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WO2015065223A1 - Solution stable de fénotérol bromhydrate - Google Patents

Solution stable de fénotérol bromhydrate Download PDF

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Publication number
WO2015065223A1
WO2015065223A1 PCT/RU2013/000956 RU2013000956W WO2015065223A1 WO 2015065223 A1 WO2015065223 A1 WO 2015065223A1 RU 2013000956 W RU2013000956 W RU 2013000956W WO 2015065223 A1 WO2015065223 A1 WO 2015065223A1
Authority
WO
WIPO (PCT)
Prior art keywords
solution
hydrobromide
solution according
excipients
sodium benzoate
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/RU2013/000956
Other languages
English (en)
Russian (ru)
Inventor
Олег Ростиславович МИХАЙЛОВ
Александр Александрович МАЛИН
Николай Александрович УВАРОВ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SHOLEX DEVELOPMENT GmbH
Original Assignee
SHOLEX DEVELOPMENT GmbH
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 SHOLEX DEVELOPMENT GmbH filed Critical SHOLEX DEVELOPMENT GmbH
Priority to PCT/RU2013/000956 priority Critical patent/WO2015065223A1/fr
Publication of WO2015065223A1 publication Critical patent/WO2015065223A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • 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 invention relates to medicine and the pharmaceutical industry, and relates to a solution of highly effective pharmaceutical substance and excipients, which allows the formation of an aerosol of small particles in order to penetrate the bronchi and alveoli of the lungs.
  • State of the art relates to medicine and the pharmaceutical industry, and relates to a solution of highly effective pharmaceutical substance and excipients, which allows the formation of an aerosol of small particles in order to penetrate the bronchi and alveoli of the lungs.
  • Bronchial asthma is one of the most common diseases of the respiratory system among people of all ages. In Russia, asthma affects 5 to 7% of the adult population. According to the severity of the disease: 30% of patients have a mild course of the disease, 50% have moderate severity and 20% have a severe form AD is the cause of 0.4% of all cases of the appeal of the population for medical care, 1.4% - hospitalizations.
  • Chronic obstructive pulmonary disease COPD is another common chronic respiratory disease, which is accompanied by the presence of chronic recurrent inflammation of the bronchial wall. COPD is characterized by steady progression, when even without exacerbation there is an increase in bronchial obstruction, adherence complications, and patients gradually lose their ability to work. According to some reports, in Russia more than Pmln. a person suffers from COPD. Thus, there is a significant need for drugs that are effective against respiratory diseases, especially for the treatment of asthma and chronic obstructive pulmonary disease.
  • nebulizers of various designs are used, using the energy of compressed air, ultrasound or driven by mechanical devices.
  • a general requirement for all types of nebulizers is the generation of an aerosol cloud with particle sizes from 0.5 ⁇ m to 10 ⁇ m, preferably from 0.5 ⁇ m to 5.0 ⁇ m, preferably from 0.5 ⁇ m to 3.0 ⁇ m.
  • Such a narrow respirable fraction can be obtained only by spraying true solutions of medicinal substances.
  • the measurement of the respirable fraction in the case of non-boiled preparations is possible both using impactors and directly measuring the particle sizes in the air stream, in particular by laser diffraction. Measurements using impactors allows you to immediately get the mass distribution and does not depend on the shape of the particles.
  • the substances that ensure the stability of the solution during storage can be added to the composition of nebulization solutions.
  • Flavor-correcting substances, aerosol particle size regulators, etc. may be added.
  • Solvents and / or cosolvents are selected from the group of biologically acceptable liquids, such as water, alcohols, glycols, etc.
  • a preferred solvent is water.
  • inhalation solutions are known, including for nebulization (application WO2008102128), containing beta-agonists as active substances, including the above excipients.
  • This source does not discuss or investigate the effect of combinations of excipients on the size of the respirable fraction.
  • Known combination solutions of fenoterol and ipratropium for the treatment of obstructive pulmonary diseases containing benzalkonium chloride as an auxiliary substance, a complexing agent such as EDTA, pH 3.2 (application W09827959).
  • the compositions are aimed at improving solubility for use in nebulizers. However, 70% alcohol is used for this, which is undesirable from the point of view of side effects on the patient.
  • Disodium edetate dihydrate 0.05 mg / ml
  • the present invention is to develop an effective inhalation composition for the treatment of bronchial asthma and COPD.
  • the solution contains phenoterol hydrobromide -5 (1-Hydroxy-2 - ((2- (4-hydroxyphenyl) - 1-methylethyl) amino) ethyl) - 1.3-benzenediol hydrobromide.
  • He is a selective adrenergic agonist of beta-adrenergic receptors and therefore has a more potent, relatively long-lasting effect in bronchospastic conditions with fewer side effects (tachycardia and other disorders of the cardiovascular system).
  • the drug has a bronchodilator effect and at the same time enhances the function of the ciliated epithelium and accelerates mucocyte pair transport.
  • Indications :
  • EDTA disodium dihydrate
  • the calculated amount of sodium benzoate and the complexing agent (if this is included in the recipe) are dissolved.
  • the solution was adjusted to pH 3.2-3.5 by adding a 1% solution of organic acid in purified water. With stirring, the required amount of fenoterol hydrobromide is introduced into the solution. Since the solution will be diluted with physiological saline before inhalation, depending on the indication and size of the nebulizer chamber, the amount of active substance is calculated from the need to obtain a 0.1% solution. After complete dissolution, the pH values are monitored again and adjusted if necessary. The finished solution is filtered through a sterilizing membrane filter with a pore size of 0.22 ⁇ m and poured into sterile glass dropper bottles.
  • the invention may be illustrated.
  • the solutions were poured into glass dropper bottles of 21-22 ml.
  • the drug obtained by the above technology, and the control drug was tested in accordance with requirements for inhalation solutions of the European Pharmacopoeia.
  • the fraction of fine particles of active substances measured in grams or percent and determined during aerodynamic tests.
  • the value of this fraction also called respirable, determines the effectiveness of the inhalation preparations intended for the treatment of respiratory organs.
  • the determination of the respirable fraction is carried out using the devices described in the European and American Pharmacopoeias.
  • the most commonly used is the eight-stage Andersen impactor (apparatus D of the European Pharmacopoeia), because it makes it possible to study in more detail the dispersed composition in the range from 0.5 microns to 10 or more microns.
  • the European Pharmacopoeia establishes the conditions for the analysis - the volume of air pumped is 4 l, the flow rate is 28.3 l / min, although it allows the use of other speeds. However, each specific Andersen impactor model is designed for a specific air flow rate and cannot be used on another.
  • respirable fractions were determined using the Andersen impactor using the above examples. They ranged from 84 to 91%. That is significantly higher than that of the prototype.
  • the analytical determination of fenoterol hydrobromide yielded a deviation value below the standard average. Thus, the uniformity of the released dose is very high.
  • the invention is applicable in the field of medicine and the pharmaceutical industry and relates to a solution of highly effective pharmaceutical substance and excipients, which allows the formation of an aerosol of small particles in order to penetrate into the bronchi and alveoli of the lungs.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dispersion Chemistry (AREA)
  • Otolaryngology (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention se rapporte au domaine de la médecine et de l'industrie pharmaceutique, et concerne une solution d'une substance pharmaceutique hautement efficace et d'excipients permettant de former un aérosol de fines particules en vue de leur pénétration dans les bronches et les alvéoles des poumons. La solution pour obtenir la préparation pour administration par inhalation comprend en qualité de substance active du fénotérol bromhydrate et, en qualité d'excipients, du benzoate de sodium, un acide organique alimentaire, de l'eau purifiée selon un contenu prédéterminé des composants. La solution possède un taux élevé de fractions respirables.
PCT/RU2013/000956 2013-10-28 2013-10-28 Solution stable de fénotérol bromhydrate Ceased WO2015065223A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/RU2013/000956 WO2015065223A1 (fr) 2013-10-28 2013-10-28 Solution stable de fénotérol bromhydrate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU2013/000956 WO2015065223A1 (fr) 2013-10-28 2013-10-28 Solution stable de fénotérol bromhydrate

Publications (1)

Publication Number Publication Date
WO2015065223A1 true WO2015065223A1 (fr) 2015-05-07

Family

ID=53004675

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/RU2013/000956 Ceased WO2015065223A1 (fr) 2013-10-28 2013-10-28 Solution stable de fénotérol bromhydrate

Country Status (1)

Country Link
WO (1) WO2015065223A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2473815A1 (fr) * 2002-04-11 2003-10-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Formulation d'aerosol contenant un sel de tiotropium pour administration par inhalation
RU2219906C2 (ru) * 1996-12-20 2003-12-27 Берингер Ингельхайм Фарма Гмбх Унд Ко. Кг Новые водные готовые лекарственные формы для получения беспропеллентных аэрозолей
RU2332217C2 (ru) * 2002-08-17 2008-08-27 БЁРИНГЕР ИНГЕЛЬХАЙМ ФАРМА ГМБХ УНД Ко.КГ Ингаляционные лекарственные средства, содержащие новое антихолинергическое средство в сочетании с кортикостероидами и бетамиметиками

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2219906C2 (ru) * 1996-12-20 2003-12-27 Берингер Ингельхайм Фарма Гмбх Унд Ко. Кг Новые водные готовые лекарственные формы для получения беспропеллентных аэрозолей
CA2473815A1 (fr) * 2002-04-11 2003-10-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Formulation d'aerosol contenant un sel de tiotropium pour administration par inhalation
RU2332217C2 (ru) * 2002-08-17 2008-08-27 БЁРИНГЕР ИНГЕЛЬХАЙМ ФАРМА ГМБХ УНД Ко.КГ Ингаляционные лекарственные средства, содержащие новое антихолинергическое средство в сочетании с кортикостероидами и бетамиметиками

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BEROTEK ®.: "Registratsionnyi nomer: P ZH) 15273/01", 14 August 2008 (2008-08-14), Retrieved from the Internet <URL:http://www.boehringer-ingetoeim.ra/content/dam/internet/opu/ra_RU/documents/Berotec.pdf> [retrieved on 20140623] *

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