US20110104255A1 - Therapeutic agent for fibroid lung - Google Patents

Therapeutic agent for fibroid lung Download PDF

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US20110104255A1
US20110104255A1 US12/933,075 US93307509A US2011104255A1 US 20110104255 A1 US20110104255 A1 US 20110104255A1 US 93307509 A US93307509 A US 93307509A US 2011104255 A1 US2011104255 A1 US 2011104255A1
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carrier
retinoid
lung
extracellular matrix
drug
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Yoshiro Niitsu
Rishu Takimoto
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Nitto Denko Corp
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • 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
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • 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
    • 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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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • 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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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
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    • C—CHEMISTRY; METALLURGY
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
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    • C12N2310/351—Conjugate
    • C12N2310/3515—Lipophilic moiety, e.g. cholesterol
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    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/32—Special delivery means, e.g. tissue-specific

Definitions

  • the present invention relates to a substance delivery carrier targeted at extracellular matrix-producing cells in the lung, and a therapeutic agent for pulmonary fibrosis and a method for treating pulmonary fibrosis utilizing the carrier.
  • Pulmonary fibrosis is a disease characterized by diffuse fibroplasia of the alveolar walls, and its main symptoms include dry cough and dyspnea on exertion. Ina restricted sense, it refers to end-stage disease states of interstitial pneumonia; while in a broad sense, it means a co-existing state of pulmonary fibrosis in a restricted sense with interstitial pneumonia. Any interstitial pneumonia can cause pulmonary fibrosis.
  • Interstitial pneumonia is a generic term for the diseases that induce inflammation in interstices of the lung (including alveolar septum in a restricted sense, and intralobular interstice and the vicinity of pleural membrane in a broad sense); it includes those induced by a specific cause such as infection, collagen disease, radiation, drug, and dust, and those without any known cause, i.e., idiopathic interstitial pneumonia.
  • Idiopathic interstitial pneumonia is further classified as follows based on the findings of video-assisted thoracoscopic surgery (VATS) and high-resolution computer tomography (HRCT): idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), lymphoid interstitial pneumonia (LIP), etc.
  • VATS video-assisted thoracoscopic surgery
  • HRCT computer tomography
  • IPF idiopathic pulmonary fibrosis
  • NIP nonspecific interstitial pneumonia
  • AIP acute interstitial pneumonia
  • COP cryptogenic organizing pneumonia
  • RB-ILD respiratory bronchiolitis-associated interstitial lung disease
  • DIP desquamative interstitial pneumonia
  • LIP lymphoid interstitial pneumonia
  • idiopathic interstitial pneumonia there is no radical treatment method to date, and only treatments such as administration of steroid drugs, azathioprine and cyclophosphamide during exacerbation of symptoms, and oxygen therapy during development of hypoxemia are performed; accordingly, there are many dead cases in which idiopathic interstitial pneumonia progresses into pulmonary fibrosis. Therefore, the average survival period after establishment of diagnosis of idiopathic interstitial pneumonia is as short as 2.5-5 years, and this disease is designated as one of the specific diseases in Japan.
  • Non Patent Literature 1 Non Patent Literature 1
  • hepatocyte growth factor Patent Literature 1
  • Rho-kinase inhibitor Patent Literature 2
  • thrombomodulin-like protein Patent Literature 3
  • bilirubin Patent Literature 4
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma activator
  • imatinib Patent Literature 6
  • interferon-y Patent Literature 7
  • Patent Literature 1 JP A No. 8-268906
  • Patent Literature 2 WO 00/57913
  • Patent Literature 3 JP A No. 2002-371006
  • Patent Literature 4 JP A No. 2003-119138
  • Patent Literature 5 JP A No. 2005-513031
  • Patent Literature 6 JP A No. 2005-531628
  • Patent Literature 7 JP A No. 2006-502153
  • Patent Literature 8 WO 2006/068232
  • Non Patent Literature 1 Ann Intern Med. 2001; 134(2): 136-51
  • An object of the present invention is to provide a carrier that can deliver a substance such as drugs specifically to extracellular matrix-producing cells in the lung, as well as a therapeutic agent for pulmonary fibrosis and a method for treating pulmonary fibrosis utilizing said carrier.
  • the inventors of the present invention have searched for novel therapeutic agents for pulmonary fibrosis, and found that the administration of a composition in which a carrier comprising a retinoid carries an inhibitor for the production of extracellular matrix can effectively treat pulmonary fibrosis; then the inventors have completed this invention.
  • the present invention relates to the following:
  • retinoid functions as a targeting agent to extracellular matrix-producing cells in the lung such as fibroblasts and myofibroblasts, and the retinoid delivers an active ingredient such as pharmaceutical agents that control activity or growth of extracellular matrix-producing cells in the lung to such cells, thereby exhibiting the effect against pulmonary fibrosis.
  • the inventive carrier significantly contributes to the human medicine and veterinary medicine.
  • the carrier of the present invention can be combined with any pharmaceutical drugs (for example, existing therapeutic agents for pulmonary fibrosis) to increase their action efficiency; therefore, it is also advantageous as its application range in terms of formulation is broad, facilitating the production of effective therapeutic agents.
  • any pharmaceutical drugs for example, existing therapeutic agents for pulmonary fibrosis
  • FIG. 1 is a schematic diagram showing induction of pulmonary fibrosis in rats and drug-administration schedule.
  • FIG. 2 is a graph showing the total number of cells in BAL liquid on day 21 after administration of bleomycin. “Control” means normal rats without administration of bleomycin.
  • FIG. 3 is a graph showing the amount of hydroxyproline (HP) in the lung on day 21 after administration of bleomycin. “Control” means normal rats without administration of bleomycin.
  • FIG. 4 shows photographs of HE-stained lung tissues on day 21 after administration of bleomycin.
  • FIG. 5 shows photographs of Azan-stained lung tissues on day 21 after administration of bleomycin.
  • FIG. 6 shows photographs showing distribution of ⁇ SMA-positive cells in the lung tissues on day 21 after administration of bleomycin.
  • the extracellular matrix-producing cells in the lung are not particularly limited as long as they are cells present in the lung and having a capability of producing extracellular matrix, and they include, for example, fibroblasts and myofibroblasts present in the lung.
  • Fibroblasts present in the lung include, for example, vascular adventitial fibroblasts and bronchiolar adventitial fibroblasts, etc.
  • Myofibroblasts present in the lung may include not only those derived from such fibroblasts present in the lung, but also those derived from fibroblasts in the circulating blood and those transformed from endothelial cells by endothelial mesenchymal transdifferentiation.
  • Myofibroblasts are characterized by expression of ⁇ -smooth muscle actin ( ⁇ -SMA).
  • the myofibroblasts in the present invention are those identified, e.g., by immunostaining using detectably-labeled anti- ⁇ -SMA antibodies.
  • fibroblasts express vimentin that is characteristic to mesenchymal cells, they do not express ⁇ -SMA; therefore, fibroblasts can be identified by double-staining with vimentin and ⁇ -SMA.
  • the retinoid of the present invention is not particularly limited as long as it promotes delivery of a substance to extracellular matrix-producing cells in the lung, and examples thereof include retinoid derivatives such as retinol (vitamin A), etretinate, tretinoin, isotretinoin, adapalene, acitretine, tazarotene, and retinol palmitate, as well as vitamin A analogues such as fenretinide (4-HPR, 4-hydroxyphenylretinamide) and bexarotene.
  • the retinoid of the present invention is that which promotes specific delivery of a substance to extracellular matrix-producing cells in the lung.
  • the mechanism of the promotion of substance delivery by retinoid has not yet been completely clarified; however, the following mechanism is considered: for example, a retinoid which has specifically bound to a retinol-binding protein (RBP) is taken into an extracellular matrix-producing cell in the lung through a certain receptor present on the surface of this cell.
  • RBP retinol-binding protein
  • a retinoid is a member of the class of compounds having a skeleton in which four isoprenoid units are bonded in a head-to-tail manner (see G. P. Moss, “Biochemical Nomenclature and Related Documents,” 2nd Ed. Portland Press, pp. 247-251 (1992)).
  • Vitamin A is a generic descriptor for a retinoid that qualitatively shows the biological activity of retinol.
  • Retinoid that can be used in the present invention are not particularly limited, and examples thereof include retinoid derivatives such as retinol, retinal, retinoic acid, an ester of retinol and a fatty acid, an ester of an aliphatic alcohol and retinoic acid, etretinate, tretinoin, isotretinoin, adapalene, acitretine, tazarotene and retinol palmitate, and vitamin A analogues such as fenretinide (4-HPR) and bexarotene.
  • retinoid derivatives such as retinol, retinal, retinoic acid, an ester of retinol and a fatty acid, an ester of an aliphatic alcohol and retinoic acid, etretinate, tretinoin, isotretinoin, adapalene, acitretine, tazarotene and retinol palmitate,
  • retinol, retinal, retinoic acid, an ester of retinol and a fatty acid such as retinyl acetate, retinyl palmitate, retinyl stearate and retinyl laurate
  • an ester of an aliphatic alcohol and retinoic acid such as ethyl retinoate
  • retinoid isomers such as cis-trans
  • the retinoid may be substituted with one or more substituents.
  • the retinoid in the present invention includes a retinoid in an isolated state as well as in a solution or mixture state with a medium that can dissolve or retain the retinoid.
  • the carrier of the present invention may be formed from the retinoid on its own or may be formed by making the retinoid bind to or enclosed in a carrier constituent component other than the retinoid. Therefore, the carrier of the present invention may comprise a carrier constituent component other than the retinoid.
  • a carrier constituent component is not particularly limited, and any component known in the medicinal and pharmaceutical fields may be used, but those that can enclose retinoid or can bind thereto are preferable.
  • a component examples include a lipid, for example, a phospholipid such as glycerophospholipid, a sphingolipid such as sphingomyelin, a sterol such as cholesterol, a vegetable oil such as soybean oil or poppy seed oil, a mineral oil, and a lecithin such as egg-yolk lecithin, but the examples are not limited thereto.
  • a phospholipid such as glycerophospholipid
  • a sphingolipid such as sphingomyelin
  • a sterol such as cholesterol
  • a vegetable oil such as soybean oil or poppy seed oil
  • mineral oil a mineral oil
  • lecithin such as egg-yolk lecithin
  • those that can forma liposome are preferable, for example, a natural phospholipid such as lecithin, a semisynthetic phospholipid such as dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), or distearoylphosphatidylcholine (DSPC), and dioleylphosphatidylethanolamine (DOPE), dilauroylphosphatidylcholine (DLPC), and cholesterol.
  • DMPC dimyristoylphosphatidylcholine
  • DPPC dipalmitoylphosphatidylcholine
  • DSPC distearoylphosphatidylcholine
  • DOPE dioleylphosphatidylethanolamine
  • DLPC dilauroylphosphatidylcholine
  • a particularly preferred component is a component that can avoid capture by the reticuloendothelial system, and examples thereof include cationic lipids 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), dioctadecyldimethylammonium chloride (DODAC), didodecylammonium bromide (DDAB), 1,2-dioleyloxy-3-trimethyl
  • the binding of the retinoid to the carrier of the present invention or the enclosing of it therein is also possible by binding or enclosing the retinoid to or in a constituent component, other than the retinoid, of the carrier by a chemical and/or physical method.
  • the binding or enclosing the retinoid to or in the carrier of the present invention can also be carried out by mixing the retinoid and a constituent component, other than the retinoid, of the carrier when preparing the carrier.
  • the amount of retinoid bound to or enclosed in the carrier of the present invention may be, as a weight ratio in the carrier constituent components, 0.01% to 100%, preferably 0.2% to 20%, and more preferably 1% to 5%.
  • the binding or enclosing of retinoid to or in the carrier may be performed before a drug, etc. is carried on the carrier, may be performed by simultaneously mixing the carrier, a retinoid derivative and a drug, etc., or may be performed by mixing a retinoid derivative with a carrier on which a drug, etc. is already carried. Therefore, the present invention also relates to a process for producing a formulation specific to extracellular matrix-producing cells in the lung, the process including a step of binding a retinoid to any existing drug binding carrier or drug encapsulating carrier, for example, a liposomal formulation such as DaunoXome®, Doxil, Caelyx®, or Myocet®.
  • the form of the carrier of the present invention may be any form as long as a desired substance or matter can be transported to a target extracellular matrix-producing cell in the lung, and although not limited thereto, examples thereof include a macromolecular micelle, a liposome, an emulsion, microspheres, and nanospheres.
  • a liposomal form is preferable among the forms, and a cationic liposome that includes a cationic lipid is particularly preferable.
  • the molar ratio of the retinoid to liposome constituent components other than the retinoid is, considering the efficiency of retinoid's binding to or enclosing in the carrier, preferably 8:1 to 1:4, more preferably 4:1 to 1:2, yet more preferably 3:1 to 1:1, and particularly preferably 2:1.
  • the carrier of the present invention may contain a substance to be transported within its interior, may be attached to the exterior of a substance to be transported, or may be mixed with a substance to be transported, as long as retinoid contained therein is present in such a form that it can function as a targeting agent.
  • “Function as a targeting agent” referred to here means that the carrier containing retinoid reaches and/or is taken up by the target cell, i.e., extracellular matrix-producing cells in the lung, more rapidly and/or in a larger quantity than with a carrier not containing retinoid, and this may easily be confirmed by, for example, adding a labeled or label-containing carrier to a culture of target cells, and analyzing the sites where the label is present after a predetermined period of time. Structurally, this requirement can be satisfied, for example, if retinoid is at least partially exposed to the exterior of a formulation containing the carrier at the latest by the time it reaches the target cell.
  • Whether or not the retinoid is exposed at the exterior of a formulation can be evaluated by contacting the formulation to a substance that specifically binds to retinoid, such as a retinol-binding protein (RBP), and evaluating the binding to the formulation.
  • a substance that specifically binds to retinoid such as a retinol-binding protein (RBP)
  • RBP retinol-binding protein
  • the substance or matter that is delivered by the present carrier is not particularly limited, and it preferably has a size such that it can physically move within the body of a living being from an administration site to a lesion site where a target cell is present. Therefore, the carrier of the present invention can transport not only a substance such as an atom, a molecule, a compound, a protein, or a nucleic acid, but also a matter such as a vector, a virus particle, a cell, a drug-releasing system formed from one or more elements, or a micromachine.
  • the above substance or matter preferably has the property of having some influence on a target cell, and examples thereof include those that label a target cell and those that control (e.g. increase or suppress) the activity or growth of a target cell.
  • the substance that the carrier delivers is “a drug controlling the activity or growth of an extracellular matrix-producing cell in the lung”.
  • the activity of an extracellular matrix-producing cell in the lung referred to here indicates various activities such as secretion, uptake, migration, etc. exhibited by an extracellular matrix-producing cell in the lung, and in the present invention among them it typically means, in particular, activities involved in the onset, progression, and/or recurrence of pulmonary fibrosis.
  • Such activities include, but are not limited to, production/secretion of a bioactive substance such as gelatinase A and gelatinase B (MMP (matrix metalloproteinase) 2 and MMP 9, respectively) and angiotensinogen, etc., and an extracellular matrix component such as collagen, proteoglycan, tenascin, fibronectin, thrombospondin, osteopontin, osteonectin, and elastin.
  • MMP matrix metalloproteinase
  • angiotensinogen etc.
  • an extracellular matrix component such as collagen, proteoglycan, tenascin, fibronectin, thrombospondin, osteopontin, osteonectin, and elastin.
  • the drug controlling the activity or growth of an extracellular matrix-producing cell in the lung may be any drug that directly or indirectly suppresses the physical, chemical, and/or physiological actions, etc. of said cell related to the onset, progression, and/or recurrence of pulmonary fibrosis, and while not being limited thereto, it includes the following: drugs inhibiting the activity or production of the above bioactive substances, MMP inhibitors such as batimastat, and antibodies and antibody fragments that neutralize the above bioactive substances, and substances that suppress expression of the above bioactive substances, such as an siRNA, a ribozyme, an antisense nucleic acid (including RNA, DNA, PNA (peptide nucleic acid), or a composite thereof), and substances that have a dominant negative effect such as a dominant negative mutant, or a vector expressing the same, drugs suppressing the production and secretion of the above extracellular matrix component, etc., for example, substances that suppress expression of the extracellular matrix component, such as an siRNA, a ribozyme,
  • the “drug controlling the activity or growth of an extracellular matrix-producing cell in the lung” in the present invention may be any drug that directly or indirectly promotes the physical, chemical, and/or physiological actions, etc. of an extracellular matrix-producing cell in the lung directly or indirectly related to the suppression of onset, progression, and/or recurrence of pulmonary fibrosis.
  • the substance delivered by the carrier of the invention include, without limitation, drugs other than those mentioned above and which suppress the onset, progression, and/or recurrence of pulmonary fibrosis, and examples include, but are 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 ⁇ activator, imatinib, interferon- ⁇ , and TGF ⁇ receptor kinase inhibitor.
  • the substance or matter delivered by the carrier of the present invention may or may not be labeled. Labeling enables monitoring of the success or failure of transport, increases and decreases in target cells, etc., and is particularly useful at the testing/research level.
  • a label may be selected from any label known to a person skilled in the art such as, for example, any radioisotope, magnetic material, substance that binds to a labeling substance (e.g. an antibody), fluorescent substance, fluorophore, chemiluminescent substance, and enzyme, etc.
  • “for an extracellular matrix-producing cell in the lung” or “for the delivery to an extracellular matrix-producing cell in the lung” means that it is suitable to use to extracellular matrix-producing cells as a target, and this includes it being possible to deliver a substance to this cell, more rapidly, efficiently, and/or in a larger quantity than to other cells, for example, normal cells.
  • the carrier of the present invention can deliver a substance to an extracellular matrix-producing cell in the lung at a rate and/or efficiency of 1.1 times or more, 1.2 times or more, 1.3 times or more, 1.5 times or more, 2 times or more, or even 3 times or more compared with other cells.
  • the present invention also relates to a composition for controlling the activity or growth of an extracellular matrix-producing cell in the lung, or for treating pulmonary fibrosis, that comprises the carrier, and the drug controlling the activity or growth of an extracellular matrix-producing cell in the lung, and to a use of the carrier in the production of such compositions.
  • pulmonary fibrosis includes not only pulmonary fibrosis in a restricted sense, but also pulmonary fibrosis in a broad sense that includes co-existence of interstitial pneumonia.
  • the pulmonary fibrosis of the present invention can be caused by any interstitial pneumonia, for example, infectious interstitial pneumonia associated with viral pneumonia, fungal pneumonia, mycoplasmal pneumonia, etc., interstitial pneumonia associated with collagen disease such as rheumatoid arthritis, systemic scleroderma, dermatomyositis, polymyositis, mixed connective-tissues disease (MCTD), etc., interstitial pneumonia associated with radiation exposure, drug-induced interstitial pneumonia caused by anticancer agents such as bleomycin, herbal medicines such as Sho-sai-ko-to, interferon, antibiotics, paraquat, etc., and idiopathic interstitial pneumonia such as idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, acute interstitial pneumonia, cryptogenic organizing
  • the carrier may contain a substance to be delivered within its interior, may be attached to the exterior of a substance to be delivered, or may be mixed with a substance to be delivered. Therefore, depending on the administration route and the manner in which the drug is released, etc., the composition may be covered with an appropriate material such as, for example, an enteric coating or a material that disintegrates over time, or may be incorporated into an appropriate drug release system.
  • composition of the present invention may be administered via various routes including both oral and parenteral routes, and examples thereof include, but are not limited to, oral, intravenous, intramuscular, subcutaneous, local, intrapulmonary, intra-airway, intratracheal, intrabronchial, nasal, rectal, intraarterial, intraportal, intraventricular, intramedullar, intra-lymph-node, intralymphatic, intrabrain, intrathecal, intracerebroventricular, transmucosal, percutaneous, intranasal, intraperitoneal, and intrauterine routes, and it may be formulated into a dosage form suitable for each administration route.
  • Such a dosage form and formulation method may be selected as appropriate from any known dosage forms and methods (see e.g. Hyojun Yakuzaigaku (Standard Pharmaceutics), Ed. by Yoshiteru Watanabe et al., Nankodo, 2003).
  • dosage forms suitable for oral administration include, but are not limited to, powder, granule, tablet, capsule, liquid, suspension, emulsion, gel, and syrup
  • examples of the dosage form suitable for parenteral administration include injections such as an injectable solution, an injectable suspension, an injectable emulsion, and a ready-to-use injection.
  • Formulations for parenteral administration may be a form such as an aqueous or nonaqueous isotonic sterile solution or suspension.
  • the carrier or the composition of the present invention may be supplied in any form, but from the viewpoint of storage stability, it is preferably provided in a ready-to-use form, for example in a form that allows a doctor and/or a pharmacist, a nurse, another paramedic, etc. to prepare it at the place of treatment or in the vicinity thereof.
  • the carrier or the composition of the present invention is provided as one or more containers containing at least one essential constituent element therefor, and it is prepared prior to use, for example, within 24 hours prior to use, preferably within 3 hours prior to use, and more preferably immediately prior to use.
  • a reagent, a solvent, preparation equipment, etc. that are normally available in a place of preparation may be used as appropriate.
  • the present invention therefore also relates to a preparation kit for the carrier or the composition, the kit including one or more containers containing singly or in combination a retinoid, and/or a substance to be delivered, and/or a carrier-constituting substance other than the retinoid, and also to a constituent element necessary for the carrier or the composition provided in the form of such a kit.
  • the kit of the present invention may contain, in addition to the above, instructions, an electronic recording medium such as a CD or DVD related to a process for preparing the carrier and the composition of the present invention, or an administration method, etc.
  • the kit of the present invention may include all of the constituent elements for completing the carrier or the composition of the present invention, but need not always include all of the constituent elements. Therefore, the kit of the present invention need not include a reagent or a solvent that is normally available at a place of medical treatment, an experimental facility, etc. such as, for example, sterile water, physiological saline, or a glucose solution.
  • the present invention further relates to a method for controlling the activity or growth of an extracellular matrix-producing cell in the lung, or a method for treating pulmonary fibrosis, the method including administering an effective amount of the composition to a subject in need thereof.
  • the effective amount referred to here is, in a method for treating pulmonary fibrosis, for example, an amount that suppresses the onset or recurrence of pulmonary fibrosis, alleviates its symptoms, or delays or stops its progression, and is preferably an amount that prevents the onset or recurrence of pulmonary fibrosis or cures it. It is also preferably an amount that does not cause an adverse effect that exceeds the benefit from administration.
  • Such an amount may be determined as appropriate by an in vitro test using cultured cells or by a test in a model animal such as a mouse, a rat, a dog, or a pig, and such test methods are well known to a person skilled in the art.
  • a model animal such as a mouse, a rat, a dog, or a pig
  • the dose of the retinoid contained in the carrier and the dose of the drug used in the method of the present invention are known to a person skilled in the art, or may be determined as appropriate by the above-mentioned test, etc.
  • the specific dose of the composition administered may be determined while taking into consideration various conditions with respect to a subject in need of the treatment, such as the severity of symptoms, general health condition of the subject, age, body weight, gender of the subject, diet, the timing and frequency of administration, a medicine used in combination, response to the treatment, compliance with the treatment, etc.
  • oral and parenteral routes there are various routes including both oral and parenteral routes, and examples thereof include oral, intravenous, intramuscular, subcutaneous, local, intrapulmonary, intra-airway, intratracheal, intrabronchial, nasal, rectal, intraarterial, intraportal, intraventricular, intramedullar, intra-lymph-node, intralymphatic, intrabrain, intrathecal, intracerebroventricular, transmucosal, percutaneous, intranasal, intraperitoneal, and intrauterine routes.
  • the frequency of administration depends on the properties of the composition used and the above-mentioned conditions of the subject, and may be a plurality of times per day (that is, 2, 3, 4, 5, or more times per day), once a day, every few days (that is, every 2, 3, 4, 5, 6, or 7 days, etc.), a few times per week (e.g. 2, 3, 4 times, etc. per week), every other week, or every few weeks (that is, every 2, 3, 4 weeks, etc.).
  • the term “subject” means any living individual, preferably an animal, more preferably a mammal, and yet more preferably a human individual.
  • the subject maybe healthy or affected by some disorder, and when treatment of pulmonary fibrosis is intended, it typically means a subject affected by interstitial pneumonia or pulmonary fibrosis, or having a risk of being affected by them.
  • typical examples include, but are not limited to, a subject affected by interstitial pneumonia, in particular by idiopathic interstitial pneumonia.
  • treatment includes all types of medically acceptable preventive and/or therapeutic intervention for the purpose of the cure, temporary remission, or prevention of a disorder, etc.
  • treatment includes medically acceptable intervention of various purposes, including delaying or stopping the progression of pulmonary fibrosis, regression or disappearance of lesions, prevention of onset and prevention of recurrence of pulmonary fibrosis.
  • the present invention also relates to a method for delivering a drug to an extracellular matrix-producing cell in the lung, utilizing the above carrier.
  • This method includes, but is not limited to, for example, a step of loading a substance to be delivered on the carrier, and a step of administering or adding the carrier having the substance to be delivered carried thereon to a living being or a medium, for example a culture medium, containing an extracellular matrix-producing cell in the lung. These steps may be achieved as appropriate in accordance with any known method or a method described in the present specification, etc.
  • the above delivery method may be combined with another delivery method, for example, another delivery method targeted at the lung.
  • the above method includes a mode carried out in vitro and a mode in which an extracellular matrix-producing cell in the lung inside the body is targeted.
  • siRNA targeted at gp46 (GenBank Accession No. M69246), which is a rat homologue of human HSP47, and a random siRNA control were purchased from Hokkaido System Science Co., Ltd. Each siRNA consists of 27 bases overhanging on the 3′ side, and the sequences are as follows.
  • siRNA that was labeled on the 5′ side with the fluorescent dye 6′-carboxyfluorescein (6-FAM) was also prepared.
  • a cationic liposome containing DC-6-14, cholesterol, and DOPE at a molar ratio of 4:3:3 (Lipotrust, Hokkaido System Science Co., Ltd.) was used. 10 nmol of liposome and 20 nmol of vitamin A (VA: all-trans retinol, Sigma) were mixed in DMSO using a 1.5-mL tube, then dissolved in chloroform, evaporated once, and then suspended in PBS (phosphate buffered saline). Subsequently, the siRNA (10 ⁇ g/mL) obtained in Example 1 and the liposome suspension were mixed at a ratio of 1:1 (w/w).
  • VA-lip-siRNA siRNA-containing VA-bound liposome
  • the VA-lip-siRNA prepared in Example 2 (0.75 mg/kg as an amount of siRNA, 1 ml/kg in volume, i.e., 200 ⁇ l for a rat of 200 g) or PBS (1 ml/kg in volume) was administered to the rats via the tail vein, starting from the day of administration of bleomycin, at a frequency of 3 times/week.
  • the rats were sacrificed 21 days after the bleomycin administration, and bronchoalveolar lavage (BAL) fluid was analyzed, hydroxyproline in the lung was quantified, and histological investigation of the lung tissue was performed (see FIG. 1 ). Student's t-test was used for the evaluation of statistically-significant difference.
  • BAL Analysis of BAL was performed as follows. The rats were intraperitoneally administered with a lethal dose of pentobarbital sodium, their thorax was opened, then the trachea was exposed and a cannula was inserted into the trachea. Subsequently, 7 ml of physiological saline was injected into the lung via the tracheal cannula and the lavage fluid was collected. This process of injection and collection was repeated 5 times, and the collected lavage fluids were combined and centrifuged at 250 ⁇ g for 10 min. The total number of cells was counted using a cytometer, and cell fraction count was performed using a May-Giemsa stained cytospin smear preparation.
  • FIG. 2 This figure shows that the number of cells in the BAL fluid of the VA-lip-siRNA administration group (BLM siRNA) significantly decreased to the level similar to that of the normal control rat administered with PBS instead of bleomycin, compared to the PBS administration group (BLM alone); suggesting that inflammation has been improved.
  • BBM siRNA VA-lip-siRNA administration group
  • the lung was removed from the rats after BAL, then one whole lung was homogenized using a polytron homogenizer, and the lung hydroxyproline was quantified using a method of Kivirikko, et al. (Kivirikko K I, et al. Analytical Biochemistry 1967; 19: 249-255). Namely, the lung tissue was homogenized in 6-N hydrochloric acid at 110° C. for 18 hr, and 25- ⁇ l aliquot was dried at 60° C. It was then dissolved in 1.2 ml of 50% isopropanol, incubated with acetate citrate, pH 6.0, and 200 ml of 0.56% chloramine-T solution at room temperature for 10 min, followed by an incubation at 50° C.
  • results shown in FIG. 3 indicate that the amount of lung hydroxyproline ( ⁇ g) of the VA-lip-siRNA administration group (BLM siRNA) significantly decreased compared to that of the PBS administration group (BLM alone), suggesting that the fibrosis of the lung was significantly suppressed.
  • HE staining hematoxylin-eosin staining
  • azocarmine aniline blue orange G solution
  • immunostaining with anti- ⁇ SMA antibody after deparaffinization, samples were reacted with a mouse anti- ⁇ SMA antibody (Nichirei Corporation, clone 1A4) as a primary antibody, then with a peroxidase-labeled anti-mouse IgG as a secondary antibody, and developed with DAB.
  • HE staining a mouse anti- ⁇ SMA antibody (Nichirei Corporation, clone 1A4) as a primary antibody, then with a peroxidase-labeled anti-mouse IgG as a secondary antibody, and developed with DAB.
  • siRNA basically acts in the cytoplasm
  • the above results indicate that the retinoid functioned as a targeting agent to extracellular matrix-producing cells in the lung, so that a drug is efficiently delivered to these cells, leading to a significant improvement in disease states of pulmonary fibrosis.

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