が8:1~1:4である上記(1)~(3)のいずれかの担体。
(5)上記(1)~(4)のいずれかの担体と、肺における細胞外マトリックス産生細胞の活性または増殖を制御する薬物とを含む、肺線維症処置用組成物。
(6)肺における細胞外マトリックス産生細胞の活性または増殖を制御する薬物が、ゼラチナーゼA、ゼラチナーゼBおよびアンギオテンシノーゲンからなる群から選択される生理活性物質の活性または産生阻害剤、細胞活性抑制剤、増殖阻害剤、アポトーシス誘導剤、および、細胞外マトリックス構成分子または該細胞外マトリックス構成分子の産生もしくは分泌に関与する分子の少なくとも1つを標的とするsiRNA、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチドおよびこれらを発現するベクターからなる群から選択される上記(5)の組成物。
(7)細胞外マトリックス構成分子の産生もしくは分泌に関与する分子がHSP47である上記(6)の組成物。
(8)薬物と担体とを、医療の現場またはその近傍で混合してなる上記(5)~(7)のいずれかの組成物。
(9)肺における細胞外マトリックス産生細胞の活性または増殖を制御する薬物、レチノイド、ならびに、必要に応じてレチノイド以外の担体構成物質を、単独でまたは組み合わせて含む1つまたはそれ以上の容器を含む、上記(5)~(8)のいずれかの組成物の調製キット。
したがって、本発明の担体により、有効成分を作用部位、さらには標的細胞に効率的に送達できるため、肺線維症、特にこれまで治療が困難であった特発性間質性肺炎などの治癒、進行の抑制または発症の予防が可能となり、ヒト医療および獣医療への貢献は極めて大きい。
また、本発明の担体は、任意の薬剤(例えば、既存の肺線維症治療薬)と組み合わせてその作用効率を高めることができるため、製剤的な応用範囲が広く、効果的な処置剤の製造を簡便に行うことができるという利点もある。
本発明におけるレチノイドは、肺における細胞外マトリックス産生細胞への特異的な物質送達を促進するものである。レチノイドによる物質送達促進の機構は未だ完全には解明されていないが、例えば、RBP(retinol binding protein)と特異的に結合したレチノイドが、肺における細胞外マトリックス産生細胞の細胞表面上に位置するある種のレセプターを介して同細胞に取り込まれることが考えられる。
レチノイドは、4個のイソプレノイド単位がヘッド-トゥー-テイル式に連結した骨格を持つ化合物の群の1員であり(G. P. Moss, “Biochemical Nomenclature and Related Documents,” 2nd Ed. Portland Press, pp. 247-251 (1992)を参照)、ビタミンAは、レチノールの生物学的活性を定性的に示すレチノイドの一般的な記述子である。本発明において用いることができるレチノイドとしては、特に限定されず、例えばレチノール、レチナール、レチノイン酸、レチノールと脂肪酸とのエステル、脂肪族アルコールとレチノイン酸とのエステル、エトレチナート、トレチノイン、イソトレチノイン、アダパレン、アシトレチン、タザロテン、パルミチン酸レチノールなどのレチノイド誘導体、およびフェンレチニド(4-HPR)、ベキサロテンなどのビタミンAアナログを挙げることができる。
これらのうち、レチノール、レチナール、レチノイン酸、レチノールと脂肪酸とのエステル(例えばレチニルアセテート、レチニルパルミテート、レチニルステアレート、およびレチニルラウレートなど)および脂肪族アルコールとレチノイン酸とのエステル(例えばエチルレチノエートなど)は、肺における細胞外マトリックス産生細胞への特異的な物質の送達の効率の点で好ましい。
レチノイドのシス-トランスを含む異性体全ては、本発明の範囲内に入る。レチノイドはまた1または2以上の置換基で置換されることもある。本発明におけるレチノイドは、単離された状態のものはもちろんのこと、これを溶解または保持することができる媒体に溶解または混合した状態のレチノイドをも含む。
このような成分としては、脂質、例えば、グリセロリン脂質などのリン脂質、スフィンゴミエリンなどのスフィンゴ脂質、コレステロールなどのステロール、大豆油、ケシ油などの植物油、鉱油、卵黄レシチンなどのレシチン類等が挙げられるが、これらに限定されない。このうち、リポソームを構成し得るもの、例えば、レシチンなどの天然リン脂質、ジミリストイルホスファチジルコリン(DMPC)、ジパルミトイルホスファチジルコリン(DPPC)、ジステアロイルホスファチジルコリン(DSPC)などの半合成リン脂質、ジオレイルホスファチジルエタノールアミン(DOPE)、ジラウロイルホスファチジルコリン(DLPC)、コレステロールなどが好ましい。
本発明の担体が送達する物質や物体は、標識されていてもいなくてもよい。標識化により、運搬の成否や、標的細胞の増減などをモニタリングすることが可能となり、特に試験・研究レベルにおいて有用である。標識は、当業者に公知な任意のもの、例えば、任意の放射性同位体、磁性体、標識化物質に結合する物質(例えば抗体)、蛍光物質、フルオロフォア、化学発光物質、および酵素などから選択することができる。
本発明において「肺における細胞外マトリックス産生細胞用」または「肺における細胞外マトリックス産生細胞送達用」とは、肺における細胞外マトリックス産生細胞を標的細胞として使用するのに適することを意味し、これは例えば、同細胞に、他の細胞、例えば正常細胞よりも迅速、高効率かつ/または大量に物質を送達できることを含む。例えば、本発明の担体は、肺における細胞外マトリックス産生細胞に、他の細胞に比べ、1.1倍以上、1.2倍以上、1.3倍以上、1.5倍以上、2倍以上、さらには3倍以上の速度および/または効率で物質を送達することができる。
本発明において肺線維症は、狭義の肺線維症のみならず、間質性肺炎との併存を含む広義の肺線維症を含む。本発明における肺線維症は、任意の間質性肺炎、例えば、ウイルス性肺炎、真菌性肺炎、マイコプラズマ肺炎などに伴う感染性間質性肺炎、関節リウマチ、全身性強皮症、皮膚筋炎、多発性筋炎、混合性結合組織病(MCTD)などの膠原病に伴う間質性肺炎、放射線被曝に伴う間質性肺炎、ブレオマイシンなどの抗癌剤、小柴胡湯などの漢方薬、インターフェロン、抗生物質、パラコートなどによる薬剤性間質性肺炎、特発性肺線維症、非特異性間質性肺炎、急性間質性肺炎、特発性器質化肺炎、呼吸細気管支炎関連性間質性肺疾患、剥離性間質性肺炎、リンパ球性間質性肺炎などの特発性間質性肺炎などに起因し得、したがって、これらの間質性肺炎が慢性化したものを含む。本発明における肺線維症は、好ましくは薬剤性間質性肺炎および特発性間質性肺炎が慢性化したものを含む。
本発明の組成物は、経口および非経口の両方を包含する種々の経路、例えば、限定することなく、経口、静脈内、筋肉内、皮下、局所、肺内、気道内、気管内、気管支内、経鼻、直腸内、動脈内、門脈内、心室内、骨髄内、リンパ節内、リンパ管内、脳内、髄液腔内、脳室内、経粘膜、経皮、鼻内、腹腔内および子宮内等の経路で投与してもよく、各投与経路に適した剤形に製剤してもよい。かかる剤形および製剤方法は任意の公知のものを適宜採用することができる(例えば、標準薬剤学、渡辺喜照ら編、南江堂、2003年などを参照)。
例えば、経口投与に適した剤形としては、限定することなく、散剤、顆粒剤、錠剤、カプセル剤、液剤、懸濁剤、乳剤、ゲル剤、シロップ剤などが挙げられ、また非経口投与に適した剤形としては、溶液性注射剤、懸濁性注射剤、乳濁性注射剤、用時調製型注射剤などの注射剤が挙げられる。非経口投与用製剤は、水性または非水性の等張性無菌溶液または懸濁液の形態であることができる。
投与経路としては、経口および非経口の両方を包含する種々の経路、例えば、経口、静脈内、筋肉内、皮下、局所、肺内、気道内、気管内、気管支内、経鼻、直腸内、動脈内、門脈内、心室内、骨髄内、リンパ節内、リンパ管内、脳内、髄液腔内、脳室内、経粘膜、経皮、鼻内、腹腔内および子宮内等の経路が含まれる。
投与頻度は、用いる組成物の性状や、上記のような対象の条件によって異なるが、例えば、1日多数回(すなわち1日2、3、4回または5回以上)、1日1回、数日毎(すなわち2、3、4、5、6、7日毎など)、1週間に数回(例えば、1週間に2、3、4回など)、1週間毎、数週間毎(すなわち2、3、4週間毎など)であってもよい。
また、用語「処置」は、疾患の治癒、一時的寛解または予防などを目的とする医学的に許容される全ての種類の予防的および/または治療的介入を包含するものとする。例えば、「処置」の用語は、肺線維症の進行の遅延または停止、病変の退縮または消失、肺線維症発症の予防または再発の防止などを含む、種々の目的の医学的に許容される介入を包含する。
実施例1 siRNAの作製
ヒトHSP47のラットホモログであるgp46(GenBank Accession No. M69246)を標的とする3種類のsiRNA、および、コントロールのrandom siRNAは、北海道システムサイエンスより購入した。各siRNAは3’側にオーバーハングを有する27の塩基からなり、配列は以下のとおりである。
配列A:5’-GUUCCACCAUAAGAUGGUAGACAACAG-3’(センス、配列番号:1)
5’-GUUGUCUACCAUCUUAUGGUGGAACAU-3’(アンチセンス、配列番号:2)
配列B:5’-CCACAAGUUUUAUAUCCAAUCUAGCAG-3’(センス、配列番号:3)
5’-GCUAGAUUGGAUAUAAAACUUGUGGAU-3’(アンチセンス、配列番号:4)
配列C:5’-CUAGAGCCAUUACAUUACAUUGACAAG-3’(センス、配列番号:5)
5’-UGUCAAUGUAAUGUAAUGGCUCUAGAU-3’(アンチセンス、配列番号:6)
random siRNA:5’-CGAUUCGCUAGACCGGCUUCAUUGCAG-3’(センス、配列番号:7)
5’-GCAAUGAAGCCGGUCUAGCGAAUCGAU-3’(アンチセンス、配列番号:8)
また、蛍光色素6’-カルボキシフルオレセイン(6-FAM)を5’側に標識したsiRNAも作製した。
リポソームとして、DC-6-14、コレステロールおよびDOPEを4:3:3のモル比で含むカチオン性リポソーム(Lipotrust、北海道システムサイエンス)を用いた。1.5mlチューブにて10nmolのリポソームと20nmolのビタミンA(VA:全トランスレチノール、Sigma)とをDMSO中で混合後、クロロホルムで溶解し、一度蒸散後、PBSに懸濁した。その後、実施例1で得たsiRNA(10μg/ml)とリポソーム懸濁液とを1:1(w/w)の割合で混合した。得られたリポソーム懸濁液に含まれる遊離のVAおよびsiRNAをマイクロパーティションシステム(Sartorion VIVASPIN 5000MWCO PES)で除去し、siRNA含有VA結合リポソーム(VA-lip-siRNA)を得た。添加したVA量と精製リポソーム内に含まれるVA量をHPLC法で測定し、リポソームに結合したVAの割合を検討したところ、VAの大部分(95.6±0.42%)がリポソームに結合したことが判明した。また、siRNAのリポソームへの取り込み効率は、RiboGreen assay(Molecular Probes)で測定したところ、94.4±3.0%と高いものであった。なお、この製剤は、VAを製剤の外部に少なくとも部分的に露出しているものであった。
(1)肺線維症の惹起および薬剤の投与
S-D雄性ラット(1群6匹、4週齢、チャールズリバー)に対して、ブレオマイシン(BLM)0.5mgを0.5ccの生理食塩水に溶解したものを、麻酔下、気管内にカニューレを挿入して経気管的に1回肺内投与し、ブレオマイシン肺線維症モデルを作製した。この方法により、通常3週間程度で肺に顕著な線維化が生じる。実施例2で調製したVA-lip-siRNA(siRNA量として0.75mg/kg、容量として1ml/kg、すなわち200gのラットで200μl)またはPBS(1ml/kgの容量)を、ブレオマイシンを投与した日から、3回/週の頻度で尾静脈より投与した。ブレオマイシン投与後21日目に動物を安楽死させ、気管支肺胞洗浄(BAL)液の分析、肺内ヒドロキシプロリンの定量および肺組織の組織学的検討を行った(図1参照)。なお、統計学的有意差の評価にはStudentのt検定を用いた。
BALは次のようにして行った。すなわち、動物に致死量のペントバルビタールナトリウムを腹腔内投与した後に開胸し、気管を露出して気管内にカニューレを挿入した。その後、7mlの生理食塩水を気管カニューレを通して肺に注入し、その洗浄液を回収した。この注入、回収操作を5回繰り返し、回収した洗浄液を合わせ、250×gで10分間遠心した。総細胞数は血球計算板を用いて計数し、細胞分画の計数はメイ・ギムザ染色した細胞遠心による塗沫標本で行なった。細胞は最低200個を計数し、通常の形態的基準に基づいて、マクロファージ、好酸球、好中球、リンパ球に分類した。総細胞数の計数結果を図2に示す。同図より、BAL液中の細胞数は、VA-lip-siRNA投与群(BLM siRNA)において、ブレオマイシンの代わりにPBSを投与した正常対照ラット(control)と同程度まで、PBS投与群(BLM alone)に比べ有意に低下しており、炎症が改善していることが示された。
BAL後、肺を摘出して、片肺全てをポリトロンホモジナイザーを用いてホモジネートし、Kivirikkoらの方法(Kivirikko KI, et al. Analytical biochemistry 1967; 19: 249-255)により、肺ヒドロキシプロリンを定量した。すなわち、肺組織を、6N塩酸中110℃で18時間ホモゲナイズし、25μlのアリコートを60℃で乾燥させた。これを1.2mlの50%イソプロパノールで溶解し、pH6.0 acetate citrate、0.56% クロラミンT溶液200mlで10分間室温でインキュベートした後、1mlのEhrlich液を添加して50℃で90分間インキュベートし、560nmの吸光度を測定した。図3に示す結果によれば、肺ヒドロキシプロリン量(μg)は、VA-lip-siRNA投与群(BLM siRNA)においてPBS投与群(BLM alone)に比べ有意に低下しており、肺の線維化が顕著に抑制されたことが示された。
摘出肺の一部を定法に従いホルマリン固定し、ヘマトキシリン・エオジン(HE)染色、アザン染色(アゾカルミン、アニリン青オレンジG液)または抗αSMA抗体による免疫染色に供した。免疫染色は、脱パラフィン後、マウス抗α-SMA抗体(ニチレイ、クローン1A4)を1次抗体として、次いでペルオキシダーゼ標識抗マウスIgGを2次抗体としてそれぞれ反応させ、DABで発色させた。図4のHE染色の結果が示すとおり、PBS投与群(BLM day 21)においては、肺胞の消失、出血像および間質の増生などの肺線維症に特徴的な所見が見られたのに対し、VA-lip-siRNA投与群(BLM+siRNA)では線維化病変が著明に改善していた。同様に、図5のアザン染色の結果が示すとおり、PBS投与群(BLM alone)においては、青色に染色された大量の膠原線維による間質の拡大を特徴とする顕著な線維化像が見られたのに対し、VA-lip-siRNA投与群(BLM+siRNA)では線維化が明白に抑制されていた。また、図6のαSMA染色の結果が示すとおり、PBS投与群(BLM alone)においては、間質に褐色を呈するαSMA陽性細胞が多数見られたのに対し、VA-lip-siRNA投与群(BLM+siRNA)ではαSMA陽性細胞が著明に減少していた。
siRNAが基本的に細胞質内で作用することを考慮すれば、以上の結果は、レチノイドが肺における細胞外マトリックス産生細胞への標的化剤として機能し、同細胞に効率的に薬物を送達することにより、肺線維症の病態を顕著に改善したことを示すものである。
Claims (9)
- レチノイドを標的化剤として含む、肺における細胞外マトリックス産生細胞への物質送達用担体。
- レチノイド誘導体がレチノールを含む、請求項1に記載の担体。
- レチノイドの含有量が担体全体の0.2~20重量%である、請求項1または2に記載の担体。
- リポソームの形態を有し、レチノイドと、リポソームに含まれる脂質とのモル比が8:1~1:4である、請求項1~3のいずれかに記載の担体。
- 請求項1~4のいずれかに記載の担体と、肺における細胞外マトリックス産生細胞の活性または増殖を制御する薬物とを含む、肺線維症処置用組成物。
- 肺における細胞外マトリックス産生細胞の活性または増殖を制御する薬物が、ゼラチナーゼA、ゼラチナーゼBおよびアンギオテンシノーゲンからなる群から選択される生理活性物質の活性または産生阻害剤、細胞活性抑制剤、増殖阻害剤、アポトーシス誘導剤、および、細胞外マトリックス構成分子または該細胞外マトリックス構成分子の産生もしくは分泌に関与する分子の少なくとも1つを標的とするsiRNA、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチドおよびこれらを発現するベクターからなる群から選択される、請求項5に記載の組成物。
- 細胞外マトリックス構成分子の産生もしくは分泌に関与する分子がHSP47である、請求項6に記載の組成物。
- 薬物と担体とを、医療の現場またはその近傍で混合してなる、請求項5~7のいずれかに記載の組成物。
- 肺における細胞外マトリックス産生細胞の活性または増殖を制御する薬物、レチノイド、ならびに、必要に応じてレチノイド以外の担体構成物質を、単独でまたは組み合わせて含む1つまたはそれ以上の容器を含む、請求項5~8のいずれかに記載の組成物の調製キット。
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US13/648,543 US8574623B2 (en) | 2004-12-22 | 2012-10-10 | Therapeutic agent for pulmonary fibrosis |
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US14/668,618 US20150259683A1 (en) | 2004-12-22 | 2015-03-25 | Agent for treating renal fibrosis |
US14/883,370 US10098953B2 (en) | 2008-03-17 | 2015-10-14 | Therapeutic agent for fibroid lung |
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- 2009-03-16 KR KR1020107018949A patent/KR20110010692A/ko active Search and Examination
- 2009-03-16 US US12/933,075 patent/US20110104255A1/en not_active Abandoned
- 2009-03-16 WO PCT/JP2009/001148 patent/WO2009116257A1/ja active Application Filing
- 2009-03-16 PL PL09722829T patent/PL2258395T3/pl unknown
- 2009-03-16 DK DK09722829.0T patent/DK2258395T3/en active
- 2009-03-16 ES ES09722829.0T patent/ES2563983T3/es active Active
- 2009-03-16 KR KR1020157034553A patent/KR101627514B1/ko active IP Right Grant
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- 2009-03-16 RU RU2010142226/15A patent/RU2547571C2/ru active
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- 2009-03-16 CN CN201610141000.2A patent/CN105727300A/zh active Pending
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2013
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2015
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