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WO2025017382A1 - Formulation de pulvérisation nasale d'azithromycine - Google Patents

Formulation de pulvérisation nasale d'azithromycine Download PDF

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Publication number
WO2025017382A1
WO2025017382A1 PCT/IB2024/055572 IB2024055572W WO2025017382A1 WO 2025017382 A1 WO2025017382 A1 WO 2025017382A1 IB 2024055572 W IB2024055572 W IB 2024055572W WO 2025017382 A1 WO2025017382 A1 WO 2025017382A1
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WO
WIPO (PCT)
Prior art keywords
azithromycin
nasal
composition
suspension
stable
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.)
Pending
Application number
PCT/IB2024/055572
Other languages
English (en)
Inventor
Sivamallikarjuna Reddy Ambati
Mounika Chityala
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.)
Aodh Lifesciences Private Ltd
Original Assignee
Aodh Lifesciences Private 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 Aodh Lifesciences Private Ltd filed Critical Aodh Lifesciences Private Ltd
Publication of WO2025017382A1 publication Critical patent/WO2025017382A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/0043—Nose
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • active ingredient when used in connection with an active ingredient denotes an amount of the active ingredient that, when administered to a subject for treating Sinusitis, produces an intended therapeutic benefit in a subject.
  • active ingredient (used interchangeably with “active” or “active substance” or “drug”) as used herein includes azithromycin or its salt.
  • mucoadhesive refers to the ability of a substance to adhere to the mucosal surfaces of the body, such as the nasal mucosa. This property enhances the retention time of a pharmaceutical formulation at the site of administration, allowing for prolonged contact and improved drug absorption. Mucoadhesive agents can form strong non-covalent bonds with mucin and epithelial cells, leading to an increased local concentration of the active pharmaceutical ingredient, improved therapeutic efficacy, and potentially reduced dosing frequency.
  • compositions for nasal administration comprising Azithromycin were prepared, the compositions generally showed physical separation in the suspension composition. This physical instability further leads to lack of dose uniformity.
  • a Suspending agent at certain concentrations (e.g. at a concentration of at least about 0.1% w/w) in the suspension composition yielded a physically stable composition (with no separation) suitable for nasal administration.
  • Yet another embodiment is a stable fixed-dose, aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human, comprising about 0.05% w/w to about 3.53% w/w azithromycin dihydrate, about 0.010% w/w to about 0.045% w/w benzalkonium chloride, about 0.015% w/w to about 0.025% w/w sorbitan monolaurate, about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate, and about 0.09% w/wto about 0.9% w/w sodium chloride.
  • Chitosan may be present at a concentration of at least about 0.1% w/w, or preferably between about 0.3% w/w and about 3% w/w of the composition.
  • Yet another embodiment is a stable fixed-dose aqueous pharmaceutical composition in the form of suspension (e.g., contained in a container) for nasal administration to a human, comprising azithromycin dihydrate, benzalkonium chloride, sorbitan monolaurate, monosodium phosphate dihydrate, and sodium chloride, a Mucoadhesive (e.g., at a concentration of at least about 0.1% w/w of the composition), and a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable excipient may be added as desired.
  • Suitable preservatives which can be employed in the aqueous nasal spray suspension include Benzalkonium halides like benzalkonium chloride and benzalkonium bromide.
  • the amount of the preservative present in the aqueous nasal spray suspension may range from about 0.010 to about 0.045 % w/w relative to the total weight of the composition.
  • the preservative is present at a concentration of about 0.02% w/w relative to the total weight of the composition.
  • the amount of the chelating agent present in the aqueous nasal spray suspension of the present invention may range from about 0.0002 to about 0.5% w/w relative to the total weight of the composition.
  • suitable buffers that can be employed in the aqueous nasal spray suspension include, Monosodium phosphate dihydrate.
  • the suspension of the present invention may comprise an amount of buffer sufficient to maintain the pH of the composition from about 3 to about 6. Preferably, the amount of buffer ranges from about 0.018% to about 0.39% w/w relative to the total weight of the composition.
  • suitable sweetener/taste masking agents that can be employed in the aqueous nasal spray suspension include, but are not limited to, sucralose, thaumatin (e.g., Talin(R)), sucrose, saccharin (including salt forms such as sodium and calcium salts), fructose, glucose, dextrose, corn syrup, aspartame, acesulfame -K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, neotame, mannitol, eucalyptus oil, camphor, and natural or artificial flavors or flavoring agents (for example, menthol, mints, vanilla, orange, etc.), or combinations of two or more of such agents.
  • a particularly preferred taste-masking agent is sucralose.
  • the amount of the sweetener/taste masking agent present in the aqueous nasal spray suspension may range from about 0.01% to about 1% w/
  • the osmolality of the composition may range between about 200 mOsm/kg and about 400 mOsm/kg, or about 250 mOsm/kg and about 350 mOsm/kg.
  • the viscosity of the composition may be about 10 cps to about 200 cps, or preferably from about 20 cps to about 150 cps.
  • the pharmaceutical composition in the form of suspension contains azithromycin dihydrate particles having a mean particle size in the range of about 1 pm to about 20 pm, or preferably from about 1 pm to about 15 pm.
  • the suspension pharmaceutical composition of the present invention has a mean particle size of less than 15 pm when determined by microscopy technique.
  • the pharmaceutical composition when delivered as a nasal spray, has a spray pattern with a longest axis of about 15-75 mm, a shortest axis of about 10-65 mm, and an ellipticity of about 1-2.
  • the viscosity can be determined by various known instruments, such as a dynamic stress rheometer or Brookfield viscometer.
  • the viscosity is determined by a Brookfield viscometer by measuring torque transmission through a sample using a rotating spindle.
  • the present invention relates to a stable, fixed-dose, aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration to a human, where the composition comprises azithromycin dihydrate at about 0.05- 3.53% w/w and a Suspending agent which comprises sorbitan monolaurate at a concentration of about 0.3% w/w of the composition, wherein the composition has a pH between about 3.5 and about 3.9.
  • aqueous pharmaceutical composition e.g., contained in a container
  • the composition comprises azithromycin dihydrate at about 0.05- 3.53% w/w and a Suspending agent which comprises sorbitan monolaurate at a concentration of about 0.3% w/w of the composition, wherein the composition has a pH between about 3.5 and about 3.9.
  • Yet another embodiment is a stable fixed-dose pharmaceutical composition in the form of suspension (e.g., contained in a container) for nasal administration to a human, comprising azithromycin dihydrate at about 0.05-3.53% w/w and a Suspending agent which comprises sorbitan monolaurate at a concentration of about 0.5% w/w of the composition, wherein the composition has a pH between about 3.5 and about 3.9.
  • suspension e.g., contained in a container
  • a Suspending agent which comprises sorbitan monolaurate at a concentration of about 0.5% w/w of the composition, wherein the composition has a pH between about 3.5 and about 3.9.
  • the suspensions of the present invention have only one phase (i.e., they are preferably a single-phase suspension).
  • the present invention relates to a kit comprising a stable fixed-dose, aqueous pharmaceutical composition of the present invention contained in a container for nasal administration and a package insert containing instructions about the use of said pharmaceutical composition.
  • the container is part of a sprayer which has an actuator. When the actuator is actuated, the composition is delivered in the form of a spray.
  • the pharmaceutical composition is contained in a sprayer and has, upon delivery, a spray of the composition to a human nose, a spray pattern having a longest axis of 15-75 mm, a shortest axis of 10-65 mm, and an ellipticity of 1-2.
  • the pharmaceutical composition when delivered as a nasal spray using a sprayer, yields a specific spray pattern and spray droplet size.
  • the spray pattern can be determined by various known techniques, such as with an ADSA with NSPUA set up (Innova System) and the spray droplet size distribution can be determined by various known techniques, such as with a Malvern Spraytec with NSPUA set up (Innova System).
  • the aqueous nasal spray suspension can be administered as a drop or in any other form suitable for topical administration.
  • the composition may also be administered using a nasal tampon or a nasal sponge.
  • the invention provides a multi-dose composition of matter, comprising: (a) a multi-unit dosage of a pharmaceutical composition of the present invention; and (b) a container comprising: (i) a squeezable chamber holding the multi-dose of the composition and having an opening wherein the dosage exits the opening when the squeezable chamber is squeezed; and (ii) a closure mechanism removably attached to the opening of the squeezable chamber.
  • the multi-dose container is made of a moldable polymer.
  • the present invention also relates to a method of treating bacterial sinusitis in a human in need thereof, comprising administering by the nasal route a stable fixed dose of the aqueous pharmaceutical composition of the present invention.
  • the pharmaceutical composition that may be contained in a container comprises about 0.05% w/w to about 3.53% w/w azithromycin dihydrate, about 0.05% w/w to about 2% w/w chitosan, about 0.010% w/w to about 0.045% w/w benzalkonium chloride, about 0.015% w/w to about 0.025% w/w sorbitan monolaurate, about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate, and about 0.09% w/w to about 0.9% w/w sodium chloride.
  • the present invention relates to the use of about 0.05% w/w to about 3.53% w/w azithromycin dihydrate, about 0.05% w/w to about 2% w/w chitosan, about 0.010% w/w to about 0.045% w/w benzalkonium chloride, about 0.015% w/w to about 0.025% w/w sorbitan monolaurate, about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate, and about 0.09% w/w to about 0.9% w/w sodium chloride in the preparation of a stable fixed dose, aqueous pharmaceutical composition (e.g., contained in a container) for the treatment of bacterial sinusitis in a human in need thereof. Any pharmaceutical composition described herein may be used.
  • the present invention relates to a stable fixed-dose, aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration comprising about 0.05% w/w to about 3.53% w/w azithromycin dihydrate, about 0.05% w/w to about 2% w/w chitosan, about 0.010% w/w to about 0.045% w/w benzalkonium chloride, about 0.015% w/w to about 0.025% w/w sorbitan monolaurate, about 0.18% w/w to about 0.39% w/w monosodium phosphate dihydrate, and about 0.09% w/w to about 0.9% w/w sodium chloride for the treatment of bacterial sinusitis in a human in need thereof.
  • Step 1 Chitosan was added to water for injection and homogenized until fully hydrated.
  • Step 2 Carboxy methylcellulose Sodium was dispersed in water for injection and added to the chitosan mixture from Step 1 with continuous homogenization.
  • Step 3 Monosodium phosphate dihydrate, Sodium chloride, and Azithromycin dihydrate were dissolved in a separate portion of water for injection. The pH of this solution was adjusted to 2.8-3.2 with Hydrochloric acid.
  • Container details The final product was packaged in a sprayer containing an HDPE bottle crimped with a pump and fitted with an actuator and cap.
  • Step 1 Chitosan was added to water for injection with homogenization and allowed to fully dissolve and hydrate.
  • Step 5 Azithromycin Slurry Preparation: Azithromycin dihydrate was dissolved in the water: ethanol (1 :1 v/v) mixture.
  • Step 9 The benzalkonium chloride solution from step 8 was added to the main mixture with homogenization.
  • Oral azithromycin is absorbed through the gastrointestinal tract. Its bioavailability is approximately 37%, and peak plasma concentrations occur within 2-3 hours post-administration. Oral administration results in higher systemic exposure, which is necessary for treating disseminated infections but increase the risk of systemic side effects.
  • azithromycin After absorption, azithromycin is widely distributed throughout the body, including significant penetration into tissues and fluids. It has a large volume of distribution, indicating extensive tissue binding, which is beneficial for systemic infections but may not guarantee high concentrations in the sinuses.
  • Azithromycin is metabolized minimally by the liver and is primarily excreted unchanged in bile and, to a lesser extent, in urine. It has a long half-life (about 68 hours), allowing for once-daily dosing. The systemic metabolism and elimination pathways would be more engaged with oral administration compared to nasal spray.
  • Azithromycin nasal spray (AO SI-04) in healthy volunteers demonstrated significant pharmacokinetic benefits. Following intranasal administration, a nominal dose of 1 mg was utilized. Pharmacokinetic modeling indicated that azithromycin achieved peak concentrations in the nasal mucosa promptly due to efficient mucosal absorption. The rapid absorption is attributed to azithromycin's lipophilicity and its ability to permeate the nasal tissues effectively. Interestingly, azithromycin showed sustained presence in the nasal tissues, with a half-life extending up to 68 hours, highlighting its prolonged tissue penetration. This extended half-life is beneficial for maintaining therapeutic drug levels at the site of infection, thereby enhancing the drug's efficacy in treating bacterial sinusitis. The azithromycin provides immediate antibacterial action, while its prolonged retention in the nasal mucosa ensures continuous therapeutic levels, reducing the frequency of dosing.
  • azithromycin's concentration in the nasal tissues was significantly above the minimum inhibitory concentration (MIC) for common pathogens like Streptococcus pneumoniae and Haemophilus influenzae. This property not only enhances the immediate bactericidal effect but also helps in disrupting bacterial biofilms, thus preventing the recurrence of infection and reducing the risk of developing antibiotic resistance.
  • MIC minimum inhibitory concentration
  • the efficacy of the Azithromycin nasal spray was evidenced by its ability to reduce nasal congestion, rhinorrhea, and facial pain significantly faster than oral formulations. Additionally, the spray's formulation includes mucoadhesive properties, which enhance drug retention and effectiveness.
  • Biofilm of S. pneumoniae was cultured for 2 days prior to treatment application. Post-treatment biofilm volume and live bacteria percentage were evaluated using Confocal Laser Scanning Microscopy. Time Point for Analysis was 12 hours after administration of AO SI-04.

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

Abstract

La présente invention concerne une nouvelle suspension aqueuse stable monophasique pour administration nasale conçue pour traiter la sinusite bactérienne. La composition comprend du dihydrate d'azithromycine en tant que principe actif et utilise un système d'agent de suspension pour empêcher une séparation de phase pendant le stockage. Des modes de réalisation comprennent des formulations avec du monolaurate de sorbitane ou une combinaison de chitosane et de monolaurate de sorbitane pour assurer une stabilité de suspension. L'invention offre plusieurs avantages, notamment l'administration localisée d'azithromycine au site d'infection, réduisant potentiellement l'exposition systémique et les effets secondaires associés par rapport à des formulations orales.
PCT/IB2024/055572 2023-07-15 2024-06-07 Formulation de pulvérisation nasale d'azithromycine Pending WO2025017382A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202341047812 2023-07-15
IN202341047812 2023-07-15

Publications (1)

Publication Number Publication Date
WO2025017382A1 true WO2025017382A1 (fr) 2025-01-23

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Family Applications (1)

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PCT/IB2024/055572 Pending WO2025017382A1 (fr) 2023-07-15 2024-06-07 Formulation de pulvérisation nasale d'azithromycine

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6780398B1 (en) * 1999-08-07 2004-08-24 Glaxo Smithkline Kabushiki Kaisha Aqueous nasal formulation
CN1720024A (zh) * 2002-10-31 2006-01-11 Umd公司 用于输送药物到覆盖上皮和通过覆盖上皮输送药物的治疗组合物
IN2015CH05075A (fr) * 2017-12-01
CN111467362B (zh) * 2020-05-09 2021-07-06 北京四环制药有限公司 一种阿奇霉素药用组合物及其制备方法和其应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2015CH05075A (fr) * 2017-12-01
US6780398B1 (en) * 1999-08-07 2004-08-24 Glaxo Smithkline Kabushiki Kaisha Aqueous nasal formulation
CN1720024A (zh) * 2002-10-31 2006-01-11 Umd公司 用于输送药物到覆盖上皮和通过覆盖上皮输送药物的治疗组合物
CN111467362B (zh) * 2020-05-09 2021-07-06 北京四环制药有限公司 一种阿奇霉素药用组合物及其制备方法和其应用

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