WO2022231532A1 - Procédé de préparation de suspensions stérilisées pour inhalation par nébulisation - Google Patents

Procédé de préparation de suspensions stérilisées pour inhalation par nébulisation Download PDF

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Publication number
WO2022231532A1
WO2022231532A1 PCT/TR2021/050409 TR2021050409W WO2022231532A1 WO 2022231532 A1 WO2022231532 A1 WO 2022231532A1 TR 2021050409 W TR2021050409 W TR 2021050409W WO 2022231532 A1 WO2022231532 A1 WO 2022231532A1
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WO
WIPO (PCT)
Prior art keywords
process according
sorbitan
rotational speed
polyoxyethylene
tank
Prior art date
Application number
PCT/TR2021/050409
Other languages
English (en)
Inventor
Emine Yilmaz
Devrim Celik
Yelda EKRAM
Fulden KUS
Original Assignee
Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
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 Arven Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority to PCT/TR2021/050409 priority Critical patent/WO2022231532A1/fr
Publication of WO2022231532A1 publication Critical patent/WO2022231532A1/fr

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Classifications

    • 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
    • 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
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • 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
    • A61K9/0078—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

Definitions

  • the invention relates to a process for the preparation of sterilized suspensions to be used in pharmaceutical formulations for inhalation by nebulization which is used in the treatment of chronic obstructive pulmonary disease (COPD), asthma and other obstructive respiratory diseases.
  • COPD chronic obstructive pulmonary disease
  • Obstructive lung disease is a significant public health problem. Asthma, chronic obstructive pulmonary disease (COPD) and other obstructive airway diseases are highly prevalent chronic diseases in the general population. These obstructive airway illnesses are manifested with chronic inflammation affecting the whole respiratory tract. Obstruction is usually intermittent and reversible in asthma but is progressive and irreversible in COPD.
  • COPD chronic obstructive pulmonary disease
  • nebulizers One alternative of MDI or DPI is the development of nebulizers in which aqueous solutions of pharmacologically-active substances are sprayed under high pressure so as to produce a mist of inhalable particles.
  • Drugs combine pharmacologic activity with pharmaceutical properties. Desirable performance characteristics expected from them are physical and chemical stability, ease of processing, accurate and reproducible delivery to the target organ, and availability at the site of action.
  • Pharmaceutical compositions for inhalation used in the treatment of obstructive respiratory diseases can comprise various active agents such as long acting muscarinic antagonists (LAMA), long acting beta agonists (LABA), short acting beta-2 agonists (SABA) and glucocorti costeroids.
  • LAMA long acting muscarinic antagonists
  • LABA long acting beta agonists
  • SABA short acting beta-2 agonists
  • glucocorti costeroids glucocorti costeroids
  • Glucocorticosteroids are a class of drug that lowers inflammation in the body. Inhaled glucocorticosteroids reduce inflammation in the airways that carry air to the lungs (bronchial tubes) and reduce the mucus made by the bronchial tubes which makes easier to breathe.
  • glucocorticosteroids such as ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynol
  • Fluticasone is the most commonly used glucocorticosteroid for inhalation.
  • Fluticasone Propionate is the propionate salt form of fluticasone, a synthetic trifluorinated glucocorticoid receptor agonist with antiallergic, anti-inflammatory and antipruritic effects.
  • Fluticasone propionate sold under the brand name Flixotide, is a steroid medication.
  • EP1494647B1 relates to a process for the preparation of aqueous suspensions of drug particles, to be administered by inhalation, which produces homogenous dispersions of particles characterized by optimal size and size distribution. Also mentioned in the patent document that the active ingredient is homogenized, again under vacuum, using the turbine system and operating at a speed of between 750 and 4000 rpm, preferably between 1000 and 3600 rpm and even more preferably between 1600 and 3000 rpm for 5-60 minutes preferably for 20-40 minutes.
  • the main object of the present invention is to provide a production method for preparing sterilized pharmaceutical glucocorticosteroid compositions for inhalation which eliminates all aforesaid problems and brings additional advantages to the relevant prior art.
  • Another object of the present invention is to provide a process for the preparation of sterilized suspensions to be used in pharmaceutical formulations for inhalation by nebulization for use in the prevention, treatment, or in the alleviation of the symptoms of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease.
  • Another object of the present invention is to provide a process for the preparation of sterilized suspensions to be used in pharmaceutical formulations for inhalation by nebulization with increased stability, enhanced fine particle dose (FPD), fine particle fraction (FPF), delivery rate and total active agent values.
  • FPD fine particle dose
  • FPF fine particle fraction
  • Another object of the present invention is to provide a process for the preparation of sterilized suspensions to be used in pharmaceutical formulations for inhalation by nebulization with enhanced uniformity and homogeneity.
  • Another object of the present invention is to provide a process for the preparation of sterilized suspensions to be used in pharmaceutical formulations for inhalation by nebulization which saves time and provides one-pot manufacturing accordingly.
  • Another object of the present invention is to provide a process for the preparation of sterilized suspensions to be used in pharmaceutical formulations for inhalation by nebulization in which the active agent(s) and excipients are added in separately and respectively and are mixed at different rotational speeds.
  • Another object of the present invention is to obtain sterilized suspensions provided by the above-mentioned process comprising glucocorticosteroids.
  • a further object of the present invention is to obtain sterilized suspensions comprising a glucocorticosteroid.
  • Another object of the present invention is to obtain inhalation compositions comprising fluticasone or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to obtain sterilized suspension compositions comprising glucocorticosteroids, isotonic agents, buffering agents, dispersing or suspending agents.
  • Another object of the present invention is to produce a much lower level of total impurities than the prior art sterilization.
  • Another object of the present invention is to describe a process for forming suspension and solution-type inhaler formulations to be delivered to the patient via nebulization.
  • Another object of the present invention is to access of inhaler formulations to the lungs is achieved by optimizing the process steps involving device, active agent and excipients.
  • Another object of the invention is to show how changes made in the process steps of the drug formulation improve the process in order to ensure effective delivery of the active substance.
  • the present invention relates to a process for the preparation of sterilized suspensions to be used in pharmaceutical formulations for inhalation by nebulization, which comprises the following steps: i. filling a tank which has homogenizer with water for injection and wetting the walls of the tank with water for injection. ii. adding the pre-weighed isotonic agent and at least two buffering agents to the water in the tank which has homogenizer, respectively, and mixing at first rotational speed. iii. adding the pre-weighed at least two dispersing or suspending agents to the mixture in the tank which has homogenizer and mixing at a second rotational speed iv. adding the active agent to the mixture in the tank which has homogenizer and mixing at a second rotational speed v.
  • mixing, homogenization and autoclaving are carried out in one tank.
  • the water for injection in the step numbered (i) is heated to 40- 60° C, more preferably 45-55° C, more preferably 50° C.
  • the liquid pharmaceutical composition typically comprises isotonic agents.
  • the isotonic agents may be any pharmaceutically acceptable isotonic agents. Suspensions will desirably be isotonic.
  • the formulations which are used present process may be adjusted to desired isotonicity by the addition of suitable isotonic agents.
  • said isotonic agent in the step numbered (ii) is selected from the group comprising mannitol, sodium chloride, potassium chloride and sodium bromide or a pharmaceutically acceptable salt thereof.
  • said isotonic agents in the step numbered (ii) is sodium chloride.
  • the liquid pharmaceutical composition comprises one or more buffering agents.
  • the buffering agents are pharmaceutically acceptable buffering agents.
  • the buffering agents may be any buffering agents suitable for use in a liquid pharmaceutical composition suitable for inhalation.
  • One or more buffering agents are typically selected from citrate or phosphate buffers.
  • Citrate buffers is selected from the group comprising citric acid, sodium citrate and mixtures thereof.
  • Phosphate buffers is selected from the group comprising phosphoric acid, monosodium phosphate, dibasic sodium phosphate and mixtures thereof.
  • the pharmaceutical composition comprises at least two buffering agents in the present invention.
  • said buffering agents is selected from the group comprising citric acid, sodium citrate, phosphoric acid, monosodium phosphate, dibasic sodium phosphate and mixtures thereof.
  • said buffering agents in the step numbered (ii) are monosodium phosphate dihydrate and dibasic sodium phosphate anhydrous.
  • Another important factor is the preparation of a suitable dissolution medium by including the dispersing or suspending agents in the process before the active agents to help dissolve the active agents that is insoluble in water.
  • said dispersing or suspending agent is selected from the group comprising polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate) and polysorbate 80 (polyoxyethylene (20) sorbitan monooleate) sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate and sorbitan monooleate, sorbitan trioleate (SpanR85), sorbitan mono-oleate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, synthetic lecithin, diethylene glycol dioleate, te
  • said dispersing or suspending agents in the step numbered (iii) are sorbitan monolaurate and polysorbate 20.
  • the active agent is selected glucocorticosteroid or pharmaceutically acceptable salt thereof.
  • said glucocorticosteroid is selected from the group comprising ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynolondane or mixtures thereof.
  • said glucocorticosteroids is fluticasone.
  • said fluticasone salt is fluticasone furoate.
  • the rotational speed at which the mixing process takes place is also critical. If a homogeneous mixing cannot be achieved at low rotational speed; the determined mixture uniformity results cannot be achieved. On the other hand, at high rotational speed, the mixture foams and the active agents attach to the foam and collect at the top of the mixture. Thus, the uniformity of mixing will not be achieved again. If the mixture cannot be homogeneous, a suitable product with desired therapeutic properties cannot be produced.
  • the steps of adding isotonic agents, buffering agents, dispersing or suspending agents and active agents used in the process to the process and the mixing speed applied are of great importance in order to ensure homogenization and prevent losses in the process.
  • the isotonic agent and buffering agents must be mixed at first rotational speed in step numbered (ii).
  • said first rotational speed in the step numbered (ii) is 18000- 33600 rpm, preferably 19000-30000 rpm, more preferably 20000-25000 rpm.
  • the high rotational speed causes the product to foam. Since the active agents adhere to the foam, the problem of loss of active agents and blend uniformity is observed in the prepared suspension. On the other hand, mixing the active agents at a very low rotational speed causes the problem of blend uniformity. It is therefore a fundamental subject of the present invention to add the mixing speed at different speeds specific to the active agents/isotonic agents/buffering agents/dispersing or suspending agents.
  • said second rotational speed in the step numbered (iii) and (iv) is 8800-18000 rpm, preferably 8800-15000 rpm, more preferably 8800-13000 rpm.
  • the effect of the final mixing time in the step numbered (iv) on the blend uniformity is great. If the final mixture is mixed for a short time, a homogeneous mixing cannot be achieved and the determined blend uniformity results cannot be achieved. On the other hand, if the final mixture is mixed for a long time; due to the action of the homogenizer, the active agents can be broken and damaged and the particle size can be reduced. In this case, the desired quality target profile cannot be achieved since the active agents targeted to reach the lungs cannot reach the lungs properly.
  • the duration of the step number (iv) is 1-15 minutes, preferably 2-13 minutes, more preferably 3-10 minutes.
  • said process reduces processing times and gives rise to suspensions with a homogenous, thus producing compositions with a high level of physical stability and therapeutic efficacy.
  • autoclaving in the step numbered (v) is at 121 °C for about 15-30 minutes.
  • the pharmaceutical compositions subjected to the invention are prepared by these steps: i. filling the tank which has homogenizer with water for injection and wetting the walls of the tank with water for injection ii. adding the pre-weighed sodium chloride, monosodium phosphate dihydrate and dibasic sodium phosphate to the water in the tank which has homogenizer, respectively, and mixing at 18000-33600 rpm, preferably 19000-30000 rpm, more preferably 20000-25000 rpm iii.
  • the invention also defines sterilized suspension compositions obtained by the process subjected to the invention.
  • a sterilized suspension composition comprises a glucocorticosteroid or pharmaceutically acceptable salt thereof.
  • a sterilized suspension composition comprises fluticasone furoate.
  • a sterilized suspension composition comprising glucocorticosteroids, isotonic agents, buffering agents, dispersing or suspending agents.
  • the amount of polysorbate 20 is between 0-1.0 % by weight of the total composition.
  • the amount of sorbitan monolaurate is between 0-0.3 % by weight of the total composition.
  • the amount of monosodium phosphate dihydrate is between 0- 2 % by weight of the total composition.
  • the amount of dibasic sodium phosphate anhydrous is between 0-1 % by weight of the total composition.
  • the amount of sodium chloride is between 0-0.9 % by weight of the total composition.
  • the concentration of active agents in the pharmaceutical composition is 1 mg/1 ml_, 0.25 mg/1 ml_, 2 mg/2 ml_ and 0.5 mg/2 ml_.
  • the process for sterilized suspension composition for nebulization subjected to the invention comprises;
  • Example 2 According to a preferred embodiment, a sterilized suspension composition subjected to the invention is used in the treatment of the respiratory diseases selected from asthma and chronic obstructive pulmonary disease and other obstructive respiratory diseases.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (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)
  • Dispersion Chemistry (AREA)
  • Otolaryngology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'une suspension stérilisée destinée à être utilisée dans des formulations pharmaceutiques pour inhalation par nébulisation, pour le traitement de la broncho-pneumopathie chronique obstructive (BPCO), de l'asthme et d'autres maladies respiratoires obstructives.
PCT/TR2021/050409 2021-04-29 2021-04-29 Procédé de préparation de suspensions stérilisées pour inhalation par nébulisation WO2022231532A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2021/050409 WO2022231532A1 (fr) 2021-04-29 2021-04-29 Procédé de préparation de suspensions stérilisées pour inhalation par nébulisation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2021/050409 WO2022231532A1 (fr) 2021-04-29 2021-04-29 Procédé de préparation de suspensions stérilisées pour inhalation par nébulisation

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WO2022231532A1 true WO2022231532A1 (fr) 2022-11-03

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004004739A1 (fr) * 2002-07-02 2004-01-15 Altana Pharma Ag Suspension aqueuse sterile contenant du ciclesonide
EP1574222A1 (fr) * 2004-03-12 2005-09-14 Cipla Ltd. Procédé de stérilisation
EP1683514A1 (fr) * 2005-01-20 2006-07-26 Eratech S.r.l. Suspensions concentrées de medicaments et leur utilisation pour la production de suspensions pour administration par inhalation
CN108175763A (zh) * 2017-12-19 2018-06-19 亿腾医药（苏州）有限公司 一种布地奈德无菌原料及其吸入用混悬液的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004004739A1 (fr) * 2002-07-02 2004-01-15 Altana Pharma Ag Suspension aqueuse sterile contenant du ciclesonide
EP1574222A1 (fr) * 2004-03-12 2005-09-14 Cipla Ltd. Procédé de stérilisation
EP1683514A1 (fr) * 2005-01-20 2006-07-26 Eratech S.r.l. Suspensions concentrées de medicaments et leur utilisation pour la production de suspensions pour administration par inhalation
CN108175763A (zh) * 2017-12-19 2018-06-19 亿腾医药（苏州）有限公司 一种布地奈德无菌原料及其吸入用混悬液的制备方法

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