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Therapeutic agent for fibroid lung

a technology for fibroid lung and therapeutic agents, which is applied in the direction of biocide, drug compositions, genetic material ingredients, etc., can solve the problems that none of these agents are satisfactory, and idiopathic interstitial pneumonia progresses into pulmonary fibrosis, so as to prevent pulmonary fibrosis onset, and reduce the risk of pulmonary fibrosis

Inactive Publication Date: 2011-05-05
NITTO DENKO CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0026]While the exact mechanism of action of the composition for treating pulmonary fibrosis of the present invention has not yet been completely clarified, the mechanism is considered as follows: with the composition, retinoid functions as a targeting agent to extracellular matrix-producing cells in the lung such as fibroblasts and myofibroblasts, and the retinoid delivers an active ingredient such as pharmaceutical agents that control activity or growth of extracellular matrix-producing cells in the lung to such cells, thereby exhibiting the effect against pulmonary fibrosis.
[0027]Accordingly, since active ingredients can be efficiently delivered to action sites, and further to targeted cells by using the carrier of the present invention, the treatment, suppression of progression, and prevention of onset of pulmonary fibrosis, in particular idiopathic interstitial pneumonia the treatment of which has been difficult to date are made possible; thus, the inventive carrier significantly contributes to the human medicine and veterinary medicine.
[0028]Moreover, the carrier of the present invention can be combined with any pharmaceutical drugs (for example, existing therapeutic agents for pulmonary fibrosis) to increase their action efficiency; therefore, it is also advantageous as its application range in terms of formulation is broad, facilitating the production of effective therapeutic agents.

Problems solved by technology

However, regarding idiopathic interstitial pneumonia, there is no radical treatment method to date, and only treatments such as administration of steroid drugs, azathioprine and cyclophosphamide during exacerbation of symptoms, and oxygen therapy during development of hypoxemia are performed; accordingly, there are many dead cases in which idiopathic interstitial pneumonia progresses into pulmonary fibrosis.
However, none of these agents is not yet satisfactory, and further development of the therapeutic agents for pulmonary fibrosis has been awaited.

Method used

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  • Therapeutic agent for fibroid lung
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  • Therapeutic agent for fibroid lung

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of siRNA

[0067]Three types of siRNA targeted at gp46 (GenBank Accession No. M69246), which is a rat homologue of human HSP47, and a random siRNA control were purchased from Hokkaido System Science Co., Ltd. Each siRNA consists of 27 bases overhanging on the 3′ side, and the sequences are as follows.

(sense, SEQ ID NO: 1)Sequence A: 5′-GUUCCACCAUAAGAUGGUAGACAACAG-3′(antisense, SEQ ID NO: 2)5′-GUUGUCUACCAUCUUAUGGUGGAACAU-3′(sense, SEQ ID NO: 3)Sequence B: 5′-CCACAAGUUUUAUAUCCAAUCUAGCAG-3′(antisense, SEQ ID NO: 4)5′-GCUAGAUUGGAUAUAAAACUUGUGGAU-3′(sense, SEQ ID NO: 5)Sequence C: 5′-CUAGAGCCAUUACAUUACAUUGACAAG-3′(antisense, SEQ ID NO: 6)5′-UGUCAAUGUAAUGUAAUGGCUCUAGAU-3′(sense, SEQ ID NO: 7) Random siRNA: 5′-CGAUUCGCUAGACCGGCUUCAUUGCAG-3′(antisense, SEQ ID NO: 8)5′-GCAAUGAAGCCGGUCUAGCGAAUCGAU-3′

[0068]Furthermore, siRNA that was labeled on the 5′ side with the fluorescent dye 6′-carboxyfluorescein (6-FAM) was also prepared.

example 2

Preparation of siRNA-Containing VA-Bound Liposome

[0069]As a liposome, a cationic liposome containing DC-6-14, cholesterol, and DOPE at a molar ratio of 4:3:3 (Lipotrust, Hokkaido System Science Co., Ltd.) was used. 10 nmol of liposome and 20 nmol of vitamin A (VA: all-trans retinol, Sigma) were mixed in DMSO using a 1.5-mL tube, then dissolved in chloroform, evaporated once, and then suspended in PBS (phosphate buffered saline). Subsequently, the siRNA (10 μg / mL) obtained in Example 1 and the liposome suspension were mixed at a ratio of 1:1 (w / w). Free VA and siRNA contained in the liposome suspension thus obtained were removed by a micropartition system (Sartorion VIVASPIN 5000 MWCO PES), thus giving an siRNA-containing VA-bound liposome (VA-lip-siRNA). The amount of VA added and the amount of VA contained in the purified liposome were measured by HPLC, and the proportion of VA bound to the liposome was examined; as a result, it was found that the majority of the VA (95.6±0.42%) wa...

example 3

In Vivo Anti-Pulmonary-Fibrosis Activity of siRNA-Containing VA-Bound Liposome

(1) Induction of Pulmonary Fibrosis and Administration of Drug

[0070]Male S-D rats (6 rats / group, 4 weeks old, Charles River Laboratories Japan, Inc.) were administered once with 0.5 mg bleomycin (BLM) dissolved in 0.5 cc of physiological saline into the lung intratracheally by intratracheal cannulation under anesthesia, to produce a bleomycin pulmonary fibrosis model. With this method, a significant fibrosis occurs in the lung generally after approximately 3 weeks. The VA-lip-siRNA prepared in Example 2 (0.75 mg / kg as an amount of siRNA, 1 ml / kg in volume, i.e., 200 μl for a rat of 200 g) or PBS (1 ml / kg in volume) was administered to the rats via the tail vein, starting from the day of administration of bleomycin, at a frequency of 3 times / week. The rats were sacrificed 21 days after the bleomycin administration, and bronchoalveolar lavage (BAL) fluid was analyzed, hydroxyproline in the lung was quantifie...

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Abstract

Disclosed are: a substance transfer carrier to an extracellular matrix-producing cell in the lung, which comprises a retinoid; a therapeutic agent for fibroid lung, which utilized the carrier; and a preparation kit of the therapeutic agent.

Description

TECHNICAL FIELD[0001]The present invention relates to a substance delivery carrier targeted at extracellular matrix-producing cells in the lung, and a therapeutic agent for pulmonary fibrosis and a method for treating pulmonary fibrosis utilizing the carrier.BACKGROUND ART[0002]Pulmonary fibrosis is a disease characterized by diffuse fibroplasia of the alveolar walls, and its main symptoms include dry cough and dyspnea on exertion. Ina restricted sense, it refers to end-stage disease states of interstitial pneumonia; while in a broad sense, it means a co-existing state of pulmonary fibrosis in a restricted sense with interstitial pneumonia. Any interstitial pneumonia can cause pulmonary fibrosis. Interstitial pneumonia is a generic term for the diseases that induce inflammation in interstices of the lung (including alveolar septum in a restricted sense, and intralobular interstice and the vicinity of pleural membrane in a broad sense); it includes those induced by a specific cause s...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K31/07A61K31/713A61K31/7088A61P11/00
CPCA61K9/007A61K31/7088C12N15/111C12N2310/11A61K47/10C12N2310/14C12N2310/3515C12N2320/32C12N2310/12A61K9/127A61K31/7105A61K45/00A61K47/28A61K48/00A61K31/713A61P11/00C12N15/113C12N2320/30
Inventor NIITSU, YOSHIROTAKIMOTO, RISHU
Owner NITTO DENKO CORP
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