WO2015065220A1 - Préparation inhalable pour le traitement de l'asthme bronchial et de maladies à obstruction chronique des poumons, et procédé de production - Google Patents

Préparation inhalable pour le traitement de l'asthme bronchial et de maladies à obstruction chronique des poumons, et procédé de production Download PDF

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Publication number
WO2015065220A1
WO2015065220A1 PCT/RU2013/000952 RU2013000952W WO2015065220A1 WO 2015065220 A1 WO2015065220 A1 WO 2015065220A1 RU 2013000952 W RU2013000952 W RU 2013000952W WO 2015065220 A1 WO2015065220 A1 WO 2015065220A1
Authority
WO
WIPO (PCT)
Prior art keywords
lactose
sodium benzoate
mcg
micronized
budesonide
Prior art date
Application number
PCT/RU2013/000952
Other languages
English (en)
Russian (ru)
Inventor
Олег Ростиславович МИХАЙЛОВ
Александр Александрович МАЛИН
Николай Александрович УВАРОВ
Original Assignee
Шолекс Девелопмент Гмбх
Олег Ростиславович МИХАЙЛОВ
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 Шолекс Девелопмент Гмбх, Олег Ростиславович МИХАЙЛОВ filed Critical Шолекс Девелопмент Гмбх
Priority to PCT/RU2013/000952 priority Critical patent/WO2015065220A1/fr
Publication of WO2015065220A1 publication Critical patent/WO2015065220A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • 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
    • A61P11/08—Bronchodilators

Definitions

  • the invention relates to medicine and the pharmaceutical industry, and relates to a dry powder preparation containing two highly effective pharmaceutical substances in microionized form, which allows penetration into the bronchi and alveoli of the lungs and specially prepared excipients that allow the dosage and disaggregation of active substances.
  • a dry powder preparation containing two highly effective pharmaceutical substances in microionized form, which allows penetration into the bronchi and alveoli of the lungs and specially prepared excipients that allow the dosage and disaggregation of active substances.
  • 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 associated with the presence of chronic recurrent inflammation. bronchial wall. COPD is characterized by steady progression, when even without exacerbation there is an increase in bronchial obstruction, the addition of complications, and patients gradually lose their ability to work. According to some reports, in Russia more than 1 1 million people suffer 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.
  • inhalation therapy The main place in the modern treatment of these diseases is inhalation therapy.
  • inhalation methods it is possible to create a high concentration of the drug substance directly in the bronchi and lungs, and the possibility of its systemic effect is reduced. This is due to the lack of binding to blood proteins, modifications in the liver, etc. drug before its action.
  • inhalation agents significantly reduces the total dose of the drug necessary to provide a therapeutic effect.
  • the particle diameter of the biologically active substance does not exceed 5 - 10 microns.
  • Finely dispersed (micronized) biologically active substances used for inhalation are characterized by a high specific surface area of the particles, which leads to a resulting distribution of interaction forces and, in turn, to an increase in the adhesion and cohesion of particles. Since the biologically active substance or mixture of substances is introduced by the patient using special devices, the drug should not linger in the specified device and not be lost when sprayed. That is, it is necessary to select such carriers that would ensure effective delivery of the drug when placed in an inhaled dosing device.
  • Known inhalation composition for the treatment of bronchial asthma containing drugs used in bronchial asthma, and sodium benzoate as a diluent.
  • the sodium benzoate content in the composition is from 20 to 99.8%.
  • the proposed composition does not cause side effects (for example, fungal diseases of the oral cavity) encountered when used as a diluent Sugars (RU 2054932 C1).
  • Lactose as carriers is used in almost all powder inhalation preparations. Its use is indicated in many foreign and Russian patents, for example, patents of the Russian Federation 2140260 and 2194497. However, as a rule, such a carrier does not provide a satisfactory fluidity of small particles, and therefore ease of penetration into the lungs.
  • the Symbicort preparation of the company Astra Zeneca can be indicated in the Turbuhaler multi-dose dry powder inhaler (http://www.rlsnet.ru/tn_index_id_17658.htm).
  • Composition of active substances Budesonide + Formoterol fumarate dihydrate.
  • Excipient lactose monohydrate - 491 mg / dose.
  • the known composition does not provide a significant amount of respirable fraction, which determines the effectiveness of inhalation.
  • the present invention is to develop an effective inhalation composition for the treatment of bronchial asthma and COPD.
  • a new drug for inhalation administration containing micronized Budesonide and micronized Formoterol fumarate dihydrate as active substances, and lactose with an average particle size of 1 to 10 microns and sodium benzoate with a bulk density in the range of 0.30-0 as a carrier. 50 g / cm 3 , preferably 0.38-0.44 g / cm 3 , with the following components per dose:
  • the drug is intended for the treatment of respiratory diseases - bronchial asthma and chronic obstructive pulmonary disease.
  • the patented composition is a powder containing budesonide and formoterol fumarate as active substances, which have different mechanisms of action and exhibit an additive effect, and lactose and sodium benzoate as auxiliary substances.
  • glucocorticosteroid budesonide with an inhalation procedure, it has a powerful anti-inflammatory effect in the bronchi, reducing the severity of symptoms and the frequency of exacerbations of bronchial asthma.
  • the selective agonist of p-adrenergic receptors formoterol has a bronchodilatory effect in patients with airway obstruction.
  • the effect of the drug occurs within 3 minutes and lasts up to 12 hours after inhalation.
  • the drug can be placed in gelatin capsules and used using a special device - a single dose dry powder inhaler, for example Inhaler CDM, from Qualitec Industria, or a multi-dose inhaler container, for example Cyclohaler, Pulmed.
  • a single dose dry powder inhaler for example Inhaler CDM, from Qualitec Industria
  • a multi-dose inhaler container for example Cyclohaler, Pulmed.
  • micronized substances are used (see the prior art) with an average particle size of from 0.1 ⁇ m to 10 ⁇ m.
  • proportion of particles of the active component with a size
  • 0.5-5 microns is at least 95%, even more preferably 99% by weight.
  • Another object of the invention is a method for producing the drug.
  • a method of obtaining a preparation for inhalation administration is characterized in that the substances of the active substances are micronized in a planetary mill, sieved through a sieve of lactose with an average particle size of 100-120 ⁇ m, followed by micronization to an average particle size of 1 to 10 ⁇ m, sieved with sodium benzoate to obtain a bulk density in the range of 0.30-0.50 g / cm 3 , preferably 0.38-0.44 g / cm 3 , preformed formoterol fumarate with micronized lactose in a ratio of 1: 16.6 -35.6, added to the resulting mixture micronized bud esonide and mix thoroughly, then injected into the mixture of sodium benzoate and the remaining amount lactose, stirred at a speed of 40-45 rpm for 12-15 minutes
  • the packaging is carried out either in hard gelatin capsules, or in containers of multi-dose inhalers, or in other devices for inhalation.
  • the drug obtained by the above technology and the control drug were tested in accordance with the requirements established for powders for inhalation of the European Pharmacopoeia.
  • the fraction of fine particles of active substances measured in ⁇ g / dose or percentage 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 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.
  • each specific Andersen impactor model is designed for a specific air flow rate and cannot be used on another.
  • micronization of the active substances is carried out in a planetary mill, for example, Retsch, PM 400. Achieve that the proportion of particles with sizes of 0.5-5 microns was at least 99% by weight.
  • the preparation of excipients is as follows ..
  • Lactose with an average particle size of 100-120 ⁇ m is sieved through a sieve with 200 ⁇ m cells. Lactose is micronized to particle sizes from 1 to 10 microns in a mill or purchased from manufacturers with the required particle sizes.
  • Sodium benzoate is sieved through a 400 ⁇ m sieve loaded with stainless steel balls on a sieve machine with intense vertical vibrations, for example Model AS 200 basic, Retsch (Germany).
  • the drug is obtained as in example 1. Pre-mixing formoterol fumarate with micronized lactose in a ratio of 1: 35.6. Stirring at a speed of 40 rpm and lead it for 15 minutes
  • the drug is obtained as in example 1. Pre-mixing formoterol fumarate with micronized lactose in a ratio of 1: 16.6. The bulk density of sifted sodium benzoate was obtained in the range of 0.38-0.44 g / cm.
  • the invention is applicable in the field of medicine and the pharmaceutical industry and relates to an effective inhalation composition for the treatment of bronchial asthma and COPD.

Abstract

L'invention se rapporte au domaine de la médecine et de l'industrie pharmaceutique et concerne une préparation sèche en poudre comprenant deux substances pharmaceutiques hautement efficaces, à savoir du budésonide et du formotérol fumarate dihydrate sous forme micronisée permettant une pénétration dans les bronches et les alvéoles des poumons, et des excipients préparés selon un procédé particulier, notamment un mélange de lactose et de benzoate de sodium, permettant de doser et de désagréger efficacement les substances actives.
PCT/RU2013/000952 2013-10-28 2013-10-28 Préparation inhalable pour le traitement de l'asthme bronchial et de maladies à obstruction chronique des poumons, et procédé de production WO2015065220A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/RU2013/000952 WO2015065220A1 (fr) 2013-10-28 2013-10-28 Préparation inhalable pour le traitement de l'asthme bronchial et de maladies à obstruction chronique des poumons, et procédé de production

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU2013/000952 WO2015065220A1 (fr) 2013-10-28 2013-10-28 Préparation inhalable pour le traitement de l'asthme bronchial et de maladies à obstruction chronique des poumons, et procédé de production

Publications (1)

Publication Number Publication Date
WO2015065220A1 true WO2015065220A1 (fr) 2015-05-07

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PCT/RU2013/000952 WO2015065220A1 (fr) 2013-10-28 2013-10-28 Préparation inhalable pour le traitement de l'asthme bronchial et de maladies à obstruction chronique des poumons, et procédé de production

Country Status (1)

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WO (1) WO2015065220A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2199322C2 (ru) * 1997-09-19 2003-02-27 Астразенека Аб Новое применение будезонида и формотерола
RU2242972C2 (ru) * 2002-09-06 2004-12-27 Закрытое акционерное общество "Пульмомед" Ингаляционный состав для лечения бронхиальной астмы
EA007374B1 (ru) * 2002-08-21 2006-10-27 Нортон Хелткэа Лтд. Способ получения сухих порошковых композиций для ингаляции
RU2327452C2 (ru) * 1999-11-30 2008-06-27 Новартис Аг Аэрозольная композиция, содержащая формотерол
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 (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2199322C2 (ru) * 1997-09-19 2003-02-27 Астразенека Аб Новое применение будезонида и формотерола
RU2327452C2 (ru) * 1999-11-30 2008-06-27 Новартис Аг Аэрозольная композиция, содержащая формотерол
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
EA007374B1 (ru) * 2002-08-21 2006-10-27 Нортон Хелткэа Лтд. Способ получения сухих порошковых композиций для ингаляции
RU2242972C2 (ru) * 2002-09-06 2004-12-27 Закрытое акционерное общество "Пульмомед" Ингаляционный состав для лечения бронхиальной астмы

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Preparat Simbikort Turbukhaler. Instruktsiia po primeneniiu", PROTIVOPOKAZANIIA, SOSTAV I TSENA, 28 September 2011 (2011-09-28), Retrieved from the Internet <URL:http://www.rlsnet.ra/tn_index_id_17658.htm> *

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