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WO2011069197A1 - Formulations inhalables - Google Patents

Formulations inhalables Download PDF

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Publication number
WO2011069197A1
WO2011069197A1 PCT/AU2010/001656 AU2010001656W WO2011069197A1 WO 2011069197 A1 WO2011069197 A1 WO 2011069197A1 AU 2010001656 W AU2010001656 W AU 2010001656W WO 2011069197 A1 WO2011069197 A1 WO 2011069197A1
Authority
WO
WIPO (PCT)
Prior art keywords
particles
particle
excipient
microns
respiratory
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.)
Ceased
Application number
PCT/AU2010/001656
Other languages
English (en)
Inventor
Hak-Kim Chan
Paul Young
Daniela Traini
Philip Chi Lip Kwok
Michiko Anada
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.)
University of Sydney
Original Assignee
University of Sydney
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
Priority claimed from AU2009905978A external-priority patent/AU2009905978A0/en
Application filed by University of Sydney filed Critical University of Sydney
Priority to CN2010800633023A priority Critical patent/CN102811715A/zh
Publication of WO2011069197A1 publication Critical patent/WO2011069197A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators

Definitions

  • the present invention relates to inhalable formulations, to methods of manufacturing inhalable formulations and to pharmaceutical compositions containing inhalable formulations.
  • DPI Dry powder inhalation
  • DPI therapy depends on a number of factors including the biological aspect of the active ingredient, the physicochemical properties of the formulation, and the performance of the inhaler.
  • the efficiency of dose delivery of dry powders also depends on the particle size, size distribution, shape and surface morphology of the powder.
  • drug particles having a size between 1 and 5 microns have a high surface area to mass ratio and therefore tend to be highly cohesive resulting in poor aerosolisation efficiency and thus respiratory deposition.
  • their delivery into the lung is traditionally enhanced when they are blended with larger and coarser inert carrier materials.
  • the aim is for the drug particles to be freed from the carriers and to enter and penetrate the lung while the carriers themselves impact in the upper airways and are ingested.
  • DPI therapy may deliver a single active or may deliver a combination of actives.
  • Combination inhalation therapy have been used to treat respiratory diseases and combination therapies include an inhaled corticosteroid (ICS) and a long-acting ⁇ 2- agonist (LABA) which offers the advantages of convenience to the patients along with synergistic pharmacological actions, leading to better patient compliance and therapeutic outcomes.
  • ICS inhaled corticosteroid
  • LAA long-acting ⁇ 2- agonist
  • APIs active pharmaceutical ingredients
  • MDI suspension metered dose inhaler
  • differences in the particle properties may cause differential suspension characteristics of the APIs and wall loss to the canister, resulting in variable product performance. Wall loss can potentially be minimized by non-sticky coating of the canister wall.
  • disparities in the formulations have been dealt with by separating them in two canisters, it would make the MDI more bulky and potentially require more effort to actuate.
  • DPI formulations rely on the use of blends in which the API particles adhere on the carrier lactose surface. Lactose is the major carrier used in DPIs and its performance is highly variable, depending on its amount of fines, surface roughness, polymorphic form, production batch, and grade.
  • the present inventors have found that it is possible to form inhalable particles from two or more active agents together with an excipient which is at least partially in a crystalline form, and that these particles may have advantageous properties, especially when used in a dry particle inhaler (DPI).
  • DPI dry particle inhaler
  • a particle which is of respirable size and which contains two or more active agents and an excipient at least partially in a crystalline form.
  • inhalable formulations comprised particles of active agent(s) of inhalable size together with a larger non-respirable carrier particle.
  • the present invention has found that it is possible to form respirable sized particles containing two or more active agents and an excipient at least partially in a crystalline form.
  • the ability to form uniform particles of a defined size containing both the actives and excipient is of great use because it allows for more uniform particle formation providing targeted delivery of active agents to patients using more manageable particles.
  • an inhalable particle comprising two or more active agents and an excipient which is at least partially in crystalline form, wherein the particle is of respirable size.
  • the present invention is useful in inhalable formulations which will generally be made up of many particles. Therefore, there will generally be a large number of particles in a given composition. This collection of particles will comprise at least one but generally a large number of the particles disclosed herein. Accordingly, in a further embodiment of the present invention there is provided inhalable particles comprising two or more active agents and an excipient which is at least partially in a crystalline form, wherein the particles are of respirable size.
  • At least 1%, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% of the particles in the total collection of particles are particles according to the invention as disclosed herein.
  • the present invention has identified a novel particle of respirable size comprising active agent(s) and excipients as disclosed herein.
  • the particles contain an excipient. This may be thought of as a bulking agent.
  • the excipient is present to assist with formulation and/or performance of the inhalable particles rather than to have a physiological effect itself on the patient.
  • the excipient may itself have a physiological effect.
  • excipients like mannitol are encompassed by the present invention. Therefore, mannitol may be thought of as an excipient or bulking agent for the purposes of the present invention regardless of the fact that mannitol has been shown to have a physiological effect on the body.
  • the traditional carrier particle system required the active agents to be milled to respirable size and then mixed with a larger carrier particle. Typical active doses were relatively small (on the milligram scale) and it was not possible to deliver such a small dose to a patient. It was therefore necessary to use additional excipients to 'bulk out' the total composition so as to facilitate manufacture and delivery.
  • the total formulation that was prepared could be of a manageable size but the patient still received the required dose of active agents.
  • using larger particles assisted in formulation because it avoided some of the difficulties associated with small particles on the 1-3 micron scale, like aggregation and poor flow properties. However, there were difficulties with this approach because the active agents did not always separate from the larger carriers during delivery in a predictable manner.
  • the present invention aims, at least in its preferred forms to overcome some or all of these difficulties by combining all of the actives and the excipient together in a single particle. This has a number of advantages. Putting multiple actives together into a single particle means that both actives will be delivered to the same target site at the same time. It avoids the problems associated with different actives having different aerodynamic characteristics.
  • the actives and excipient together means that all of the particles of the composition contain the active agents rather than a small amount of active particles and a large amount of non- functioning carrier or bulking agents. Furthermore, the particles are at least partially ' crystalline. It is possible for the first time to prepare particles of defined uniform shapes which may improve and standardise their aerodynamic performance. The crystallinity may also help with stability and long term storage for a number of reasons including: avoiding or minimising the transformation of amorphous particles into more crystalline forms with the associated degradation in the particle morphology, and improved surface properties which may reduce or minimise aggregation or other unwanted surface phenomenon like undesirable interactions with the containers.
  • particles of the present invention can be formed from a combination of at least one active agent and an excipient, where the particles are at least partially, or substantially hollow. This has advantages because a hollow particle, when compared against an equivalent sized solid particle, will have a lower density which can lead to improvements in aerodynamic and aerosolisation properties. This can be seen when considering the aerodynamic diameter of a particle which depends on both the physical diameter and density of the particle.
  • the dynamic shape factor accounts for the effect of shape on particle motion. It is the ratio of the resistance force experienced by the non-spherical particle moving in air to that of a sphere with the same volume and velocity.
  • hollow inhalable particles comprising one or more active agents and an excipient which is at least partially in a crystalline form, wherein the particles are of respirable size.
  • Particular embodiments include two or more active agents.
  • an inhalable particle comprising one or more active agents and an excipient which is at least partially in crystalline form, wherein the particle is of respirable size and is hollow.
  • the particles of the present invention consist essentially of a single or two or more active agents and an excipient.
  • respirable it is meant a particle which has an aerodynamic diameter of less than 20 microns. This allows for targeted delivery of particles to comprising two or more active agents and an excipient which is at least partially in a crystalline form to areas of the respiratory tract. Particles are considered respirable if they can be inhaled and deposited onto one or more of the oropharynx and upper airways (including the trachea), lower airways (including the bronchus and bronchioles) or deposited in the alveoli. In particular embodiments the respirable particles can be deposited onto the lower airways. This provides particles which can be used in inhalation therapy. The present invention allows for better design of particles with advantageous size distributions. Thus, it is possible to prepare particles which are easy to handle and which can deliver active agents to areas with better specificity and success.
  • the excipient may be selected from any excipient which may at least partially be in crystalline form in the particle and which may be suitable for pulmonary administration.
  • exemplary excipients include sugars, sugar alcohols, amino acids and other excipients.
  • the excipient may be selected from sugars and sugar alcohols (including mannitol, sucrose, glucose, trehalose, lactose, dextrose, sorbitol, maltilol, maltodextrin); amino acids (including glycine, leucine, trileucine, arginine, threonine, phenylalanine, aspartic acid); and other excipients such as sodium chloride, poly-lactic glycolic acid or poly ethylene glycol.
  • a particular excipient is mannitol.
  • a further particular excipient is glucose. Both excipients have a relatively low Tg. This means that the excipients will be more likely to be in crystalline form in the particle.
  • the excipient is chosen on the basis that it has a Tg ⁇ 150°C. In a further embodiment the excipient is chosen on the basis that it has a Tg ⁇ 100°C, Tg ⁇ 60°C or Tg ⁇ 50°C.
  • Tg values are ⁇ 40°C, ⁇ 35°C, ⁇ 30°C, ⁇ 25°C, ⁇ 20°C, ⁇ 15°C, ⁇ 10°C, ⁇ 5°C, ⁇ 0°C, ⁇ - 5°C, ⁇ -01°C, ⁇ -15°C, ⁇ -20°C, ⁇ -25°C.
  • the particles may contain a single excipient. In further embodiments, the particles may contain two or more excipients. The particles may contain 1 , 2, 3, 4, 5, 6, 7, 8 or more excipients.
  • the excipient is present at least partially in a crystalline form.
  • the excipient is present in a majority crystalline form.
  • the excipient is present in about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% , about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100% crystalline form.
  • a specific embodiment of the invention has an excipient comprising mannitol which is present in a majority crystalline form, which may be about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100%-crystalline form.
  • At least one active agent is in crystalline form in the particle.
  • an active is present in about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% crystalline form.
  • two or more actives are present in about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% crystalline form.
  • the particles comprise about at least 10% excipient.
  • the particles comprise about at least 20% excipient.
  • the particles comprise about at least 30% excipient.
  • the particles comprise about at least 40% excipient.
  • the particles comprise about at least 50% excipient. In a yet further embodiment, the particles comprise about at least 60% excipient. In a yet further embodiment, the particles comprise about at least 70% excipient. In a yet further embodiment, the particles comprise about at least 80% excipient. In a yet further embodiment, the particles comprise about at least 90% excipient. In a yet further embodiment, the particles comprise about at least 95% excipient. In a yet further embodiment, the particles comprise about at least 99% excipient.
  • Particular embodiments contain at least about 40% excipient. Further particular embodiments contain at least 50% excipient. Yet further particular embodiments contain about at least 80% excipient.
  • Increasing the amount of excipient may increase the degree of crystallinity of the particles.
  • the amount of excipient may be chosen to achieve the desired degree of crystallinity. There may be a linear relationship between the amount of excipient and the degree of crystallinity. However, for some particles there may be a non-linear relationship between the degree of crystallinity and the percentage amount of excipient.
  • the percentage degree of crystallinity is greater than or equal to the percentage amount of excipient present in the particle.
  • a particle containing 80% excipient would be at least 80% or more crystalline.
  • the percentage degree of crystallinity is greater than the percentage amount of excipient present in the particle.
  • the percentage degree of crystallinity exceeds the percentage amount of excipient present in the particle.
  • the percentage degree of crystallinity is at least 1 % greater than the percentage amount of excipient.
  • a particle with 80% excipient would have at least 81% crystallinity.
  • the percentage degree of crystallinity is at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30%, greater than the percentage amount of excipient.
  • higher percentage crystallinity values vs percentage excipient have not been seen.
  • the present invention provides for the first time a system to produce highly crystalline particles combining an active and an excipient. By forming the components together it is possible to achieve improved particle performance due, at least in part, to the crystalline nature of the particles.
  • inhalable particles of respirable size comprising one or more active agents and an excipient wherein the percentage crystallinity of the particle is greater than the percentage amount of excipient present in the particle.
  • Particular embodiments include two or more active agents.
  • an inhalable particle of respirable size comprising one or more active agents and an excipient wherein the percentage crystallinity of the particle is greater than the percentage amount of excipient present in the particle.
  • the amount of active agent present in the particle can influence the physical properties of the particle, for example the morphology or aerodynamic performance of the particles. Having a small amount of actives present in the overall composition will mean that the particle is primarily made up of the excipient and the physical characteristics of the excipient may dominate the characteristics of the particle as a whole. For example, if the excipient adopts a predominantly crystalline structure and is present in sufficient amounts in the particle as a whole then it may force an otherwise amorphous active agent into a crystalline composition. However, if the active agents are predominantly present in the composition then they may dominate the overall properties of the particle. The amount of each active will also have an effect on the physiological properties of the particle.
  • the total amount of active agents present in the particle is about 1%. In further embodiments, the total amount of active agents present is about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%. In a further embodiment, the amount of actives present in the particle is up to about 50%. In yet further embodiments, the amount of actives present in the particle is up to about 40%, up to about 30%, up to about 20%, up to about 15%, or up to about 10%.
  • the present invention provides particles which can be used in inhalation therapy. It is therefore important that a sufficient quantity of the particles are of respirable size. This allows sufficient quantity of the active agents to reach the target areas of the patient. Such target areas include one or more of the alveoli, the lower airways including the bronchus and bronchioles, the upper airways, for example the trachea and/or the oropharynx. Appropriate selection of the particle characteristics allows for targeting delivery to particular areas of the respiratory tract. When designing respirable particles it is desirable to be able to carefully control the particle characteristics to ensure that sufficient particles are of the required respirable size so that enough of the active agent is delivered to the required area.
  • particles of the present invention When forming particles of the present invention it is appreciated that a large number of physical particles are formed and that a large number of particles are used in an inhalation treatment. When considering large numbers of particles it is expected that there will be a distribution of individual particles sizes, ranging from very small through to large. There may be a normal distribution of particle sizes with a percentage of the particles within a given size range. Thus, when considering the particles of the present invention the particle size may be thought of as the average particle size. Thus, for example, if the particles are said to be about 1-3 microns in size, this represents an average particle size, with some particles being smaller or larger than the average particle size.
  • the present invention is intended to cover particles which, on average, have a size of about 7 microns.
  • this average size may be the mean particle size.
  • the particle size may be the median particle size.
  • the present invention provides particles of respirable size.
  • the actual diameters of the particles in a sample will range depending on factors like particle composition and method of synthesis.
  • the distribution of particle sizes can be chosen to achieve the desired delivery of the active agents to the target areas in the respiratory tract.
  • a percentage of the particles may be of respirable size.
  • a powder formed using the particles of the present invention may contain 10% particles of respirable size with the remaining particles being non-respirable. It is generally preferable that the amount of respirable particles is maximised. The more particles that can reach the target delivery area, a lower overall dose of active agents may be needed. It is generally preferred to minimise the dose provided to a patient.
  • about 1% of the particles (do.oi) are of respirable size.
  • the particles may be measured in terms of their aerodynamic diameter.
  • aerodynamic diameter (d ae ) P° '5 d p , where p is the density of the particle and d p the physical diameter of the particle.
  • the advantage of considering an aerodynamic diameter is that it differentiates between otherwise similar physically sized particles that have different aerodynamic properties. As an example, a hollow sphere will have a lower density than an equally sized solid sphere.
  • the aerodynamic diameter of the two spheres will be different with the hollow sphere being lower, even though the physical diameter is the same. Equally, seemingly differently shaped or sized particles may have the same aerodynamic diameter.
  • An advantage of considering the aerodynamic diameter of a collection of particles is that it can be measured empirically in an impactor and it is not necessary to look at each particle individually to measure its physical size. The inhalation properties of the particles are assessed and the average aerodynamic properties of the particles determined to arrive at the average aerodynamic diameter of the particles are obtained. A typical measurement will identify what percentage of the total particles are within various aerodynamic diameter size ranges.
  • the average aerodynamic diameter of the particles is between from about 0.01 to about 20 microns. In a further embodiment, the average particle size is between from about 0.1 to about 20 microns. In a yet further embodiment, the average particle size is between from about 0.1 to about 15 microns, about 0.2 to about 15 microns, about 0.2 to about 10 microns, about 0.5 to about 10 microns, about 0.8 to about 10 microns, about 1 to about 10 microns, about 1 to about 9 microns, about 1 to about 8 microns, about 1 to about 7 microns, about 1 to about 6 microns, about 1 to about 5 microns, about 1 to about 4 microns, about 1 to about 3 microns, from about 1 to about 2 microns.
  • Particular average aerodynamic diameter ranges are between from about 1 micron to about 5 microns, between from about 1 micron to about 4 microns, and between from about 1 micron to about 3 microns. In a yet further embodiment, the average aerodynamic diameter is ⁇ about 10 microns,
  • the average aerodynamic diameter is about 1 micron, about 2 microns, about 3 microns, about 4 microns, about 5 microns, about 6 microns, about 7 microns, or about 8 microns.
  • the average aerodynamic diameter is from about 5-20 microns (large particles) which may deposit in the oropharynx and upper airways, for example the trachea. In a yet further embodiment, the average aerodynamic diameter is from about 1-5 microns (small particles) which may deposit in the lower airways, for example the bronchus and bronchioles. In a yet further embodiment, the average aerodynamic diameter is from about 0.01 to about 1 micron (submicron particles) which may deposit in the alveoli.
  • the average aerodynamic diameter is from about 1 to about 3 microns.
  • about 90% of the particles (do.9) have an average size of ⁇ about 10 microns, ⁇ about 9 microns, ⁇ about 8 microns, ⁇ about 7 microns, ⁇ about 6 microns, ⁇ about 5 microns, ⁇ about 4 microns, ⁇ about 3 microns, ⁇ about 2 microns,
  • 80% of the particles (do.g), 70% of the particles (do.7), 60% of the particles (do.6), 50% of the particles (do.5), 40% of the particles (do. 4 ), 30% of the particles (do. 3 ), 20% of the particles (do 2), or 10% of the particles (do.i), are less than at least one of the abovementioned sizes.
  • the particles can have an average size of 2 microns +/- 1 micron, +/- 0.5 micron, +/- 0.2 micron, or +/- 0.1 micron; 3 microns +/- 1 micron, +/- 0.5 micron, +/- 0.2 micron, or +/- 0.1 micron; 4 microns +/- 1 micron, +/- 0.5 micron, +/- 0.2 micron, or +/- 0.1 micron; 5 microns +/- 1 micron, +/- 0.5 micron, +/- 0.2 micron, or +/- 0.1 micron; 6 microns +/- 1 micron, +/- 0.5 micron, +/- 0.2 micron, or +/- 0.1 micron; 7 microns +/- 1 micron, +/- 0.5 micron, +/- 0.2 micron, or +/- 0.1 micron; 8 microns +/- 1 micron, +/- 0.5 micron, +/- 0.2 micron;
  • the present invention specifically encompasses the situation where a percentage of the particles are of an average size as outlined above.
  • Specific percentages include about 1% of the particles (do.oi), about 5% of the particles (do.os). about 10% (do.i), about 20% (do. 2 ), about 30% (do. 3 ), about 40% (do. ), about 50% (do. 5 ), about 60% (doe), about 70% (do.?), about 80% (dog), about 90% (do. 9 ), about 95% (do.95), about 98% (do.98), about 99% (do.w). or about 100% (di) of the particles are of an aerodynamic diameter outlined above.
  • the fine particle dose which is the total mass of particles with aerodynamic diameters ⁇ 5 micron.
  • the fine particle fraction is > about 10%.
  • the FPF is > about 20%, > about 30%, > about 40%, . > about 50%, > about 60%, > about 70%, > about 80%, > about 90%, > about 95%, or about 100%. The greater the FPF, the more active agent reaches the target area. Particular FPF are > 10 % of the loaded dose, > 30 % of the loaded dose, or > 50 % of the loaded dose.
  • the aerodynamic diameter instead of the aerodynamic diameter, it is possible to measure the specific dimensions of particles and to determine their average size. This may be the average particle diameter, including the mean or median diameter. These embodiments are not limited to spherical particles and can be used to measure irregular particles. It may be considered the average length, width and or height of the particles.
  • the present invention can allow for defined doses to reach the same target areas, for example the same cells. This may have advantages in terms of therapy because targeted therapy with defined doses is possible. This may also allow for synergistic effects between the combination products because they may, for example, be simultaneously deposited the same target cell hi the lung epithelium. This has distinct advantages over physical mixtures of individual active agents.
  • the particles, compositions methods and uses of the present invention allow for delivery of more than one active to the same target site, for example the same target cell in the lung epithelium.
  • components may be added to the particles to allow for controlled release. This may be achieved by further coating the particles with a polymer.
  • the particles may further contain surfactants or polymers. These may be used to control crystal growth during co-precipitation in some techniques, such as by anti-solvent.
  • Other excipients may be pH modifiers, antioxidants, and flavouring agents.
  • the active agents and the excipient are evenly mixed throughout the particle.
  • one active agent is predominantly present on the surface of the particle.
  • two or more actives are predominantly present on the surface of the particle.
  • one active agent is predominantly present in the interior of the particle.
  • two or more actives are predominantly present in the interior of the particle.
  • the present invention encompasses the situation where the active agents and excipient are homogeneously mixed throughout the particle and also the situation where the components are not homogeneously mixed.
  • the shape of the particles may affect the properties and or performance of combination products made using them.
  • the shape of the particles can have an effect on their aerosolisation properties.
  • the shape of the particles can have an effect on their handling properties.
  • substantially uniform and/or substantially spherical particles may have improved aerosolisation properties and may be less likely to stick together. These particles may have improved flow properties which may make capsule and/or device filling easier.
  • the particles are predominantly spherical.
  • the particles are ovoid.
  • the particles are predominantly ellipsoidal.
  • the particles are predominantly needle or fibre shaped.
  • the particles are predominantly plate like or flaked.
  • the particles are predominantly pyramidal.
  • the particles are spiky.
  • the particles are irregularly shaped.
  • the particles have a substantially uniform shape.
  • the surface conditions of the particles may be affected by the formation conditions and also by the selection of active agents.
  • the surface of the particles may be substantially uniform.
  • the surface may be dimpled.
  • the surface may contain crystals shaped particles adhered to the surface.
  • the surface may contain a clay like material.
  • the surface may be smooth.
  • the surface may be roughened.
  • the surface may be corrugated.
  • the surface may have plate like materials on the surface.
  • the surface may have spikes on the particle surface.
  • the particles are at least partially, or are substantially hollow. This has advantages in terms of the aerodynamic diameter of the particles and allows for larger particles which can still deliver active agents to the lower airways (or elsewhere). The ability to form larger particles with the same aerodynamic performance has advantages because larger particles are easier to handle.
  • the individual components do not homogeneously mix. Without wishing to be bound by theory, one reason for this could be that the individual components have different solubilities, and/or different rates of crystallisation! This could lead to a non-uniform distribution of component in the final particle. For example, if the particle contains two active agents, both of which are more soluble than the excipient in the initial solution, then as the particle is formed the excipient comes out of solution first and adopts a predominantly crystalline form while the active agents remain in solution.
  • the excipient crystallises at the liquid-air interface you may end up with a predominance of excipient on or near the surface of the particle with the active agents forming predominantly at or near the centre of the particle since the solution will dry from the outside-in for a given droplet as it dries into a particle.
  • the active agents are less soluble than the excipient then they may come out of solution before the excipient.
  • the active agents may be on or near the surface of the particle with the inside of the particle being predominantly excipient.
  • the active agents may be fully formed on the surface of the particle or may be embedded to some degree or fully in the outer surface of the particle.
  • one of the active agents is less soluble than the excipient where as one active is more soluble. Under these circumstances it may be that one active is predominantly found on or near the surface of the particle and the other particle is predominantly found at or near the centre of the particle.
  • the particle may contain one or more actives predominantly on or near the surface of the particle.
  • two actives are found on or near the surface of the particle.
  • the particle may contain one or more actives predominantly at or near the centre of the particle. According to a further embodiment, two actives are found predominantly at or near the centre of the particle. According to yet further embodiments, the particle may contain one or more actives predominantly on or near the surface of the particle and one or more actives predominantly at or near the centre of the particle.
  • the particle may contain excipient predominantly on or near the surface of the particle.
  • the particle may contain excipient predominantly at or near the centre of the particle.
  • the particle may contain a substantially homogeneous mixture of active agents and excipient.
  • the present invention includes particles containing two or more active agents.
  • the particles contain two active agents.
  • the particles contain 3 active agents.
  • the particles contain 4 active agents.
  • the particles contain a single active agent.
  • the particles contain an inhaled corticosteroid (ICS) and a long-acting P2-agonist (LABA).
  • drugs which can be used include acetonide, albuterol, albuterol sulfate, beclomethasone, budesonide, cortisone, cromolyn, cromolyn sodium, dexamethasone, flunisolide, fluticasone, formoterol, formoterol fumarate, hydrocortisone, pratropium, ipratropium / albuterol, levalbuterol HC1, metaproterenol, methylprednisolone, mometasone, montelukast, nedocromil, nedocromil sodium, omalizumab, pirbuterol, prednisolone, propionate, salbutamol, salmeterol, salmeterol xinafoate, terbutaline, theophylline, tiotropium, triamcinolone, zafirlukast or zileuton.
  • “Drugs”, for the purposes of the invention, include a variety of pharmaceutically active ingredients, such as, for example, those which are useful in inhalation therapy.
  • the term “drug” is to be broadly construed and include, without limitation, actives, drugs and bioactive agents, as well as biopharmaceuticals.
  • drug is interchangeable with the term medicament or active agent.
  • Appropriate drugs may thus be selected from, for example, analgesics, (e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine); anginal preparations, (e.g., diltiazem); anti-allergies, (e.g., cromoglicate, ketotifen or nedocromil); antiinfectives (e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine); antihistamines, (e.g., methapyrilene); antiinflammatories, (e.g., antiinflammatory steroids, beclomethasone (e.g.
  • beclomethasone dipropionate fluticasone (e.g. fluticasone propionate), flunisolide, budesonide, rofleponide, mometasone (e.g. mometasone furoate), ciclesonide, triamcinolone (e.g.
  • the medicaments may be used in the form of salts, (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and/or stability of the medicament.
  • the medicaments may be used in the form of a pure isomer, for example, R-salbutamol or R-formoterol.
  • Particular medicaments for administration using pharmaceutical formulations in accordance with the invention include anti-allergies, bronchodilators, beta agonists (e.g., long-acting beta agonists), and anti-inflammatory steroids of use in the treatment of respiratory conditions, as defined herein, by inhalation therapy, for example, cromoglicate (e.g. as the sodium salt), salbutamol (e.g. as the free base or the sulphate salt), salmeterol (e.g. as the xinafoate salt), bitolterol, formoterol (e.g. as the fumarate salt), terbutaline (e.g.
  • cromoglicate e.g. as the sodium salt
  • salbutamol e.g. as the free base or the sulphate salt
  • salmeterol e.g. as the xinafoate salt
  • bitolterol e.g. as the fumarate salt
  • terbutaline e.g.
  • a beclomethasone ester e.g. the dipropionate
  • a fluticasone ester e.g. the propionate
  • a mometasone ester e.g., the furoate
  • budesonide e.g. the hydrochloride salt
  • Medicaments useful in erectile dysfunction treatment e.g., PDE-V inhibitors such as vardenafil
  • hydrochloride along with alprostadil and sildenafil citrate
  • alprostadil and sildenafil citrate may also be employed. It should be understood that the drugs that may be used in conjunction with the inhaler are not limited to those described herein.
  • antibiotics erythromycin oleandomycin kitasamycin spiramycin josamycin midecamycin crarythromycin tetracycline antibiotics chlortetracycline oxytetracycline tetracycline doxycycline minocycline chloramphenicol thiamphnicol lincomycin clidamycin fosfomycin pyridonecarboxylic acids nalidixic acid pipemidic acid norfloxacin ofloxacin
  • agent/analgesic agent acetoaminophen aminopyrine etc. hypoglycemic agent tolbutamide gliclazide etc. anticancer agent methotrexate etc.
  • Combinations of two or more agents selected from the group consisting of salmeterol, especially salmeterol xinafoate, salbutamol, fluticasone propionate, formoterol, budesonide, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof are specifically exemplified.
  • the particle contains a combination of two active ingredients known for the treatment and/or prophylaxis of respiratory disorders.
  • the particle may comprise formoterol (e.g. as the fumarate) and budesonide.
  • the particle may comprise salmeterol (e.g. as the xinafoate salt) and fluticasone (e.g. as the propionate ester).
  • the particle may comprise salbutamol (e.g. as free base or sulphate salt) and beclomethasone (as the dipropionate ester).
  • the particles of the present invention may be used directly in inhalable compositions. Alternatively, they may be combined with additional components, carriers and/or components which are therapeutically acceptable.
  • an inhalable composition comprising particles as disclosed herein, together with a therapeutically acceptable carrier.
  • a dry powder inhaler containing particles as defined herein.
  • a dry powder inhaler containing a composition as defined herein.
  • the particles may be suitable for use in a metered dose inhaler (MDI).
  • MDI metered dose inhaler
  • an MDI containing particles as defined herein there is provided an MDI containing a composition as defined herein.
  • the particles may be suitable for use in a nebuliser.
  • a nebuliser containing particles as defined herein there is provided a nebuliser containing a composition as defined herein.
  • the particles may be used directly without further modifications or further components. In particular, in a DPI there is no need for a propellant.
  • the particles may be part of a composition containing additional components, for example a therapeutically acceptable carrier.
  • the composition may further comprise a propellant, for example a hydrofluorocarbon propellant.
  • a propellant for example a hydrofluorocarbon propellant.
  • Example propellants include HFA 134a and 227ea.
  • the composition may further include water, salts (for example for tonicity adjustment), pH modifiers (for example weak acids), and/or polymers for viscosity adjustment.
  • the present invention encompasses any way to make the particles.
  • the present invention encompasses any method to dry a solution to form particles.
  • Example methods of manufacture include: spray drying an aqueous solution of the components; co-precipitation by anti-solvents, co-precipitation by other means (for example by chemical reaction including pH changes) followed by drying including spray drying; co-precipitation by super-critical fluid precipitation; mechanofusion (coating crystalline particles with additional drugs onto the surface), optionally with annealing afterwards to crystallise an amorphous surface; or freeze drying, spray drying an organic solution; spray drying a solution containing a co-solvent mixture of water and organic solvent(s); spray freeze drying (this is different to simple spray drying or freeze drying a solution, involving spraying a solution into liquid nitrogen, the frozen droplets are then dried in a freeze dryer).
  • the solvent does not need to be aqueous, it can be totally organic or a mixture of water and organic solvent(s).
  • a co-solvent system could comprise water and ethanol.
  • an organic solvent/water mixture could be used and this may be used to increase the crystallinity of the particles compared to an aqueous solution alone.
  • the particles are formed by spray drying.
  • the active agents together with the excipient may be dissolved in an aqueous solution.
  • This solution may be, for example, water or a mixture of water and an alcohol such as ethanol.
  • the feed solution may then be spray dried.
  • Crystallization depends on Tg of the components and also other factors including the material and systems.
  • One additional factor is the inlet temperature of the spray drying equipment.
  • the inlet temperature is higher than Tg of the excipient that is expected to be crystalline.
  • the outlet temperature will be lower than the inlet temperature.
  • a method of delivering a combination of two or more active agents to a patient in need thereof comprising administering particles as defined herein.
  • a method of delivering a combination of two or more active agents to a patient in need thereof comprising inhaling particles as defined herein.
  • the present invention comprises a method of delivering a combination of two or more active agents to a patient, the method comprising forming particles as defined herein and aerosolising the particles to be suitable for inhalation by the patient.
  • the present invention comprises particles as defined herein for use as a medicament.
  • the present invention may be used to treat a wide array of diseases and/or conditions. Particular conditions include a respiratory or non-respiratory condition.
  • a method of treating a patient having a respiratory or non-respiratory condition comprising administering particles as defined herein.
  • the present invention comprises use of the particles as defined herein in the manufacture of a medicament for treatment of a respiratory or non-respiratory condition of a patient.
  • the present invention comprises particles as defined herein for use in the treatment of a respiratory or non-respiratory condition of a patient. According to a further aspect, the present invention provides the use of particles as defined herein for the manufacture of a medicament for the treatment of a respiratory or non-respiratory condition.
  • the present invention provides a method of delivering a medicament to a patient in need thereof comprising administering particles as defined herein.
  • the present invention provides a pharmaceutical composition comprising particles as defined herein.
  • the present invention provides particles as defined herein for use as a medicament.
  • the present invention provides the use of particles as defined herein as a medicament.
  • the present invention provides particles as defined herein for use in the treatment of respiratory or non-respiratory conditions.
  • the present invention provides the use of particles as defined herein in the treatment of respiratory or non-respiratory conditions.
  • Diseases or conditions for which the present invention may apply include respiratory or non-respiratory conditions.
  • Respiratory conditions include, COPD, bronchitis, allergy, rhinitis, cystic fibrosis, pulmonary infection, tuberculosis, influenza, other lung infections, lung cancer and asthma.
  • Non-respiratory conditions include diabetes, hypertension, hypercholesterolaemia, gout, infections (bacterial or viral), fever, pairi (neurological or muscular).
  • the respiratory condition is COPD. In a further embodiment, the respiratory condition is bronchitis. In a yet further embodiment, the respiratory condition is allergy. In a yet further embodiment, the respiratory condition is rhinitis. In a yet further embodiment, the respiratory condition is cystic fibrosis. In a yet further embodiment, the respiratory condition is pulmonary infection. In a yet further embodiment, the respiratory condition is asthma.
  • COPD COPD
  • asthma COPD
  • the medicament can be manufactured using the methods as defined herein.
  • the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
  • budesonide (a) budesonide, (b) formoterol fumarate dihydrate, (c) fluticasone propionate, (d) salmeterol xinafoate, (e) mannitol
  • B/F/M-SD and its raw materials, (a) B/F/M-SD, (b) mannitol, (c) budesonide, (d) formoterol fumarate dihydrate
  • F/S/M-SD and its raw materials (e) F/S/M-SD, (f) mannitol, (g) fluticasone propionate, (h) salmeterol xinafoate
  • B/F/M-SD spray dried budesonide/formoterol fumarate dehydrate/mannitol
  • F/S/M-SD spray dried fluticasone propionate/salmeterol xinafoate/mannitol
  • M-SD spray dried mannitol
  • B/F/M-SD spray dried budesonide/formoterol/mannitol fumarate dehydrate
  • F/S/M-SD spray dried fluticasone propionate/salmeterol xinafoate/mannitol
  • M-SD spray dried mannitol
  • Fig. 8 shows cross section images of B/F/M-SD (budesonide / formoterol fumarate dihydrate / mannitol spray dried) particles.
  • FIG. 9 Cross section images of F/S/M-SD (fluticasone propionate / salmterol xinafoate / mannitol spray dried) particles.
  • the following description describes methods of forming particles of the present invention from mannitol and active agents selected budesonide / fluticasone propionate, and formoterol fumarate dihydrate / salmeterol xinafoate. It will be appreciated that other components, including other active agents and/or other excipients, such as other sugars, can be utilised to form suitable carrier particles.
  • the particles as formed herein can be used to form compositions suitable for inhalation by a patient requiring the drug.
  • the drug can be suitable for treating respiratory conditions such as cystic fibrosis, COPD, bronchitis, allergy, rhinitis and asthma. It will also be appreciated that the drug can be suitable for delivery via the lungs and be used to treat non-pulmonary conditions.
  • the following information is intended to demonstrate how the aerodynamic diameter can be measured. This provides a method to determine the aerodynamic diameter of a given particle sample.
  • the aerodynamic particle size is measured by dispersing 5 mg of the powder from an Aerolizer ® through a Next Generation Impactor (British Pharmacopoeia Apparatus E) without the pre-separator at 60 and 100 L min air flow for 4 and 2.4 s, respectively.
  • the experimental procedure largely follows that detailed in the British Pharmacopoeia.
  • the flow rate and solenoid valve timer are adjusted appropriately prior to sampling.
  • a known amount of powder may be weighed into a Size 3 hydroxypropyl methylcellulose capsule and loaded into the capsule compartment in the Aerolizer ® .
  • the capsule is pieced and the inhaler is inserted into the induction port via a rubber adaptor flush with the inhaler mouthpiece to discharge the dose. Repeat the sampling procedure with more loaded capsules if necessary.
  • the number of discharges should be minimised (typically ⁇ 10) to obtain sufficient powder for an accurate and precise quantification.
  • the powder deposits of actives and excipient in the capsule, Aerolizer ® , rubber adaptor, induction port, and all impactor stages of the NGI are assayed chemically.
  • Suitable assay methods include, but are not limited to, the following: ultraviolet spectrophotometry, high performance liquid chromatography (HPLC), gas chromatography (GC), or liquid chromatography-mass spectrometry (LC-MS). Both actives should deposit concurrently on all assayed parts.
  • the loaded dose is defined as the total amount of powder weighed into the capsules for aerosol sampling.
  • the fine particle dose (FPD) is the total mass of particles with aerodynamic diameters ⁇ 5 ⁇ .
  • the fine particle fraction (FPF) is calculated by dividing the FPD by the loaded dose.
  • the examples show particles made from a combination of an inhaled corticosteroid (ICS) and a long-acting p2-agonist (LABA). Preparation of spray dried particles
  • ICS, LABA and mannitol were dissolved in ethanol/water to prepare the feed solutions for spray drying.
  • Spray drying was performed using a B-290 mini spray dryer (Buchi Labortechnik AG, Falwil, Switzerland) with operating conditions detailed in Table 2.
  • the spray dried powder samples were kept in a glass desiccator containing silica gel at 22 °C until used. (mg/mL)
  • Particle size distributions of the powders were determined by laser diffraction using Mastersizer 2000 (Malvern Instruments, Worcs, UK). The powders were dispersed through the measurement zone with compressed air at 4 bars of pressure by a Scirocco 2000 dry powder feeder (Malvern Instruments, Worcs, UK). The particle refractive index and absorption were 1.52 and 0.1, respectively. The dispersant refractive index was 1.000 for air. All measurements were conducted in triplicate. Drug quantification
  • Drug content in the spray dried powders after preparation and in the aerosol samples obtained from the dispersion study were determined using high performance liquid chromatography (HPLC) (Model LC-20; Shimadzu, Kyoto, Japan).
  • HPLC high performance liquid chromatography
  • a LiChrosphere 60 ® RP-select B column (4 x 125 mm, 5 ⁇ ) (Merck, Darmstadt, Germany) was used as the stationary phase with the mobile phase comprising methanol, water and acetic acid (550:450:1).
  • a flow rate of 1 mL/min and UV absorption wavelength at 230 nm was employed for parallel detection of both drugs (retention times were 4.9 min and 15.8 min for formoterol fumarate dehydrate and budesonide, respectively).
  • an Intersil ODS2 column (4.6 x 200 mm, 5 ⁇ ) (Capital HPLC, Scotland, UK) was used as stationary phase with methanol and 0.6% ammonium acetate buffer (75:25) being the mobile phase.
  • a flow rate of 1 mL min and wavelength 228 nm was used for parallel detection of salmeterol xinafoate and fluticasone propionate, at retention times of 2.7 min and 7.1 min, respectively.
  • Mannitol content in the powders was determined by HPLC using refractive index detection as described previously (20). Briefly, a CI 8 Radial-Pack column (Waters, USA) was used as stationary phase with deionized water as mobile phase running at 1 mL min.
  • DSC Differential scanning calorimetry
  • TGA Thermal gravimetric analysis
  • X-ray powder diffraction (XRD) measurement was carried out at room temperature using an X-ray diffractometer (Model D5000; Siemens, Kunststoff, Germany). Cu a radiation at 30mA and 40kV was used with an angular increment of 0.04° at 3 sec per step covering a 2 ⁇ range of 5-50°. Morphological observation
  • the morphology of the spray-dried particles was investigated using scanning electron microscopy (SEM). Samples were deposited on carbon sticky tape and mounted on a SEM stubs, followed by sputter coating with gold (15 nm thick) on a 550X sputter coater (Quorum Emitech, Kent, UK). The specimens were then imaged using a field emission SEM (Zeiss Ultra Plus; Carl Zeiss SMT AG, Oberkochen, Germany) at 1.90- 1.99 kV using an in-lens detector. Internal structure observation
  • Focused-ion-beam (FIB) milling of the particles was performed in an FIB/scanning electron microscope dual beam system (Nova 200, FEI, USA) using a similar procedure described previously, but without the cleaning step (21).
  • the powder samples were coated with a 50 nm layer of platinum.
  • Vertical cutting of the sample was performed at a stage tilt of 52 degrees with an accelerating voltage of 10 kV and a beam current of 19 pA. Milling times were kept under 5 min. The milled samples were later examined at 2 kV to examine the cut surface.
  • Atomic force microscopy Atomic force microscopy
  • Particle-particle cohesion force was evaluated using the colloid probe microscopy technique. Individual particle was mounted onto the apex of V-shaped tipless atomic force microscopy (AFM) cantilever (NP-0 silicon nitride cantilevers with gold reflective coating, nominal spring constant 0.58 nN; Veeco Inc., New York, USA) using a micromanipulation technique described elsewhere. The force of adhesion between each probe and particles mounted on a thermoplastic adhesive (Tempfix ® ; Piano, Wetzlar, Germany) was investigated using force-volume imaging.
  • AFM tipless atomic force microscopy
  • XPS X-ray photoelectron spectroscopy
  • the instrument comprises a Thermo VG ESCALAB250 spectrometer with a non-monochromatic Al alpha (1486.6 eV) X-ray source. Analysis was carried out under a pass energy of 20 eV. The powders were pressed onto double sided conductive adhesive tapes. Experimental molar percentages of all elements except hydrogen were derived from the XPS peak areas as described elsewhere (30). The molar percentages (At%) were multiplied by the appropriate atomic mass to obtain weight percentages (Wt%) (Table 5 and Table 7).
  • the surface elemental composition of the raw materials (mannitol, budesonide, formoterol fumarate dihydrate, fluticasone propionate and salmeterol xinafoate) and the three spray dried powders (M-SD, B/F M-SD and F/S/ - SD) were measured.
  • the type of molecules present on the particle surface can be deduced from the detected elements and elemental percentages.
  • the expected elemental percentages of the spray dried powders were calculated from the percentages measured on the raw materials. All components of the ternary powders were assumed to be distributed evenly on the surface for the calculation. The expected elemental percentages are shown in Table 6 and Table 7.
  • the expected Wt% of an element in the powder was the sum of the products obtained by multiplying the Wt of that element in the raw materials by the Wt% of the corresponding materials in the powder (Table 6). Differences between the experimental and expected percentages suggest an over- or under-abundance of certain types of molecules on the surface.
  • the dispersion test was performed for 2.4 sec at 100 IJmin and 4 sec at 60 L/min, with the flow rate measured by a flow meter (Model 3063; TSI Incorporated, Minnesota, USA). Dispersions were performed in triplicate for each powder. FPF was defined as the mass fraction of particles ⁇ 5.0 urn with respect to the loaded dose in the capsules. The cut-off diameters of the NGI stages at 100 L min were calculated with the cut-off adjustment equations given in Appendix XII C of the British Pharmacopoeia.
  • the drug content of each component in the powder was determined by HPLC to be close to 100 % (Table 4). In addition, the drug content ratios of the two combination powders were confirmed to be the same as those of the feed solutions.
  • M-SD spray dried mannitol
  • B/F/M-SD spray dried budesonide / formoterol fumarate dihydrate / mannitol
  • F/S/M-SD spray dried fluticasone propionate /salmeterol xinafoate / mannitol
  • B/F/M-SD also had a smooth surface but the packing of mannitol crystals was not observed. Small crystal-shaped particles adhered onto the surface. The surface of F/S/M-SD particles seemed roughly covered with mixture of clay-like material and small particles. It also had many dimples on the surface.
  • this inhomogeneity could be caused by the difference of solubility of mannitol and drugs. Solidification of drugs and mannitol would have occurred at the different time points during the spray drying process as the solvent evaporated. It could be that the active agents solidified first on the surface of the droplets and then mannitol came out inside of the outer shell of drugs. As the particles are mainly composed of mannitol, the crystallinity of drugs could not be examined using XRD and DSC.
  • Focus ion beam-scanning electron, microscopy is similar to scanning electron microscopy (SEM) but it uses a liquid metal source as the filament to produce a finely focused beam of energetic metal ions that can be applied for both imaging and milling.
  • the particle is cut with ion beam and its cross section is viewed under SEM.
  • condition adjustment can be difficult when the specimen is sensitive because it can easily deteriorate under the ion or electron beam. Since the ion beam removes material from the specimen surface, mild conditions preferable to reduce the deteriorating effect on the specimen. However, it becomes more difficult to obtain clear images at lower accelerating voltages and lower beam currents. Therefore, the mildest condition that can give acceptably clear image should be applied.
  • FIB-SEM revealed partially hollow interior structures (Figure 2).
  • the partially hollow interior structures may lead to a lower particle density and smaller aerodynamic diameter resulting in better dispersibility. Additional FIB-SEM images are shown in figures 8 and 9.
  • XRD patterns showed that both B/F/M-SD and F/S/M-SD contained a-mannitol, while M-SD contained ⁇ -mannitol ( Figure 5). Although ICS contents were approaching the detection limit of XRD, the patterns were able to reveal the major diffraction peaks of budesonide at 2 ⁇ angles of 6.1, 12.0, 15.5 & 16.0 degrees and fluticasone propionate at 10.0, 13.0, 14.8 & 16.2 degrees.
  • the inhalable particle size range and consistent drug contents show the potential applicability of ICS/LABA/mannitol powder for DPI formulations.
  • the consistent drug contents indicate no selective adsorption or loss of the drugs in the spray drying line, nor segregation of the drugs in the powders.
  • the drug content ratios are considered to be constant throughout the whole particle size range based on the concomitant deposition of ICS/LABA shown in the aerosol data ( Figure 6 and Figure 7).
  • the high and similar FPF values of B F M-SD and F/S/M-SD are in accordance with the inhalable particle size range (Table 3) as well as similar AFM force values for the powders (Table 8).
  • the relatively high FPF in the aerosol also showed that the powders were not particularly cohesive, hence a good dispersion could be achieved even at a low air flow rate with minimal inhalation effort.
  • Using a comfortable inspiratory effort would generate 105 L min through the Aerolizer.
  • Increasing the flow from 60 to 100 L/min simply reduces the capsule and device retention by providing more energy to empty the powder from the inhaler, while augmenting the deposition on the throat and Stages 1 and 2 of the impactor by increasing the air velocity for impaction at those sites.
  • Co-precipitates of fluticasone propionate and salmeterol xinafoate showed a FPF of 22% when formulated with lubricant and 36% with lactose carrier.
  • the ICS/LABA/mannitol co-spray dried powders in the present study are similar to mannitol in their cohesive force (Table 8) and FPF values. Surface roughness of these particles is likely to have contributed to the low cohesiveness and high dispersibiliry.
  • Another contributing factor may be the crystallinity of the mannitol and possibly of the ICSs (as confirmed by DSC & XRD). Compared with previous studies, the inlet temperature of the spray drying process was higher, hence allowing glass transition and subsequent crystallization of the drugs.
  • the ICS/LABA mannitol system provides an innovative approach for combination formulations at appropriate doses without the need of physical blending.
  • the powders showed high aerosol performance and uniform deposition of the two drugs. Storage stability is an important consideration for product development. Preliminary results showed that compared to the initial values, there was no significant difference (P ⁇ 0.05) in the dispersion of the B/F/M-SD powder after storage over silica gel at 22 °C for 11 weeks (FPF at 60 L/min: 53.7 ⁇ 1.5% for formoterol fumarate dihydrate and 53.4 ⁇ 1.7% for budesonide). Additional Spray Dried Powders
  • the drug solutions are shown in Table 9 below and were spray dried using the conditions as those for B/F/M-SD.
  • Respirable-sized (D50 of 2 ⁇ ) crystalline mannitol particles containing two drugs with at least one confirmed to be also crystalline were successfully obtained from co-spray drying two different ternary systems containing budesonide/formoterol furnarate dihydrate/mannitol and fluticasone propionate/salmeterol xinafoate/mannitol.
  • the powders When dispersed using an Aerolizer at 60 and 100 IJmin, the powders showed a concomitant in vitro deposition patterns of ICS LABA with a FPF of 54 - 62 %.
  • the aerosol performance can be due to the low interparticulate force, resulting from a combination of the rough surface and crystalline nature of the particles.
  • the particles of the present invention provide an alternative simple method for effective one-step processing of combination formulations for inhalation.

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Abstract

La présente invention concerne des particules inhalables respirables comprenant un/des agent(s) actif(s) et des excipients sous une forme au moins partiellement cristalline et leurs utilisations.
PCT/AU2010/001656 2009-12-08 2010-12-08 Formulations inhalables Ceased WO2011069197A1 (fr)

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US8765725B2 (en) 2012-05-08 2014-07-01 Aciex Therapeutics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
WO2016090260A1 (fr) 2014-12-04 2016-06-09 Microdose Therapeutx, Inc. Système et procédé de surveillance d'inhalation
US9815865B2 (en) 2013-01-07 2017-11-14 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US10174071B2 (en) 2012-05-08 2019-01-08 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
WO2019060595A1 (fr) 2017-09-20 2019-03-28 Teva Branded Pharmaceutical Products R&D, Inc. Médicament inhalable en poudre sèche comprenant du glycopyrronium
WO2020020957A1 (fr) * 2018-07-27 2020-01-30 Chiesi Farmaceutici S.P.A. Nouvelles particules de support pour formulations de poudre sèche pour inhalation
WO2020022975A3 (fr) * 2017-12-29 2020-02-27 Neutec Ar-Ge Sanayi Ve Ticaret Anonim Sirketi Nouvelles compositions pharmaceutiques dans le traitement de la bpco
EP3288541B1 (fr) * 2015-05-01 2020-09-02 Board of Regents, The University of Texas System Compositions matricielles fragiles à médicaments multiples
EP3910324A1 (fr) * 2018-08-07 2021-11-17 Norton (Waterford) Limited Application de spectroscopie raman pour la fabrication de poudres à inhaler

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CN111658661B (zh) * 2020-06-12 2021-06-01 深圳大佛药业股份有限公司 一种硫酸沙丁胺醇吸入制剂及其制备方法

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US10954263B2 (en) 2012-05-08 2021-03-23 Nicox Ophthalmics, Inc Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US9822142B2 (en) 2012-05-08 2017-11-21 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US10174071B2 (en) 2012-05-08 2019-01-08 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US8765725B2 (en) 2012-05-08 2014-07-01 Aciex Therapeutics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US9815865B2 (en) 2013-01-07 2017-11-14 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
WO2016090260A1 (fr) 2014-12-04 2016-06-09 Microdose Therapeutx, Inc. Système et procédé de surveillance d'inhalation
EP3583899A1 (fr) 2014-12-04 2019-12-25 Norton (Waterford) Limited Système et procédé de surveillance d'inhalation
EP3838319A1 (fr) 2014-12-04 2021-06-23 Norton (Waterford) Limited Système et procédé de surveillance d'inhalation
AU2015393953B2 (en) * 2015-05-01 2021-09-02 Board Of Regents, The University Of Texas System Multidrug brittle matrix compositions
EP3288541B1 (fr) * 2015-05-01 2020-09-02 Board of Regents, The University of Texas System Compositions matricielles fragiles à médicaments multiples
WO2019060595A1 (fr) 2017-09-20 2019-03-28 Teva Branded Pharmaceutical Products R&D, Inc. Médicament inhalable en poudre sèche comprenant du glycopyrronium
WO2020022975A3 (fr) * 2017-12-29 2020-02-27 Neutec Ar-Ge Sanayi Ve Ticaret Anonim Sirketi Nouvelles compositions pharmaceutiques dans le traitement de la bpco
WO2020020957A1 (fr) * 2018-07-27 2020-01-30 Chiesi Farmaceutici S.P.A. Nouvelles particules de support pour formulations de poudre sèche pour inhalation
JP2021531948A (ja) * 2018-07-27 2021-11-25 シエシー ファルマセウティチィ ソシエタ ペル アチオニ 吸入用乾燥粉末製剤のための新規担体粒子
US11813360B2 (en) 2018-07-27 2023-11-14 Chiesi Farmaceutici S.P.A. Carrier particles for dry powder formulations for inhalation
JP7439084B2 (ja) 2018-07-27 2024-02-27 シエシー ファルマセウティチィ ソシエタ ペル アチオニ 吸入用乾燥粉末製剤のための新規担体粒子
EP3910324A1 (fr) * 2018-08-07 2021-11-17 Norton (Waterford) Limited Application de spectroscopie raman pour la fabrication de poudres à inhaler
US12174121B2 (en) 2018-08-07 2024-12-24 Norton (Waterford) Limited Application of raman spectroscopy for the manufacture of inhalation powders

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