WO2015065222A1 - Préparation pharmaceutique inhalable pour le traitement de l'asthme bronchial et de maladies à obstruction chronique des poumons contenant du bromure de tiotropium micronisé en qualité de substance active, et procédé de production - Google Patents

Préparation pharmaceutique inhalable pour le traitement de l'asthme bronchial et de maladies à obstruction chronique des poumons contenant du bromure de tiotropium micronisé en qualité de substance active, et procédé de production Download PDF

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Publication number
WO2015065222A1
WO2015065222A1 PCT/RU2013/000955 RU2013000955W WO2015065222A1 WO 2015065222 A1 WO2015065222 A1 WO 2015065222A1 RU 2013000955 W RU2013000955 W RU 2013000955W WO 2015065222 A1 WO2015065222 A1 WO 2015065222A1
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WO
WIPO (PCT)
Prior art keywords
sodium benzoate
micronized
lactose
tiotropium bromide
sieved
Prior art date
Application number
PCT/RU2013/000955
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/RU2013/000955 priority Critical patent/WO2015065222A1/fr
Publication of WO2015065222A1 publication Critical patent/WO2015065222A1/fr

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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
    • A61K47/26—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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K9/0075—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

Definitions

  • a pharmaceutical inhalation preparation for the treatment of bronchial asthma and chronic obstructive pulmonary disease containing micronized tiotropium bromide as an active substance, and a method for its preparation
  • the invention relates to medicine and the pharmaceutical industry, and relates to a dry powdered preparation containing two highly effective pharmaceutical substances in micronized 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 population seeking medical help, 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, the addition of complications, and patients gradually lose their ability to work. According to some reports, in Russia more than 11 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.
  • 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 the 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.
  • Active substance tiotropium bromide monohydrad 22.5 ⁇ g / capsule (18 ⁇ g in terms of tiotropium).
  • lactose monohydrate micronized 0.275 mg / capsule.
  • 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 inhalation drug for the treatment of bronchial asthma and chronic obstructive pulmonary disease containing micronized tiotropium bromide as the active substance, and sieved sodium benzoate sifted with a bulk density of 0, as a carrier of lactose with an average particle size of 120 - 200 microns. 30-0.50 g / cm 3 and sodium benzoate micronized with average particle sizes 0.5 -10 microns, with the following content of components per dose of the drug:
  • the proportion of micronized particles of the active component with sizes of 0.5-5 microns is at least 99% by weight.
  • Tiotropium is an m-anticholinergic and bronchodilating drug used to treat chronic obstructive pulmonary diseases, including chronic bronchitis and emphysema. The effect of the drug occurs within a few minutes and lasts up to 24 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 CDM Inhaler, Qualitec Industria, or a multi-dose inhaler, for example, Cyclohaler, Pulmed. W
  • a single-dose dry powder inhaler for example CDM Inhaler, Qualitec Industria, or a multi-dose inhaler, 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.
  • the proportion of particles 5 of the active component with a size of 0.5-5 microns is at least 95%, even more preferably 99% by weight.
  • the packing is carried out either in hard gelatin capsules, or in containers of 20 multi-dose inhalers, or in other devices for inhalation.
  • the preparation obtained by the above technology and the control preparation were tested in accordance with the requirements established for powders.
  • for inhalation of the European Pharmacopoeia Of particular importance for inhaled preparations is 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 model of the Andersen impactor is designed for a specific air flow rate and cannot be used on another.
  • the uniformity of the released dose was within the requirements of the European Pharmacopoeia. Examples are given for the content of tiotropium 18 ⁇ g / dose, because it turned out that a change in its quantity within the claimed limits practically does not affect the value of the respirable fraction. The best example of carrying out the invention
  • Micronization of the active substance is carried out in a planetary mill, for example, Retsch, PM 400.
  • the proportion of particles with sizes of 0.5-5 microns is 99% by weight.
  • Lactose with an average particle size of 120 microns
  • the bulk density of sifted sodium benzoate obtained in the range of 0.30-0.38 g / cm 3 .
  • Part of the sodium benzoate is micronized in a mixer with steel balls to a particle size of not more than 10 microns (at least 90%).
  • micronized tiotropium bromide is mixed with micronized sodium benzoate with a particle size of 0.5 ⁇ m. This procedure ensures that the ratios of active substances in the drug are unchanged.
  • the packing is carried out either in hard gelatin capsules, or in containers of multi-dose inhalers, or in other devices for inhalation.
  • Example 2 Thiotropium bromide 30 mcg;
  • Example 2 The preparation of the preparation in Example 2 is carried out analogously to Example 1, but lactose is taken with a particle size of 200 ⁇ m, sodium benzoate with a bulk density of 0.4 - 0.5 g / cm 3 , and micronized sodium benzoate with an average particle size of 10 ⁇ m.
  • the proportion of micronized particles of the active component with sizes of 0.5-5 ⁇ m is 99.5%, and mixing is carried out at a speed of 45 rpm for 12 minutes
  • Tiotropia bromide 22.5 Sodium benzoate micronized 0.05 mg; Lactose 15 mg;
  • the invention is applicable in the field of medicine and the pharmaceutical industry and relates to a dry powder preparation containing two highly effective pharmaceutical substances in micronized 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (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)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Otolaryngology (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte au domaine de la médecine et de l'industrie pharmaceutique et concerne une préparation sèche en poudre comprenant contenant du bromure de tiotropium sous forme micronisée permettant une pénétration dans les bronches et les alvéoles des poumons, et des excipients préparés selon un procédé particulier consistant en un mélange de lactose et de benzoate de sodium permettant de doser et de désagréger efficacement les substances actives.
PCT/RU2013/000955 2013-10-28 2013-10-28 Préparation pharmaceutique inhalable pour le traitement de l'asthme bronchial et de maladies à obstruction chronique des poumons contenant du bromure de tiotropium micronisé en qualité de substance active, et procédé de production WO2015065222A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/RU2013/000955 WO2015065222A1 (fr) 2013-10-28 2013-10-28 Préparation pharmaceutique inhalable pour le traitement de l'asthme bronchial et de maladies à obstruction chronique des poumons contenant du bromure de tiotropium micronisé en qualité de substance active, et procédé de production

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU2013/000955 WO2015065222A1 (fr) 2013-10-28 2013-10-28 Préparation pharmaceutique inhalable pour le traitement de l'asthme bronchial et de maladies à obstruction chronique des poumons contenant du bromure de tiotropium micronisé en qualité de substance active, et procédé de production

Publications (1)

Publication Number Publication Date
WO2015065222A1 true WO2015065222A1 (fr) 2015-05-07

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PCT/RU2013/000955 WO2015065222A1 (fr) 2013-10-28 2013-10-28 Préparation pharmaceutique inhalable pour le traitement de l'asthme bronchial et de maladies à obstruction chronique des poumons contenant du bromure de tiotropium micronisé en qualité de substance active, et procédé de production

Country Status (1)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030389A1 (fr) * 2000-10-12 2002-04-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelle poudre a inhaler a teneur en tiotropium
WO2002038154A1 (fr) * 2000-11-13 2002-05-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles compositions de medicaments a base de sels de tiotropium et de sels de salmeterol
RU2242972C2 (ru) * 2002-09-06 2004-12-27 Закрытое акционерное общество "Пульмомед" Ингаляционный состав для лечения бронхиальной астмы
EA200801629A1 (ru) * 2006-01-04 2008-12-30 Бёрингер Ингельхайм Интернациональ Гмбх Применение солей тиотропия для лечения персистирующей астмы средней тяжести

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002030389A1 (fr) * 2000-10-12 2002-04-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelle poudre a inhaler a teneur en tiotropium
WO2002038154A1 (fr) * 2000-11-13 2002-05-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles compositions de medicaments a base de sels de tiotropium et de sels de salmeterol
RU2242972C2 (ru) * 2002-09-06 2004-12-27 Закрытое акционерное общество "Пульмомед" Ингаляционный состав для лечения бронхиальной астмы
EA200801629A1 (ru) * 2006-01-04 2008-12-30 Бёрингер Ингельхайм Интернациональ Гмбх Применение солей тиотропия для лечения персистирующей астмы средней тяжести

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Preparat Spiriva.", POSLEDNIAYA AKTUALIZATSIYA OPISANIYA PROIZVODITELEM, Retrieved from the Internet <URL:http://www.rlsnet.ra/tn_index_id_22477.htm.> [retrieved on 20140623] *

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