WO2006078066A1 - Medicament transbronchique pour l’infection respiratoire - Google Patents

Medicament transbronchique pour l’infection respiratoire Download PDF

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Publication number
WO2006078066A1
WO2006078066A1 PCT/JP2006/301264 JP2006301264W WO2006078066A1 WO 2006078066 A1 WO2006078066 A1 WO 2006078066A1 JP 2006301264 W JP2006301264 W JP 2006301264W WO 2006078066 A1 WO2006078066 A1 WO 2006078066A1
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WO
WIPO (PCT)
Prior art keywords
respiratory
respiratory tract
infection
therapeutic agent
administration
Prior art date
Application number
PCT/JP2006/301264
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English (en)
Japanese (ja)
Inventor
Katsunori Kanazawa
Makoto Sunagawa
Original Assignee
Dainippon Sumitomo Pharma Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dainippon Sumitomo Pharma Co., Ltd. filed Critical Dainippon Sumitomo Pharma Co., Ltd.
Priority to JP2006554008A priority Critical patent/JPWO2006078066A1/ja
Publication of WO2006078066A1 publication Critical patent/WO2006078066A1/fr

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a therapeutic agent for trans-respiratory tract respiratory infection, comprising force rubapenem as an active ingredient. More specifically, the present invention relates to a therapeutic agent for respiratory tract respiratory infections comprising active rubabenem as an active ingredient for administration to the respiratory tract in combination with respiratory infection patients who are systemically administered with an antibacterial agent.
  • the present invention also provides a method for treating respiratory infections comprising a step of administering respiratory tract Lvapenem together with respiratory tract infection to patients with respiratory infections who have been systemically administered with antibacterial agents, and
  • the present invention relates to the use of force rubapenem for the manufacture of a therapeutic agent for transrespiratory respiratory infections for combined administration to the respiratory tract of patients with respiratory infections being administered.
  • Rubapenem Due to its wide range of antibacterial spectrum and strong bactericidal activity, Rubapenem can be expected to have the best infection treatment effect among existing injectable antibacterial agents, and its usefulness in the treatment of severe respiratory infections Is very high (Journal of Japanese Society of Chemotherapy, Vol. 50 No. 3, 161-170 (2002)).
  • An object of the present invention is to provide a patient who has a respiratory infection, particularly severe pneumonia, who cannot obtain a sufficient effect by systemic administration of an antibacterial agent or needs long-term administration. And effective therapeutic agent for transrespiratory tract respiratory infection.
  • the present inventors have found that administration of a therapeutic agent for transrespiratory respiratory tract infections containing force lubapenem as an active ingredient is combined with systemic administration of antibacterial agents. It was found that a synergistic effect was exhibited in an infectious disease model, and further studies were made, and the present invention was completed.
  • the present invention provides the following.
  • a method for treating respiratory infection comprising a step of administering carbapenem via the respiratory tract to a patient with respiratory infection who has been systemically administered an antibacterial agent.
  • kits comprising a solution preparation capable of administration to the respiratory tract and a administration device comprising a solution containing the therapeutic agent for respiratory tract respiratory tract infection according to any one of [1] to [5].
  • a kit comprising a suspension preparation capable of administration to the respiratory tract comprising a suspension containing the therapeutic agent for respiratory tract respiratory tract infection according to any one of [1] to [5] and an administration device.
  • [10] comprising a solid preparation capable of administration to the respiratory tract comprising a micronized solid containing the therapeutic agent for respiratory tract respiratory tract infection according to any one of [1] to [5] and an administration device. kit.
  • Figure 4 is a photograph of the lung tissue of an untreated mouse with Klebsiella pneumoniae (nasal infection 48 hours after infection). The part surrounded by the dotted line is the pneumonia onset site.
  • Fig. 5 is a photograph of the lung tissue of Klebsiella pneumoniae nasal infection single-mouth penem Z-cilastatin treatment (subcutaneous / nasal combination) (48 hours after infection).
  • the therapeutic agent for respiratory tract respiratory infection of the present invention is particularly useful for severe patients with bacterial pneumonia.
  • Pneumonia is classified as mild, moderate, or severe based on the spread of shadows on chest radiographs and physical findings such as body temperature, pulse rate, respiratory rate, and the presence or absence of dehydration.
  • Body temperature is 38.6 ° C or higher.
  • 'Pulse is more than 1 30Z minutes.
  • CRP C-reactive protein
  • ⁇ P a ⁇ 2 (arterial oxygen partial pressure) is 60 Torr or less.
  • the active ingredient of the therapeutic agent for respiratory tract respiratory tract infections of the present invention is force rubabenem, that is, force ruba to be administered via the respiratory tract in combination with respiratory infection patients who are systemically administered with antibacterial agents.
  • the penem is not particularly limited as long as it is a powerful rubapenem that has antibacterial activity according to the pathological condition, but specific examples include meropenem, imipenem, panipenem, and bierpem sold as ethical drugs. Nem, Doripenem and the like. A preferred example is meropenem.
  • Meropenem is particularly effective when the pneumonia-causing microorganism is pneumococci, Haemophilus influenzae, meropenem sensitive staphylococci, Klebsiella, Pseudomonas aeruginosa, Moraxella catarrhalis, anaerobic bacteria.
  • any known method for administering respiratory tract respiratory tract can be used, and the method is not limited, and examples thereof include the following methods.
  • Dissolve strong rubapenem in an appropriate isotonic solvent such as physiological saline. Dissolve so that the single dose of the drug is about 5 to 1 OmL. This is administered for about 20 to 40 minutes with an ultrasonic nebulizer or a compressor nebulizer.
  • Dissolve strong rubapenem in an appropriate isotonic solvent such as physiological saline.
  • a bronchoscope, etc. intubate to the vicinity of the lesion and inject the drug solution.
  • the antibacterial agent administered systemically and the force Lubapenem administered via the respiratory tract may be administered simultaneously, or if combined effects of the present invention can be obtained, these are administered together at intervals. May be. Although it is most preferable to administer at the same time, a preferable interval when the concomitant administration is performed at intervals is 0 to 180 minutes, and a more preferable interval is 0 to 60 minutes.
  • the daily dose of force rubapenem administered by the respiratory tract is preferably in the range of 0.25 to 3 gZday, more preferably in the range of 0.5 to 1.5 g / day for adults. In this case, it is preferably selected from the range of 5 to 6 OmgZk g / day, more preferably from the range of 10 to 30 mgZk gZday.
  • the frequency of administration is preferably 1 to 4 times / day.
  • the single dose of force rubapenem administered via the respiratory tract is preferably in the range of 0.0625 g to 3 gZ, more preferably 0.125 g to l.5 gZ in the case of adults. In the case of children, it is preferably selected from the range of 1.25 to 60 mgZk gZ times, more preferably from the range of 2.5 to 3 OmgZk g / times.
  • the daily dose, number of doses and single dose of force rubapenem administered via the respiratory tract are preferably selected from the following ranges.
  • the antibacterial agent administered systemically is not particularly limited as long as it is considered effective against the microorganism causing the respiratory tract infection to be treated.
  • Preferable examples include strong ruba penem antibacterial agents. Specific examples include meropenem, imipenem, panipenem, beer penem, and drippenem. Preferable examples include merobenem.
  • the daily dose of systemic antibiotics is preferably 0.2 for adults. Select from 5 to 3 gZday, more preferably 0.5 to 1.5 gday, preferably 5 to 60 mgZk gZday for children, more preferably l O SOmgZk g / day To do.
  • the frequency of administration of the antibacterial agent administered systemically is preferably 1 to 4 times Z0.
  • the single dose of antimicrobials administered systemically is preferably in the range of 0.0625 g to 3 g / dose for adults, more preferably in the range of 0.125 g to l. 5 times for children. Preferably, it is selected from a range of 1.25-6 OmgZk gZ times, more preferably 2.5-30 mgZk g Z times.
  • the daily dose, the number of doses and the single dose of systemically administered lubapenem are preferably selected from the following ranges.
  • Banipenem for adults • Daily dosage: 1-2 g
  • Examples of the administration target of the therapeutic agent for respiratory tract respiratory tract infection of the present invention include various mammals such as humans, monkeys, mice, rats, rabbits, pigs, innu, horses, tusks, etc. Excellent therapeutic effect on respiratory infections in subjects.
  • the agent for treating respiratory tract respiratory tract infections of the present invention is preferably administered in a liquid or suspension as an aerosol agent or a nebulizer together with appropriate additives, and in a powdered inhalant, it is in a solid state in a fine particle form.
  • an aerosol agent or a nebulizer together with appropriate additives, and in a powdered inhalant, it is in a solid state in a fine particle form.
  • a known solvent When formulating the therapeutic agent for respiratory tract respiratory tract infection of the present invention as a liquid preparation, a known solvent, a solubilizing agent, a suspending agent, an isotonic agent, a buffering agent, a soothing agent, etc. are added as necessary. It can be formulated by dissolving, suspending or emulsifying in water, physiological saline or the like to obtain a constant amount.
  • the average particle size is obtained by pulverizing, freeze-drying or spray-drying the antibacterial agent in advance as necessary. It is desirable to form fine particles with a diameter of 1 to 50 ⁇ m, preferably 1 to 10; um.
  • the average particle diameter refers to mass average aerodynamic diameter (MMAD).
  • MMAD mass average aerodynamic diameter
  • a known additive may be used as necessary when forming particles.
  • the antibacterial agent is pulverized, freeze-dried or spray-dried, etc., and the average particle size is 50 / m or less, preferably 1 to 10 / zm. It can be manufactured by making fine particles.
  • the average particle diameter here refers to the mass average aerodynamic diameter (MMAD). If necessary, it can be atomized together with a physiologically acceptable base or additive.
  • the finely divided antibacterial agent is uniformly dispersed and adhered to a physiologically acceptable base, or is agglomerated with the finely divided base or additive to obtain an average particle size 2 5 0 Secondary particles of m or less may be used.
  • lubricants binders, diluents, coloring agents, preservatives, preservatives, flavoring agents, protein-degrading enzyme inhibitors, water-absorbing and poorly water-soluble bases, water-soluble groups Agents, water-absorbing and gel-forming bases, and mixtures thereof may be added.
  • meropenem 0.25 g (Sumitomo Pharma Co., Ltd.) for commercially available meropen was used.
  • silastatin sodium commercially available silastatin sodium (Wako Pure Chemical Industries) was used.
  • test strain was inoculated into TSB medium and cultured overnight at 37 ° C with shaking. Overnight cultured bacterial solution (about 10 9 CF U / m 1) was diluted 1 or 10 or 1 Z 100 00 with sterile physiological saline, and each was used as a bacterial solution for infection. Ket am ine (100 mg / kg) / xy 1 azin (1 Omg / kg) The anesthetized mouse was inoculated nasally with the above-described bacterial solution for infection at 30 ⁇ 1 / head.
  • An untreated group was set as a control group. The number of animals in each group was 7-8 animals / group.
  • the survival rate after 2 days of infection was 12.5% in the subcutaneous administration group (8 per animal), and in the nasal administration group It was 0% (0 animals, 8 animals) and 42.9% (3 animals, 7 animals) in the subcutaneous nasal administration combination group.
  • 1 0 5 CFU infection model result of comparing the therapeutic effect of the administration of, the survival rate after infection 3, 2 5% subcutaneous dose group (8 animals 2 animals Roh), 2 nasal administered group 52.5 (2 animals 8 animals) and 62.5% (5 animals 8 animals) in the subcutaneous and nasal administration combination group.
  • the survival rate at 6 days after infection was 0% (0 mice / 8 animals) in the subcutaneous administration group, 0% (0 animals / 8 animals) in the nasal administration group, and 3 7 in the subcutaneous administration / nasal administration combination group. It was 5% (3 animals 8 animals).
  • meropenem 0.25 g (Sumitomo Pharma Co., Ltd.) for commercially available meropen was used.
  • silastatin sodium commercially available silastatin sodium (Wako Pure Chemical Industries) was used.
  • Klebsiella pneumoniae ⁇ -543 ⁇ 4 was used.
  • the test strain was inoculated in TSB medium and cultured overnight at 37 ° C with shaking. Overnight cultured bacterial solution (approximately 10 9 C FU m 1) was diluted 1100 with sterile physiological saline to obtain a bacterial solution for infection. Ketamine (100 mg / kg) / xy 1 azin (1 Omg / kg) Mice under anesthesia were inoculated intranasally with the above bacterial solution for infection at 30 ⁇ / ea. About 24 hours after inoculation with the fungus solution, the oral penem ⁇ cilastatin was administered subcutaneously (100 mg / kg) and nasally (2.5 / 2.5 mg / kg). An untreated group was set as a control group.
  • mice 4 8 hours after infection K etamine (lO Omg / kg) / xylazin (10 mg / kg) Anesthetized mice were lethal from the abdominal aorta and then thoracotomy was performed. In addition, the presence or absence of inflammation was observed, and observational observations were compared between meropenem Z silastatin-treated individuals and control individuals.
  • the present invention is useful for improving the therapeutic effect of patients with respiratory infections and shortening the treatment period.
  • the present invention is useful for the treatment of patients who have severe pneumonia and the like, for which systemic administration of an antibacterial agent does not provide a sufficient effect or requires long-term administration.
  • This application is based on Japanese Patent Application No. 2005-0 14 1 33 filed in Japan, the contents of which are incorporated in full in this application.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un médicament transbronchique pour soigner une infection respiratoire comprenant du carbapenem en tant que substance active qui présente un effet thérapeutique efficace chez un patient souffrant d’une infection respiratoire (en particulier, une pneumonie sévère), sur lequel des effets suffisants ne peuvent être atteints par l’administration systémique d’un agent antibactérien ou sur lequel l’administration à long terme est nécessaire, et qui doit être administré transbronchiquement en tant qu’association médicamenteuse chez un patient sous administration systémique d’un agent antibactérien; un procédé pour traiter une infection respiratoire qui comporte l’étape consistant à administrer transbronchiquement du carbapenem en tant qu’association médicamenteuse chez un patient souffrant d’une infection respiratoire et qui est sous administration systémique d’un agent antibactérien; et l’utilisation du carbapenem pour produire un médicament transbronchique pour soigner une infection respiratoire qui doit être administré transbronchiquement en tant qu’association médicamenteuse chez un patient souffrant d’une infection respiratoire et qui est sous administration systémique d’un agent antibactérien.
PCT/JP2006/301264 2005-01-21 2006-01-20 Medicament transbronchique pour l’infection respiratoire WO2006078066A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2006554008A JPWO2006078066A1 (ja) 2005-01-21 2006-01-20 経気道呼吸器感染症治療剤

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JP2005-014133 2005-01-21
JP2005014133 2005-01-21

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WO2006078066A1 true WO2006078066A1 (fr) 2006-07-27

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011520889A (ja) * 2008-05-15 2011-07-21 バクスター・インターナショナル・インコーポレイテッド 安定な医薬製剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003075889A1 (fr) * 2002-03-05 2003-09-18 Transave, Inc. Systeme d'inhalation pour le traitement d'infections intracellulaires

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003075889A1 (fr) * 2002-03-05 2003-09-18 Transave, Inc. Systeme d'inhalation pour le traitement d'infections intracellulaires

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ISHIMINE A.: "Ryokuno Kinsei Kokyuki Kansensho ni Taisuru Kokinyaku Kyunyu Ryoho no Kento", RYOKUNOKIN KANSENSHO KENKYUKAI KOEN KIROKU, December 2002 (2002-12-01), pages 122 - 125, XP003007797 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011520889A (ja) * 2008-05-15 2011-07-21 バクスター・インターナショナル・インコーポレイテッド 安定な医薬製剤

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