Therapeutic agent applicable in pulmonary fibrosis

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a method for reducing extracellular matrix producing cells in lungs or suppressing an increase of the extracellular matrix producing cells in lungs, involving administering into an individual a composition containing (i) a carrier containing retinoid as a targeting agent, and (ii) a pro-drug specified in a group consisting of siRNA, RNA enzyme, anti-sense nucleic acid and DNA/RNA chimeric polynucleotide, which is targeted on HSP47, and vectors expressing said siRNA, RNA enzyme, anti-sense nucleic acid and/or DNA/RNA chimeric polynucleotide.

EFFECT: invention provides using retinoic acid as a targeting agent for the drug delivery to the extracellular matrix producing cells in the lungs.

8 cl, 6 dwg, 3 ex

 

Area of technology

The invention relates to a carrier for delivery of a substance aimed at producing extracellular matrix cells in the lungs, and therapeutic agent used in pulmonary fibrosis, and method of treatment of pulmonary fibrosis with the use of media.

The level of technology

Pulmonary fibrosis is a disease characterized by diffuse p. alveolar walls, and its main symptoms include dry cough and dyspnea on exertion. In a narrow sense, it refers to the final stage of the disease interstitial pneumonia; while in a broad sense, it means that pulmonary fibrosis is characteristic in a narrow sense interstitial pneumonia. Any interstitial pneumonia can cause pulmonary fibrosis. Interstitial pneumonia is a General term for diseases that cause inflammation of the interstitium of the lung tissue (including alveolar septum in the narrow sense and intralobular interstitium and surrounding space of the pleural membrane in the broad sense); it includes diseases caused by a specific cause, such as infection, collagen disease, irradiation, drug, and dust, and diseases that arise without identified cause, i.e. idiopathic interstitial pneumonia. Idiopathic interstitial PN�wmania divided into the following types, based on the results of video-assisted thoracoscopic surgery (WWFC) and computed tomography high-resolution (CTVR): idiopathic pulmonary fibrosis (ILP), nonspecific interstitial pneumonia (NIP), acute interstitial pneumonia (UIP), cryptogenic organized pneumonitis (COP), associated with respiratory bronchiolitis interstitial lung disease (RB-IBL), desquamative interstitial pneumonia (DIP), lymphoid interstitial pneumonia (LIP), etc. Many of interstitial pneumonia with specific causes are treated by addressing these causes and taking anti-inflammatory agents such as steroid drugs. However, for idiopathic interstitial pneumonia still there is no radical method of treatment and is performed only such treatment as the administration of steroid drugs, azathioprine and cyclophosphamide, during an exacerbation of symptoms, oxygen therapy with the development of hypoxemia; accordingly, there are many fatalities when idiopathic interstitial pneumonia goes into pulmonary fibrosis. Therefore, the average period of survival after diagnosis of idiopathic interstitial pneumonia is 2.5-5 years, and this disease is called one of the more specific�it to Japan.

In this regard, many research works had been done in the development of therapeutic agents used in pulmonary fibrosis. As a result there have been reports that pharmaceutical agents, such as colchicine, D-penicillamine, pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridon), interferon-β1, relaxin, lovastatin, beractant, N-acetylcysteine, a growth factor for keratinocytes, captopril (non-Patent Literature 1), a growth factor for hepatocytes (Patent Literature 1), an inhibitor of Rho-kinase (Patent Literature 2), thrombomodulin-like protein (Patent Literature 3), bilirubin (Patent Literature 4), PPARγ (receptor γ that activates peroxisome proliferation) activator (Patent Literature 5), imatinib (Patent Literature 6), interferon-γ (Patent Literature 7), are shown to have some efficacy in animal models of pulmonary fibrosis or in clinical trials. However, none of these agents does not meet the requirements and anticipated further development of therapeutic agents used in pulmonary fibrosis.

References

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

PA�Etna 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

Summary of the invention

Problems that will be solved by the invention

The object of this invention is to provide a carrier that can deliver a substance such as a drug, a specific way to produce extracellular matrix cells in the lungs, as well as providing a therapeutic agent used in pulmonary fibrosis, and treatment of pulmonary fibrosis with the use of the specified media.

Means for solving the problems

The authors of this invention have investigated new therapeutic agents used in pulmonary fibrosis, and found that the introduction of the composition in which a carrier containing a retinoid, is an inhibitor of the production of extracellular matrix, can effectively treat pulmonary fibrosis; then the authors have completed this invention.

Although it was known that the media containing vitamin a, can deliver the drug to stellate cells that store vitamin a (refers to Patent literature 8), the relationship with pulmonary fibrosis until now was completely unknown.

Specifically, this invention relates to the following:

(1) a Carrier for delivering a substance to produce uncle�CNY matrix cells in the lungs, containing a retinoid as a directing agent.

(2) the Carrier according to the above item (1), where the derivative retinoid contains retinol.

(3) the Carrier according to the above paragraphs (1) or (2), where the content of retinoid is 0.2-20 wt.% the total weight of the carrier.

(4) the Carrier according to any one of the above paragraphs (1) to(3), where the carrier has a form of liposome, and the molar ratio of retinoid to the lipid contained in the liposome is 8:1-1:4.

(5) a Composition for the treatment of pulmonary fibrosis, which contains a carrier according to any one of the above paragraphs (1) to(4), and a drug that controls the activity or growth producing extracellular matrix of cells in the lungs.

(6) the Composition according to the above item (5), where a drug that controls the activity or growth producing extracellular matrix of cells in the lungs, is selected from the group consisting of an agent for inhibiting activity or production of a bioactive substance selected from the group consisting of gelatinase And, gelatinase and In the angiotensinogen gene inhibitor of cellular activity, growth inhibitor, induces apoptosis agent, as well as miRNAs (small interfering RNA), ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide, which is aimed at, minicamera, one of the molecules that make up the extracellular matrix, or molecules involved in the production or secretion of these molecules, components of the extracellular matrix, and a vector that expresses the indicated miRNA, a ribozyme, antisense nucleic acid and DNA/RNA chimeric polynucleotide.

(7) the Composition according to the above item (6), where a molecule involved in the production or secretion of components of the extracellular matrix molecules, is HSP (heat shock protein) 47.

(8) the Composition according to any one of the above paragraphs (5) to(7), where the drug and carrier are mixed on the spot therapeutic treatment, or in the immediate vicinity.

(9) a Kit for preparing a composition according to any one of the above paragraphs (5) to(8), where a set contains one or more containers containing singly or in combination a medicament for inhibiting the activity or growth producing extracellular matrix of cells in the lungs, a retinoid, and optionally forming the carrier substance that is different from retinoid.

The effects of the present invention

While the exact mechanism of action of the composition for treatment of pulmonary fibrosis according to the present invention is not clear, suggest that it appears as follows: in the composition of the retinoid acts as the guide and�cient to produce extracellular matrix cells in the lungs, such as fibroblasts and myofibroblasts, and the retinoid delivers the active ingredient, such as pharmaceutical agents that control the activity or growth producing extracellular matrix of cells in the lungs, to such cells, thereby showing the effect against pulmonary fibrosis.

Accordingly, since the active ingredients can be effectively delivered to sites of action and further to the target cells using the carrier of the present invention, it is now possible treatment, prevention of the development or prevention of pulmonary fibrosis, especially idiopathic interstitial pneumonia, the treatment of which has been difficult so far; thus, the carrier according to the invention is a significant contribution to medicine and veterinary science.

Moreover, the carrier of the present invention may be combined with any pharmaceutical drugs (for example, existing therapeutic agents for pulmonary fibrosis), increasing the effectiveness of their actions; therefore, its advantage lies in the fact that he has a wide range of application from the point of view of composition that accelerates the production of effective therapeutic agents.

Brief description of the drawings:

Fig.1 is a schematic diagram showing the induction of pulmonary �of Broza in rats and schedule of drug administration.

Fig.2 is a graph showing the number of cells in the fluid taken from a bronchoalveolar lavage (BAL), on the 21st day after administration of bleomycin. "Control" are normal rats who were administered bleomycin.

Fig.3 is a graph showing the amount of hydroxyproline (HP) in the lungs on the 21st day after administration of bleomycin. "Control" are normal rats who were administered bleomycin.

Fig.4 shows photographs of lung tissue, stained with hematoxylin-eosin, on the 21st day after administration of bleomycin.

Fig.5 shows photographs of lung tissue, stained with azan, on the 21st day after administration of bleomycin.

Fig.6 shows photographs showing the distribution of αSMA-positive cells in lung tissue at 21 days after administration of bleomycin.

Description of embodiments of the invention

In the present invention for producing the extracellular matrix of cells in the lungs there is no particular limitation, as they are cells present in the lungs and has the ability of producing extracellular matrix, and include, for example, fibroblasts and myofibroblasts present in the lungs. The fibroblasts present in the lungs, include, for example, vascular adventitial fibroblasts and bronchial hell�intitially fibroblasts, etc. Myofibroblasts present in the lungs, may include not only those formed from fibroblasts present in the cells, but also those that are formed from fibroblasts in the circulating blood, and those that are transformed from endothelial cells by endothelial-mesenchymal transdifferentiation. Myofibroblasts are characterized by expression of α-smooth muscle actin (α-GMA). The myofibroblasts in the present invention are those that are identified, for example, immune staining using an anti-α-GMA antibodies marked for further detection. In addition, while fibroblasts Express vimentin, which is typical for mesenchymal cells, they do not Express α-GMA; therefore, the fibroblasts can be identified by double staining with vimentin and α-GMA.

For retinoid of the present invention there is no particular limitation, as it speeds up delivery of a substance to produce extracellular matrix cells in the lungs, and examples of retinoids include derivatives such as retinol (vitamin a), etretinate, tretinoin, isotretinoin, adapalene, acitretin, tazarotene and retinol palmitate, as well as analogues of vitamin A, such as fenretinide (4-FIU, 4-hydroxyphenylethylamine) and bexarotene.

The retinoid of the present invention is one that uskorea� specific delivery of a substance to produce extracellular matrix cells in the lungs. Mechanism to accelerate the delivery of a retinoid substances still not clear; however, suggest that it appears as follows: for example, retinoid, which forms a specific binding to retinol-binding protein (SCR), is involved in producing extracellular matrix cell in the lung via a specific receptor present on the surface of the cell.

A retinoid is a representative class of compounds having a skeleton in which four isoprenoid units are connected according to the type of "head-to-tail" (see, e.g., G. P. Moss, "Biochemical Nomenclature and Related Documents," 2nd Ed. Portland Press, pp.247-251 (1992)). Vitamin a is a generic descriptor for retinoids, which shows qualitatively the biological activity of retinol. For retinoid, which can be used in the present invention, there is no particular limitation, and examples of retinoids include derivatives such as retinol, retinal, retinoic acid, an ester of retinol and a fatty acid, an ester of aliphatic alcohol and retinoic acid, etretinate, tretinoin, isotretinoin, adapalene, acitretin, tazarotene and retinol palmitate and analogues of vitamin A, such as fenretinide (4-FIU) and bexarotene.

Among them, retinol, retinal, retinoic acid, an ester of retinol and a fatty acid (such as retinyl acetate, retinyl palmitate, retinyl St�Arat and retinyl laurate) and an ester of aliphatic alcohol and retinoic acid (such as ethyl, retinoate) are preferred from the viewpoint of the efficiency of specific delivery of a substance to the intracellular matrix-producing the cells in the lungs.

All isomers of retinoids, such as CIS-TRANS, are included in the scope of the invention. A retinoid may be substituted by one or more Deputy. The retinoid of the present invention includes a retinoid in an isolated state, as well as in the state of solution or mixture to the environment, which can dissolve or store the retinoid.

The carrier of the present invention can be formed from retinoid by itself or by creating a connection with retinoid or inclusion in a component carrier different from retinoid. Consequently, the carrier of the present invention may contain a component carrier different from retinoid. For this feature there is no particular limitation, can be used by any component known in the medical and pharmaceutical fields, but preferred are those that can include a retinoid or contact him.

Examples of such components include a lipid such as a phospholipid, such as glycerophospholipid, sphingolipid, such as sphingomyelin, Sterol, such as cholesterol, vegetable oil, such as soybean or poppy seed oil, mineral oil and lecithin, such as egg yolk lecithin, but examples are not limited. Among them, preferred are those which can form liposomes, such as natural phospho�of ipid, such as lecithin, semisynthetic phospholipid, such as dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC) or distearoylphosphatidylcholine (DSPC) and dioleoylphosphatidylcholine (DOPE), dilauroyllecithin (DLPC) and cholesterol.

Particularly preferred is a component that can avoid capture by the reticuloendothelial system, and examples of such components include cationic lipids such as N-(α-trimethylammonio-acetyl)-didodecyl-D-glutamate chloride (TMAG), N,N',N",N"'-tetramethyl-N,N',N",N"'-metropolitician (TMTPS), 2,3-valerossi-N-[2(sprintersexual)ethyl]-N,N-dimethyl-1-propanamine triptorelin (DOSPA)N-[1-(2,3-valerossi)propyl]-N,N,N-trimethylammonium chloride (DOTMA), dictatorially chloride (DODAC), deterimine bromide (DDAB), 1,2-valerossi-3-trimethylammonium-propane (DOTAP), 3β-[N-(N',N'-dimethylaminoethyl)carbamoyl]cholesterol (DC-Chol), 1,2-demeritorious-3-dimethylhydroxylamine (DMRIE) and O,O'-ditetradecyl-N-(α-trimethylammonio-acetyl)diethanolamine chloride (DC-6-14).

The binding of retinoid with the carrier of the present invention or the inclusion is also possible by linking or inclusion of retinoid with or in a component carrier different from retinoid, using chemical and/or physical way. On the other hand, the binding of retinoid with the media or inclusion in �Eitel of the present invention can also be carried out through a mix of retinoid and composite component carrier, other than retinoid, upon receipt of the carrier. The number of retinoid associated with or included in the media of the present invention, in the form of the mass fraction of components in a composite media that may be from 0.01 to 100%, preferably from 0.2% to 20% and, more preferably, from 1% to 5%. The binding of retinoid with or inclusion in the media can be done before the drug, etc. is combined with a carrier, can be realized by simultaneous mixing of the medium, derived retinoid and medicines, etc. or by mixing a derivative retinoid with media that already contains a medicament, etc. Therefore, the present invention also relates to the process of creating the composition, specific for producing extracellular matrix of cells in the lungs, wherein the process includes the step of linking retinoid with any existing media, linking a drug, or a carrier encapsulating the drug, for example, the liposome composition, such as DaunoXome®, Doxil, Caelyx® or Myocet®.

Form of media of the present invention can be any, if only the desired substance or object can be transported by producing extracellular matrix target cells in the lung, and non-limiting examples of carriers include macromolecules�rye micelles, liposomes, emulsions, microspheres and nanospheres. In the present invention, from the viewpoint of high efficiency delivery of a wide range of substances that will be delivered, and ease of establishment staff, etc.), liposomal form is preferred among the forms, and a cationic liposome, which comprises a cationic lipid, is especially preferred. In the case where the carrier is a liposomal form, the molar ratio of retinoid to composite components liposomes than retinoid is, given the efficiency of binding of retinoid with the media or turn on retinoid in the carrier, preferably from 8:1 to 1:4, more preferably from 4:1 to 1:2, even more preferably from 3:1 to 1:1 and particularly preferably 2:1.

The carrier of the present invention may contain a substance that will be transported inside its inner space, can be attached to the outer part of the substance that will be transported or may be mixed with a substance that will be transported, if only the retinoid contained therein is present in a form that could function as the guide agent. The phrase "to function as a directing agent" referred to here means a carrier containing a retinoid, reaches and/or is absorbed �year-old target, i.e. producing extracellular matrix by cells in the lungs, faster and/or more than with the carrier containing a retinoid, and this can easily confirm, for example, by adding labeled or containing the label media to the culture of target cells and analyzing the sites, where, after a predetermined period of time label. In a structural sense, this requirement may be satisfied, for example, if a retinoid, at least partially exposed on the external parts of the composition containing a carrier, at the latest when it reaches the target cell. Exposed or not a retinoid on the outer part of the composition, can be evaluated by contacting the composition with a substance that specifically binds to a retinoid, such as retinol-binding protein (SCR), and assessment of binding to the composition.

For a substance or object that are delivered by this media, there is no particular limitation, and they preferably have such a size that can physically move within the body of the living being from the place of introduction to the place of pathological changes, where there is a target cell. Consequently, the carrier of the present invention can convey not only the substance, such as atom, molecule, compound, protein or nucleic acid, but also an object such as age�'or viral particle, cell, releasing the medicinal agent system consist of one or more elements, or micro-machines. The above-mentioned substance or object preferably have a property of some effect on the target cell, and examples of such substances or objects include those that mark the target cell, and such that control (e.g. increase or inhibit) the activity or growth of the target cell.

Therefore, in one embodiment of the present invention, a substance which is delivered to the carrier, is a "drug controlling the activity or growth producing extracellular matrix cells in the lungs". The activity of producing extracellular matrix cells in the lungs, which is here referred to, involves a variety of activities, such as secretion, absorption, migration, etc., exhibited by producing extracellular matrix cell in the lungs, and in the present invention the activity usually implies, in particular, the activity involved at the beginning, the progression and/or recurrence of pulmonary fibrosis. Examples of such activities include, but are not limited to, the production/secretion of bioactive substances, such as gelatinase and gelatinase In (MMP (matrix metalloproteinase) 2 and MMP 9, respectively) and angiotensinogen, etc., and a component of the�NTA extracellular matrix, such as collagen, proteoglycan, tenascin, fibronectin, thrombospondin, osteopontin, osteonectin and elastin.

Therefore, a drug that controls the activity or growth producing extracellular matrix cells in the lungs, may be any drug that directly or indirectly suppresses the physical, chemical and/or physiological actions, etc. of the specified cells associated with the initiation, progression and/or recurrence of pulmonary fibrosis, these drugs include, but are not limited to drugs that inhibit the activity or production of the above bioactive substances, inhibitors of MMP (matrix metalloproteinases), such as batimastat, and antibodies and fragments of antibodies that neutralize the above bioactive substances, and substances which inhibit the expression of the above bioactive substances, such as miRNA, a ribozyme, antisense nucleic acid (including RNA, DNA, NCP (peptide nucleic acid), or a composite), and substances that have a dominant negative effect such as a dominant negative mutant, or a vector expressing these substances, medicines that suppress the production and secretion of the above-mentioned component of the extracellular matrix, etc., for example substances which �tableout the expression of a component of the extracellular matrix, such as miRNA, a ribozyme, antisense nucleic acid (including RNA, DNA, NCP or composite), and substances that have a dominant negative effect such as a dominant negative mutant, or a vector expressing these substances, inhibitors of cellular activity, such as a sodium channel blocker, cell growth inhibitors, such as alkylating agents (such as phosphamide, nimustine, cyclophosphamide, dacarbazine, melphalan and ranimustine), antitumor antibiotics (such as idarubicin, epirubicin, daunorubicin, doxorubicin, pirarubicin, bleomycin, peplomycin, mitoxantrone and mitomycin C), antimetabolites such as gemcitabine, enocitabine, cytarabine, tegafur/uracil, tegafur/gimeracil/oteracil sodium mixture, doxifluridine, hydroxyurea, fluorouracil, methotrexate, and mercaptopurine), alkaloids such as etoposide, irinotecan, vinorelbine, docetaxel hydrate, paclitaxel, vincristine, vindesine and vinblastine, and platinum complexes such as carboplatin, cisplatin, nedaplatin, and apoptosis inducers such as compound 861, gliotoxin, lovastatin and beractant. Moreover, a drug controlling the activity or growth producing extracellular matrix cells in the lungs" in the present invention may be any drug that directly or indirectly promotes �eticheskim, chemical and/or physiological actions, etc. cells that produce extracellular matrix in the lungs, directly or indirectly related to the suppression of the beginning, progression and/or recurrence of pulmonary fibrosis.

Substances delivered by the carrier of the invention, include without limitation drugs, other than those mentioned above, which inhibit the onset, progression and/or recurrence of pulmonary fibrosis, and examples of such substances include, but are not limited to, colchicine, D-penicillamine, pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridon), interferon-β1, relaxin, N-acetylcysteine, a growth factor for keratinocytes, captopril, a growth factor for hepatocytes, an inhibitor of Rho-kinase, thrombomodulin protein, bilirubin, a PPARγ activator, imatinib, γ-interferon and the inhibitor of TGFβ receptor kinase.

The substance or matter delivered by the carrier of the present invention may or may not be labeled. Tagging allows you to monitor successful or unsuccessful delivery, a greater or lesser portion of the injectate reached cells-targets, etc., and is particularly useful at the stage of testing/research. The label can be selected from any known to those skilled in the art, such as, for example, any radioisotope, magnetic material, a substance that binds with a substance-label (e.g., an antibody), the flu�ressentie substance fluorophore, chemiluminescent substance and an enzyme, etc.

In the present invention, the expression "for cells producing extracellular matrix in the lung or for delivery to a cell, producing extracellular matrix in the lung" means that the specified suitable for use as a target to the cells that produce extracellular matrix, and also means that the capable of delivering substance to a cell more quickly, effectively and/or in greater numbers than to other cells, such as normal cells. For example, the carrier of the present invention can deliver a substance to a cell that produces the extracellular matrix in the lung, with speed and/or efficiency, 1.1 times or more, 1.2 times or more and 1.3 times or more, 1.5 times or more, 2 times or more, or even 3 or more times greater than to other cells.

The present invention also relates to a composition for controlling the activity or growth of cells producing extracellular matrix in the lungs, or for the treatment of pulmonary fibrosis, wherein the composition comprises a carrier and a drug controlling the activity or growth of cells producing extracellular matrix in the lungs, and also relates to the use of media for obtaining such compositions.

In the present invention pulmonary fibrosis includes not only pulmonary fibrosis � narrow sense, but also pulmonary fibrosis in a broad sense, which includes associated interstitial pneumonia. Pulmonary fibrosis according to the present invention can be caused by any interstitial pneumonia, such as infectious interstitial pneumonia associated with viral pneumonia, fungal pneumonia, Mycoplasma pneumonia, etc., interstitial pneumonia associated with collagen disease, such as rheumatoid arthritis, systemic sclerosis, dermatomyositis, polymyositis, mixed connective tissue disease (SSST), etc., interstitial pneumonia associated with radiation exposure, drug-induced interstitial pneumonia caused by antitumor 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 itself pneumonia associated with respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, etc., and accordingly, pulmonary fibrosis can also be in�called chronic conditions such interstitial pneumonias. Pulmonary fibrosis according to the present invention preferably covers chronic conditions of drug-induced interstitial pneumonia and idiopathic interstitial pneumonia.

In the compositions according to the present invention, while the retinoid contained in the carrier is present in a form that functions as a directing agent, the carrier may contain a substance to be delivered, within its inner space, can be attached to the outer surface of the substance to be delivered, or may be mixed with a substance that will be delivered. Therefore, depending on the route of administration and the manner in which drug is released, etc., the composition may be covered with a suitable material, such as, for example, enteric-coated or material that decays with time, or may be included in a suitable system of release of the drug.

A composition according to the present invention may be administered by various routes including both oral and parenteral route, and examples of these pathways include, but are not limited to, oral, intravenous, intramuscular, subcutaneous, local, intrapulmonary, through the respiratory tract, intratracheal, intrabronchial, nasal, re�rest, intra-arterial, through the portal vein, intraventricular, intramedullary, through the lymph nodes, vnutripoliticheskie, intracerebral, intrathecal, intracerebroventricularly, transmucosally, subcutaneous, intranasal, intraperitoneal, and intrauterine path, and the composition may be enclosed in a dosage form suitable for each route of administration. A suitable dosage form and method of preparation of the composition can be selected from any known dosage forms and methods (see, for example, Hyojun Yakuzaigaku (Standard Pharmaceutics), Ed. by Yoshiteru Watanabe et al., Nankodo, 2003).

Examples of dosage forms suitable for oral administration include, but are not limited to, powder, granule, tablet, capsule, liquid, suspension, emulsion, gel and syrup, and examples of pharmaceutical dosage forms suitable for parenteral administration include injections, such as the injected solution, the injected slurry injected emulsion and injection, which is obtained immediately before use. Formulations for parenteral administration can be in forms such as aqueous and non-aqueous isotonic sterile solution or suspension.

The carrier or composition according to the present invention can be presented in any form, but from the point of view of stability during storage, it is preferable that �are in the form which is obtained immediately before use, for example in the form that will allow the doctor and/or pharmacist, nurse, other medical personnel, etc. to prepare them at the treatment site or in the immediate vicinity. In this case, the carrier or composition according to the present invention provided in the form of one or more containers containing at least one essential component, and it is prepared to use, for example in the 24 hours before use, preferably for 3 hours to use and more preferably immediately prior to use. When cooking can be used suitable reagent, solvent, cooking tools, etc., which are commonly available on the preparation.

Therefore, the present invention also relates to a kit for the preparation of the carrier or the composition, wherein the kit includes one or more containers, separately or in combination a retinoid and/or a substance to be delivered, and/or substance constituting the carrier that is different from retinoid, and also to compound element required for the presentation of media or compositions in the form of such a set. Additionally, the kit of the present invention may include instructions, digital media, t�such as a CD or DVD, related to the process of making media and compositions of the present invention or the method of administration, etc. moreover, the kit of the present invention may include all the elements to create media compositions of the present invention, but not necessarily always includes all the elements. Therefore, the kit of the present invention does not necessarily include a reagent or a solvent, which is usually available on the spot or therapeutic use of the experimental setup, such as, for example, sterile water, physiological saline or glucose solution.

Further, the present invention relates to a method for controlling the activity or growth of cells producing extracellular matrix in the lungs, or the method of treating pulmonary fibrosis, wherein the method comprises administering an effective amount of the composition to a subject in need of it. Mentioned effective amount of a method for the treatment of pulmonary fibrosis represents, for example, the amount that suppresses beginning or recurrence of pulmonary fibrosis, partially relieves symptoms, delaying or stopping its progression, and preferably is an amount which prevents or recurrence of pulmonary fibrosis or cures it. It is also preferred that the amount does not cause negative�enforcement actions greater than the benefit from the introduction. A suitable amount can be determined with a test in vitro using culture cells, or by using the test model animal, such as mouse, rat, dog or pig, and such test methods are well known to the person skilled in the art. Moreover, the dose of retinoid contained in the carrier, and dose of medications used in the method according to the present invention, known to the person skilled in the art or are available through the above mentioned test, etc.

In the method according to the present invention, a specific dose of the composition administered can be determined in consideration of various conditions, each subject in need of treatment, such as severity of symptoms, General health of the subject, age, weight, gender of the subject, diet, time and frequency of administration used in the combination drug, response to treatment, adherence to treatment, etc.

As the route of administration may be used various ways, including both oral and parenteral route, and examples of these pathways include, but are not limited to, oral, intravenous, intramuscular, subcutaneous, local, intrapulmonary, through the respiratory tract, intratracheal, intrabronchial, nasal, rectal, votearticle�th, through the portal vein, intraventricular, intramedullary, through the lymph nodes, vnutripoliticheskie, intracerebral, intrathecal, intracerebroventricularly, transmucosally, subcutaneous, intranasal, intraperitoneal, and intrauterine path.

Frequency of administration depends on the properties of the compositions used and the above-mentioned conditions of the subject, and the introduction can be repeated in a day (i.e. 2, 3, 4, 5 or more times per day), once a day, every few days (or once every 2, 3, 4, 5, 6 or 7 days, etc.), several times a week (e.g., 2, 3, 4, etc. times per week), a week or every few weeks (i.e., every 2, 3, 4 weeks, etc.).

In the method according to the present invention, the term "subject" means any living organism, preferably an animal, more preferably a mammal and more preferably a human individual. In the present invention the subject may be healthy or suffering from any disease, and the treatment of pulmonary fibrosis, under the subject usually refers to the subject suffering from interstitial pneumonia or pulmonary fibrosis, or those who have the risk of getting them. For example, when it is assumed prevention of pulmonary fibrosis, typical examples include, but without limiting to this, the subject suffering from interstitial pneu�nia, in particular idiopathic interstitial pneumonia.

Moreover, the term "treatment" includes all types of preventive and/or therapeutic effects that are acceptable for medical use, in order to cure, temporary remission, or prevention of disease, etc. for Example, the term "treatment" includes acceptable for medical use impacts for different purposes, including delay or stop the progression of pulmonary fibrosis, regression or disappearance of lesions, prevention of the beginning and the recurrence of pulmonary fibrosis.

The present invention also relates to a method for drug delivery to the cell that produces the extracellular matrix in the lung, using the above media. This method includes, but is not limited to, for example, the stage of loading on the carrier of the substance to be delivered, and the stage of introduction or addition of media with a portable substance that will be delivered, living creature or the environment, for example a culture medium containing a cell that produces the extracellular matrix in the lungs. These stages may be considered appropriate in accordance with any known method or a method described in the present description, etc. of the Above-mentioned delivery method can be combined with another delivery method, for example Dr�GIM method of delivery, focus on the lungs. Moreover, the aforementioned method includes the variant carried out in vitro, and a variant in which the cell that produces the extracellular matrix in the lung, inside the body is a target.

Examples

The present invention is illustrated in detail through specific examples, but these examples are for illustrative purposes and do not limit the scope of the invention.

Example 1. Preparation of miRNAs

Three types of miRNAs that target protein gp46 (GenBank Accession No. M), which is the rat homologue of human HSP47, and random control miRNAs were acquired in Hokkaido System Science Co., Ltd. Each of miRNAs consists of 27 bases with a protruding 3'-end, and sequence are as follows.

Sequence A: 5'-GUUCCACCAUAAGAUGGUAGACAACAG-3' (sense, SEQ ID NO:1)

5'-GUUGUCUACCAUCUUAUGGUGGAACAU-3' (antisense, SEQ ID NO:2)

Sequence: 5'-CCACAAGUUUUAUAUCCAAUCUAGCAG-3' (sense, SEQ ID NO:3)

5'-GCUAGAUUGGAUAUAAAACUUGUGGAU-3' (antisense, SEQ ID NO:4)

The sequence: 5'-CUAGAGCCAUUACAUUACAUUGACAAG-3' (sense, SEQ ID NO:5)

5'-UGUCAAUGUAAUGUAAUGGCUCUAGAU-3' (antisense, SEQ ID NO:6)

Random miRNAs: 5'-CGAUUCGCUAGACCGGCUUCAUUGCAG-3' (sense, SEQ ID NO:7)

5'-GCAAUGAAGCCGGUCUAGCGAAUCGAU-3' (antisense, SEQ ID NO:8)

Moreover, it was also cooked miRNAs labeled at the 5'end with a fluorescent dye 6'-carboxyfluorescein (6'-FAM).

Example 2. Preparation of mi-RNA-containing liposomes, ne�provide to VA

As liposomes was used cationic liposomes containing DC-6-14, cholesterol and DOPE (dioleoylphosphatidylcholine) in a molar ratio of 4:3:3 (Lipotrust, Hokkaido System Science Co., Ltd.). 10 nmol liposomes, and 20 nmol of vitamin A (VA: TRANS-retinol by all provisions, Sigma) were mixed in DMSO, using a test tube of 1.5 ml, and then dissolved in chloroform, evaporated once and then suspended in PBS (phosphate-saline buffer solution). Then miRNAs (10 μg/ml) obtained in Example 1 and the liposomal suspension was mixed in a ratio of 1:1 (wt./wt.). Free VA and miRNAs contained in the resulting liposomal suspensions were removed by a system of microsattelite (Sartorion VIVASPIN 5000MWCO PES), was formed mi-RNA-containing liposome, associated with VA (VA-lip-miRNAs). The number of added VA and the amount of VA contained in the purified liposome was measured using HPLC and measured the fraction of VA that is associated with the liposome; as a result, it was found that the majority of VA (95,6±0,42%) was associated with a liposome. Moreover, the absorption efficiency of miRNAs in liposome was measured by analysis of RiboGreen (Molecular Probes), and she was compared to 94.4±3,0%. Here, in this part, VA has been at least partially exposed on the surface of the composition.

Example 3. Activity against pulmonary fibrosis in vivo mi-RNA-containing liposomes associated with WA

(1) the Induction �egocheaga fibrosis and the introduction of medicines

Rats S-D male (6 rats in the group, age 4 weeks, Charles River Laboratories Japan, Inc.) were once introduced into the lungs, intratracheally, with catheterization of the trachea, under anesthesia, 0.5 mg of bleomycin (BLM), dissolved in 0.5 cm3saline solution, in order to obtain the model bleomycine pulmonary fibrosis. When using this method, pronounced fibrosis of the lungs mostly occurs after approximately 3 weeks. VA-lip-miRNAs, prepared in Example 2 (0.75 mg/kg - number of miRNAs, or in volume units 1 ml/kg, i.e. 200 μl per rat weighing 200 g), or PBS (1 ml/kg in volume) was injected into rats via the tail vein, starting from the day of injection of bleomycin, with a frequency of 3 times per week. Rats were killed on day 21 after administration of bleomycin and analyzing the fluid using bronchoalveolar lavage (BAL), then determined the amount of hydroxyproline in the lungs and carried out histological examination of lung tissue (See. Fig.1). To assess statistically significant differences was used the student's t test.

(2) Analysis of BAL fluid

Analysis BAL was performed as follows. Rats were injected intraperitoneally with a lethal dose of pentobarbital sodium, opened their chest and freed the trachea, into which is inserted the tube. Then 7 ml of saline was injected into the lungs celestrak in the trachea and collected lavage fluid. This process of injection and collection was repeated 5 times, the collected lavage fluid was pooled and centrifuged at 250×g for 10 min. the total number of cells counted on the cytometer, counting of cell fractions was carried out using drug-smear stained according to the method of May-Himsi on cytocentrifuge. At least 200 cells were counted and classified on macrophages, eosinophils, neutrophils and lymphocytes in accordance with the General morphological criteria. The results of counting the total number of cells shown in Fig.2. This figure shows that the number of cells in BAL fluid obtained in the case of the introduction of the group VA-lip-miRNAs (BLM miRNAs), were significantly decreased to the level similar to the level of normal control rats injected with PBS instead of bleomycin, compared with results for a group of FSBR (only BLM); thus believe that the inflammation has decreased.

(3) determining the amount of hydroxyproline in the lung tissue

Lungs were removed from rats after holding the BALL, then one whole lung homogenized using polychrony homogenizer, and determined the amount of hydroxyproline in the lung, using the method of Kivirikko et al. (Kivirikko KI, et al. Analytical Biochemistry 1967; 19: 249-255). More specifically, the lung tissue homogenized in 6N hydrochloric acid at 110°C for 18 hours, and an aliquot of 25 μl was dried at 6°C. Then it was dissolved in 1.2 ml of 50% isopropanol, incubated with acetat-citrate, pH 6.0, and 200 ml of 0.56% solution of chloramine-T at room temperature for 10 min, followed by incubation at 50°C for 90 min after adding 1 ml of Ehrlich; and then measured the absorbance at 560 nm. The results shown in Fig.3, demonstrate that the amount of hydroxyproline in the lungs (mcg) in the case of the introduction of the group VA-lip-miRNAs (BLM + miRNAs) were significantly decreased, compared with the same indicator for the group FSBR (only BLM), believe that the lung fibrosis was significantly suppressed.

(4) Histological study

The remote part of the lung was fixed in formalin in the usual way, and subjected to staining with hematoxylin and eosin (he) and azan staining (azocarmine, aniline blue/orange G solution) or immunoablation with anti-αSMA. As to immunoablative, after dewaxing the samples interacted with murine antibodies anti-αSMA (Nichirei Corporation, clone 1A4) as primary antibodies and then with peroxidase-labeled intimissimi immunoglobulins IgG as secondary antibody, with subsequent manifestation with the help of diaminobenzidine (DUB). As the results of the GOE staining in Fig.4, in the case of the introduction of the group FSBR (21-day introduction BLM), were observed record�, characteristic of pulmonary fibrosis, such as the disappearance of the alveoli of the lungs, the presence of hemorrhage and interstitial hyperplasia, while in the case of the introduction of group VA-lip-miRNAs (BLM + miRNAs) fibrous lesions significantly normalized. Similarly, as the results azan staining (Fig.5, in the case of the introduction of the group FSBR (only BLM), there was marked fibrous pattern, characterized by an increase in the interstitium due to the large number painted in blue collagen fibrils, while in the case of the introduction of the group VA-lip-miRNAs (BLM + miRNAs) fibrosis was undoubtedly depressed. Moreover, as the results of aSMA-staining Fig.6, while in the interstitium with the introduction of the group FSBR (only blms) observed a large number of aSMA-positive cells with brown color, the number of aSMA-positive cells when administered group VA-lip-miRNAs (BLM + miRNAs) were significantly reduced.

Given that miRNAs mainly acts in the cytoplasm, the above results suggest that the retinoid functioned as the sending agent to the cells that produce extracellular matrix in the lungs, the drug is effectively delivered to these cells, resulting in a significant improvement in the course of pulmonary fibrosis.

1. A method of reducing p�doziruuschih extracellular matrix of cells in the lungs, or suppressing an increase in producing the extracellular matrix of cells in the lungs, introducing to the subject a composition comprising (i) a carrier containing a retinoid as a directing agent, and (ii) a medicament selected from the group consisting of miRNA, ribozyme, antisense nucleic acid and DNA/RNA chimeric polynucleotide, which aims to HSP47, and vectors expressing the indicated miRNA, a ribozyme, antisense nucleic acid and/or DNA/RNA chimeric polynucleotide.

2. A method according to claim 1, wherein the retinoid contains retinol.

3. A method according to claim 1, where the content of retinoid is 0.2-20 wt. % from all media.

4. A method according to claim 1, wherein the carrier has a form of liposome, and the molar ratio of retinoid to the lipid contained in the liposome is 8:1-1:4.

5. A method according to claim 1, where the drug and carrier are mixed on the spot therapeutic treatment, or in the immediate vicinity.

6. A method according to any one of claims. 1-5, where the subject suffers from lung fibrosis.

7. A method of reducing producing extracellular matrix of cells in the lungs, or suppressing an increase in producing the extracellular matrix of cells in the lungs that contains: (a) providing a set that contains one or more containers containing singly or in combination a medicament selected from the group consisting of miRNA, ribozyme, antisense nucleic acid and DN�/RNA chimeric polynucleotide, aimed at HSP47, and vectors expressing the indicated miRNA, a ribozyme, antisense nucleic acid and/or DNA/RNA chimeric polynucleotide, a retinoid, and optionally forming the carrier substance that is different from retinoid, (b) a composition which contains (i) a carrier containing a retinoid as a directing agent, and (ii) a specified drug, and (C) introducing the composition to the subject.

8. A method according to claim 7, where the subject is suffering from pulmonary fibrosis.



 

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,

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