WO2011150441A1 - Medical aerosol formulation comprising ribavirin - Google Patents

Medical aerosol formulation comprising ribavirin Download PDF

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Publication number
WO2011150441A1
WO2011150441A1 PCT/AU2010/000686 AU2010000686W WO2011150441A1 WO 2011150441 A1 WO2011150441 A1 WO 2011150441A1 AU 2010000686 W AU2010000686 W AU 2010000686W WO 2011150441 A1 WO2011150441 A1 WO 2011150441A1
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WO
WIPO (PCT)
Prior art keywords
aerosol formulation
surfactant
metered dose
polyethylene glycol
dose inhaler
Prior art date
Application number
PCT/AU2010/000686
Other languages
French (fr)
Inventor
Shou-Chung Chao
Wen-Pao Tseng
Hui-lan CHEN
Hsueh-Min Jen
Chung-Shen Huang
Woei-Jia Jiang
Ko-Chia Ho
Original Assignee
Wholesome Biopharm Pty Ltd
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Application filed by Wholesome Biopharm Pty Ltd filed Critical Wholesome Biopharm Pty Ltd
Priority to PCT/AU2010/000686 priority Critical patent/WO2011150441A1/en
Publication of WO2011150441A1 publication Critical patent/WO2011150441A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/007Pulmonary tract; Aromatherapy
    • A61K9/0073Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/12Ketones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • This disclosure in general relates to a medical aerosol formulation. More particularly, this disclosure relates to an aerosol formulation for use in a metered dose inhaler (MDI), the aerosol formulation is characterized in having micronized particles of ribavirin for treating asthma.
  • MDI metered dose inhaler
  • Delivery of drugs to the lung by way of inhalation is an important means for treating a variety of conditions, including common conditions as pneumonia, bronchial asthma and chronic obstructive pulmonary disease and some systemic conditions, such as pain management, hormonal therapy and etc.
  • ribavirin when applied intranasally, is effective in treating allergic disease, such as asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock (see Chiang and Huang, WO 2007/104070). Accordingly, there exist in this art a need to develop a formulation of ribavirin, which contains ribavirin in respirable size and the ribavirin particles may be administered through oral inhalation and/or nasal inhalation, to treat allergic disease of a subject.
  • This invention address such need by providing an aerosol formulation, which contains micronized particles of ribavirin in respirable size, and the micronized particles are incorporated into a dispersion containing a propellent as a pressurized metered dose inhaler (MDI).
  • MDI pressurized metered dose inhaler
  • the prepared aerosol formulation is subsequently filled into an aerosol canister equipped with a metered dose valve. Patients can then dispense the formulation via an actuator adapted to direct the dose from the valve to the patient.
  • disclosure herein features a novel aerosol formulation for use in a metered dosage inhaler (MDI) and is useful for treating an allergic disease of a subject, particularly, the human suffers from asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock.
  • the aerosol formulation comprises respirable or inhalable micronized particles of an active agent that may be delivered to a subject with an aid of a fluid carrier.
  • the aerosol formulation for use in a metered dosage inhaler (MDI).
  • the aerosol formulation comprises about 0.0001 to 1% by weight of ribavirin; about 0.0001 to 15% by weight of a co-solvent; about 0.0001 to 1% by weight of a surfactant; and about 83 to 99% by weight of a non-chlorofluorocarbon (non-CFC) propellent.
  • non-CFC non-chlorofluorocarbon
  • the non-CFC propellent is any of 1 ,1 ,1 ,2-tetrafluoroethane (HFA-134a), 1 ,1 ,1 ,2,3,3,3-heptafluoropropane (HFA-227) or a mixture thereof.
  • the non-CFC propellent is HFA-134a.
  • the co-solvent is selected from the group consisting of propane, butane, n-pentane, isopentane, neopentane, ethanol, isopropanol and propylene glycol.
  • the co-solvent is ethanol.
  • the surfactant is selected from the group consisting of sorbitan monolaurate (SPAN 20), sorbitan monooleate (SPAN 80), sorbitan trioleate (SPAN 85), polyoxyethylene sorbitan monolaurate (TWEEN 20), polyoxyethylene sorbitan monoleate (TWEEN 80), lecithins (EPIKURON 200), oleyl polyoxyethylene ether (BRJI 92), stearyl polyoxyethylene ether (BRJI 72), lauryl polyoxyethylene ether (BRJI 30), block copolymers of oxyethylene and oxypropylene, oleic acid, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monolaurate, glyceryl monoricinoleate
  • the surfactant is less than about 1 % by weight of polyethylene glycol. In aconther example, the surfactant is a combination of about 0.5% by weight of polyethylene glycol, and about 0.5% by weight of oleic acid.
  • an aerosol formulation particularly, an aerosol formulation for use in a metered dose inhaler (MDI) and contains ribavirin as a sole active agent for treating an allergic disease such as asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock.
  • MDI metered dose inhaler
  • an aerosol formulation for use in the MDI comprises about 0.0001 to 1 % by weight of ribavirin; about 0.0001 to 15% by weight of a co-solvent; about 0.0001 to 1 % by weight of a surfactant; and about 83 to 99% by weight of a non-chlorofluorocarbon (non-CFC) propellent.
  • non-CFC non-chlorofluorocarbon
  • Ribavirin is conventionally used as an anti-infectious agent for treating viral infection, recently, it has also been identified that ribavirin alone is effective in treating allergic disease, which includes, but is not limited to, asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock (see Chiang and Huang, WO 2007/104070).
  • allergic disease which includes, but is not limited to, asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock (see Chiang and Huang, WO 2007/104070).
  • the medicament or drug is preferably micronized, whereby a therapeutically effective amount of the drug is particulate.
  • each drug particle has a mean diameter of about 1 to 10 ⁇ , preferably about 1 to 6 ⁇ , and most preferably about 3 ⁇ , in order that the drug particles can be inhaled into the respiratory tract and/or lungs.
  • the medicament or drug is present in a therapeutically effective amount, that is, an amount such that the drug can be administered as a dispersion, aerosol, via oral or nasal inhalation, and causes its desired therapeutic effects, typically preferred with one dose, or through several doses.
  • the drug is typically administered as an aerosol from a conventional valve, e.g., a metered dose valve, through an aerosol adapter also known as an actuator.
  • the aerosol formulation is prepared by micronizing the active drug, ribavirin, and thereby forming particles that are about 1 to 10 ⁇ in diameter; and selecting particles such that the formulation comprising at least or greater than about 90%, such as about 91 , 92, 93, 94, 95, 96, 97, 98, 99% or 100% of the micronized ribavirin particles of about 1 to 0 ⁇ in diameter; and mixed the selected micronized ribavirin particles with other ingredients such as cosolvents, surfactants and propellents and sealed the mixture in a crimped canister.
  • the particle size is desirably less than 10 ⁇ in diameter; and preferably between 1 to 6 ⁇ in diameter, and more preferably, about 3 ⁇ in diameter.
  • the particle size of ribavirin is reduced so as to permit absorption of a substantial amount of ribavirin into the lungs upon inhalation of the formulation.
  • the particle size may be reduced by any known means, for example, by milling or micronization. Micronization technique typically involves placing bulk drug into suitable mill. Such mill is commercially available from, for example, Jetpharma (Switzerland), under the trade name, JET MILL ® MC-50D.
  • the drug ribavirin
  • the housing enclosing the cavity may turn or rotate such that the bulk drug is forced against the moving parts.
  • Some mills such as fluid energy mill or airjet mill, include a high-pressure air stream that forces the bulk powder into the air within the enclosed cavity to contact against internal parts.
  • the particle size of ribavirin is reduced by milling the dry powders of ribavirin to a suitable average size, preferably, between 1 to 10 ⁇ in diameter, and more preferably between 1 to 6 ⁇ in diameter, and most preferably, about 3 ⁇ in diameter, which is a range suitable for inhalation.
  • a suitable average size preferably, between 1 to 10 ⁇ in diameter, and more preferably between 1 to 6 ⁇ in diameter, and most preferably, about 3 ⁇ in diameter, which is a range suitable for inhalation.
  • the overall particle range may be broader than the preferred range as stated above. It should be understood that although a large percentage of the particles will be in the narrow range desired, however, this will not generally be true for all particles.
  • the portion of particles within the preferred range may be greater than about 90%, such as about 91 , 92, 93, 94, 95, 96, 97, 98, 99% or 100%, depending on the needs of a specific formulation.
  • the particle size may also be reduced by sieving, homogenization, and/or granulation, among others. These techniques are used either separately or in combination with one another. Typically, milling, homogenization and granulation are applied, followed by sieving to obtain the micronized ribavirin particles having desired particle size.
  • the aerosol formulation of the present disclosure comprises finely dispersed micronized ribavirin particles that are relatively free flowing and capable of being readily dispersed in an inhalation device, such as a metered dose inhaler (MDI); and subsequently inhaled by a patient so that the particles can reach the intended region of the lung.
  • MDI metered dose inhaler
  • the aerosol formulation of the present disclosure can be prepared by combining (1 ) the micronized ribavirin particles prepared as described above in an amount sufficient to provide a plurality of therapeutically effective doses; (2) the cosolvent in an amount sufficient to help disperse the micronized ribavirin particles therein and forms a suspension; (3) the surfactant in an amount sufficient to stabilize the formulation; and (4) the fluid or propellent in an amount sufficient to propel a plurality of doses, e.g., from an aerosol canister.
  • Suitable cosolvents for use in the present aerosol formulation include, but are not limited to, propane, butane, n-pentane, isopentane, neopentane, ethanol, isopropanol and propylene glycol.
  • the aerosol formulation of the present disclosure preferably comprises about 0.0001 to 15% by weight of a cosolvent, and most preferably comprises about 10% by weight of a coslovent. In one example, the formulation comprises about 10% by weight of ethanol as the coslovent.
  • Suitable surfactants include both non-fluorinated surfactants and fluorinated surfactants known in the art.
  • suitable surfactants include, but are not limited to, oils derived from natural sources, such as corn oil, olive oil, cotton seed oil and sunflower seed oil; SPAN surfactants such as sorbitan monolaurate (SPAN 20), sorbitan monooleate (SPAN 80), sorbitan trioleate (SPAN 85), polyoxyethylene sorbitan monolaurate (TWEEN 20); polyoxyethylene sorbitan monoleate (TWEEN 80); lecithins (EPIKURON 200); BRJI surfactants such as oleyl polyoxyethylene ether (BRJI 92), stearyl polyoxyethylene ether (BRJI 72) and lauryl polyoxyethylene ether (BRJI 30); block copolymers of oxyethylene and oxypropylene; oleic acid; diethylene glycol dioleate;
  • the formulation may comprise less than about 1% by weight of a surfactant.
  • the surfactant is polyethylene glycol.
  • the formulation comprises a surfactant, which is a combination of about 0.5% by weight of polyethylene glycol, and about 0.5% by weight of oleic acid.
  • Fluorinated lower alkanes, particularly, non-chlorofluorocarbon (non-CFC) gases are particularly suitable propellents for use in this invention. They are generally present in an amount of at least 83% by weight in the formulation, for example, between about 83 to 99% by weigh in the formulation.
  • the non-CFC gas includes, but is not limited to, 1 ,1 ,1 ,2-tetrafluoroethane (HFA-134a), 1 ,1 ,1 ,2,3,3,3-heptafluoropropane (HFA-227) and a mixture thereof.
  • the formulation preferably comprises about 83 to 99% by weight of a non-CFC propellent; and more preferably about 90% by weight of a non-CFC propellent.
  • the non-CFC propellent is HFA-134a. In other examples, the non-CFC propellent is HFA-227.
  • the components of the formulation of this invention including micronized ribavirin particles, a cosolvent, a surfactant and a propellent, can be dispersed using conventional mixer or homogenizer, by shaking, or by ultrasound energy. Bulk formulation can be transferred to smaller individual aerosol vials by using valve to valve transfer methods or pressure filling. Aerosol canisters equipped with conventional valves, preferably metered dose valves, can be used to deliver formulations of the invention.
  • the formulation of the invention can be delivered to the respiratory track and/or lung by oral inhalation in order to affect bronchodilation or in order to treat a condition susceptible of treatment by inhalation, e.g., asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock.
  • a condition susceptible of treatment by inhalation e.g., asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock.
  • Ribavirin was purchased from Archimica (Origgo, Italy) and micronized using a jet milling apparatus (Jet Mill ® MC-50D). Approximately 60 g sample was passed through the jet mill. The particles from each milling run were tested on an Aerodynamic Particle Sizer 3225 (USA) to determine the particle size distribution of ribavirin after milling. It was found that over 90% of unmilled ribavirin has a particle size less than 29.6 + 2 ⁇ ; over 90% of the micronized ribavirin has a particle size less than 5.3 + 0.3 ⁇ and the micronized ribavirin has a mean particle size of about 3.4 + 0.1 ⁇ . The yield of micronized ribavirin that passed through jet mill was about 72%.
  • Example 2 Preparation of Aerosol Formulation Using Micronized Ribavirin of Example 1
  • Aerosol formulations of Examples 3 to 16 were formulated based on the weight ratio of the components listed in Table 1 , and each formulation was prepared in accordance with procedures described above in Example 2.
  • Aerosol formulations in Comparative Examples 1 to 4 were formulated based on the weight ratio of the components listed in Table 1 , and each formulation was prepared in accordance with procedures described above in Example 2 except the surfactant and/or co-solvent were eliminated in the formulations of comparative examples.
  • RBV is the abbreviation of the micronized ribavirin particles prepared in accordance with the procedures described in Example 1.
  • the crimped canister comprising any aerosol formulation as described above and equipped with a metered dose valve was tested for the delivered-dose uniformity and the dose content uniformity in accordance with MDI/DPI Draft Guidance published by US Food and Drug Administration (FDA) in year of 1998, and/or the Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products published by European Medicines Agency (EMEA) in year of 2006. It was identified that the mean of total ten doses is not outside 250 ⁇ g/puff + 15%, or 212.5 - 287.5 ⁇ /puff.

Abstract

Disclosed herein is an aerosol formulation for use in a metered dose inhaler (MDI) for treating an allergic disease such as asthma. The formulation uses a combination of a non-cholrofluorocarbon (non-CFC) propellent, a co-solvant, and a surfactant to suspend, solubilize, and emulsify ribavirin into micronized particles for easy delivery to the respiratory tract and/or lung of a subject by oral or nasal inhalation in order to treat the allergic disease.

Description

MEDICAL AEROSOL FORMULATION COMPRISING RIBAVIRIN
TECHNICAL FIELD
This disclosure in general relates to a medical aerosol formulation. More particularly, this disclosure relates to an aerosol formulation for use in a metered dose inhaler (MDI), the aerosol formulation is characterized in having micronized particles of ribavirin for treating asthma.
BACKGROUND ART
Description of Related Art
Delivery of drugs to the lung by way of inhalation is an important means for treating a variety of conditions, including common conditions as pneumonia, bronchial asthma and chronic obstructive pulmonary disease and some systemic conditions, such as pain management, hormonal therapy and etc.
Recently, it has been identified that a well known anti-infectious agent, ribavirin, when applied intranasally, is effective in treating allergic disease, such as asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock (see Chiang and Huang, WO 2007/104070). Accordingly, there exist in this art a need to develop a formulation of ribavirin, which contains ribavirin in respirable size and the ribavirin particles may be administered through oral inhalation and/or nasal inhalation, to treat allergic disease of a subject.
This invention address such need by providing an aerosol formulation, which contains micronized particles of ribavirin in respirable size, and the micronized particles are incorporated into a dispersion containing a propellent as a pressurized metered dose inhaler (MDI). For MDI application, the prepared aerosol formulation is subsequently filled into an aerosol canister equipped with a metered dose valve. Patients can then dispense the formulation via an actuator adapted to direct the dose from the valve to the patient. SUMMARY
As embodied and broadly described herein, disclosure herein features a novel aerosol formulation for use in a metered dosage inhaler (MDI) and is useful for treating an allergic disease of a subject, particularly, the human suffers from asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock. The aerosol formulation comprises respirable or inhalable micronized particles of an active agent that may be delivered to a subject with an aid of a fluid carrier.
Therefore, it is the first objective of this disclosure to provide an aerosol formulation for use in a metered dosage inhaler (MDI). The aerosol formulation comprises about 0.0001 to 1% by weight of ribavirin; about 0.0001 to 15% by weight of a co-solvent; about 0.0001 to 1% by weight of a surfactant; and about 83 to 99% by weight of a non-chlorofluorocarbon (non-CFC) propellent.
According to specific embodiments of this disclosure, the non-CFC propellent is any of 1 ,1 ,1 ,2-tetrafluoroethane (HFA-134a), 1 ,1 ,1 ,2,3,3,3-heptafluoropropane (HFA-227) or a mixture thereof. In some examples, the non-CFC propellent is HFA-134a.
According to specific embodiments of this disclosure, the co-solvent is selected from the group consisting of propane, butane, n-pentane, isopentane, neopentane, ethanol, isopropanol and propylene glycol. In some examples, the co-solvent is ethanol. According to specific embodiments of this disclosure, the surfactant is selected from the group consisting of sorbitan monolaurate (SPAN 20), sorbitan monooleate (SPAN 80), sorbitan trioleate (SPAN 85), polyoxyethylene sorbitan monolaurate (TWEEN 20), polyoxyethylene sorbitan monoleate (TWEEN 80), lecithins (EPIKURON 200), oleyl polyoxyethylene ether (BRJI 92), stearyl polyoxyethylene ether (BRJI 72), lauryl polyoxyethylene ether (BRJI 30), block copolymers of oxyethylene and oxypropylene, oleic acid, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monolaurate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol, propoxylated polyethylene glycol, diethylene glycol monoethyl ether, polyvinyl pyrrolidone (PVP), olive oil, corn oil, cotton seed oil, sunflower seed oil and a combination thereof. In one example, the surfactant is less than about 1 % by weight of polyethylene glycol. In aconther example, the surfactant is a combination of about 0.5% by weight of polyethylene glycol, and about 0.5% by weight of oleic acid.
It is the second objective of this disclosure to provide a metered dose inhaler, characterized in having the as-described aerosol formulation of the present disclosure.
The details of one or more embodiments of the invention are set forth in the accompanying description below. Other features and advantages of the invention will be apparent from the detail descriptions, and from claims.
It is to be understood that both the foregoing general description and the following detailed description are by examples, and are intended to provide further explanation of the invention as claimed. DISCLOSURE OF INVENTION
The practices of this invention are hereinafter described in detail with respect to an aerosol formulation, particularly, an aerosol formulation for use in a metered dose inhaler (MDI) and contains ribavirin as a sole active agent for treating an allergic disease such as asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock.
In accordance with one embodiment of the disclosure, an aerosol formulation for use in the MDI is provided. The aerosol formulation comprises about 0.0001 to 1 % by weight of ribavirin; about 0.0001 to 15% by weight of a co-solvent; about 0.0001 to 1 % by weight of a surfactant; and about 83 to 99% by weight of a non-chlorofluorocarbon (non-CFC) propellent.
Ribavirin is conventionally used as an anti-infectious agent for treating viral infection, recently, it has also been identified that ribavirin alone is effective in treating allergic disease, which includes, but is not limited to, asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock (see Chiang and Huang, WO 2007/104070). For purposes of the formulation of this invention, which are intended for inhalation into the lungs, the medicament or drug is preferably micronized, whereby a therapeutically effective amount of the drug is particulate. Typically, each drug particle has a mean diameter of about 1 to 10 μιτι, preferably about 1 to 6 μιτι, and most preferably about 3μΐτι, in order that the drug particles can be inhaled into the respiratory tract and/or lungs. The medicament or drug is present in a therapeutically effective amount, that is, an amount such that the drug can be administered as a dispersion, aerosol, via oral or nasal inhalation, and causes its desired therapeutic effects, typically preferred with one dose, or through several doses. The drug is typically administered as an aerosol from a conventional valve, e.g., a metered dose valve, through an aerosol adapter also known as an actuator. In the present disclosure, the aerosol formulation is prepared by micronizing the active drug, ribavirin, and thereby forming particles that are about 1 to 10 μηι in diameter; and selecting particles such that the formulation comprising at least or greater than about 90%, such as about 91 , 92, 93, 94, 95, 96, 97, 98, 99% or 100% of the micronized ribavirin particles of about 1 to 0 μΐη in diameter; and mixed the selected micronized ribavirin particles with other ingredients such as cosolvents, surfactants and propellents and sealed the mixture in a crimped canister. The particle size is desirably less than 10 μηη in diameter; and preferably between 1 to 6 μΐη in diameter, and more preferably, about 3 μιη in diameter. The particle size of ribavirin is reduced so as to permit absorption of a substantial amount of ribavirin into the lungs upon inhalation of the formulation. The particle size may be reduced by any known means, for example, by milling or micronization. Micronization technique typically involves placing bulk drug into suitable mill. Such mill is commercially available from, for example, Jetpharma (Switzerland), under the trade name, JET MILL® MC-50D. Briefly, the drug, ribavirin, is placed in an enclosed cavity and subjected to mechanical forces from moving internal parts, e.g., plates, blades, balls, pebbles, and the like. Alternatively, or in addition to parts striking the bulk drug, the housing enclosing the cavity may turn or rotate such that the bulk drug is forced against the moving parts. Some mills, such as fluid energy mill or airjet mill, include a high-pressure air stream that forces the bulk powder into the air within the enclosed cavity to contact against internal parts. Once the size of the drug is achieved, the process may be stopped and drug having the appropriate size is recovered. Typically, the particle size of ribavirin is reduced by milling the dry powders of ribavirin to a suitable average size, preferably, between 1 to 10 μΐτι in diameter, and more preferably between 1 to 6 μΐτι in diameter, and most preferably, about 3 μιη in diameter, which is a range suitable for inhalation. Thus, it is expected that the overall particle range may be broader than the preferred range as stated above. It should be understood that although a large percentage of the particles will be in the narrow range desired, however, this will not generally be true for all particles. The portion of particles within the preferred range may be greater than about 90%, such as about 91 , 92, 93, 94, 95, 96, 97, 98, 99% or 100%, depending on the needs of a specific formulation. The particle size may also be reduced by sieving, homogenization, and/or granulation, among others. These techniques are used either separately or in combination with one another. Typically, milling, homogenization and granulation are applied, followed by sieving to obtain the micronized ribavirin particles having desired particle size. For optimal function of an aerosol formulation, suitable surfactants and co-solvents are commonly used in combination with a propellent to prevent the active drug, e.g., micronized ribavirin particles, in the formulation from setting so quickly after agitation, so as to prevent the need of repetitive dosing. Thus, the aerosol formulation of the present disclosure comprises finely dispersed micronized ribavirin particles that are relatively free flowing and capable of being readily dispersed in an inhalation device, such as a metered dose inhaler (MDI); and subsequently inhaled by a patient so that the particles can reach the intended region of the lung. Thus, the particles are respirable and suitable for pulmonary delivery.
Generally, the aerosol formulation of the present disclosure can be prepared by combining (1 ) the micronized ribavirin particles prepared as described above in an amount sufficient to provide a plurality of therapeutically effective doses; (2) the cosolvent in an amount sufficient to help disperse the micronized ribavirin particles therein and forms a suspension; (3) the surfactant in an amount sufficient to stabilize the formulation; and (4) the fluid or propellent in an amount sufficient to propel a plurality of doses, e.g., from an aerosol canister.
Suitable cosolvents for use in the present aerosol formulation include, but are not limited to, propane, butane, n-pentane, isopentane, neopentane, ethanol, isopropanol and propylene glycol. The aerosol formulation of the present disclosure preferably comprises about 0.0001 to 15% by weight of a cosolvent, and most preferably comprises about 10% by weight of a coslovent. In one example, the formulation comprises about 10% by weight of ethanol as the coslovent.
Surfactants are commonly used to stabilize an aerosol formulation. Suitable surfactants include both non-fluorinated surfactants and fluorinated surfactants known in the art. Examples of suitable surfactants include, but are not limited to, oils derived from natural sources, such as corn oil, olive oil, cotton seed oil and sunflower seed oil; SPAN surfactants such as sorbitan monolaurate (SPAN 20), sorbitan monooleate (SPAN 80), sorbitan trioleate (SPAN 85), polyoxyethylene sorbitan monolaurate (TWEEN 20); polyoxyethylene sorbitan monoleate (TWEEN 80); lecithins (EPIKURON 200); BRJI surfactants such as oleyl polyoxyethylene ether (BRJI 92), stearyl polyoxyethylene ether (BRJI 72) and lauryl polyoxyethylene ether (BRJI 30); block copolymers of oxyethylene and oxypropylene; oleic acid; diethylene glycol dioleate; tetrahydrofurfuryl oleate; ethyl oleate; isopropyl myristate; glyceryl monooleate; glyceryl monostearate; glyceryl monolaurate; glyceryl monoricinoleate; cetyl alcohol; stearyl alcohol; polyethylene glycol; propoxylated polyethylene glycol; diethylene glycol monoethyl ether; polyvinyl pyrrolidone (PVP); and a combination thereof. The formulation may comprise less than about 1% by weight of a surfactant. In one example, the surfactant is polyethylene glycol. In aconther example, the formulation comprises a surfactant, which is a combination of about 0.5% by weight of polyethylene glycol, and about 0.5% by weight of oleic acid.
Fluorinated lower alkanes, particularly, non-chlorofluorocarbon (non-CFC) gases are particularly suitable propellents for use in this invention. They are generally present in an amount of at least 83% by weight in the formulation, for example, between about 83 to 99% by weigh in the formulation. Examples of the non-CFC gas includes, but is not limited to, 1 ,1 ,1 ,2-tetrafluoroethane (HFA-134a), 1 ,1 ,1 ,2,3,3,3-heptafluoropropane (HFA-227) and a mixture thereof. The formulation preferably comprises about 83 to 99% by weight of a non-CFC propellent; and more preferably about 90% by weight of a non-CFC propellent. In some examples, the non-CFC propellent is HFA-134a. In other examples, the non-CFC propellent is HFA-227. The components of the formulation of this invention, including micronized ribavirin particles, a cosolvent, a surfactant and a propellent, can be dispersed using conventional mixer or homogenizer, by shaking, or by ultrasound energy. Bulk formulation can be transferred to smaller individual aerosol vials by using valve to valve transfer methods or pressure filling. Aerosol canisters equipped with conventional valves, preferably metered dose valves, can be used to deliver formulations of the invention.
The formulation of the invention can be delivered to the respiratory track and/or lung by oral inhalation in order to affect bronchodilation or in order to treat a condition susceptible of treatment by inhalation, e.g., asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock. The formulation of the invention can also be delivered by nasal inhalation in order to treat a condition susceptible of treatment by inhalation, e.g., asthma, pollinosis, bronchial asthma, allergic rhinitis, atopic dermatitis, and anaphylactic shock.
It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice of the present invention, exemplary methods and materials are described for illustrative purposes. The following Examples are provided to illustrate certain aspects of the present invention and to aid those of skilled in the art in practicing this invention. These Examples are in no way to be considered to limit the scope of the invention in any manner. EXAMPLES
Example 1 Airjet Milling of Ribavirin
Ribavirin was purchased from Archimica (Origgo, Italy) and micronized using a jet milling apparatus (Jet Mill® MC-50D). Approximately 60 g sample was passed through the jet mill. The particles from each milling run were tested on an Aerodynamic Particle Sizer 3225 (USA) to determine the particle size distribution of ribavirin after milling. It was found that over 90% of unmilled ribavirin has a particle size less than 29.6 + 2 μηι; over 90% of the micronized ribavirin has a particle size less than 5.3 + 0.3 μιτι and the micronized ribavirin has a mean particle size of about 3.4 + 0.1 μητι. The yield of micronized ribavirin that passed through jet mill was about 72%.
Example 2 Preparation of Aerosol Formulation Using Micronized Ribavirin of Example 1
7.5 g of polyethylene glycol 400 (PEG 400) and 170.4 g of ethanol were stirred mixed for 10 minutes. 7.5 g of micronized ribavirin of Example 1 were added to the PEG 400/ethanol mixture, and stirred mixed for another 20 minutes, followed by sonication for 10 minutes. The resulted ribavirin suspension was fed to Iprocomsa mixer under stirring (about 300 rpm), followed by approximately 1532.4 g HFA-34a propellent and the mixture was used to fill 120 crimped canisters to form the desired aerosol formulation. The thus prepared aerosol formulation comprises ribavirin, PEG 400, ethanol and HFA-134a in a weight ratio of about 0.5: 0.5: 10: 90.
Examples 3 to 16
Aerosol formulations of Examples 3 to 16 were formulated based on the weight ratio of the components listed in Table 1 , and each formulation was prepared in accordance with procedures described above in Example 2.
Comparative Examples 1 to 4
Aerosol formulations in Comparative Examples 1 to 4 were formulated based on the weight ratio of the components listed in Table 1 , and each formulation was prepared in accordance with procedures described above in Example 2 except the surfactant and/or co-solvent were eliminated in the formulations of comparative examples.
Table 1
Figure imgf000012_0001
Example 7 0.5 - 1.0 - - 10 90
Example 8 0.5 - 0.05 - - 10 90
Example 9 0.5 0.125 0.125 - - 10 90
Example 10 0.5 0.45 0.05 - - 10 90
Example 11 0.5 - 0.45 0.05 - 10 90
Example 12 0.5 - 0.45 - 0.05 10 90
Example 13 0.5 0.45 - - 0.05 10 90
Example 14 0.5 - 0.45 - 0.05 10 90
Example 15 0.5 - - 0.05 - 10 90
Example 16 0.5 - - - 0.05 10 90
Comparative 0.5 00 Example 1
Comparative 0.5 10 90 Example 2
Comparative 0.5 15 85 Example 3
Comparative 0.5 20 80 Example 4
Note: RBV is the abbreviation of the micronized ribavirin particles prepared in accordance with the procedures described in Example 1. The crimped canister comprising any aerosol formulation as described above and equipped with a metered dose valve was tested for the delivered-dose uniformity and the dose content uniformity in accordance with MDI/DPI Draft Guidance published by US Food and Drug Administration (FDA) in year of 1998, and/or the Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products published by European Medicines Agency (EMEA) in year of 2006. It was identified that the mean of total ten doses is not outside 250 μg/puff + 15%, or 212.5 - 287.5 μς/puff.
OTHER EMBODIMENTS
All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features. From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.

Claims

Claims
1 . An aerosol formulation for use in a metered dose inhaler (MDI), comprising:
about 0.0001 to 1 % by weight of ribavirin;
about 0.000 to 15% by weight of a co-solvent;
about 0.0001 to 1 % by weight of a surfactant; and
about 83 to 99% by weight of a non-chlorofluorocarbon (non-CFC) propellent. 2. The aerosol formulation of claim 1 , wherein the non-CFC propellent is any of 1 ,1 ,1 ,2-tetrafluoroethane (HFA-134a), 1 ,1 ,1 ,
2,3,3,3-heptafluoropropane (HFA-227) or a mixture thereof.
3. The aerosol formulation of claim 2, wherein the non-CFC propellent is 1 ,1 ,1 ,2-tetrafluoroethane (HFA-134a).
4. The aerosol formulation of claim 1 , wherein the co-solvent is selected from the group consisting of propane, butane, n-pentane, isopentane, neopentane, ethanol, isopropanol and propylene glycol.
5. The aerosol formulation of claim 1 , wherein the surfactant is selected from the group consisting of sorbitan monoiaurate, sorbitan monooleate, sorbitan trioleate, polyoxyethylene sorbitan monoiaurate, polyoxyethylene sorbitan monoleate, lecithins, oleyl polyoxyethylene ether, stearyl polyoxyethylene ether, lauryl polyoxyethylene ether, block copolymers of o'xyethylene and oxypropylene, oleic acid, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monolaurate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol, propoxylated polyethylene glycol, diethylene glycol monoethyl ether, polyvinyl pyrrolidone (PVP), olive oil, corn oil, cotton seed oil, sunflower seed oil and a combination thereof.
6. The aerosol formulation of claim 5, wherein the surfactant is polyethylene glycol.
7. The aerosol formulation of claim 5, wherein the surfactant is a combination of polyethylene glycol and oleic acid, each is about 0.5% by weight in the aerosol formulation.
8. A metered dose inhaler comprising the aerosol formulation of claim 1.
9. The metered dose inhaler of claim 8, wherein the non-CFC propellent is any of 1 ,1 ,1 ,2-tetrafluoroethane (HFA-134a), 1 ,1 ,1 ,2,3,3,3-heptafluoropropane (HFA-227) or a mixture thereof.
10. The metered dose inhaler of claim 9, wherein the non-CFC propellent is 1 ,1 ,1 ,2-tetrafluoroethane (HFA-134a).
11. The metered dose inhaler of claim 8, wherein the co-solvent is selected from the group consisting of propane, butane, n-pentane, isopentane, neopentane, ethanol, isopropanol and propylene glycol.
12. The metered dose inhaler of claim 8, wherein the surfactant is selected from the group consisting of sorbitan monolaurate, sorbitan monooleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monoleate, lecithins, oleyl polyoxyethylene ether, stearyl polyoxyethylene ether, lauryl polyoxyethylene ether, block copolymers of oxyethylene and oxypropylene, oleic acid, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monolaurate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol, propoxylated polyethylene glycol, diethylene glycol monoethyl ether, polyvinyl pyrrolidone (PVP), olive oil, corn oil, cotton seed oil, sunflower seed oil and a combination thereof.
13. The metered dose inhaler of claim 12, wherein the surfactant is polyethylene glycol.
14. The metered dose inhaler of claim 13, wherein the surfactant is a combination of polyethylene glycol and oleic acid, and each is about 0.5% by weight in the aerosol formulation.
PCT/AU2010/000686 2010-06-03 2010-06-03 Medical aerosol formulation comprising ribavirin WO2011150441A1 (en)

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JP2016531306A (en) * 2013-09-17 2016-10-06 ビオメリューBiomerieux Solution for dissociating vitamin D from vitamin D binding protein, its associated detection method and use
CN107320728A (en) * 2016-04-30 2017-11-07 浙江台州绿源气体有限公司 Propellant and its preparation method and application

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JP2016531306A (en) * 2013-09-17 2016-10-06 ビオメリューBiomerieux Solution for dissociating vitamin D from vitamin D binding protein, its associated detection method and use
CN107320728A (en) * 2016-04-30 2017-11-07 浙江台州绿源气体有限公司 Propellant and its preparation method and application

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