WO1998007419A1 - Aerosol pour le traitement de l'asthme - Google Patents

Aerosol pour le traitement de l'asthme Download PDF

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Publication number
WO1998007419A1
WO1998007419A1 PCT/JP1997/002907 JP9702907W WO9807419A1 WO 1998007419 A1 WO1998007419 A1 WO 1998007419A1 JP 9702907 W JP9702907 W JP 9702907W WO 9807419 A1 WO9807419 A1 WO 9807419A1
Authority
WO
WIPO (PCT)
Prior art keywords
aerosol
furosemide
asthma
spray
hfa227
Prior art date
Application number
PCT/JP1997/002907
Other languages
English (en)
Japanese (ja)
Inventor
Yuko Saso
Shuji Kondo
Shinzo Kobayashi
Original Assignee
Hoechst Marion Roussel 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 Hoechst Marion Roussel Ltd. filed Critical Hoechst Marion Roussel Ltd.
Priority to AU38675/97A priority Critical patent/AU3867597A/en
Publication of WO1998007419A1 publication Critical patent/WO1998007419A1/fr

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Classifications

    • 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]
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/124—Aerosols; Foams characterised by the propellant
    • 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

Definitions

  • the present invention relates to an aerosol for treating asthma. More specifically, the present invention relates to a metered dose spray aerosol for asthma treatment comprising furosemide as an active ingredient and 1,1,1,1,2,3,3,3-hepnofluoropropane as a propellant.
  • Metered dose aerosols have been widely used, primarily as a method of administration suitable for treating asthma.
  • Metered aerosol is vaporized during morphism liquefied gas high pressure filled injection, black hole which has been used as a rich portable apparatus for generating a fine drug particles c but conventionally propellant (liquefied gas)
  • chlorofluorocarbon CFC
  • CFC chlorofluorocarbon
  • Inhalation methods for the treatment of asthma mainly include metered dose aerosols, dry powder sprays, and nebulizers.Either method requires considerable patient training to ensure that the active ingredient reaches the affected area sufficiently. Needed.
  • metered dose aerosols most of the patients who use inhalation methods for treating asthma use metered dose aerosols. Since the burden associated with the application is considered to be light, we have developed a metered dose aerosol for asthma treatment using furosemide as the active ingredient using a propellant that does not contain CFC.
  • propellants that are expected to be used as medical inhalants are 1,1,1,1,2-tetraf ⁇ And 1,1,1,2,3,3,3-heptafluopropane (1,1,1,2,3,3,3-heptafluopropane) : HFA227).
  • formulations containing these propellants and additives For example, Japanese Patent Application Laid-Open No. 7-53353 discloses a preparation in which a sparingly soluble fine particle drug such as furosemide is coated with an amphoteric surfactant and dispersed and suspended in HFA227.
  • a sparingly soluble fine particle drug such as furosemide
  • JP-A-5-279249 discloses a pharmaceutical aerosol formulation comprising a pharmaceutical, HFA227 and a surfactant which has been used as a medical aerosol.
  • a pharmaceutical aerosol formulation comprising a pharmaceutical, HFA227 and a surfactant which has been used as a medical aerosol.
  • auxiliary solvent such as alcohol
  • problems with storage stability and sealing materials for containers cannot be solved.
  • Sealing material is rubber (natural rubber) used to improve the sealing between cans and valves.
  • Japanese Patent Application Laid-Open No. 5-503523 discloses a method for producing an aerosol using a fluorinated surfactant which is a novel surfactant, but here again, the safety of these additives has not been confirmed.
  • JP-T-Hei 6-511235 describes an example of using an additive without using an auxiliary solvent in a formulation using HFA227, but all additives used are medical aerosol additives. It is unprecedented use, and its safety is a concern. For those that do not use additives, their practicality, such as spray uniformity and valve operability, will be verified.
  • Furosemide has the chemical name 4-chloro-1-N-furfuryl 5-5-sulfa moinolean traninoleic acid (— ch l oro— N—fu rf ury 1—5 su-lf araoy 1-anthrani lic acid)
  • a salt diuretic developed by Hext GmbH (Germany) and widely used clinically as a diuretic or antihypertensive.
  • the acute toxicity of furosemide (LD 5 () , oral administration) is 3. k. 2,000mg / kg for dogs and S OOmgZkg for dogs.
  • O_ Japanese Patent Publication No. 7-20862 reported that Bianco et al.
  • the present invention comprises an aerosol for treating asthma comprising furosemide particles and liquefied HFA227.
  • the formulation of the present invention contains 2 to 4% by weight of furosemide particles (the same applies hereinafter) and 96 to 98% of liquefied HFA227.
  • the particle size of furosemide particles is preferably in the range of 0.5 to 7 / in.
  • the preparation of the present invention is prepared by suspending liquefied HFA227 as a propellant in furosemide particles prepared by pulverization and spray drying to a particle size of 0.5 to 7 ⁇ m, which is suitable for medical inhalers. Easily manufactured.
  • metered dose aerosols that use CFC as a propellant add one or more surfactants for medical inhalants to improve the dispersibility of the suspended drug and the operability of the valve. I was assisting.
  • the aerosol of the present invention does not contain these surfactants. Dissolving these surfactants in HFA227 requires a considerable amount of co-solvent, such as ethanol, which may have side effects that promote local irritation during inhalation.
  • co-solvent such as ethanol
  • the safety of new surfactants and additives remains uncertain because of their unprecedented use.
  • a fixed dose aerosol suspension for asthma treatment using the furosemide of the present invention as an active ingredient requires a suspension containing 2 to 4% of the drug in a solid state in order to administer the effective amount. There is.
  • furosemide has a good "wetting" power and a good dispersibility with respect to HFA227.
  • “wetting” means the familiarity (affinity) of the drug with the propellant. Therefore, it was possible to prepare a preparation in which HFA227 was added as a propellant to furosemide without using an additive such as a surfactant. This preparation was filled into a pressure-resistant glass bottle, and its dispersibility, sedimentation velocity and redispersibility were measured.
  • a similar test was performed on a suspension of beclomethone diproionate and HFA227, which are listed as examples in JP-T-Hei 5-511235. The results showed that the drug floated and separated in the control product and was not suitable as a metered dose aerosol. On the other hand, it was found that the suspension of furosemide and HFA227 showed surprisingly good results in dispersibility and redispersibility.
  • the aerosol for the treatment of asthma of the present invention is a formulation with a high powder concentration, and when using a fixed quantity valve, there were concerns about valve operability such as clogging.
  • the metering valve is a pump for aerosol spraying a fixed amount of propellant and furosemide suspension at a time. It is anticipated that the aerosol for treating asthma of the present invention, which does not use a surfactant in particular, will affect the operability of the valve and fail to obtain good uniformity of spray amount and uniformity of spray content.
  • an aerosol for treating asthma of the present invention was prepared and subjected to a spray amount uniformity and spray content uniformity test. As a result, despite the fact that no surfactant was used as a lubricant, the spray accuracy and the uniformity of the spray content were surprisingly equal to or better than those of commercially available CFC-based aerosols. The above results were obtained.
  • the particle size is limited to 0.5 to 7 zm, which can reach the lungs. Therefore, the particle size after spraying was measured by a laser particle size distribution size and aerodynamic method, and surprisingly, it was confirmed that 10% or more of particles that could reach the lung were obtained. The results were equal to or better than those of a fixed-quantity spray suspension aerosol.
  • HFA227 has already been confirmed in IPACT-II (International Parmaceutical Aerosol Consortium for Toxicology Testing of HFA227).
  • IPACT-II International Parmaceutical Aerosol Consortium for Toxicology Testing of HFA227).
  • the aerosol for the treatment of asthma of the present invention was continuously sprayed into the mouth of a egret for 14 days. As a result, no abnormalities were observed in the macroscopic observation of the oral cavity and the histopathological examination of the oral mucosa, trachea and lungs.
  • the aerosol for treating asthma of the present invention comprises furosemide particles having a particle size in the range of 0.5 to 7 zm prepared by a pulverization and spray drying method as an active ingredient. It contains liquefied HFA227 as a propellant, It is a new formulation that does not contain CFC, and its practicality and safety have been confirmed.
  • a fixed dose spray aerosol for the treatment of asthma was prepared with the following composition. Furosemide particles (average particle size 2 ⁇ m) : 0.5g
  • composition was filled using a can (C326: 28 ml volume, 20-part, manufactured by Presspart) and a valve (DF10 / 100 ACT HFA227, manufactured by Sequist Barova).
  • the spray amount uniformity and spray content uniformity test were performed on the quantitative spray aerosol suspension for asthma prepared according to the above formulation examples (hereinafter, all tests were performed at room temperature).
  • a spray amount uniformity test the amount of each spray was weighed and the variation with respect to the average was calculated.
  • Spray content uniformity As a test, this product was shaken for 5 seconds, then sprayed one spray at a time into an aerosol collection bottle, and the furosemide in the collection bottle was dissolved with methanol to make exactly 50 ml and used as a sample solution. .
  • 20 mg of furosemide was taken as a standard solution, and adjusted to exactly 200 ml with methanol.
  • the furosemide content in each spray was measured by HPLC (Water) for the sample solution and the standard solution.
  • the HPLC conditions are as follows.
  • Table 1 shows the test results. Test item Average value Variation from the average Spray amount uniformity test 145 mg ⁇ 10% or less
  • the particle size distribution of the quantitative spray aerosol for the treatment of asthma prepared according to the formulation examples was measured as follows.
  • the fixed-quantity spray suspension aerosol for asthma treatment prepared according to the above formulation example was filled in a pressure-resistant glass container for aerosol study.
  • 0.1% of beclomethasone dipropionate 99.9% of HFA227 and HFA227 were filled in the same container, and a comparative test of the dispersibility and separation rate of each was performed.
  • each preparation was shake-dispersed for 30 seconds, and the dispersed state was visually observed.
  • the separation rate test each preparation was shake-dispersed for 30 seconds, allowed to stand, and the separation of drug and liquid was measured after 20 seconds.
  • Table 2 The test results are shown in Table 2.
  • an azole agent for treating asthma which has a high rate of reaching an affected part and has excellent therapeutic effects.
  • the aerosol for treating asthma of the present invention uses liquefied HFA227 with high safety as a propellant, and is excellent in safety because it is not necessary to use another agent such as a surfactant.
  • another agent such as a surfactant.
  • there is no danger of damaging the global environment because CFCs are not used as propellants, which may cause destruction of the ozone layer.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un aérosol pour le traitement de l'asthme comportant des particules de furosémide et du 1,1,1,2,3,3,3-heptafluoropropane (HFA227). Ledit aérosol, qui permet au furosémide qui en constitue le principe actif d'atteindre le site affecté dans une proportion plus élevée, offre par ailleurs une très grande sécurité. Il est de plus sans danger pour l'ozonosphère en raison de l'utilisation du HFA227 comme propulseur.
PCT/JP1997/002907 1996-08-23 1997-08-21 Aerosol pour le traitement de l'asthme WO1998007419A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU38675/97A AU3867597A (en) 1996-08-23 1997-08-21 Aerosol for the therapy of asthma

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8222016A JPH1067655A (ja) 1996-08-23 1996-08-23 喘息治療用エアゾール剤
JP8/222016 1996-08-23

Publications (1)

Publication Number Publication Date
WO1998007419A1 true WO1998007419A1 (fr) 1998-02-26

Family

ID=16775793

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/002907 WO1998007419A1 (fr) 1996-08-23 1997-08-21 Aerosol pour le traitement de l'asthme

Country Status (3)

Country Link
JP (1) JPH1067655A (fr)
AU (1) AU3867597A (fr)
WO (1) WO1998007419A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06501710A (ja) * 1990-10-18 1994-02-24 ミネソタ　マイニング　アンド　マニュファクチャリング　カンパニー ベクロメタゾン１７，２１ジプロピオネートを含んで成るエアロゾル製剤
JPH0753353A (ja) * 1993-07-15 1995-02-28 Hoechst Ag コーティングされたきわめて水難溶性の薬剤からなる吸入医薬剤形用医薬製剤およびその製造方法
JPH0720862B2 (ja) * 1989-01-27 1995-03-08 ヘキスト・アクチエンゲゼルシヤフト 吸入用喘息治療剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0720862B2 (ja) * 1989-01-27 1995-03-08 ヘキスト・アクチエンゲゼルシヤフト 吸入用喘息治療剤
JPH06501710A (ja) * 1990-10-18 1994-02-24 ミネソタ　マイニング　アンド　マニュファクチャリング　カンパニー ベクロメタゾン１７，２１ジプロピオネートを含んで成るエアロゾル製剤
JPH0753353A (ja) * 1993-07-15 1995-02-28 Hoechst Ag コーティングされたきわめて水難溶性の薬剤からなる吸入医薬剤形用医薬製剤およびその製造方法

Also Published As

Publication number Publication date
JPH1067655A (ja) 1998-03-10
AU3867597A (en) 1998-03-06

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