WO2005004914A1 - NF-κBデコイを含む呼吸器疾患用治療および予防のための薬学的組成物およびその使用方法 - Google Patents
NF-κBデコイを含む呼吸器疾患用治療および予防のための薬学的組成物およびその使用方法 Download PDFInfo
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- WO2005004914A1 WO2005004914A1 PCT/JP2004/009838 JP2004009838W WO2005004914A1 WO 2005004914 A1 WO2005004914 A1 WO 2005004914A1 JP 2004009838 W JP2004009838 W JP 2004009838W WO 2005004914 A1 WO2005004914 A1 WO 2005004914A1
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- 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
- A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- 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
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
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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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- 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
- A61P11/02—Nasal agents, e.g. decongestants
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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
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/00—Antineoplastic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- composition for treatment and prevention of respiratory diseases containing NF- ⁇ B decoy and method of using the same containing NF- ⁇ B decoy and method of using the same
- the present invention relates to a composition
- a composition comprising a compound (eg, a nucleic acid and an analog thereof) that specifically binds to a transcription regulatory factor present on a chromosome, in particular, a site to which NF- ⁇ B binds, and a method for using the same.
- a compound eg, a nucleic acid and an analog thereof
- the present invention provides a composition comprising a NF-? K B decoy compound and a method of using the same.
- the present invention has an excellent effect as a therapeutic, ameliorating, or prophylactic agent for suppressing airway inflammation, airway stenosis or nasal inflammation and a method of using the same.
- the number of asthma patients in Japan is approximately 2 to 3 million (approximately 2 to 3% of the total population), and asthma dies from 6,000 to 7,000 a year. There is also an estimate.
- Inflammation in the airway mucosa plays an important role in the pathogenesis of bronchial asthma.
- inflammatory cells such as mast cells and eosinophils produce various cytokins and tissue-damaging proteins.
- NF- ⁇ B, AP-1 and other transcription factors activated by various factors.
- inflammatory factors such as cytodynamics are factors involved in the interaction between cells involved in immunity, and play an important role in the immune mechanism against allergens and microorganisms.
- Mast cells and eosinophils have a receptor for cytodynamic force in the cell membrane, and when they receive the cytodynamic force produced by other cells or self, this information is transmitted to the nucleus via intracellular signaling.
- the transcription of various genes is promoted to the inside, and new cytokins, chemokines, cell adhesion molecules, etc. are produced based on the genetic information.
- the transcription factor regulates the transcriptional activity of genetic information in the nucleus
- transcription factors considered to be important in airway inflammation include NF- ⁇ B, AP-1, and NF-.
- AT nuclear factor of activated T cells
- NF- ⁇ is particularly noticed!
- factors produced by the enhancement of gene transcription through NF- ⁇ ⁇ include a wide variety of factors such as inflammatory cytokines, chemokines, cytotoxic proteins, cell adhesion molecules, and cell membrane receptors involved in immunity. I have.
- IgE-dependent NF- ⁇ B was activated by stimulation of inflammatory antibodies in human lung mast cells (mast cells; MC), and TNF-o; (tumor necrosis factor ⁇ ; tumor necro sis factor-a) has been found to promote NF- ⁇ B activation. It has also been recognized that eosinophils can be activated by GM-CSF (Granulocyte Macrophage Colony Stimulating Factor) for NF- ⁇ B activation. (J. Immunol., 169 (9), 5287-93, 2002.).
- GM-CSF Granulocyte Macrophage Colony Stimulating Factor
- TNF- ⁇ present in the respiratory tract has a biological action very similar to IL1, and is associated with enhanced respiratory responsiveness of the airway and inflammation of the airway.
- adhesion molecules expressed on the airway epidermis and endothelium activated by IL-1 and IL-4, especially VCAM-1 cause infiltration of airway eosinophils.
- administration of ICAM-1 antibodies has been shown to suppress eosinophil infiltration and airway reactivity!
- inhaled steroids, antiallergic agents, sustained-release theophylline agents, and the like are widely used as controllers, and as inhalers, inhalation receptor stimulants and aminofiles are used as controllers.
- Intravenous steroids have been used.
- NF- ⁇ a typical transcription factor
- NF- ⁇ is a transcriptional regulatory factor composed of ⁇ 65 and ⁇ 50 heterodimers.
- NF- ⁇ usually exists in the cytoplasm in a form bound with its inhibitor I ⁇ , and its nuclear translocation is prevented.
- I ⁇ is phosphorylated and degraded, thereby activating NF- ⁇ and nuclear
- Move to NF- ⁇ translocated into the nucleus binds to the NF ⁇ binding site on the chromosome and promotes the transcription of genes downstream of it.
- Genes downstream of the NF-KB binding site include, for example, IL-1, IL6, IL8, inflammatory cytodynamics such as tumor necrosis factor a (TNFa), and adhesion of VCAM-1, ICAM-1, etc. Factors are known.
- Asthma such as bronchial asthma, allergic asthma, and pediatric asthma, is also a disease that is difficult to treat fundamentally despite many affected patients! Is one of the diseases. Current treatments are largely palliative. In the case of a seizure, bronchodilators such as theophylline are often used. However, with such symptomatic treatments, seizures must be dealt with to cope, and the patient's symptoms cannot be completely suppressed, nor can he be completely cured. Therefore, There is a long-awaited need for a therapy that cuts the cause.
- Rhinitis is classified into several types, such as allergic rhinitis, hay fever, acute rhinitis, chronic rhinitis, hypertrophic rhinitis, chronic sinusitis (pyometra), and nasal septum curvature, depending on the Z-causing substance or clinical symptoms. Have been.
- Allergic rhinitis is a nasal symptom such as sneezing and nasal congestion caused by inhalation of inhalable antigens such as dust, mites, and pollen. Inhalation of a substance often causes no symptoms, but the number of antibodies in the body gradually increases each time the substance is inhaled. When the antibody titer exceeds a certain level, it occurs when the antigen substance is inhaled.
- the condition is basically considered to be allergic inflammation. (Rhinology,
- Allergic rhinitis is rhinitis in which the nasal mucosa reacts to a specific substance. Symptoms, runny nose, and nasal congestion are the three major symptoms, and itching, redness, and general symptoms (anorexia, fatigue) ) May be accompanied.
- Allergen-causing substances include pollen (cedar, cypress, etc.), butterbur, mites, house dust, pet hair loss, etc. Pollen) and year-round! /
- COPD chronic obstructive pulmonary disease
- COPD is a disease in which the number of patients is increasing in recent years, and the number of patients is expected to further increase in the future. At present, there is no fundamental treatment method, and the burden of social medical expenses is large.
- the disease is a pathological condition characterized by irreversible respiratory flow limitation. Airflow restriction is usually progressive and depends on the amount and type of harmful gas inhaled. Airflow restriction results from destruction of the lung parenchyma caused by an inflammatory response of the peripheral airways in response to inhaled gas. According to a study conducted by the World Health Organization and the World Bank, the global prevalence in 1990 was 9.34 men and 7.33 women per 1,000 people. It is currently on an upward trend and is expected to rise from the sixth largest cause of death in 1990 to the third largest in 2020.
- COPD is a disease in which the respiratory function slowly decreases due to an obstacle in the "airway" through which air passes when breathing.
- Diseases formerly referred to as emphysema and chronic bronchitis are now collectively referred to as COPD.
- COPD starts with common symptoms and progresses slowly, so when a patient is diagnosed with an abnormality, he / she may be severely ill and often ⁇ a "pulmonary lifestyle-related disease"! / .
- COPD is a severely afflicted disease, such as difficulty in breathing and loss of freedom due to difficulty breathing in severe cases, and treatment from the viewpoint of improvement of symptoms is also required. Long-awaited.
- Patent Literature 1 (WO03Z105780) and Patent Literature 2 (US6303582) disclose techniques for micronizing nucleic acids.
- small nucleic acids such as decoys maintain the function against inflammatory diseases. Whether or not it can be micronized is completely described.
- the present invention relates to a respiratory disease caused by expression of a gene regulated by NF- ⁇ B.
- compositions and methods of use suitable for treating eg, airway inflammatory, airway stricture or rhinoinflammation diseases, disorders, conditions, etc.
- the present invention comprises a NF- ⁇ B decoy as a main component, and treats respiratory diseases, disorders and diseases or symptoms caused by expression of a gene controlled by NF- ⁇ B (treatment and treatment). Prophylaxis) and a method for treating the disease.
- the present inventors have identified a disease, disorder and / or symptom of the respiratory system or abnormalities of eosinophils and / or neutrophils caused by expression of a gene regulated by NF- ⁇ .
- the present inventors have found that it is effective to administer an NF- ⁇ decoy for treating diseases, disorders, and Z or symptoms, and have completed the present invention.
- the present invention relates to a pharmaceutical composition for treating and preventing a disease, disorder and / or condition caused by the expression of a gene controlled by NF- ⁇ .
- the present invention comprises a decoy of ⁇ or a derivative, variant or fragment thereof, and a pharmaceutically acceptable carrier, and the derivative, variant or fragment is a decoy having biological activity.
- the present invention also relates to a pharmaceutical composition for treating and / or preventing respiratory diseases, disorders and ⁇ or conditions associated with eosinophil abnormalities, comprising a NF- ⁇ And a composition comprising a pharmaceutically acceptable carrier.
- the disease is asthma, COPD or rhinitis.
- the disease is a disease associated with eosinophil abnormality.
- diseases associated with eosinophil abnormalities include, for example, asthma (bronchial asthma, pediatric asthma, allergic asthma, atopic asthma, steroid refractory asthma (steroid-resistant asthma; SRA), non-allergic Sexual asthma (endogenous asthma, extrinsic asthma, for example, aspirin asthma, cardiac asthma, infectious asthma), and other eosinophil abnormalities (for example, allergic diseases such as rhinitis).
- the pharmaceutically acceptable carrier is a hydrophilic polymer, a non-soluble or ribosome, a carbohydrate or a non-soluble additive.
- the pharmaceutically acceptable carrier is at least one selected from the group consisting of ribosome, lactose, trehalose, sucrose, mannitol and xylitol.
- the NF- ⁇ decoy is a decoy represented by SEQ ID NO: 1.
- the disease, disorder and / or symptom of the respiratory system is airway inflammatory disease, airway stricture or nasal inflammatory disease.
- the respiratory disease, disorder and condition or symptom is COPD, asthma or rhinitis.
- the disease, disorder and Z or symptom of the respiratory system is COPD.
- the disease, disorder and Z or symptom of the respiratory system is asthma.
- the disease, disorder and Z or symptom of the respiratory system is rhinitis.
- the respiratory disease, disorder and Z or symptom are bronchial asthma, pediatric asthma, allergic asthma, atopic asthma, steroid refractory asthma, non-allergic asthma, endogenous asthma, exogenous asthma Asthma selected from the group consisting of asthma, aspirin asthma, cardiac asthma and infectious asthma, or allergic rhinitis, hay fever, acute rhinitis, chronic rhinitis, hypertrophic rhinitis, chronic sinusitis (pyometra) and nasal septum It is rhinitis selected from the group that also has curvaceous power.
- the present invention provides a method for treating and Z or preventing a disease caused by expression of a gene regulated by NF- ⁇ B, or a disease associated with eosinophil abnormality,
- the present invention relates to the use of a NF- ⁇ B decoy for the treatment and Z or prevention of disorders and Z or conditions, or for the preparation of pharmaceutical compositions for the treatment and Z or prevention.
- the invention comprises the above composition of the invention, wherein the composition is adapted for administration to the respiratory tract.
- the administration to the respiratory tract comprises intra-airway administration or trans-airway absorption.
- the administration to the respiratory tract is performed by injection or inhalation into the respiratory tract.
- administration to the respiratory tract comprises administration by a metered dose inhaler (MDI), a dry powder inhaler (DPI) or a nebulizer.
- MDI metered dose inhaler
- DPI dry powder inhaler
- nebulizer a nebulizer
- the composition is provided as a dry powder.
- the fine particles are produced using a means selected from the group consisting of the above-mentioned dry powder force ball mill, bead mill, jet mill, vomizer mortar, stone mill, spray drying and supercritical fluid force. It is characterized by.
- the dry powder has an aerodynamic average particle diameter of about 0.01 to about 50 ⁇ m.
- the aerodynamic average particle size of the dry powder is about 0.05 to about 30 ⁇ m.
- the aerodynamic average particle size of the dry powder is about 0.1 to about 10 ⁇ m. And features.
- the above-mentioned preparation has a dose of 10 / zg-lOOmg per dose.
- the above-mentioned preparation has a dose of 50 g to 50 mg per dose.
- the above-mentioned preparation has a dose of 10 mg or less per dose.
- the respiratory administration comprises nasal absorption.
- the preparation is characterized in that it is a preparation selected from the group consisting of nasal drops, nasal sprays, nebulizer preparations, resabilizer preparations, and powder administration preparations.
- the preparation is a nasal drop for rhinitis.
- the present invention is characterized in that the decoy of NF- ⁇ B is encapsulated in an HVJ-E envelope vector.
- the respiratory administration comprises pulmonary administration.
- a device for respiratory treatment comprising a composition of the present invention and a means for administering the composition to a respiratory tract.
- the means for administration to the respiratory tract includes a means selected from the group consisting of a pulmonary administration means, an intratracheal administration means, an airway absorption means and a nasal absorption means.
- the respiratory administration means includes a metered dose inhaler (MDI), a dry powder-one inhaler (DPI) or a nebulizer.
- MDI metered dose inhaler
- DPI dry powder-one inhaler
- nebulizer a nebulizer
- the present invention provides a method for producing particles containing a decoy of NF- ⁇ B, comprising the steps of: A) providing the decoy and a pharmaceutically acceptable carrier; D) drying the decoy and carrier and heating to a temperature sufficient to form particles; C) removing particles having a desired particle size.
- the temperature is not higher than 50 ° C.
- the temperature is not higher than 100 ° C.
- the particle diameter is about 0.01 to about 50 ⁇ m as an aerodynamic average particle diameter.
- the particle diameter is about 0.05 to about 30 ⁇ m as an aerodynamic average particle diameter.
- the particle diameter is about 0.1 to about 10 m as an aerodynamic average particle diameter.
- the present invention relates to a method for treating and Z or preventing a respiratory disease, disorder and Z or condition caused by expression of a gene regulated by NF- ⁇ B. And A) administering to the subject's respiratory system a composition comprising a decoy of NF- ⁇ B and a pharmaceutically acceptable carrier.
- the disease, disorder and Z or symptom of the respiratory system is airway inflammatory disease, airway stricture or nasal inflammatory disease.
- the respiratory disease, disorder and Z or symptom is COPD, asthma or rhinitis.
- the above-mentioned administration includes an administration method selected from the group consisting of intra-airway administration, airway absorption and nasal inhalation input.
- the administration to the respiratory tract is performed by injection or inhalation into the respiratory tract.
- administration to the respiratory tract comprises administration by a metered dose inhaler (MDI), a dry powder inhaler (DPI) or a nebulizer.
- MDI metered dose inhaler
- DPI dry powder inhaler
- nebulizer a nebulizer
- the administration is performed by a means selected from the group consisting of nasal spray, nasal spray, nebulizer, resiliator and powder administration.
- the present invention relates to a method for treating and Z or preventing a respiratory disease, disorder and Z or condition associated with eosinophil abnormalities, comprising: A) NF- ⁇ Administering to the subject's respiratory system a thread comprising the decoy of B and a pharmaceutically acceptable carrier;
- a method includes:
- the present invention relates to a medicament for treating and Z or preventing a respiratory disease, disorder and Z or condition caused by expression of a gene regulated by NF- ⁇ B.
- NF- ⁇ B decoys for production.
- the present invention has made it possible to treat (treat and prevent) respiratory diseases such as airway inflammatory, airway stricture, and nasal inflammatory diseases.
- FIG. 1 is an example of an experimental protocol showing the effect of the pharmaceutical composition of the present invention when using an asthma model (FIG. 1A).
- Figures IB and 1C show the decoy inhalation.
- FIG. 1B is an example of an experimental protocol showing the effect of the pharmaceutical composition of the present invention when using an asthma model (FIG. 1A).
- Figures IB and 1C show the decoy inhalation.
- FIG. 1C is an example of an experimental protocol showing the effect of the pharmaceutical composition of the present invention when using an asthma model (FIG. 1A).
- Figures IB and 1C show the decoy inhalation.
- FIG. 2 shows the results showing the effect of the pharmaceutical composition of the present invention in bronchoalveolar lavage fluid of ovalbumin challenged animals.
- Figures 2A and 2B show the basic data for eosinophil counting.
- FIG. 2C the results of control, ovalbumin challenge, aerosol treatment (2 mg ⁇ 2), and liquid treatment (0.5 mg ⁇ l) are shown from the left.
- FIG. 2 shows the results showing the effect of the pharmaceutical composition of the present invention in bronchoalveolar lavage fluid of ovalbumin challenged animals.
- Figures 2A and 2B show the basic data for eosinophil counting.
- FIG. 2C the results of control, ovalbumin challenge, aerosol treatment (2 mg ⁇ 2), and liquid treatment (0.5 mg ⁇ l) are shown from the left.
- FIG. 2 shows the results showing the effect of the pharmaceutical composition of the present invention in bronchoalveolar lavage fluid of ovalbumin challenged animals.
- Figures 2A and 2B show the basic data for eosinophil counting.
- FIG. 2C shows the results of control, ovalbumin challenge, aerosol treatment (2 mg ⁇ 2), and liquid treatment (0.5 mg ⁇ l) are shown from the left.
- FIG. 3 shows the results showing the effect of the pharmaceutical composition of the present invention in bronchoalveolar lavage fluid of ovalbumin challenged animals.
- FIG. 3A number of eosinophil cells
- 3B (% eosinophil), from the left, control, ovalbumin cyanide, naked decoy 500 ⁇ g, HVJ (200; The results of HVJ-ElOOOOAUAU and 200 ⁇ g of decoy), HVJ (500; containing HVJ-E25000HAU and 500 ⁇ g of decoy) and vector (HVJ-E25000HAU only, no decoy) are shown. # Indicates statistical significance for ovalbumin challenge.
- FIG. 3 shows the results showing the effect of the pharmaceutical composition of the present invention in bronchoalveolar lavage fluid of ovalbumin challenge animals.
- FIG. 3A number of eosinophil cells
- FIG. 3B % eosinophil
- HVJ-ElOOOOAUAU naked decoy 500 ⁇ g
- HVJ 500; containing HVJ-E25000HAU and 500 ⁇ g of decoy
- vector HVJ-E25000HAU only, no decoy
- FIG. 4 shows an example of eosinophil behavior by decoy.
- FIG. 5 shows the results of preparing a powder inhalant of the NF- ⁇ B decoy of the present invention.
- FIG. 6 shows the results of preparing a powder inhalant of lactose used as a control.
- FIG. 7 shows the effect of NF- ⁇ B decoy on a rat asthma model (AHR).
- AHR rat asthma model
- FIG. 8 shows the effect of NF- ⁇ decoy on a rat asthma model (BALF).
- BALF rat asthma model
- FIG. 9 shows the effect of NF- ⁇ B decoy on a rat rhinitis model.
- the explanation of the symbols is as follows. # #: P ⁇ 0.01 vs saline group (Student 'st test); water, water: p ⁇ 0.05, 0.011 vs control group (Dunnett' sm ultiple comparison test).
- SEQ ID NO: 1 is an NF- ⁇ B decoy.
- SEQ ID NO: 2 is an NF- ⁇ B scrambled decoy.
- SEQ ID NO: 3 is a modified NF- ⁇ B decoy.
- NF- ⁇ B binds to a site on a chromosome that case (hereinafter referred to as a target binding site)
- NF - refers to a compound which antagonizes the binding to the target binding site of K B.
- decoy or decoy dani The compound is a nucleic acid and its analogs.
- a decoy comprises at least one nucleic acid sequence capable of binding to a target binding sequence.
- the decoy can be used for preparing the pharmaceutical composition of the present invention as long as it has the binding activity to the target binding sequence.
- Examples of preferred decoys are: 5, 1 CCT- 1 TGA- AGG- GAT- TTC- 1 CCT- 1 CC- 3,
- Oligonucleotides containing (NF- ⁇ B decoy) or their complement, mutants thereof, or compounds containing these in the molecule are not limited thereto.
- Oligonucleotides may be DNA or RNA, or may contain nucleic acid modifications ("derivative nucleotides”) and Z or pseudonucleic acids (“derivative oligonucleotides”) in the oligonucleotide.
- these oligonucleotides, mutants thereof, or compounds containing these in the molecule may be single-stranded or double-stranded, linear or cyclic, and may be branched. And may be linear.
- Mutants are those in which a part of the above sequence is mutated, substituted, inserted, or deleted. Indicates a nucleic acid that specifically antagonizes the site. More preferred decoys for other transcriptional regulators of NF- ⁇ B regulated genes include double-stranded oligonucleotides containing one or more of the above nucleic acid sequences or variants thereof. Representative variants of NF- ⁇ B include, but are not limited to, those having the nucleic acid sequence set forth in SEQ ID NO: 3.
- the oligonucleotide used in the present invention is an oligonucleotide having a thiophosphoric acid diester bond (S-oligo) in which the oxygen atom of the phosphoric acid diester bond is replaced with an ⁇ atom, or the phosphodiester bond has a charge.
- Oligonucleotides that have been modified to make oligonucleotides less susceptible to degradation in vivo such as oligonucleotides that have been substituted with unexistent methyl phosphate groups, and the like, are included.
- nucleic acid refers to a polymer (polymer) comprising a series of nucleotides.
- a nucleotide refers to a nucleoside that has been converted to a phosphate ester.
- the base moiety includes pyrimidine or purine base nucleotides (pyrimidine nucleotides and purine nucleotides).
- Nucleotides constituting a polynucleotide include DNA and RNA. As mentioned above, decoys typically take this form of nucleic acid.
- homology search is performed on genomic data such as the Human Genome Project and a genetic information database such as GenBank using software such as BLAST and FASTA.
- genomic data such as the Human Genome Project
- GenBank a genetic information database
- biological screening e.g., under stringent conditions against a library created from such a database. The sequence obtained by doing so is also within the scope of the present invention.
- corresponding gene or sequence refers to the same action as a given gene or sequence in a species to be compared in a certain species
- corresponding gene or sequence of a gene or sequence can be an ortholog of that gene or sequence.
- genes or sequences that “correspond” to a gene or sequence such as mouse NF- ⁇ B can also be found in other animals (humans, rats, pigs, mice, etc.).
- corresponding genes are: It can be identified using techniques well known in the art. Thus, for example, the corresponding gene or sequence in an animal can be determined by using the sequence of the corresponding gene or sequence reference gene (eg, a sequence of mouse NF- ⁇ B or the like) as a query sequence, , Rat) by searching a sequence database or library. Thus, it is intended that the present invention also include sequences corresponding to particular sequences of the present invention (eg, SEQ ID NO: 1).
- derivative oligonucleotide and “derivative polynucleotide” refer to an oligonucleotide containing a derivative of a nucleotide or having an unusual bond between nucleotides.
- oligonucleotides include derivative oligonucleotides in which a phosphodiester bond in an oligonucleotide is converted to a phosphorothioate bond, and phosphodiester bonds in an oligonucleotide in which N3, -P5, and Derivative oligonucleotide converted to midate bond, derivative in which ribose and phosphodiester bond in oligonucleotide are converted to peptide nucleic acid bond Oligonucleotide, derivative in which peracyl in oligonucleotide is substituted by C5 propyl peracyl Oligonucleotides, derivative oligonucleotides in which peracyl in the oligonucleotide is substituted with C-5 thiazoleperacyl, derivative oligonucleotides in which cytosine in the oligonucleotide is substituted with C5 propyl-cytosine, oligonu
- biological activity refers to an activity that a certain factor (for example, a polynucleotide or a polypeptide) may have in a living body, and an activity that exerts various functions. Included.
- a certain factor when a certain factor is a transcription factor, it includes an activity of regulating transcriptional activity. Where a factor is an enzyme, its biological activity includes that enzyme activity.
- an agent is a ligand, the ligand involves binding to the corresponding receptor.
- the biological activity includes binding activity to at least one of the transcription factors. Binding activity of such transcription factors Can be achieved by mixing the transcription factor binding sequence with the transcription factor and measuring the complex resulting from the binding (eg, observation by electrophoresis). Such methods are well known and commonly used by those skilled in the art.
- nucleotide may be natural or non-natural.
- “Derivative nucleotide” refers to a nucleotide that is different from a naturally occurring nucleotide but has the same function as the original nucleotide. Such derivative nucleotides are well-known in the art. Examples of such derivative nucleotides and nucleotide analogs include phosphorothioates, phosphoramidates, methylphosphonates, chiral methylphosphonates, 2-O-methylribonucleotides, peptide nucleic acids (PNA) It is not limited to these.
- the "variant" refers to a substance in which a part of a substance such as an original polynucleotide has been changed. Such variants include substitutional variants, addition variants, deletion variants, truncated variants, allelic variants, and the like. Alleles refer to genetic variants that belong to the same locus and are distinct from each other.
- a chemical synthesis method or a biochemical synthesis method known in the art can be used as a method for producing a decoy used in the present invention.
- a nucleic acid when used as a decoy compound, a nucleic acid synthesis method generally used in genetic engineering can be used.
- a target decoy nucleic acid may be directly synthesized using a DNA synthesizer, or After synthesizing these nucleic acids, the nucleic acids containing the nucleic acids, or a part thereof, the nucleic acids may be amplified using a PCR method or a Crowning vector.
- nucleic acid obtained by these methods may be cleaved with a restriction enzyme or the like, and bound with a DNA ligase or the like to produce the desired nucleic acid.
- a chemical modification such as alkylation, acylation or the like may be applied to the base, sugar or phosphate of the nucleic acid.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the decoy compound described above alone or in combination with a stabilizing compound, a diluent, a carrier, or another component or another drug such as a drug. .
- the "subject” refers to the treatment or composition of the present invention. Creature.
- the patient can be any animal (eg, primate, rodent, etc.) so long as the treatment or composition of the present invention can be applied.
- the patient can preferably be a human.
- NF-KB which is a transcription factor (for example, translation, transcription, etc.). Is controlled (eg, increased, decreased, delayed, etc.) by the disease, disorder, or condition.
- diseases, disorders or conditions include, but are not limited to, for example, asthma or rhinitis, COPD.
- the term "disease, disorder, or Z or condition associated with eosinophil abnormalities” refers to any level of eosinophil levels in the body (eg, in blood) that is not normal, as a cause or as a result.
- Eosinophils have an IgE receptor on their surface and are known to play a major role in allergic diseases.
- Such diseases associated with eosinophil abnormalities include, for example, asthma (bronchial asthma, infant asthma, allergic asthma, atopic asthma, steroid refractory asthma (steroid-resistant asthma; SRA), These include non-allergic asthma (endogenous asthma, exogenous asthma, eg, aspirin asthma, cardiac asthma, infectious asthma), and other eosinophil abnormalities (eg, allergic diseases such as rhinitis). Not limited.
- disease, disorder or symptom of the respiratory system refers to any disease, disorder or symptom (or condition) associated with the respiratory system.
- respiratory diseases can include, but are not limited to, for example, airway inflammatory, airway stricture or nasal inflammatory diseases.
- examples of the disease, disorder or symptom of the respiratory system include COPD, asthma, rhinitis and the like.
- COPD Chronic (Chronic) Obstructive (Pulmonary) Disease
- C Symptoms of OPD include, for example, the fact that Sekitan lasts almost every day even though it is not a cold Symptoms such as shortness of breath when moving the body, such as going up and down stairs. It is said that some people find it hard to walk at the same pace as people of the same age without Seki and Tan. Although it is a common symptom, it is easy to misunderstand that it is due to aging, but it is characterized by chronic symptoms such as the continued appearance of cough, tan and shortness of breath.
- COPD is broadly classified into bronchial and bronchiole bronchial lesions, which have been conventionally referred to as “chronic bronchitis", and alveolar lesions, which have been referred to as “emphysema”.
- chronic bronchitis and alveolar lesions, which have been referred to as “emphysema”.
- emphysema alveolar lesions
- the airway lesion type is almost always the case where the surface of the airway becomes inflamed and the secretion of mucus increases.
- the airway wall becomes thicker and narrows, often causing poor air passage.
- the emphysema type refers to one in which the alveoli are destroyed and fused due to chronic inflammation, and the lungs are inflated by air. The lungs lose their elasticity and let air in and out. Forces are not good, and the inflated lung tissue crushes the airway, causing poor air flow.
- Diagnosis of COPD is made by a simple respiratory function test (spiro test) using a spy mouth meter and a ⁇ ⁇ instrument.
- the spy mouth test is a test to check the vital capacity and the ease with which air passes when exhaling.
- Symptoms, smoking situation, living environment, illness Check by interview, and if necessary, other tests (other tests; for example, chest x-ray, CT or other diagnostic imaging to check for other possible respiratory illness, lack of oxygen in the body It can also perform blood gas measurements to check for blood pressure, such as using blood collected from an artery or using a pulse oximeter or other small device at the fingertip. In some cases, tests to check the general condition, such as urinalysis, blood tests, and blood pressure measurements, are also performed as needed) before diagnosing COPD.
- the severity of COPD is determined as necessary.
- the severity of COPD is categorized based on the% predicted 1 second dose (% FEV 1.0) as determined by spy mouth examination.
- FEV1.0 1 second volume
- FVC Forced vital capacity
- asthma refers to a condition in which the respiratory tract (for example, the respiratory tract (nasal cavity, pharynx, larynx, trachea, bronchi) and lungs) causes edema of mucous membranes, viscous secretions, or any other irritation. It increases responsiveness to airway, narrowing the airway and causing expiratory dyspnea.
- respiratory tract for example, the respiratory tract (nasal cavity, pharynx, larynx, trachea, bronchi) and lungs
- edema of mucous membranes, viscous secretions, or any other irritation increases responsiveness to airway, narrowing the airway and causing expiratory dyspnea.
- examples of asthma include bronchial asthma, pediatric asthma, allergic asthma, atopic asthma, steroid refractory asthma, non-allergic asthma, endogenous asthma, extrinsic asthma, aspirin asthma, cardiac asthma and infectious asthma And the like, but are not limited thereto.
- rhinitis refers to any inflammation of the nasal mucosa. Rhinitis includes, but is not limited to, for example, allergic rhinitis, hay fever, acute rhinitis, chronic rhinitis, hypertrophic rhinitis, chronic sinusitis (pyometra) and septal curvature. Allergic rhinitis is rhinitis mainly caused by sneezing, secretion of a large amount of watery nasal secretions, and nasal congestion due to edematous thickening of the nasal mucosa. The allergens (house antigens) are house dust, Poles such as mites and cedar can be mentioned, and it is estimated that there are 15 million patients in Japan.
- compositions and methods of the present invention if the patient is a human, it is preferably in vitro, and then in vivo, and at an animal level, prior to use in humans. Tested for appropriate amount for treatment or prevention. The effect of the compositions on cell lines and Z or animal models as preliminary experiments can be determined using techniques known to those of skill in the art. In vitro assays that can be used to determine whether or not the administration of a particular compound is indicated in accordance with the present invention include observing the binding of a transcription factor to a transcription factor binding sequence.
- the determination can be made by administering the composition in the same manner as in a human, and confirming the therapeutic effect level (for example, observing changes in eosinophils). It is understood in the art that if a therapeutic and Z or prophylactic effect is usually demonstrated in model animals, a similar effect will be achieved in humans.
- the pharmaceutical composition of the present invention is used in such a form that the decoy is taken into the cells of the affected area or the cells of the target tissue.
- compositions of the present invention can be administered in any sterile biocompatible pharmaceutical carrier, including, but not limited to, saline, buffered saline, dextrose, and water. . Any of these molecules, alone or in combination with other agents, in a pharmaceutical composition mixed with a suitable excipient, adjuvant, and Z or a pharmaceutically acceptable carrier It can be administered to a patient.
- the pharmaceutically acceptable carrier is pharmaceutically inert.
- parenteral delivery includes local, intraarterial, intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, intrabronchial, intraalveolar, or intranasal administration Is mentioned.
- these pharmaceutical compositions may contain any suitable pharmaceutical, including excipients or other compounds that facilitate the processing of the decoy compound, in order to prepare pharmaceutically usable formulations. May include an acceptable carrier. Further details on techniques for formulation and administration can be found, for example, in "REMINGTON, S PHARMACEUTICAL SCIENCESJ ( Maack Publishing Co., Easton, PA).
- compositions for administration may be formulated using pharmaceutically acceptable carriers well known in the art in dosage forms suitable for administration. Such carriers enable the pharmaceutical composition to be formulated into microparticles, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., suitable for consumption by the patient. I do.
- Pharmaceutically acceptable carriers include ribosome, lactose, trehalose, sucrose, mannitol, xylitol, crystalline cellulose, chitosan, calcium carbonate, talc, titanium oxide or silica (silicon oxide), etc. But not limited to them.
- the pharmaceutical compositions are prepared by combining the active compound with solid excipients and, if desired, grinding the resulting mixture, if desired, with additional compounds suitable for obtaining tablets or dragee cores.
- Suitable excipients are carbohydrate or protein fillers, including but not limited to: sugars, including ratatose, sucrose, mannitol, or sorbitol; corn, wheat, rice, potato, or other Starches of plant origin; celluloses, such as methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose sodium; and gums, including gum arabic and tragacanth; and proteins, such as gelatin and collagen.
- disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate.
- Dragee cores are provided with suitable coatings, such as concentrated sugar solutions. It may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and Z or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragees for product identification or to characterize the amount (ie, dosage) of the active compound.
- compositions that can be used include, for example, gelatin capsules, soft sealed capsules consisting of gelatin and a coating, such as glycerol or sorbitol.
- Gelatin capsules contain active ingredients in admixture with fillers or binders such as ratatose or starch, lubricants such as talc or magnesium stearate, and, if desired, stabilizers.
- sexual components may be contained.
- the decoy compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycol, with or without stabilizers.
- compositions for parenteral administration include aqueous solutions of the active compound.
- the pharmaceutical compositions of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or buffered saline.
- Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
- suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
- Suitable lipophilic solvents or vehicles include fatty acids, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or ribosomes.
- the suspension may contain suitable agents or agents which increase the solubility of the compounds or stabilizers, which allow for the preparation of highly concentrated solutions.
- penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
- composition of the present invention can be prepared in the same manner as known in the art (for example, pulverization, pulverization, conventional mixing, dissolving, granulating, sugar-coating, elutriation, emulsification, capsule). , Entrapment, or lyophilization).
- nebulization or inhalation e.g, microparticles such as dry powder
- MDI metered dose inhaler
- DPI dry powder inhaler
- aqueous solutions and the like may be found to be suitable. It can be seen that for pulmonary administration, it is preferable to have finer particles similar or finer than for airway administration.
- Dry powder is selected from ball mill, bead mill, jet mill, horrin mortar, millstone, spray drying and supercritical fluid force It is possible to manufacture using the means performed.
- the aerodynamic average particle size is typically about 0.01 to about 50 m, preferably about 0.1 to about 30 ⁇ m, and more preferably about 0.1 to about 10 ⁇ m. It is desirable to produce m.
- pulmonary administration it is preferable, but not limited, to produce those having a size of about 3 m or less in consideration of reaching the alveoli.
- the aerodynamic mean particle size or aerodynamic size is defined as the size of a particle with the same sedimentation velocity, a density of 1 (g / cm3) and a spherical shape.
- a cascade impactor is used to collect and collect particles according to the particle size.
- aerodynamic particle size is based on the idea that the percentage of particles that are drawn into the body by respiration and deposited at each site can be determined by the aerodynamic particle size. based on.
- dynamic light scattering for example, HORIBA LB-550
- laser diffraction for example, HORIBA LB-500
- centrifugal sedimentation for example, HORIBA CAPA-500
- the dynamic light scattering method irradiates a laser beam to particles in a solution and obtains the Brownian velocity (diffusion coefficient) of the particles from the temporal fluctuation of the scattered light that emerges.
- the laser diffraction method is a method to determine the particle size using the light diffraction phenomenon (Fraunhofer phenomenon) and the Mie scattering phenomenon, and the centrifugal sedimentation light transmission method is This method measures the particle size from the relationship between the size of the particles and the sedimentation velocity.
- the pharmaceutical composition of the present invention when topically administered into cells of an affected area or cells of a target tissue, contains a synthetic or natural hydrophilic polymer as a carrier.
- hydrophilic polymers include hydroxypropyl cellulose and polyethylene glycol.
- the decoy compound of the present invention is mixed with such a hydrophilic polymer in a suitable solvent, and the solvent is removed by a method such as air-drying to form a desired form, for example, a sheet. May be applied to the site.
- the preparation containing such a hydrophilic polymer has a low water content and thus has excellent storage properties. In use, the preparation absorbs water and becomes a gel, and thus has excellent storage properties for decoy compounds.
- such a sheet is prepared by mixing a polyhydric alcohol with cellulose, starch, a derivative thereof, or a synthetic polymer to adjust the hardness.
- a hydrophilic sheet formed by the above method can also be used.
- Such a sheet can be laparoscopically applied to a target site using laparoscopic techniques, for example.
- laparoscopic surgery has evolved remarkably as a non-invasive procedure and, in combination with the pharmaceutical compositions of the present invention, may provide a non-invasive and repeatable treatment for diseases.
- the pharmaceutical composition of the present invention may be in a form used in a commonly used gene transfer method, for example, membrane fusion using a Sendai virus or the like.
- Ribosome preparations Ribosome preparations, ribosome preparations such as liposomal preparations utilizing endocytosis, preparations containing cationic lipids such as lipofectamine (manufactured by Life Tech Oriental), or retrovirus vectors, adenovirus vectors It is advantageous to use a virus preparation using the above-mentioned method, and in particular, a membrane fusion ribosome preparation is suitable.
- the ribosome preparation may be any of a large single-walled ribosome (LUV), a multi-layered ribosome (MLV), and a small single-walled ribosome (SUV).
- the size can be as large as 200 nm for LUV, 1000 nm for MLV, 400-3500 nm for MLV, and about 20-50 nm for SUV.
- the particle system 200-lOOOnm MLV can be used. Preferred to use! / ,.
- the method for producing ribosomes is not particularly limited as long as the decoy is retained, for example, a reverse phase evaporation method (Szoka, F et al., Biochim. Biophys. Acta, Vol. 601 559 (1980)), ether injection method (Deamer, DW: Ann. NY Aca d. Sci., Vol. 308 250 (1978)), surfactant method (Brunner, J et al .: Biochim. Biophys. Acta, Vol. 455 322 (1976)).
- a lipid for forming a ribosome structure phospholipids, cholesterols, nitrogen lipids, and the like are used.
- phospholipids are preferable, and phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, and phosphatidyl are generally used.
- Natural phospholipids such as ethanolamine, phosphatidic acid, cardiolipin, sphingomyelin, egg yolk lecithin, soybean lecithin, and lysolecithin, or those obtained by hydrogenating them according to a standard method, dicetyl phosphate, distearoyl phosphatidylcholine Synthetic phospholipids such as dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidylserine, eleostearoylphosphatidylcholine, eleostearoylphosphatidylethanolamine, and eleostearoylphosphatidylserine can be used.
- lipids including phospholipids can be used alone, but two or more lipids can be used in combination.
- an atom group having a positive group such as ethanolamine-choline in the molecule the binding rate of the electrically negative decoy nucleic acid can be increased.
- additives generally known as ribosome formation additives such as cholesterols, stearylamine, and heart tocopherol can also be used.
- the ribosomes thus obtained include a membrane fusion promoting substance, for example, a Sendai virus, an inactivated Sendai virus, a Senda virus, in order to promote the uptake of the diseased cell or target tissue into the cell.
- a membrane fusion promoting substance for example, a Sendai virus, an inactivated Sendai virus, a Senda virus, in order to promote the uptake of the diseased cell or target tissue into the cell.
- Viral activity can also be obtained by adding a purified membrane fusion promoting protein, polyethylene glycol, or the like.
- a method for producing a ribosome preparation will be specifically described.
- the above-mentioned ribosome-forming substance is dissolved together with cholesterol in an organic solvent such as tetrahydrofuran, chloroform, ethanol and the like, and placed in an appropriate container.
- the solvent is distilled off under reduced pressure to form a ribosome-forming substance film on the inner surface of the container.
- a buffer containing decoy is added thereto, and the mixture is stirred.
- the liposome is isolated.
- the ribosome containing the decoy thus obtained can be suspended in an appropriate solvent, or once lyophilized, re-dispersed in an appropriate solvent, and used for treatment.
- the membrane fusion promoting substance may be added after ribosome isolation and before use.
- treatment refers to the prevention of a disease or disorder from occurring when such a condition occurs, preferably the status quo is maintained. More preferably, it means reducing, and more preferably reducing.
- prevention refers to the prevention of a disease or disorder from occurring before such condition is caused. Treatment. Thus, for a disease or disorder, prevention of such conditions, delay, etc., and prevention of illness are included.
- treatment refers to any medical action performed on a certain disease, disorder or condition, and includes actions performed to contribute to diagnosis, treatment, prevention, prognosis, and the like.
- drugs used for drug therapy for the treatment of respiratory diseases include seizure remedies (relever) for seizure remission and long-term seizures for seizure prevention.
- seizure remedies relever
- NF- ⁇ B decoy can be used for both prevention and treatment. This is especially true because seizure prevention is the treatment of asthma itself, and it is important that seizure prevention be an essential therapeutic agent rather than a seizure reliever.
- seizure prevention is the treatment of asthma itself, and it is important that seizure prevention be an essential therapeutic agent rather than a seizure reliever.
- rhinitis, COPD, etc. it can be understood that it can be used for treatment as well, and on the other hand, it can be used for treatment once. It is understood that they can be used for prevention as well. Therefore, in the present invention, if an appropriate dose for prophylaxis or treatment is sufficient, a person skilled in the art can easily calculate an appropriate dose for the other therapy or prevention from the amount. Understood.
- compositions of the present invention include compositions wherein the decoy compounds are contained in an amount effective to achieve the intended purpose.
- a “prophylactically effective amount,” “therapeutically effective amount,” or “pharmacologically effective amount” is a term well-recognized by those skilled in the art and is intended to describe the intended pharmacological result (eg, treatment, prevention). Refers to the amount of drug effective to produce.
- a prophylactically effective amount is an amount sufficient to prevent onset and a therapeutically effective amount is an amount sufficient to reduce the symptoms of the disease to be treated.
- One useful technique for identifying an effective amount (eg, a therapeutically effective amount) for a given application is to determine the degree of recovery of the target disease.
- the actual amount administered will depend on the individual to whom the treatment is to be applied, and will preferably be an amount that is optimized such that the desired effect is achieved without significant side effects. Determination of a prophylactically and therapeutically effective amount is well within the capability of those skilled in the art.
- a prophylactically effective amount and a therapeutically effective amount are first estimated in cell culture assays or in any appropriate animal model. obtain. Animal models are also used to achieve a desired concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
- the prophylactically effective amount and the therapeutically effective amount refer to the amount of a decoy compound sufficient to prevent the onset of a disease and the amount of a decoy compound that reduces a symptom or condition of a disease, respectively.
- Therapeutic effects and toxicity of such compounds will be assessed by standard pharmaceutical procedures in cell culture or experimental animals (e.g., ED, therapeutically effective dose in 50% of the population;
- the dose ratio between the results and the toxic effects is the therapeutic index, which is expressed as the ratio ED ZLD.
- compositions that exhibit large therapeutic indices are preferred.
- Cell culture assays and animal experimental powers The data powers obtained are used to formulate ranges of quantities for human use.
- the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED with little or no toxicity. This dose depends on the dosage form used,
- the dosage of decoy is appropriately selected depending on the age and other conditions of the patient, the type of disease, the type of decoy used, and the like. Generally, 1 ⁇ g—100 mg per dose can be administered several times a day.
- the exact dose will be selected by the individual clinician, taking into account the patient to be prevented or treated. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Additional factors that may be considered include the severity of the disease state (e.g., patient's age, body weight, and gender; diet time limit and frequency of administration, drug combination, response susceptibility, and resistance to treatment Z response). . Depending on the half-life and clearance rate of the particular formulation, a long-acting pharmaceutical composition may
- it can be administered every 3-4 days, every week, or once every two weeks.
- Guidance on specific dosages and methods of delivery is provided in the literature known in the art.
- the drug containing a decoy as a main component obtained in this manner can be administered by various methods depending on the type of disease, the type of decoy used, and the like. Inhalation using an inhaler (MDI'BDI), nebulizer, etc. Can be administered more. For example, in rhinitis, it can be administered by inhalation or inhalation.
- MDI'BDI inhaler
- nebulizer nebulizer
- inhalation method currently used as an administration method via the nasal cavity, respiratory tract, nasal passage, and the like will be described.
- inhaled drugs in intra-respiratory preparations, trans-airway absorption preparations or nasal absorption preparations, it is usually preferable to atomize the drug solution or to make it into a fine powder (dry powder).
- dry powder dry powder
- those processed into chemicals are nebulizers, and those processed into powders are filled with gas-sprayed MDI (Metered dose inhaler) or expiratory inhalation DPI (Dry Powder Inhaler), and then inhaled. Is administered.
- DPI dry powder inhalers
- drypowder inhaler drypowder inhaler
- slow-inhaling type metered dose inhaler MDI
- DPI further includes a Multi-dose reservoir (trade name; Turbuhaler, manufactured by AstraZeneca),
- Multi-unit dose product name; Accuhaler / Diskus, manufactured by GSK
- unit dose many manufacturers
- the inhaler is a kit including a mouthpiece and a cartridge (tube), and the tube is usually sealed at both ends with aluminum oil. If the tube is attached to the mouthpiece before use, the aluminum oil breaks and the fine powder inside can be sucked.
- a nebulizer On the other hand, a nebulizer, a respirator (Respirator), and the like are generally used for inhaling a drug solution.
- the drug aerosol generated by the nebulizer floats at a slow speed, so that anyone can easily inhale it.
- a bead mill is a device in which beads are filled in a container, and a bead is moved by rotating a central rotation axis, and a raw material is fed into the container and crushed by the beads to perform pulverization and dispersion.
- a jet mill is a device that utilizes high-pressure airflow, accelerates particles in an airflow at speeds around the sonic speed, and performs pulverization by collision.
- the agitzer is an ultra-high-speed, ultra-high-speed counter-collision between powders injected with a gas such as air or nitrogen gas or raw materials in the form of a slurry. It is a device to make a child.
- a method for producing fine particles using a supercritical fluid is to put a drug (solubilized in a solvent if necessary) into a high-pressure vessel, dissolve it in supercritical CO, then rapidly expand it with a nozzle cap and spray-dry.
- the average particle size of the dry powder used in the present invention is not limited, but is usually about 0.01 to about 50 m, preferably about 0.05 to about 30 m, and more preferably about 0.05 to about 30 m. 0.1 is about one.
- an average aerodynamic particle size of about 10 to 30 m is generally used for acting on the trachea, and about 3 to 10 m is generally used for acting on the bronchi.
- the particles In order to act on the alveoli, it is generally preferred that the particles have a uniform particle size of about 3 m or less, preferably about 2 m or less.
- the dose of the NF- ⁇ B decoy in the present invention is not limited.
- the dose when dry powder is administered as an intra-respiratory administration preparation or a trans-respiratory absorption preparation, the dose is usually ⁇ / zg / adult once. — 100 mg, preferably 50 / zg per dose — 50 mg, more preferably 10 mg or less per dose.
- the dose when administered as a nasal absorption preparation, particularly as a nasal drop for rhinitis, the dose is usually ⁇ / zg-100 mg / adult, preferably 50 g / 50 mg / dose, more preferably once / adult. Per lOmg or less. This may be increased or decreased as appropriate depending on the target disease, symptoms (degree), and age.
- the NF- ⁇ B decoy of the present invention may be administered naked, or may be administered by being encapsulated in various vectors, for example, HVJ-E envelope vector!
- an excipient is usually used.
- the excipient to be used is inactive to NF- ⁇ B decoy, and is not particularly limited as long as it is generally used as an excipient for pharmaceuticals.
- monosaccharides such as galatatoose, mannose and sorbose, disaccharides such as lactose, sucrose and trehalose, and polysaccharides such as starch, raffinose and dextran
- sugar alcohols glycerin, erythritolone, glycerol, arabitol, xylitoleone, etc.
- Sonorebitone and mannitol Sonorebitone and mannitol
- glycolones including ethylene glycol, propylene glycol, polyethylene glycolone and polypropylene glycol
- cellulosic polymers hydroxycellulose, hydrocellulose) Xypropylcellulose
- insoluble additives crystalline cellulose, chitosan, calcium carbonate, talc, titanium oxide or si
- lactose lactose, sucrose, trehalose, mannitol, xylitol, crystalline cellulose, chitosan, calcium carbonate, talc, oxidized titanium or silica [acidified silicon]) or a mixture thereof Mixtures are more preferred.
- an aerosol system in the form of a spray an aerosol system without a force propellant has been developed, for example, a container containing a propellant.
- the aerosol system contains the active ingredient, for example, the propellant together with conventional auxiliaries such as ratatose.
- the composition of these components determines the properties of the aerosol inhalant, ie, for example, the particle size distribution, delivery rate, viscosity, and the like.
- Aerosols can be obtained as two-phase aerosols (gas and liquid) or three-phase aerosols (gas, liquid, and solid or liquid).
- Two-phase aerosols consist of a solution of the active substance in a liquefied propellant and a nebulized propellant.
- Solvents include, for example, a propellant or a mixture of a propellant and a co-solvent such as an alcohol or propylene glycol.
- Polyethylene render recall is often used to improve the solubility of the active substance.
- Three-phase systems each include a suspension or emulsion of one or more active ingredients, with an atomized propellant.
- Suspensions contain the active material dispersed in a propellant system using conventional auxiliaries such as wetting agents and solid carriers such as Z or talc or colloidal silica.
- the propellants are known and can include carbohydrates, V, without damaging effects to the ozone layer.
- Solution power for inhalation Inhalation is only possible when atomized into very small particles in the size range of 11-10 / zm. It is preferable to inhale the finely dispersed aerosol. In the case of other conventional aerosols, it is preferable not to inhale.
- aerosol inhalants for example, the Pharmacopoeia (eg, Japanese Pharmacopoeia, United States Pharmacopeia), which is incorporated herein by reference in its entirety, may be taken into account.
- the ribosomes used according to the invention preferably have a size in the range of 0.1 ⁇ m to 2 ⁇ m, particularly preferably 0.4 m.
- the use of monolayer ribosomes is preferred.
- Liposo The preparation of the foam is carried out by means of an extruder by means of a type of high-pressure filtration.
- ribosomes are prepared by reconstituting a dry lipid film in the desired liquid (column f, Parthasarathy et al., Cancer Chemother, and Pharmacol. 1999, 43 (4), 277-283). This gives a so-called multilayer ribosome (ie a ribosome with several lipid layers surrounding the aqueous core).
- Such ribosomes are very uniform in size.
- the present invention provides a system for prevention or treatment of lung tissue, which comprises a means for pulmonary administration, and a NF- ⁇ decoy in a form suitable for pulmonary administration.
- a system for prevention or treatment of lung tissue which comprises a means for pulmonary administration, and a NF- ⁇ decoy in a form suitable for pulmonary administration.
- a system for prevention or treatment of lung tissue which comprises a means for pulmonary administration, and a NF- ⁇ decoy in a form suitable for pulmonary administration.
- a system for prevention or treatment of lung tissue which comprises a means for pulmonary administration, and a NF- ⁇ decoy in a form suitable for pulmonary administration.
- I will provide a. It is understood that such a system may be in any form as long as it realizes pulmonary administration of a cell growth factor.
- Means for realizing such pulmonary administration include, but are not limited to, inhalation devices, bronchoscopes, and the like.
- the NF- ⁇ decoy used can be used in any form such as dry powder, ribosome, and fine particles.
- the NF- ⁇ decoy used in the composition of the present invention is
- Such concentrations can be easily determined in in vitro experiments. Such experiments include, for example, labeling with a radioisotope (e.g., I 125 ).
- a radioisotope e.g., I 125
- Examples include, but are not limited to, a method for confirming NF- ⁇ decoy by scintigram. It is advantageous to use scintigrams, preferably of clinical specifications. This is because confirmation can be performed with large animals such as dogs.
- the NF- ⁇ decoy used is selectively administered to a tissue of interest, such as lung tissue.
- tissue of interest such as lung tissue.
- Such selective administration can be achieved using the means described in the Preferred V, Means for Administration in Systems of the Invention (eg, inhalation device or bronchoscope). Therefore, more preferably, the NF- ⁇ decoy is substantially not administered except to the desired tissue (eg, lungs).
- the desired tissue eg, lungs.
- a pulmonary administration system that can be used is capable of allowing the NF- ⁇ decoy of the present invention to reach the lung. Any system that can be used. Examples of such a pulmonary administration system include an inhalation device and a bronchoscope. For example, a bronchoscope system commercially available from Olympus Corporation can be used.
- NF- ⁇ B decoy variant (SEQ ID NO: 3)
- decoy solutions were stored at 100 mg / vial, frozen (at 20 ° C) until use.
- the asthma model was basically created based on the method described in Eur J Pharmacol. 1995 Dec 7; 293 (4): 401-12.
- Brown Norway rats (8-10 weeks old, weighing 200-300 g) were obtained from Charles Charles Riva Japan Co., Ltd. Rats were bred and tested in compliance with the animal welfare policy prescribed by Osaka University. The rats were sensitized by subcutaneous cervical injection of a solution containing 1 mg of ovalbumin (OVA; Sigma, grade V) with 4 mg of aluminum hydroxide in 1 ml of pyrogen-free saline. As an adjuvant, the Bordetel la pertussis vaccine (containing 3 ⁇ 10 9 heat-inactivated bacteria) was injected intraperitoneally. As a control, rats injected intraperitoneally with the same solution except that ovalbumin was not used as a negative control.
- OVA ovalbumin
- Bordetel la pertussis vaccine containing 3 ⁇ 10 9 heat-inactivated bacteria
- Sendai virus (HVJ) envelope vector HVJ-E was prepared as follows. Briefly, the virus suspension (1.0 ⁇ 10 4 hemagglutinating units (HAU)) was inactivated by UV irradiation (99 mi / cm 2 ) and decoy oligonucleotide (200 ⁇ g) and 0 ⁇ g 3% Triton-X was mixed. After centrifugation, the virus suspension inactivated with 1 ml of balanced salt solution (BSS; 10 mM Tris-C1, pH 7.5, 137 mM NaCl, and 5.4 mM KCl) is washed to remove detergent and incorporated Missing oligonucleotides were removed. After centrifugation, the envelope vector was suspended in an appropriate amount of phosphate buffered saline (PBS). This vector was stored at 4 ° C until use.
- PBS phosphate buffered saline
- rats Twelve days after sensitization, rats were treated as follows. After oral bronchial injection, (1) 0.5 ml of saline as control; (2) 0.5 ml of 500 g of naked decoy Z; (3) 1.0 ⁇ 10 4 H AU / 0.5 ml of HVJ— E treated with decoy 200 / zg;. (4) 2. 5 X 10 4 HAU / 0 decoy 500 was treated with 5ml of HVJ-E mu g;. and (5) 2. 5 X 10 4 HAU / 0 5ml Of HVJ-E was administered respectively. On the 14th day, the rats were challenged with 5% aerosolized ovalbumin using a nebulizer (PARI turbo) for 5 minutes. The air velocity was 7-8 liters Z of air. This induced airway hyperreactivity.
- Figure 1 shows a flowchart of this experimental procedure.
- Decoy can be administered by nasal inhalation (by aerosol) or intubation (liquid, aerosol, And administered to rats.
- BAL fluid was collected 24 hours after the ovalbumin challenge. Rats were euthanized by intraperitoneal administration of sodium barbital sodium in excess. BAL was performed four times with 5 ml of phosphate buffered saline (PBS; 137 mM NaCl, 10 mM sodium phosphate buffer pH 7.4, 2.7 mM KC1). Total cell number of BAL fluid was determined using a erythrometer. Differential cell counting was performed by counting more than 300 cells stained with Diff-Quick staining (IBMC Inc., Chicago, IL: Catalog # K7124).
- PBS phosphate buffered saline
- FIG. 2 shows the% eosinophil behavior in BAL in the first experiment.
- FIG. 3 shows the effect of the decoy of the present invention when Sendai virus is used as another administration method.
- Treatment of the ovalbumin challenge with the HVJ-E decoy formulation described above showed that HVJ-E was significantly more effective than naked decoy (see also Figure 4).
- the HVJ-E formulation with a 2.5-fold increase also showed a statistically significant therapeutic effect. Since it was shown that the effect of HVJ-E was not the effect of the vector itself, it was clarified that the formulation with HVJ-E had a higher therapeutic effect in the present invention.
- the present invention is not limited to a specific NF- ⁇ B decoy, but is a variant of NF- ⁇ B as long as the biological activity (ie, the binding activity to a transcription factor sequence) is maintained. Have the same therapeutic and prophylactic effects.
- NF- ⁇ B decoy The effect of NF- ⁇ B decoy on a rat asthma model was clarified as follows. In this example, a powdered inhalant of naked NF- ⁇ B decoy was administered.
- NF— ⁇ ⁇ Decoy was placed in a transparent glass bottle (body diameter 25.5 mm, height 48.5 mm) with 18 mg of zirconia beads ( ⁇ 3.0 mm) together with 100 mg, and the ball mill was rotated by Asahi. (Manufactured by Rika Seisakusho) and crushed at 200 rpm for 10 hours.
- lactose (trade name; Pharmatose 450M, manufactured by DMV) was pulverized by a jet mill (trade name; A-0 Jet Mill, manufactured by Seishin Enterprise Co., Ltd.).
- the NF- ⁇ B decoy and the lactose thus obtained were observed with a scanning electron microscope (S-570, manufactured by Hitachi, Ltd.) to examine the particle size.
- the results are shown as photographs in FIG. 5 (NF- ⁇ B decoy) and FIG. 6 (lactose).
- the magnification of the photograph was 1000 times and the particle size was less than 10 / zm each.
- a dose of 10 / zm or less is desirable for bronchial administration, but is not so limited. It is generally known that when the diameter is 3 m or less, administration to the alveoli becomes possible.
- Milled NF- ⁇ - decoy 100 mg, milled lactose 3700 mg and light anhydrous cake 200 mg of acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) was mixed for 1 minute with a small grinder (manufactured by Shibata Kagaku Co., Ltd.) to obtain NF- ⁇ B decoy mixed powder (25 ⁇ g / mg). .
- NF-KB decoy mixed powder (2.5; z gZmg) were obtained by mixing 1 mg of the powder and 180 mg of light caffeic anhydride with a small grinder for 1 minute.
- NF- ⁇ decoy mixed powder 800 mg of 0.25 gZmg
- 3040 mg of ground lactose 3040 mg of ground lactose
- 160 mg of light anhydrous silicic acid were mixed for 1 minute using a small grinder.
- Compound (0.05 / z gZmg) was obtained.
- the antigen ovalbumin OA (lmgZrat) was injected intramuscularly into thigh muscle and B. pertussis (1.
- Figures 7 and 8 Effect of NF- ⁇ B decoy on rat asthma model # #: p-0.01 vs saline group (Student's st-test): p ⁇ 0.0
- control group showed a clear increase in airway responsiveness (airway hypersensitivity) and eosinophilicity compared to the negative control (saline) group.
- airway responsiveness airway hypersensitivity
- eosinophilicity compared to the negative control (saline) group.
- the NF- ⁇ B decoy inhibited these changes more dose-dependently than 5 gZkg, and reached the maximum inhibitory effect at 25, 125 / z gZkg. This demonstrated the efficacy of NF- ⁇ B decoy powder inhaler in a rat asthma model.
- DNP-OA 2,4-dinitrophenyl ovalbumin
- B. pertussis (1.25 ⁇ 10 1 (> )
- the antigen was instilled into both sides (10% DNP-OAX 0.02 mL Zsite X 2 site) to induce an allergic reaction, and 6 hours after the onset of rhinitis (Bontamine Sky Blue) was administered intravenously and dissected 9 hours after the peak .
- the tissue around the nasal septum was excised and the amount of dye leakage was measured.
- a group in which physiological saline was instilled into the sensitized rats, and a group in which the antigen was instilled into the sensitized rats and the solvent was administered were set as a control group.
- the NF- ⁇ B decoy was dissolved in physiological saline at a concentration of 5 and 125 ⁇ g ZmL, and administered intranasally 20 days on one side, 0.2 g and 5 g per rat 3 days before administration. Since the average weight of the SD rat used in this experiment was 200 g, the dose of NF- ⁇ B decoy was equivalent to 1 ⁇ gZkg and 25 ⁇ gZkg, respectively.
- Fig. 9 (Effect of NF- ⁇ decoy on rat rhinitis model; # #: ⁇ -ku 0.011 vs sa line group (Student's st-test) Water, water: p ⁇ 0.05, 0.011 vs control group (Dunnett's multiple comparison test)), a clear increase in vascular permeability was observed in the control group as compared to the yin 'control group (saline), which caused rhinitis symptoms. That was confirmed.
- NF- ⁇ B decoy suppressed this increase in vascular permeability more than 1 ⁇ g / kg in a dose-dependent manner, and gZkg almost completely suppressed the increase in vascular permeability. That is, the effectiveness of NF- ⁇ B decoy in a rat rhinitis model was clarified.
- An anesthetic for animals was subcutaneously injected into a beagle dog (body weight: 9 to 14 kg) to perform general anesthesia. Perform endotracheal intubation and insert the bronchoscope into the bronchi. Pig spleen elas Dissolve 50 mg (3,750 units) of Tasase (Nacalai Tester) in 5 ml of physiological saline, and take the spray catheter (power such as Olympus is also available) to the peripheral bronchus and spray it 5-10 times throughout the right lung. One month after spraying was used as a COPD model lung. The comparison is performed using the left lung as a normal lung.
- the NF- ⁇ B decoy was pulverized by the method described in Example 4 to produce a fine powder having a particle size of 3 ⁇ m or less.
- NF- ⁇ B decoy 200 ⁇ g of NF- ⁇ B decoy is diffusely sprayed as a NF- ⁇ decoy mixed powder into the lung of a COPD model in 5-10 times throughout the right lung using a bronchoscope. Observe changes before and after treatment with NF- ⁇ B decoy Measure blood flow by MRI and compare.
- the beagle dog After MRI, the beagle dog is anesthetized and photographed in the supine position.
- a venous route is secured in the right internal carotid artery and a general commercially available contrast medium is injected
- the blood vessels in the lungs are imaged after about 3 seconds, and the MRI signal value increases due to the contrast effect. Since the MRI signal value is proportional to the blood flow, the signal value is higher at a site where the blood flow is higher. Since there is an individual difference in pulmonary artery blood flow, the right and left doses of the administered right lung divided by the normal left lung to eliminate the individual difference are compared by the left-right ratio of the MRI signal values. Start MRI imaging after injecting 3 ml of commercially available contrast agent.
- compositions for treating a disease caused by expression of a gene controlled by NF- ⁇ B or a disease associated with eosinophil abnormality and a carrier used therefor.
- Topical administration of the pharmaceutical compositions of the present invention provides a non-invasive and repeatable method of treatment.
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Abstract
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002531629A CA2531629A1 (en) | 2003-07-09 | 2004-07-09 | Medicinal composition containing nf-.kappa.b decoy for treating and preventing respiratory diseases and method of using the same |
JP2005511547A JPWO2005004914A1 (ja) | 2003-07-09 | 2004-07-09 | NF−κBデコイを含む呼吸器疾患用治療および予防のための薬学的組成物およびその使用方法 |
AU2004255083A AU2004255083A1 (en) | 2003-07-09 | 2004-07-09 | Medicinal composition containing NF-kappaB decoy for treating and preventing respiratory diseases and method of using the same |
EP04747306A EP1642591A4 (en) | 2003-07-09 | 2004-07-09 | MEDICINAL COMPOSITION CONTAINING NF-KAPPA B LURE FOR TREATMENT AND PREVENTION OF RESPIRATORY DISEASES AND METHOD USING THE SAME |
US10/564,269 US20070183983A1 (en) | 2003-07-09 | 2004-07-09 | Medical composition containing nf-kb decoy for treating and preventing respir atory diseases and method of using the same |
Applications Claiming Priority (2)
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JPPCT/JP03/08740 | 2003-07-09 | ||
PCT/JP2003/008740 WO2005004913A1 (ja) | 2003-07-09 | 2003-07-09 | デコイを含む薬学的組成物およびその使用方法 |
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WO2005004914A1 true WO2005004914A1 (ja) | 2005-01-20 |
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PCT/JP2003/008740 WO2005004913A1 (ja) | 2003-07-09 | 2003-07-09 | デコイを含む薬学的組成物およびその使用方法 |
PCT/JP2004/009838 WO2005004914A1 (ja) | 2003-07-09 | 2004-07-09 | NF-κBデコイを含む呼吸器疾患用治療および予防のための薬学的組成物およびその使用方法 |
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PCT/JP2003/008740 WO2005004913A1 (ja) | 2003-07-09 | 2003-07-09 | デコイを含む薬学的組成物およびその使用方法 |
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US (1) | US20070183983A1 (ja) |
EP (1) | EP1642591A4 (ja) |
JP (1) | JPWO2005004914A1 (ja) |
CN (1) | CN1819845A (ja) |
AU (2) | AU2003252493A1 (ja) |
CA (1) | CA2531629A1 (ja) |
WO (2) | WO2005004913A1 (ja) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006132204A1 (ja) | 2005-06-06 | 2006-12-14 | Anges Mg, Inc. | 転写因子デコイ |
WO2007072909A1 (ja) | 2005-12-22 | 2007-06-28 | Anges Mg, Inc. | 新規オリゴヌクレオチド及びそれから成るNF-κBデコイ |
WO2008099906A1 (ja) | 2007-02-16 | 2008-08-21 | Anges Mg, Inc. | 歯周病、及び外科手術による歯槽骨欠損の治療剤 |
JP2019511556A (ja) * | 2016-04-15 | 2019-04-25 | チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッドChia Tai Tianqing Pharmaceutical Group Co., Ltd. | イソグリチルリチン酸またはその塩の吸入製剤および呼吸器疾患を治療する薬物の製造におけるそれらの応用 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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US7482158B2 (en) | 2004-07-01 | 2009-01-27 | Mathison Brian H | Composite polynucleic acid therapeutics |
JPWO2006075776A1 (ja) * | 2005-01-13 | 2008-06-12 | アンジェスMg株式会社 | 慢性閉塞性肺疾患(COPD)、嚢胞性線維症(CysticFibrosis)または肺高血圧症(pulmonaryhypertension)治療剤 |
ES2526705T3 (es) | 2005-10-25 | 2015-01-14 | The Johns Hopkins University | Métodos y composiciones para el tratamiento de síndrome de Marfan y trastornos asociados |
WO2007123793A2 (en) * | 2006-04-04 | 2007-11-01 | Stc.Unm | Swellable particles for drug delivery |
JP5777240B2 (ja) * | 2009-08-07 | 2015-09-09 | 株式会社ジーンデザイン | 新規オリゴヌクレオチド誘導体及びそれから成るNF−κBデコイ |
US9855216B2 (en) * | 2015-05-27 | 2018-01-02 | Ghasem Amoabediny | Targeted nano-liposome co-entrapping anti-cancer drugs |
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- 2003-07-09 AU AU2003252493A patent/AU2003252493A1/en not_active Abandoned
- 2003-07-09 WO PCT/JP2003/008740 patent/WO2005004913A1/ja not_active Application Discontinuation
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2004
- 2004-07-09 WO PCT/JP2004/009838 patent/WO2005004914A1/ja active Application Filing
- 2004-07-09 AU AU2004255083A patent/AU2004255083A1/en not_active Abandoned
- 2004-07-09 JP JP2005511547A patent/JPWO2005004914A1/ja active Pending
- 2004-07-09 EP EP04747306A patent/EP1642591A4/en not_active Withdrawn
- 2004-07-09 US US10/564,269 patent/US20070183983A1/en not_active Abandoned
- 2004-07-09 CN CNA2004800196986A patent/CN1819845A/zh active Pending
- 2004-07-09 CA CA002531629A patent/CA2531629A1/en not_active Abandoned
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006132204A1 (ja) | 2005-06-06 | 2006-12-14 | Anges Mg, Inc. | 転写因子デコイ |
WO2007072909A1 (ja) | 2005-12-22 | 2007-06-28 | Anges Mg, Inc. | 新規オリゴヌクレオチド及びそれから成るNF-κBデコイ |
WO2008099906A1 (ja) | 2007-02-16 | 2008-08-21 | Anges Mg, Inc. | 歯周病、及び外科手術による歯槽骨欠損の治療剤 |
JP2019511556A (ja) * | 2016-04-15 | 2019-04-25 | チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッドChia Tai Tianqing Pharmaceutical Group Co., Ltd. | イソグリチルリチン酸またはその塩の吸入製剤および呼吸器疾患を治療する薬物の製造におけるそれらの応用 |
JP2021176903A (ja) * | 2016-04-15 | 2021-11-11 | チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッドChia Tai Tianqing Pharmaceutical Group Co., Ltd. | イソグリチルリチン酸またはその塩の吸入製剤および呼吸器疾患を治療する薬物の製造におけるそれらの応用 |
JP7166929B2 (ja) | 2016-04-15 | 2022-11-08 | チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド | イソグリチルリチン酸またはその塩の吸入製剤および呼吸器疾患を治療する薬物の製造におけるそれらの使用 |
US11534398B2 (en) | 2016-04-15 | 2022-12-27 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Inhaled preparation of isoglycyrrhizic acid or salt thereof, and use in preparing drugs for treating respiratory system diseases |
JP7309791B2 (ja) | 2016-04-15 | 2023-07-18 | チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド | イソグリチルリチン酸またはその塩の吸入製剤および呼吸器疾患を治療する薬物の製造におけるそれらの使用 |
Also Published As
Publication number | Publication date |
---|---|
EP1642591A4 (en) | 2009-08-19 |
US20070183983A1 (en) | 2007-08-09 |
CN1819845A (zh) | 2006-08-16 |
WO2005004913A1 (ja) | 2005-01-20 |
CA2531629A1 (en) | 2005-01-20 |
AU2003252493A1 (en) | 2005-01-28 |
EP1642591A1 (en) | 2006-04-05 |
AU2004255083A1 (en) | 2005-01-20 |
JPWO2005004914A1 (ja) | 2006-10-05 |
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