WO1999016420A9 - Stabilized preparations for use in nebulizers - Google Patents
Stabilized preparations for use in nebulizersInfo
- Publication number
- WO1999016420A9 WO1999016420A9 PCT/US1998/020603 US9820603W WO9916420A9 WO 1999016420 A9 WO1999016420 A9 WO 1999016420A9 US 9820603 W US9820603 W US 9820603W WO 9916420 A9 WO9916420 A9 WO 9916420A9
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- WIPO (PCT)
- Prior art keywords
- thε
- dispersion
- microstructures
- surfactant
- stabilized
- Prior art date
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- 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
- A61K9/008—Sprays 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]
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- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- 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
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/906—Drug delivery
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/926—Topical chemical, e.g. cosmetic or sunscreen
Definitions
- the present invention generally relates to formulations and methods for the administration of bioactive agents to a patient via the respiratory tract More particularly, the present invention relates to methods, systems and compositions comprising relatively stable dispersions that are preferably administered via nebulization both for topical delivery to the lung, and for delivery via the lung to the systemic circulation.
- Targeted drug delivery means are particularly desirable where toxicity or bioavailability of the pharmaceutical compound is an issue.
- Specific drug delivery methods and compositions that effectively deposit the compound at the site of action potentially serves to minimize toxic side effects lower dosing requirements and decrease therapeutic costs.
- the development of such systems for pulmonary drug delivery has long been a goal of the pharmaceutical industry.
- DPIs dry powder inhalers
- MDIs metered dose inhalers
- nebulizers nebulizers
- MDIs the most popular method of inhalation administration, may be used to deliver medicaments in a solubilized form or as a dispersion
- MDIs comp ⁇ se a Freon or other relatively high vapor pressure propellant that forces aerosolized medication into the respiratory tract upon activation of the device
- DPIs generally rely on the patient's inspiratory efforts to introduce a medicament in a dry powder form to the lungs.
- nebulizers form a medicament aerosol to be inhaled by imparting energy to a liquid solution
- direct pulmonary delivery of drugs dunng liquid ventilation or pulmonary lavage using a fluorochemical medium has also been explored. While each of these methods and associated systems may prove effective in selected situations, inherent drawbacks, including formulation limitations, can limit their use.
- air jet nebulizers compressed air is forced through an orifice. A liquid may then be withdrawn from a perpendicular nozzle (the Bernoulli effect) to mix with the air jet to form droplets. A baffle (or series of baffles) within the nebulizer is used to facilitate formation of the aerosol cloud.
- ultrasonic nebulizers rely on the generation of ultrasound waves in an ultrasonic nebulizer chamber by a ceramic piezoelectnc crystal that vibrates at a precise frequency when electrically excited. The ultrasonic energy sets up high energy waves in the nebulizer solution, facilitating generation of an aerosol cloud.
- Formulations for nebulizatio ⁇ typically comprise aqueous based solutions Assuming that the solubility and stability of the active drug are adequate, an aqueous based formulation administered by ⁇ ebulization is reasonable when the estimated minimal effective dose exceeds about 200 ⁇ _.
- Continuous nebulization has long been an option for the delivery of topical lung therapy for the treatment of various lung diseases such as asthma, chronic obstructive pulmonary disease, emphysema, and bronchitis More recently, proteins such as DMase have been delivered by conventional jet nebulizers for their local effect on the lung. Unfortunately, continuous nebulization is an int ⁇ nsically inefficient way to deliver aerosolized medication.
- the first category comp ⁇ ses pure piezoelectnc single-bolus nebulizers such as those described by Mutterlein, et. al., (J. Aerosol Med. 1988; 1 :231 ).
- the desired aerosol cloud may be generated by icrochannel extrusion single-bolus nebulizers such as those described in U.S. Pat No. 3,812,854.
- a third category comprises devices exemplified by Robertson, et. al , (WO 9211 1050) which desc ⁇ bes cyclic pressunzation single bolus nebulizers.
- the methods and associated compositions of the present invention provide, in a broad aspect, for the improved delivery of bioactive agents using stabilized preparations.
- the bioactive agents are delivered to a patient via the respiratory tract.
- the present invention provides for the formation and use of stabilized dispersions (also referred to as stabilized respiratory dispersions) and inhalation systems, including nebulizers comprising such dispersions, as well as individual components thereof.
- the present invention preferably employs novel techniques to reduce attractive forces between the dispersed constituents and to reduce density fluctuations in the stabilized dispersion thereby retarding degradation of the disclosed preparations by fiocculation, sedimentation or creaming.
- the stabilized preparations of the present invention preferably comp ⁇ se a suspension medium that further serves to reduce the rate of degradation with respect to the incorporated bioactive agent.
- the suspension medium will comp ⁇ se a fluo ⁇ nated compound or fluorocarbo ⁇ .
- the stabilized dispersions of the present invention incorporate colloidal preparations compnsing a nonaqueous continuous phase wherein the stabilized dispersions are capable of being nebulized or aerosolized to provide effective dosing to a patient in need thereof.
- the stabilized dispersions may comprise any reverse emulsion or particulate dispersion that allows for the effective delivery of a bioactive agent to the pulmonary air passages of a mammal.
- the disperse phase of such preparations may comprise liquid particulates in the case of reverse emulsions or non liquid particulates in the case of stabilized suspensions
- the term "stabilized dispersion" shall be held to comp ⁇ se colloidal systems compnsing reverse emulsions and particulate suspensions unless otherwise dictated by contextual constraints
- the stabilized dispersion may be used with a nebulizer to provide the desired aerosolized medicament for pulmonary administration
- the stabilized preparations of the present invention provide these and other advantages through the use of particulate suspensions compnsing hollow andlor porous perforated microstructures that substantially reduce attractive molecular forces, such as van der Waals forces, which dominate prior art dispersion preparations. More particularly, the use of perforated (or porous) microstructures or microparticulates that are permeated or filled by the surrounding fluid medium, or suspension medium, significantly reduces disruptive attractive forces between the particles. Additionally, the components of the dispersions may be selected to minimize differences in pola ⁇ zabilities (i.e. reduced Hamaker constant differentials) and further stabilize the preparation.
- dispersions comprising perforated microstructures are particularly compatible with inhalation therapies compnsing administration of the bioactive preparation to at least a portion of the pulmonary air passages.
- these stabilized dispersions intended for pulmonary drug delivery may be termed respiratory dispersions
- such respiratory dispersions are used in conjunction with nebulizers to effectively deliver a bioactive agent to the pulmonary air passages or nasal passages of a patient.
- perforated microstructures may be formed of any biocompatible mate ⁇ al providing the desired physical characteristics or morphology that allows for the preparation of stabilized dispersions
- the perforated microstructures comprise pores, voids, defects or other interstitial spaces that allow the fluid suspension medium to freely permeate, or perfuse, the particulate boundary, thus reducing or minimizing density differences between the dispersion components
- any mate ⁇ al or configuration may be used to form the microstructure mat ⁇ x.
- the microstructure incorporates at least one surfactant
- this surfactant will comp ⁇ se a phospholipid or other surfactant approved for pulmonary use
- particularly preferred embodiments of the invention incorporate spray d ⁇ ed, hollow microspheres having a relatively thin porous wall defining a large internal void, although, other void containing or perforated structures are contemplated as well.
- select embodiments of the invention provide for stable respiratory dispersions for use in a nebulizer compnsing a suspension medium having dispersed therein a plurality of perforated microstructures compnsing at least one bioactive agent wherein said suspension medium substantially permeates said perforated microstructures.
- relatively nonporous or solid particulates may also be used to prepare dispersions that are compatible with the teachings herein That is, respiratory dispersions compnsing suspensions of relatively nonporous or solid particulates in a nonaqeous suspension medium are also contemplated as being within the scope of the present invention
- relatively nonporous particulates may comprise micromzed particles or nanocrystals.
- pill shall be interpreted broadly to mean any non liquid particle comprising the discontinuous phase of a dispersion or suspension More specifically, it will be appreciated that the term “particulate” shall be held to comprise particles of any porosity, including both perforated microstructures and relatively nonporous particles
- the nonaqueous continuous phase or suspension medium may be any liquid or compound that is in liquid form, under appropriate thermodynamic conditions, for formation of a compatible particulate dispersion or reverse emulsion.
- the terms "suspension medium,” “suspension media” and “nonaqueous continuous phase” are held to be equivalent for the purposes of the instant application and may be used interchangeably.
- the suspension medium preferably comprises hydrocarbons or fluorocarbons having a vapor pressure less than about one atmosphere. That is, it will preferably be a liquid under standard conditions of one atmosphere and 25° C
- suspension mediums or nonaqueous continuous phases compnse fluorochemicals
- fluorochemicals have a proven history of safety and bioco patibility in the lung.
- fluorochemicals do not negatively impact gas exchange
- fluorochemicals may be able to carry an aerosolized stream of particles deeper into the lung, thereby improving systemic delivery
- fluorochemicals are also bactenostatic thereby decreasing the potential for microbial growth in compatible nebulizer devices
- the present invention provides for the use of a liquid fluorochemical in the manufacture of a medicament for the pulmonary delivery of a bioactive agent whereby the medicament comprises a stabilized dispersion having a fluorochemical continuous phase which is nebulized using a nebulizer to form an aerosolized medicament compnsing said bioactive agent wherein said aerosolized medicament is administered to at least a portion of the pulmonary air passages of a patient in need thereof
- the present invention comp ⁇ ses methods for forming dispersions which comprise combining a plurality of particulates compnsing at least one bioactive agent with a predetermined volume of suspension medium, to provide a respiratory blend. The respiratory blend may then be mixed or otherwise agitated to provide a substantially homogeneous dispersion.
- the particulates will comp ⁇ se perforated microstructures which allow for the perfusion or permeation of the selected suspension medium
- the dispersion may comp ⁇ se a reverse emulsion.
- preferred embodiments of the invention provide for the formation of stabilized respiratory dispersions compnsing the steps of. combining a plurality of perforated microstructures compnsing at least one bioactive agent with a predetermined volume of a nonaqueous suspension medium to provide a respiratory blend wherein said suspension medium permeates said perforated microstructures; and mixing said respiratory blend to provide a substantially homogeneous respiratory dispersion.
- the stability of the formed particulate dispersions may be further increased by reducing, or minimizing, the Hamaker constant differential between incorporated particulates, or perforated microstructures, and the suspension medium Those skilled in the art will appreciate that Hamaker constants tend to scale with refractive indices.
- the present invention further provides methods for stabilizing a respiratory dispersion by reducing attractive van der Waals forces compnsing the steps of: providing a plurality of perforated microstructures; combining the perforated microstructures with a suspension medium comprising at least one fluorochemical wherein the suspension medium and the perforated microstructures are selected to provide a refractive index differential value of less than about 0 5
- the particulates preferably comp ⁇ se perforated microstructures and, in particularly preferred embodiments, the particulates will comp ⁇ se hollow, porous microspheres
- another aspect of the present invention is directed to liquid inhalation systems for the administration of one or more bioactive agents to a patient
- the present invention provides for inhalation systems for the pulmonary administration of a bioactive agent to a patient comprising- a fluid reservoir, a stable respiratory dispersion in said fluid reservoir wherein said stabilized dispersion composes a fluorochemical continuous phase and at least one bioactive agent; and a nebulizer operably associated with said fluid reservoir wherein the nebulizer is capable of aerosolizing and discharging the stable respiratory dispersion.
- the respiratory dispersion may comp ⁇ se a reverse emulsion, microemulsion or particulate suspension
- the dispersion compnses a suspension medium having dispersed therein a plurality of perforated microstructures, which comprise at least one bioactive agent and are substantially permeated by the suspension medium
- the nebulizer may comp ⁇ se an ultrasonic nebulizer, an air jet nebulizer and, most preferably, a single-bolus nebulizer.
- the disclosed systems of the present invention allow for the reproducible administration of bioactive agents having aerosolized particle size small enough to travel deep within the lung More specifically, the aerosolized medicament will preferably exhibit a fine particle fraction of greater than approximately 20% w/w.
- bioactive agent refers to a substance which is used in connection with an application that is therapeutic or diagnostic in nature, such as methods for diagnosing the presence or absence of a disease in a patient and/or methods for treating disease in a patient
- bioactive agent may be selected from the group consisting of a ⁇ tialiergics, bronchodilators, bro ⁇ choconstnctors, pulmonary lung surfactants, analgesics, antibiotics, leukotnene inhibitors or antagonists, anticholinergics, mast cell inhibitors, antihistamines, antnnfiammato ⁇ es, antineoplastics, anesthetics, anti tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic mate ⁇ al, viral vectors, anti
- the bioactive agent may be incorporated, blended in, coated on or otherwise associated with the perforated microstructure.
- the bioactive agent may be associated with the disperse phase (e.g , aqueous phase) of a reverse emulsion.
- the present invention provides methods for the pulmonary delivery of one or more bioactive agents compnsing the steps of- providing a stabilized respiratory dispersion compnsing one or more bioactive agents wherein the respiratory dispersion comp ⁇ ses a fluorochemical continuous phase; nebulizing said respiratory dispersion with a nebulizer to provide an aerosolized medicament; and ad iniste ⁇ ng a therapeutically effective amount of said aerosolized medicament to at least a portion of the pulmonary passages of a patient in need thereof.
- the bioactive agent preferably will be substantially associated with the dispersed droplets.
- the selected bioactive agent, or agents may be used as the sole structural component of the particulates or perforated microstructures
- the particulates, or perforated microstructures may comprise one or more components (i e structural matenals, surfactants, excipients, etc ) in addition to the incorporated bioactive agents
- the suspended particulates or perforated microstructures will comprise relatively high concentrations of surfactant (greater than about 10% w/w) along with the incorporated bioactive agent(s)
- the particulate or perforated microstructure may be coated, linked or otherwise associated with the bioactive agent in a non integral manner. Whatever configuration is selected, it will be appreciated that the associated bioactive agent may be used in its natural form, or as one or more salts known in the art
- the present invention provides for the nebulization and pulmonary delivery of relatively stable particulate dispersions Those skilled in the art will appreciate that, due to other physiochemical characteristics, the morphology of incorporated particulates may vary without destabilizing the dispersion As such, stabilized dispersions may be formed with compatible particulates even if they exhibit relatively low porosity, or are substantially solid. That is, while particularly preferred embodiments of the present invention will comp ⁇ se perforated microstructures or microspheres, acceptable dispersions may be formed using relatively low porosity particulates such as ⁇ a ⁇ ocrystals, or micro ⁇ ized drugs. In this respect, such embodiments are specifically contemplated as being within the scope of the present invention
- the stabilized dispersions of the invention may optionally comp ⁇ se one or more additives to further enhance stability or increase biocompatibility
- vanous surfactants, co solvents, osmotic agents, stabilizers, chelators, buffers, viscosity modulators, solubility modifiers and salts can be associated with the perforated microstructure, suspension medium, or both.
- vanous surfactants, co solvents, osmotic agents, stabilizers, chelators, buffers, viscosity modulators, solubility modifiers and salts can be associated with the perforated microstructure, suspension medium, or both.
- the specific quantities, ratios, and types of agents can be determined empirically without undue expe ⁇ mentatio ⁇ .
- Figs. 1 A1 to 1 F2 illustrate changes in particle morphology as a function of variation in the ratio of fluorocarbon blowing agent to phospholipid (PFC/PC) present in the spray dry feed
- the micrographs produced using scanning electron microscopy and transmission electron microscopy techniques, show that in the absence of FCs, or at low PFC/PC ratios, the resulting spray dried microstructures comprising gentamicin sulfate are neither particularly hollow nor porous
- the particles contain numerous pores and are substantially hollow with thin walls.
- Fig. 2 is a scanning electron microscopy image of perforated microstructures comprising cromolyn sodium illustrating a preferred hollow/porous morphology
- Fig 3 presents results of in vitro Andersen cascade impactor studies comparing the same hollow porous cromolyn sodium formulation delivered via MDI in HFA 134a, or from a long chain fluorocarbon (perfluorooctyl ethane) via nebulization Nebulized particles are observed to deposit onto later stages in the impactor, corresponding to improved systemic delivery in vivo.
- a long chain fluorocarbon perfluorooctyl ethane
- the present invention provides systems, methods and compositions that allow for the formation and administration of stabilized suspensions or dispersions, having a ⁇ onaqeous continuous phase, that may advantageously be used for the pulmonary delivery of bioactive agents in conjunction with a nebulizer
- the stabilized dispersions may comprise any colloidal system, including, reverse emulsions, microemulsions or particulate (i e non liquid particles) dispersions that may be nebulized to effectively deliver a bioactive agent to the pulmonary air passages of a patient.
- Particularly preferred embodiments comprise stabilized dispersions incorporating a liquid fluorochemical continuous phase or suspension medium
- the stabilized dispersion will preferably be administered to the pulmonary air passages of a patient using a nebulizer (e g a single bolus type nebulizer)
- the present invention overcomes these and other difficulties by providing stabilized dispersions with a nonaqueous continuous phase that preferably comprises a fluo ⁇ nated compound (i e a fluorochemical, fluorocarbon or perfluorocarbon).
- a fluo ⁇ nated compound i e a fluorochemical, fluorocarbon or perfluorocarbon.
- Particulariy preferred embodiments of the present invention comprise fluorochemicals that are liquid at room temperature
- fluorochemicals have a proven history of safety and biocompatibility in the lung
- fluorochemicals do not negatively impact gas exchange following pulmonary administration To the contrary, they may actually be able to improve gas exchange and, due to their unique wettability characteristics, are able to carry an aerosolized stream of particles deeper into the lung, thereby improving systemic delivery of the desired pharmaceutical compound
- the relatively non reactive nature of fluorochemicals acts to retard any degradation of an incorporated bioactive agent
- inhalation preparations compatible with the present invention may comprise any colloidal system that is capable of nebulization or aerosolization
- the following discussion will largely be directed to particularly preferred embodiments of the present invention comprising stabilized particulate dispersions.
- the scope and content of the present invention is not limited to these specific illustrative embodiments and, in particular, is not limited to those embodiments comprising particulate dispersions. While such dispersions are particularly effective in terms of stability and pulmonary distribution, nebulized reverse emulsions may also provide for the efficient pulmonary delivery of bioactive compounds As such, their use is specifically contemplated as being within the scope of the present invention
- the enhanced stability provided by the suspensions of the present invention may be achieved by lowering the van der Waals attractive forces between the suspended particles, and by reducing the differences in density between the suspension medium and the particles.
- the increases in suspension stability may be imparted by engineering perforated microstructures that are then dispersed in a compatible suspension medium.
- the perforated microstructures comprise pores, voids, hollows, defects or other interstitial spaces that allow the fluid suspension medium to freely permeate or perfuse the particulate boundary
- Particularly preferred embodiments comprise perforated microstructures that are both hollow and porous, almost honeycombed or foam like in appearance
- the perforated microstructures comprise hollow, porous spray dried microspheres.
- the suspension medium When perforated microstructures are placed in the suspension medium, the suspension medium is able to permeate the particles, thereby creating a "homodispersio ⁇ ", wherein both the continuous and dispersed phases are essentially indistinguishable Since the defined or "virtual" particles (i.e comprising the volume circumscribed by the microstructure matrix) are made up almost entirely of the medium in which they are suspended, the forces driving particle aggregation (fiocculation) are minimized Additionally, the differences in density between the defined or virtual particles and the continuous phase are minimized by having the microstructures filled with the medium, thereby effectively slowing particle creaming or sedimentation As such, the stabilized suspensions of the present invention are particularly compatible with inhalation therapies and may be used in conjunction with metered dose inhalers (MDIs), dry powder inhalers, and nebulizers More specifically, the particulate suspensions of the present invention may be designed to decrease the attractive forces between particles.
- MDIs metered dose inhalers
- dry powder inhalers dry
- Van der Waals forces are quantum mechanical in origin, and can be visualized as attractions between fluctuating dipoles (i.e. induced dipole-i ⁇ duced dipole interactions).
- Dispersion forces are extremely short range and scale as the sixth power of the distance between atoms. When two macroscopic bodies approach one another, the dispersion attractions between the atoms sum up. The resulting force is of considerably longer range, and depends on the geometry of the interacting bodies.
- V A the magnitude of the van der Waals potential
- v - A ,JJ R t R _
- a eff the effective Hamaker constant which accounts for 6 H ⁇ ( ⁇ , + ⁇ . ) the nature of the particles and the medium
- H 0 is the distance between particles
- R, and R 2 are the radii of spherical particles 1 and 2.
- a and A P4RT are the Hamaker constants for the suspension medium and the particles, respectively As the suspended particles and the dispersion medium become similar in nature, A M and A PART become closer in magnitude, and A eff and V A become smaller. That is, by reducing the differences between the Hamaker constant associated with suspension medium and the Hamaker constant associated with the dispersed particles, the effective Hamaker constant (and corresponding van der Waals attractive forces) may be reduced.
- the components of the structural matrix (defining the perforated microstructures) will preferably be chosen so as to exhibit a Hamaker constant relatively close to that of the selected suspension medium.
- the actual values of the Hamaker constants of the suspension medium and the particulate components may be used to determine the compatibility of the dispersion ingredients and to provide a good indication as to the stability of the preparation.
- refractive index values of many compounds tend to scale with the corresponding Hamaker constant Accordingly, easily measurable refractive index values may be used to provide a fairly good indication as to which combination of suspension medium and particle excipients will provide a dispersion having a relatively low effective Hamaker constant and associated stability It will be appreciated that, since refractive indices of compounds are widely available or easily derived, the use of such values allows for the formation of stabilized dispersions in accordance with the present invention without undue experimentation. For the purpose of illustration only, the refractive indices of several compounds compatible with the disclosed dispersions are provided in Table I immediately below.
- the formation of dispersions wherein the components have a refractive index differential of less than about 0.5 is preferred. That is, the refractive index of the suspension medium will preferably be within about
- the refractive index of the suspension medium and the particles may be measured directly or approximated using the refractive indices of the major component in each respective phase.
- the major component may be determined on a weight percent basis.
- the major component will typically be derived on a volume percentage basis.
- the refractive index differential value will preferably be less than about 0.45, about 0 4, about 0.35 or even less than about 0.3.
- particularly preferred embodiments comprise index differentials of less than about 0.28, about 0.25, about 0.2, about 0.15 or even less than about 0.1. It is submitted that a skilled artisan will be able to determine which dispersion components are particularly compatible without undue experimentation given the instant disclosure. The ultimate choice of preferred components will also be influenced by other factors, including biocompatibility, regulatory status, ease of manufacture and cost In contrast to prior art attempts to provide stabilized suspensions which require surfactants that are soluble in the suspension medium, the present invention may provide stabilized dispersions, at least in part, by immobilizing the bioactive agent(s) within the structural matrix of the hollow, porous microstructures.
- preferred excipients useful in the present invention are substantially insoluble in the suspension medium. Under such conditions, even surfactants like, for example, lecithin cannot be considered to have surfactant properties in the present invention since surfactant performance requires the amphiphile to be reasonably soluble in the suspension medium. The use of insoluble excipients also reduces the potential for particle growth by Ostwald ripening.
- the minimization of density differences between the particles and the continuous phase may be improved by the perforated and/or hollow nature of incorporated microstructures, such that the suspension medium constitutes most of the particle volume.
- particle volume corresponds to the volume of suspension medium that would be displaced by the incorporated hollow/porous particles if they were solid, i e. the volume defined by the particle boundary
- these fluid filled particulate volumes may be referred to as "virtual particles.”
- the average volume of the bioactive agent and/or excipient shell or matrix i.e. the volume of medium actually displaced by the perforated microstructure
- the volume of the microparticulate matrix comprises less than about 50%, 40%, 30% or even 20% of the average particle volume. Even more preferably, the average volume of the shell/matrix comprises less than about 10%, 5% or 3% of the average particle volume Those skilled in the art will appreciate that such matrix, or shell volumes typically contribute little to the virtual particle density that is overwhelmingly dictated by the suspension medium found therein. Of course, in selected embodiments the excipients or bioactive agents used to form the perforated microstructure may be chosen so the density of the resulting matrix or shell approximates the density of the surrounding suspension medium.
- the use of such microstructures will allow the apparent density of the virtual particles to approach that of the suspension medium.
- the components of the microparticulate matrix are preferably selected, as much as possible given other considerations, to approximate the density of suspension medium.
- the virtual particles and the suspension medium will have a density differential of less than about 0.6 g/cm 3 . That is, the mean density of the virtual particles (as defined by the matrix boundary) will be within approximately 0.6 g/cm 3 of the suspension medium. More preferably, the mean density of the virtual particles will be within 0.5, 0.4, 0.3 or
- the density differential will be less than about 0.1 , 0.05, 0.01 , or even less than 0.005 g/cm 3 .
- the use of hollow, porous particles allows for the formation of free-flowing dispersions comprising much higher volume fractions of particles in suspension. It should be appreciated that, the formulation of prior art dispersions at volume fractions approaching close packing generally results in dramatic increases in dispersion viscoeiastic behavior. Rheological behavior of this type is not appropriate for inhalation applications Those skilled in the art will appreciate that, the volume fraction of the particles may be defined as the ratio of the apparent volume of the particles (i.e. the particle volume) to the total volume of the system.
- Each system has a maximum volume fraction or packing fraction. For example, particles in a simple cubic arrangement reach a maximum packing fraction of 0.52, while those in a face centered cubic/hexagonal close packed configuration reach a maximum packing fraction of approximately 0 74 For non spherical particles or polydisperse systems, the derived values are different. Accordingly, the maximum packing fraction is often considered to be an empirical parameter for a given system.
- porous structures in the present invention did not introduce undesirable viscoeiastic behavior even at high volume fractions approaching close packing To the contrary, they remain as free flowing, low viscosity suspensions having little or no yield stress when compared with analogous suspensions comprising solid particulates
- the low viscosity of disclosed preferred suspensions is thought to be due, at least in large part, to the relatively low van der Waals attraction between the fluid filled hollow, porous particles.
- the volume fraction of the disclosed dispersions is greater than approximately 0.3.
- Other embodiments may have packing values on the order of 0.3 to about 0.5 or, on the order of 0 5 to about 0.8, with the higher values approaching a close packing condition Moreover, as particle sedimentation tends to naturally decrease when the volume fraction approaches close packing, the formation of relatively concentrated dispersions may further increase formulation stability
- the methods and compositions of the present invention may be used to form relatively concentrated suspensions, the stabilizing factors work equally well at much lower packing volumes and, such dispersions are contemplated as being within the scope of the instant disclosure.
- dispersions comprising low volume fractions are extremely difficult to stabilize using prior art techniques.
- dispersions incorporating perforated microstructures comprising a bioactive agent as described herein are particularly stable even at low volume fractions Accordingly, the present invention allows for stabilized dispersions, and particularly respiratory dispersions, to be formed and used, at volume fractions less than 0 3.
- the volume fraction is approximately 0 0001 0.3, or more preferably 0.001 - 0 01.
- Yet other preferred embodiments comprise stabilized suspensions having volume fractions from approximately 0 01 to approximately 0.1
- perforated microstructures may be used to stabilize dilute suspensions of micromzed bioactive agents.
- the perforated microstructures mav be added to increase the volume fraction of particles in the suspension, thereby increasing suspension stability with respect to creaming or sedimentation.
- the incorporated microstructures may also act in preventing close approach (aggregation) of micromzed drug particles.
- the perforated microstructures incorporated in such embodiments do not necessarily comprise a bioactive agent. Rather, they may be formed exclusively of various excipients, including surfactants.
- the stabilized dispersions of the present invention may comprise relatively solid or non perforated particulates without the addition of perforated microstructures That is, depending on the size, composition and density of the suspended microparticulates, as well as the selection of suspension medium, effective particulate dispersions for nebulization may be formed using relatively non porous or micromzed particulates.
- the suspended particulates may comprise ⁇ anocrystals such as those disclosed in U.S. Pat. No 5,667,809 which is incorporated herein by reference.
- such preparations will preferably comprise a fluorochemical suspension medium.
- the present invention provides for the formation and pulmonary administration of stabilized dispersions comprising relatively non porous particulates (e.g. micromzed particles), porous particulates (i e. hollow porous microspheres or perforated microstructures) and combinations thereof
- the stabilized dispersions may comprise particulates exhibiting various morphologies
- particularly preferred embodiments of the present invention comprise a plurality of perforated microstructures or microparticulates that are dispersed, or suspended in the suspension medium.
- the perforated microstructures comp ⁇ se a structural matrix that exhibits, defines or composes voids, pores, defects, hollows, spaces, interstitial spaces, apertures, perforations or holes that allows the surrounding suspension medium to freely permeate, fill or pervade the microstructure
- the absolute shape (as opposed to the morphology) of the perforated microstructure is generally not c ⁇ tical and.
- any overall configuration that provides the desired stabilization characteristics is contemplated as being within the scope of the invention Accordingly, while preferred embodiments incorporating perforated microstructures can comprise approximately microspherical shapes, collapsed, deformed or fractured particulates are also compatible. With that caveat, it will be appreciated that particularly preferred embodiments of the invention comp ⁇ se spray d ⁇ ed hollow, porous microspheres.
- the mean geometric particle size of the perforated microstructures is preferably about 0.5 50 m, more preferably 1 30 m. It will be appreciated that, large particles (i.e. greater than 50 m) should not be used as large particles may tend to aggregate or, separate from the suspension and not be effectively nebulized.
- the mean geomet ⁇ c particle size (or diameter) of the perforated microstructures is less than 20 m or less than 10 m. More preferably, the mean geomet ⁇ c diameter is less than about 5 m.
- the perforated microstructures will comp ⁇ se a powder of dry, hollow, porous microspherical shells of approximately 1 to 10 m m diameter, with shell thicknesses of approximately 0.1 m to approximately 0 5 m. It is a particular advantage of the present invention that, the particulate concentration of the dispersions and structural mat ⁇ x components can be adjusted to optimize the delivery charactenstics of the selected particle size
- the dispersions of the present invention are preferably stabilized.
- the term "stabilized dispersion” will be held to mean any dispersion that resists aggregation, fiocculation or creaming to the extent required to provide for the effective delivery of a bioactive agent. While those skilled in the art will appreciate that there are several methods that may be used to assess the stability of a given dispersion, a preferred method for the purposes of the present invention comprises determination of creaming or sedimentation time. In this regard, the creaming time shall be defined as the time for the suspended drug particulates to cream to 1/2 the volume of the suspension medium.
- the sedimentation time may be defined as the time it takes for the particulates to sediment in 1 /2 the volume of the liquid medium
- the creaming time of a preparation is to provide the particulate suspension in a sealed glass vial. The vials are agitated or shaken to provide relatively homogeneous dispersions which are then set aside and observed using approp ⁇ ate instrumentation or by visual inspection. The time necessary for the suspended particulates to cream to 1 /2 the volume of the suspension medium (i.e , to rise to the top half of the suspension medium), or to sediment within 1/2 the volume (i.e., to settle in the bottom 1 /2 of the medium), is then noted.
- Suspension formulations having a creaming time greater than 1 minute are preferred and indicate suitable stability. More preferably, the stabilized dispersions comp ⁇ se creaming times of greater than about 2, 5, 10, 15, 20 or 30 minutes. In particularly preferred embodiments, the stabilized dispersions exhibit creaming times of greater than about 1, 1 5, 2, 2.5, 3, 4 or even 5 hours Substantially equivalent periods for sedimentation times are indicative of compatible dispersions.
- the porosity of incorporated microstructures may contribute significantly to establishing dispersion stability.
- the mean porosity of the perforated microstructures may be determined through electron microscopy coupled with modern imaging techniques More specifically, electron micrographs of representative samples of the perforated microstructures may be obtained and digitally analyzed to quantify the porosity of the preparation. Such methodology is well known in the art and, may be undertaken without undue experimentation.
- the mean porosity i.e the percentage of the particle surface area that is open to the interior and/or a central void
- the mean porosity may range from approximately 0.5% to approximately 80% In more preferred embodiments, the mean porosity will range from approximately 2% to approximately 40%. Based on selected production parameters, the mean porosity may be greater than approximately,
- the mean porosity of the microstructures may be greater than about 40%, 50%, 60%, 70% or even 80%.
- the pores themselves, they typically range in size from about 5 nm to about 400 nm, with mean pore sizes preferably in the range of from about 20 nm to about 200 nm.
- the mean pore size will be in the range of from about 50 nm to about 100 nm.
- the perforated or porous and/or hollow design of microstructures can also play an important role in the resulting aerosol properties during nebulization.
- the perforated structure, and relatively high surface area of the dispersed microparticles enables them to be earned along in the aerosol cloud during inhalation with greater ease and, for longer distances, than non perforated particles of comparable size.
- the density of the particles is significantly less than 1.0 g/cm 3 , typically less than 0.5 g/cm 3 , more often on the order of 0.1 g/cm 3 , and as low as 0.01 g/cm 3 .
- d aer the geometric diameter.
- the mean aerodynamic diameter of the perforated microstructures is preferably less than about 5 ⁇ m, more preferably less than about 3 ⁇ m, and, in particularly preferred embodiments, less than about 2 ⁇ m.
- Such particle distributions will act to increase the deep lung deposition of the administered agent.
- the particle size distribution of the aerosol formulations of the present invention are measurable by conventional techniques such as cascade i paction, or by time of flight analytical methods. Determination of the emitted dose in nebulized inhalations was done according to the proposed U S Pharmacopeia method [Pharmacopeia!
- the formulations of the present invention will preferably have a fine particle fraction for local airway delivery of approximately 20% or more, by weight of the perforated microstructures (w/w) More preferably, they will exhibit a fine particle fraction of from about 25% to 80% w/w, and even more preferably from about 30 to 70% wlw.
- the present invention will preferably comprise a fine particle fraction of greater than about 30%, 40%, 50%, 60%, 70% or 80% by weight.
- the fine particle fraction will preferably be greater than 80% by weight, more preferably, greater than 90% by weight
- the composition thereof may comp ⁇ se any one of a number of biocompatible materials.
- the terms "structural mat ⁇ x" or "microstructure matrix” are equivalent and shall be held to mean any solid material forming the perforated microstructures which define a plurality of voids, apertures, hollows, defects, pores, holes, fissures, etc. that promote the formation of stabilized dispersions as explained above.
- the structural matnx may be soluble or insoluble in an aqueous environment.
- the perforated microstructure defined by the structural mat ⁇ x comp ⁇ ses a spray dried hollow porous icrosphere incorporating at least one surfactant.
- the particulate material may be coated one or more times with polymers, surfactants or other compounds which aid suspension.
- particulates useful in the stabilized dispersions of the present invention may be formed of any biocompatible mate ⁇ al that is relatively stable and preferably insoluble with respect to the selected suspension medium. While a wide variety of materials may be used to form the particles, in particularly preferred embodiments, the particles (or structural matrix) is associated with, or comprises, a surfactant such as phospholipid or fluo ⁇ nated surfactant. Although not required, incorporation of a compatible surfactant can improve the stability of the respiratory dispersions, increase pulmonary deposition and facilitate the preparation of the suspension.
- a surfactant such as phospholipid or fluo ⁇ nated surfactant
- the density of the particle or structural mat ⁇ x may be adjusted to approximate the density of the surrounding medium and further stabilize the dispersion, finally, as will be discussed in further detail below, perforated microstructures preferably comp ⁇ se at least one bioactive agent.
- the relatively non porous particles or perforated microstructures of the present invention may optionally be associated with, or comp ⁇ se, one or more surfactants.
- miscible surfactants may optionally be combined with the suspension medium liquid phase. It will be appreciated by those skilled in the art that, the use of surfactants, while not necessary to practice the instant invention, may further increase dispersion stability, simplify formulation procedures or increase bioavailability upon administration.
- surfactants including the use of one or more in the liquid phase and one or more associated with the perforated microstructures are contemplated as being within the scope of the invention.
- association with or comprise it is meant that the particle or perforated microstructure may incorporate, adsorb absorb, be coated with or be formed by the surfactant
- surfactants suitable for use in the present invention include any compound or composition that aids in the formation and maintenance of the stabilized respiratory dispersions by forming a layer at the interface between the particle and the suspension medium.
- the surfactant may comp ⁇ se a single compound or any combination of compounds, such as in the case of co surfactants.
- Particularly preferred surfactants are substantially insoluble in the medium, no ⁇ fluori ⁇ ated, and selected from the group consisting of saturated and unsaturated lipids, nonio ⁇ ic detergents, nonionic block copolymers, ionic surfactants, and combinations of such agents.
- suitable (i.e. biocompatible) flu ⁇ nated surfactants are compatible with the teachings herein and may be used to provide the desired stabilized preparations.
- Lipids including phospholipids, from both natural and synthetic sources are particularly compatible with the present invention and may be used in varying concentrations to form the particle or structural mat ⁇ x.
- Generally compatible lipids comprise those that have a gel to liquid crystal phase transition greater than about 40°C.
- the incorporated lipids are relatively long chain (i.e. C l8 Cy saturated lipids and more preferably comp ⁇ se phospholipids.
- Exemplary phospholipids useful in the disclosed stabilized preparations comprise egg phosphatidylcholine, dilauro ⁇ lphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidyl c olme, distero ⁇ lphosphatidylchohne, short-chain phosphatidylcholines, phosphatidyletha ⁇ olamine, dioleylphosphatidylethanolamine, phosphatidylse ⁇ ne, phosphatidylglycerol, phosphatidylinositol, glyco pids, ga ⁇ glioside GM1, sphingom ⁇ eh ⁇ , phosp atidic acid, cardiolipin; lipids bea ⁇ ng polymer chains such as polyethylene gl ⁇ col, chitin, hyaluronic acid, or poiyvinylp ⁇ rrolidone; lipids bearing sulfonated mono , di ,
- Compatible ⁇ omomc detergents comprise: sorbitan esters including sorbita ⁇ t ⁇ oleate (Span 01 85), sorbitan sesquiol ⁇ ate, sorbita ⁇ monooleate, sorbita ⁇ mo ⁇ olaurate, polyoxyethylene (20) sorbita ⁇ monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, glycerol esters, and sucrose esters.
- sorbitan esters including sorbita ⁇ t ⁇ oleate (Span 01 85), sorbitan sesquiol ⁇ ate, sorbita ⁇ monooleate, sorbita ⁇ mo ⁇ olaurate, polyoxyethylene (20) sorbita ⁇ monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether
- Preferred block copolymers include diblock and t ⁇ block copolymers of polyoxyethylene and polyoxypropylene, including poloxamer 188 (Pluromc" F 68), poloxamer 407 (Pluromc " F 127), and poloxamer 338.
- Ionic surfactants such as sodium sulf osuccmate, and fatty acid soaps may also be utilized.
- the microstructures may compnse oleic acid or its alkali salt.
- catio ⁇ 'c surfactants or lipids are preferred especially in the case of delivery or RNA or DNA
- suitable cationr lipids include- cetylpy ⁇ dinium chloride, DOTMA, N [1-12,3 d ⁇ oleyloxy)propyl]-N,I ⁇ l, ⁇ M t ⁇ methylammon ⁇ um chlo ⁇ de; DOTAP, 1,2 dioleyioxy 3
- surfactants comprising the porous particles may also be useful in the formation of precursor oil in water emulsions (i.e. spray drying feed stock) used during processing to form the structural matrix or bioactive particulate
- the incorporation of relatively high levels of surfactants may be used to increase the stability of the disclosed dispersions. That is, on a weight to weight basis, the structural matnx of the perforated microstructures may comprise relatively high levels of surfactant.
- the perforated microstructures will preferably comp ⁇ se greater than about 1 %, 5%, 10%, 15%, 18%, or even 20% w/w surfactant.
- the perforated microstructures will comprise greater than about 25%, 30%, 35%, 40%, 45%, or 50% w/w surfactant Still other exemplary embodiments will comprise perforated microstructures wherein the surfactant or surfactants are present at greater than about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or even 95% w/w In selected embodiments the perforated microstructures will comp ⁇ se essentially 100% w/w of a surfactant such as a phospholipid. Those skilled in the art will appreciate that, in such cases, the balance of the structural mat ⁇ x (where applicable) will likely comp ⁇ se a bioactive age ⁇ t(s) or non surface active exc ⁇ p ⁇ ent(s) or add ⁇ t ⁇ ve(s)
- stabilized dispersions comprising perforated microstructures merely represent a preferred embodiment of th ⁇ present invention
- equivalent surfactant levels may also be used to provide stabilized systems compnsing relatively nonporous, or substantially solid, particulates
- acceptable dispersions may be formed using relatively low or non porous particulates (e g micro zed particulates) of the same surfactant concentration In this respect such embodiments are specifically contemplated as being within the scope of the present invention.
- relatively non porous particles or the structural mat ⁇ x defining the perforated microstructures optionally comp ⁇ ses synthetic or natural polymers or combinations thereof.
- useful polymers comp ⁇ se polylactides, polylactide glycolides, cyclodext ⁇ ns, polyacrylates, methylcellulose carboxymethylcellulose, polyvinyl alcohols, polyanhyd ⁇ des, polylactons, polyvi ⁇ yl pyrrolido ⁇ es, polysacchandes (dextra ⁇ s, starches, chitin, chitosan, etc ), hyaluronic acid, proteins, (albumin, collagen, gelatin, etc )
- the delivery profile of the respiratory dispersion may be tailored to optimize th ⁇ effectiveness of the bioactive agent
- excipients include, but are not limited to: coloring agents, taste masking agents, buffers, hygroscopic agents, antioxida ⁇ ts, and chemical stabilizers. Further, excipients may be incorporated in, or added to, the particles or particulate matrix to provide structure and form to the perforated microstructures (i.e. microspheres). Such excipients may include, but are not limited to, carbohydrates including monosaccha ⁇ des, disaccha ⁇ des and polysacchandes.
- monosacchandes such as dextrose (anhydrous and mo ⁇ ohydrate), galactose, mannitol, D ma ⁇ ose, sorbitol, sorbose and the like, disaccha ⁇ des such as lactose, maltos ⁇ , sucrose, trehalose, and the like; t ⁇ saccha ⁇ des such as raffmose and the like; and other carbohydrates such as starches (hydroxyethylstarch), cyclodextn ⁇ s and maltodextnns.
- Ammo acids are also suitable excipients with glycine pref ⁇ rred. Mixtures of carbohydrates and ammo acids are further held to be within the scope of the present invention.
- inorganic e.g. sodium chloride, calcium chloride
- organic salts e.g. sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochlo ⁇ de
- buffers e.g. sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochlo ⁇ de
- the selected excipients may be added to the dispersion as separate particles or perforat ⁇ d microstructures
- non porous particles or perforated microstructures that may comprise, or may be coated with, charged speci ⁇ s that prolong residence time at th ⁇ point of contact or enhance penetration through mucosae.
- anionic charges are known to favor mucoadhesion while cationic charges may be used to associate the formed microparticulate with negatively charged bioactive agents such as genetic mate ⁇ al.
- the charges may be imparted through the association or incorporation of polyanionic or polycationic mate ⁇ als such as polyacrylic acids, polylysin ⁇ , polylactic acid and chitosan
- the particles, perforated microstructures or aqueous emulsion droplets will preferably comprise at least one bioactive agent.
- bioactive agent refers to a substance which is used in connection with an application that is therapeutic or diagnostic in nature, such as in methods for diagnosing the pres ⁇ nce or absence of a disease in a patient and/or in methods for treating a dis ⁇ as ⁇ in a patient.
- bioactive agents for use in accordance with the invention include anti allergies, peptides and proteins, bronchodilators and anti inflammatory steroids for use in the treatm ⁇ nt of respiratory disorders such as asthma by inhalation therapy.
- the distributed particles or perforated microstructures of the present invention may exclusively comp ⁇ se one or more bioactive agents (i.e. 100% w/w).
- the particles or perforat ⁇ d microstructures may incorporat ⁇ much less bioactive agent depending on th ⁇ activity thereof. Accordingly, for highly active mate ⁇ als, the particles may incorporate as little as 0.001 % by weight, although a concentration of greater than about 0 1 % w/w is preferred
- Other ⁇ mbodim ⁇ nts of th ⁇ invention may comp ⁇ se greater than about 5%, 10%, 15%, 20%, 25%, 30% or, even 40% w/w bioactive agent.
- the particles or perforated microstructures may comp ⁇ se greater than about 50%, 60%, 70%, 75%, 80% or, even 90% w/w bioactive agent.
- the final stabilized respiratory dispersion desirably contains from about 40% 60% w/w, more preferably 50% - 70% w/w, and even more preferably, 60% 90% w/w of bioactive agent relative to the weight of the microparticulate matrix or particulate.
- the precise amount of bioactive agent incorporated in the stabilized dispersions of the present invention is dependent upon th ⁇ agent of choice, the required dose, and the form of the drug actually used for incorporation Those skilled in the art will appreciate that, such determinations may be made by using well-known pharmacological techniques, in combination with the teachings of the present invention.
- bioactive agents that may be administered in th ⁇ form of aerosolized medicaments in conjunction with the teachings herein include any drug that may be presented in a form which is subject to pulmonary uptake in physiologically effective amounts.
- the incorporated agent will preferably be relatively insoluble in the suspension medium.
- th ⁇ s ⁇ l ⁇ cted ag ⁇ nt may b ⁇ substantially soluble in the disperse phase
- compnsing a reverse emulsion will preferably comprise a hydrophilic bioactive agent.
- compatible bioactive agents may comp ⁇ se hydrophilic and lipophilic respiratory agents, bronchodilators, antibiotics, antivirals, anti inflammato ⁇ es, steroids, antihistaminics, histamine antagonists, leukotnene inhibitors or antagonists, anticholinergics, antineoplastics, anesthetics, enzym ⁇ s, lung surfactants, cardiovascular agents, genetic material including DNA and RNA, viral vectors, immu ⁇ oactive agents, imaging agents, vaccines, immunosuppressive agents, peptides, proteins and combinations thereof
- Particularly pref ⁇ rred bioactive agents, for local administration using aerosolized medicaments in accordance with the present invention include, mast cell inhibitors (anti allergies), bronchodilators, and anti inflammatory steroids for use in the treatment of respiratory disorders such as asthma by inhalation therapy, for example cromoglycate (e g. the sodium salt), and albuterol
- peptides and proteins are particularly pref ⁇ rred.
- Exemplary medicaments or bioactive agents may b ⁇ sel ⁇ cted from for example, analgesics, e g codein ⁇ , dihydromorphine, ergotamine, fenta ⁇ yl, or morphine, anginal preparations, e.g. diltiazem, mast cell inhibitors, e.g. cromolyn sodium; anti fectives, e g cephalospo ⁇ ns, macrolides, qumolines, penicillins, streptomycin, sulphonarnides, tetracychnes and pentamidi ⁇ e, antihistamines, e.g methapy ⁇ lene, anti-i ⁇ flammato ⁇ es, e.g.
- analgesics e g codein ⁇ , dihydromorphine, ergotamine, fenta ⁇ yl, or morphine
- anginal preparations e.g. diltiazem
- mast cell inhibitors e.g. cro
- fluticasone propionate heclom ⁇ thason ⁇ dipropionate, flumsolide budesonide, tnpedane, cortisone, prednisone, prednisilone, dexamethaso ⁇ e, betamethasone, or t ⁇ amcinolone acetonide
- antitussives e g. noscapi ⁇ e, bronchodilators, e g ephed ⁇ n ⁇ , adrenaline, fenot ⁇ rol, formot ⁇ rol, isopr ⁇ nahne, metaproter ⁇ nol, salbutamol, albuterol, saimeterol, terbutali ⁇ e; diuretics, e.g.
- amilo ⁇ de e.g. ipatropium, atropine, or oxitropium
- lung surfactants e.g Surfaxin, Exosurf, Survanta
- xanthines e.g ammophylline, theophylline, caffeine
- therapeutic proteins and peptides e.g.
- bioactive agents that comprise an RNA or DNA sequence particularly those useful for gene therapy, genetic vaccination or tolenzation or antisense applications, may be incorporated in the disclosed dispersions as desc ⁇ bed herein.
- Representative DNA plasmids include pCMV ⁇ (available from Genzyme Corp, Framington, MA) and pCMV ⁇ gal (a
- th ⁇ s ⁇ l ⁇ ct ⁇ d bioactive agent(s) may b ⁇ associat ⁇ d with, or incorporated in, the particles or perforated microstructures in any form that provides the desired efficacy and is compatible with the chosen production techniques.
- the incorporated bioactive agent may be associated with the discontinuous phase of a reverse emulsion.
- the terms "associate” or “associating" mean that th ⁇ structural matrix, perforated microstructure, relatively non porous particle or discontinuous phase may comp ⁇ s ⁇ , incorporate, adsorb, absorb, be coated with or be formed by the bioactive agent. Wher ⁇ appropriate, the medicaments may be used in the form of salts ( ⁇ g.
- the form of the bioactive agents may be selected to optimize the activity and/or stability of th ⁇ medicament and/or, to minimize the solubility of the m ⁇ dicam ⁇ nt in the suspension medium.
- the aerosolized formulations according to the invention may, if desired, contain a combination of two or more active ingredients
- the agents may be provided in combination in a single species of perforated microstructure or particle or individually in separate species that are combined in the suspension medium or continuous phase
- two or mor ⁇ bioactive agents may b ⁇ incorporated in a single f ⁇ ed stock preparation and spray dried to provide a single microstructure species comprising a plurality of medicaments Conv ⁇ rs ⁇ ly, the individual medicaments could be added to separate stocks and spray dried separately to provide a plurality of microstructure species with different compositions.
- These individual species could be added to the medium in any desired proportion and placed in inhalation delivery systems as described below.
- the perforated microstructures (with or without an associated medicament) may be combined with on ⁇ or mor ⁇ conventionally micromzed bioactive agents to provide the desired dispersion stability.
- bioactive agents may be incorporated in th ⁇ disclosed stabilized dispersions. Accordingly, the list of preferred bioactive agents above is exemplary only and not intend ⁇ d to be limiting It will also b ⁇ appr ⁇ ciat ⁇ d by those skilled in the art that, the proper amount of bioactive agent and the timing of the dosages may be determined for the formulations in accordance with already existing information and without undue expe ⁇ mentation As seen from the passages above, various components may be associat ⁇ d with, or incorporated in the discontinuous phase, perforated microstructures or particles of the present invention.
- perforated microstructures or particles compatible with the instant invention may be formed by techniques including lyophilization, spray drying, multiple emulsion, micr ⁇ nization, or crystallization
- relatively non porous particles may be produced using techniques such as micro ⁇ ization, crystallization or milling.
- spray drying consists of bringing tog ⁇ th ⁇ r a highly dispersed liquid, and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets.
- the preparation to be spray dried or feed (or feed stock) can b ⁇ any solution, course suspension, slurry, colloidal dispersion or paste that may be atomized using the selected spray drying apparatus.
- the feed is sprayed into a current of warm filtered air that evaporates the solvent and conveys th ⁇ d ⁇ d product to a collector The spent air is then exhausted with the solvent
- a collector Typically, the feed is sprayed into a current of warm filtered air that evaporates the solvent and conveys th ⁇ d ⁇ d product to a collector The spent air is then exhausted with the solvent
- Those skilled in the art will appreciate that several different types of apparatus may be used to provide the desired product For example, commercial spray dryers manufactured by Buchi Ltd or Niro Corp will effectively produce particles of desired size.
- these spray dryers may be modified or customized for specialized applications, i.e. the simultaneous spraying of two solutions using a double nozzle technique. More specifically, a water in oil emulsion can be atomized from one nozzle and, a solution containing an anti adher ⁇ nt such as mannitol can be co atomized from a second nozzle In other cases it may be desirable to push the feed solution though a custom designed nozzle using a high pressure liquid chromatography (HPLC) pump Provided that microstructures compnsing the correct morphology and/or composition are produced, the choice of apparatus is not c ⁇ tical and would be apparent to the skilled artisan in view of the teachings herein.
- HPLC high pressure liquid chromatography
- th ⁇ resulting spray dried powdered particles typically are approximately spherical in shap ⁇ , nearly uniform in size and frequently are hollow, there may be some degree of irregularity in shape depending upon the incorporated medicament and the spray drying conditions In many instances, th ⁇ dispersion stability of spray dried microspheres or particles appears to be more effective if an inflating agent (or blowing agent) is used in their production.
- Particularly preferred embodiments may comp ⁇ se an emulsion with the inflating agent as the disperse or continuous phase (the oth ⁇ r phas ⁇ b ⁇ ing aqueous in nature)
- the inflating agent is preferably dispersed with a surfactant solution, using, for instance, a commercially available microfluidizer at a pressure of about 5,000 to 15,000 psi.
- This process forms an emulsion, preferably stabilized by an incorporated surfactant, typically compnsing submicron droplets of water immiscible blowing agent dispersed in an aqueous continuous phase.
- the blowing agent is preferably a fluo ⁇ nated compound (e.g. perfluorohexane, perfluorooctyl bromide, perfluorodecalm, perfluorobutyl ethane) which vaporizes during th ⁇ spray drying proc ⁇ ss, leaving behind generally hollow, porous aerodynamically light microspheres.
- fluo ⁇ nated compound e.g. perfluorohexane, perfluorooctyl bromide, perfluorodecalm, perfluorobutyl ethane
- suitable blowing agents include chloroform, Fr ⁇ ons, and hydrocarbons Nitrogen gas and carbon dioxide are also co ⁇ t ⁇ mplat ⁇ d as suitable blowing agents.
- perforated microstructures are preferably formed using a blowing agent as described above, it will b ⁇ appreciated that, in some instances, no additional blowing agent is requir ⁇ d and an aqueous dispersion of the medicament and surfactant(s) are spray dried directly.
- the formulation may be amenable to process conditions ( ⁇ g , elevated temperatures) that generally lead to the formation of hollow, relatively porous microparticles.
- the medicament may possess special physicochemical properties (e.g., high crystallinity, elevated melting temp ⁇ ratur ⁇ , surfac ⁇ activity, etc.) that make it particularly suitable for use in such techniques.
- the degree of porosity of the perforated microstructure appears to depend, at least in part, on the nature of th ⁇ blowing ag ⁇ nt, its concentration in the fe ⁇ d stock (i. ⁇ as an emulsion), and the spray drying conditions.
- the use of compounds, heretofore unappreciated as blowing agents may provide particulates or perforat ⁇ d microstructures having particularly desirable characteristics. More particularly, in this novel and unexpected aspect of the pres ⁇ nt invention, it has been found that the use of fluo ⁇ nated compounds having relatively high boiling points (i.e.
- blowing agents having boiling points of greater than about 70°C, 80°C, 90°C or even 95°C.
- Particularly preferred blowing agents have boiling points greater than the boiling point of water, i.e. greater than 100°C (e.g. perflubro ⁇ , perfluorodecalm)
- blowing agents with relatively low water solubility ⁇ 10 ° M are preferred since they enable the production of stable emulsion dispersions with mean weighted particle diameters less than 0.3 um.
- blowing agents will preferably be incorporated in an emulsified feed stock prior to spray drying
- this feed stock will also preferably comprise one or more bioactive agents, one or more surfactants, or one or more excipients.
- bioactive agents one or more surfactants, or one or more excipients.
- surfactants one or more excipients.
- excipients combinations of the aforem ⁇ ntion ⁇ d compon ⁇ nts are also within the scope of the invention.
- This migration apparently slows during the drying process as a result of increased resistanc ⁇ to mass transf ⁇ r caus ⁇ d by an incr ⁇ as ⁇ d int ⁇ rnal viscosity. Onc ⁇ the migration ceases, the particle solidifies, leaving vesicles, vacuoles or voids where the emulsifying agent resided.
- the number of pores, their size, and the resulting wall thickness is largely dep ⁇ nd ⁇ nt on the nature of the selected blowing agent (i.e. boiling point), its concentration in the emulsion, total solids concentration, and the spray-drying conditions.
- th ⁇ spray d ⁇ d p ⁇ rforated microstructur ⁇ s may comprise as much as 5%, 10%, 20%, 30% or even 40% w/w of the blowing agent.
- higher production yields were obtained as a result an increased particle density caus ⁇ d by residual blowing ag ⁇ nt
- this retained fluonnated blowing agent may alter the surface characteristics of the perforated microstructures and further increase th ⁇ stability of the respiratory dispersions
- the residual blowing agent can easily be removed with a post production evaporation step in a vacuum oven.
- pores may b ⁇ form ⁇ d by spray drying a bioactive ag ⁇ nt and an excipi ⁇ nt that can b ⁇ removed from the formed microspheres under a vacuum.
- typical co ⁇ c ⁇ ntrations of blowing ag ⁇ nt in th ⁇ feed stock are between 5% and 100% w/v, and more preferably, between about 20% to 90% w/v.
- blowing agent concentrations will pref ⁇ rably b ⁇ greater than about 10%, 20%, 30%, 40% 50% or even 60% w/v
- Yet other fe ⁇ d stock emulsions may comprise 70%, 80%, 90% or even 95% w/v of the selected high boiling point compound.
- another method of identifying th ⁇ concentration of blowing agent us ⁇ d in the f ⁇ ed is, to provide it as a ratio of the concentration of the blowing ag ⁇ nt to that of the stabilizing surfactant (i.e. phospholipid) in th ⁇ precursor emulsion
- the ratio may be termed a perfluorocarbon/phosphatidylcholine ratio (or PFC/PC ratio).
- oth ⁇ r compatible surfactants may also be us ⁇ d to provid ⁇ compatible particulates.
- the PFC/PC ratio will typically range from about 1 to about 60 and more preferably, from about 10 to about 50. For preferred embodiments the ratio will generally be greater than about 5, 10, 20, 25, 30, 40 or even 50
- Fig. 1 shows a series of pictures taken of perforat ⁇ d microstructures formed of phosphatidylcholme (PC) using various amounts of perfluorooctyl bromide (PFC), a relatively high boiling point fluorocarbon as the blowing agent.
- PC phosphatidylcholme
- PFC perfluorooctyl bromide
- the PFC/PC ratios are provid ⁇ d und ⁇ r ⁇ ach subs ⁇ t of pictures, i.e. from
- th ⁇ column on th ⁇ left shows the intact microstructures while the column on the right illustrates cross-sections of fractured microstructures from the same preparations.
- Fig. 2 a micrograph which will be discussed in more detail in Example II below, illustrates a preferably porous morphology obtained by using higher boiling point blowing agents (in this case perfluorodecalm)
- the inflating agent can be any mate ⁇ al that will turn to a gas at some point dunng the spray drying or post production process.
- Suitable agents include: 1. Dissolved low boiling (below 100 C) solvents with limited miscibility with aqueous solutions, such as methyle ⁇ chlo ⁇ d ⁇ , acetone and carbon disulfid ⁇ used to saturate th ⁇ solution at room t ⁇ mp ⁇ ratur ⁇ . 2.
- a gas e.g.
- Emulsions of immiscible low boiling (below 100 C) liquids such as Freo ⁇ 113, perfluoropentane. perfluorohexane, perfluorobutane, pentan ⁇ , butane, FC 1 1 , FC 11 B1 , FC 1 1 B2, FC 12B2, FC 21, FC 21 B1, FC
- FC 31 B2 FC 31 B1, FC 113A, FC 122, FC 123, FC-132, FC 133, FC-141, FC 141 B, FC 142, FC 151 , FC-152, FC 1112, FC 1121 and FC 1131.
- these lower boiling point inflating agents are typically added to the feed stock in quantities of about 1 % to 40% v/v of the surfactant solution Approximately 15% v/v inflating agent has been found to produce a spray d ⁇ ed powder that may be used to form the stabilized dispersions of the present invention.
- th ⁇ inlet t ⁇ mp ⁇ ratur ⁇ and th ⁇ outl ⁇ t t ⁇ mp ⁇ rature of the spray drier are not critical but will be of such a level to provide the desired particle size and to result in a product that has th ⁇ d ⁇ sir ⁇ d activity of th ⁇ medicament
- the inlet and outlet temperatures are adjusted depending on the melting characteristics of th ⁇ formulation components and the composition of th ⁇ feed stock.
- the inlet temperature may thus be between 60°C and 170°C, with the outlet t ⁇ mperatures of about 40°C to 120°C depending on the composition of the feed and the desired particulate characteristics.
- these temperatur ⁇ s will be from 90°C to 120°C for the inlet and from 60°C to 90°C for th ⁇ outlet.
- the flow rate which is used in the spray drying equipment will generally be about 3 ml per minute to about 5 ml per minute.
- Th ⁇ atomiz ⁇ r air flow rate may vary between values of 1,200 liters per hour to about 3,900 liters per hour.
- Commercially available spray dryers are well known to those in the art, and suitable settings for any particular dispersion can be readily determined through standard empirical testing, with due reference to the examples that follow. Of course, the conditions may be adjusted so as to preserve biological activity in larger molecul ⁇ s such as prot ⁇ ins or peptides.
- Particularly preferred embodim ⁇ nts of the present invention comp ⁇ se spray drying preparations comprising a surfactant such as a phospholipid and at least one bioactive agent.
- the spray drying preparation may further comprise an excipient compnsing a hydrophilic moi ⁇ ty such as, for example, a carbohydrate
- various starches and de ⁇ vatized starches are suitable for use in the pres ⁇ nt invention.
- Other optional components may include conventional viscosity modifiers, buffers such as phosphate buffers or, other conventional biocompatible buffers or pH adjusting agents such as acids or bases, and osmotic agents (to provide isotomcity, hyperosmola ⁇ ty, or hyposmola ⁇ ty).
- buffers such as phosphate buffers or, other conventional biocompatible buffers or pH adjusting agents such as acids or bases
- osmotic agents to provide isotomcity, hyperosmola ⁇ ty, or hyposmola ⁇ ty.
- suitable salts include sodium phosphate (both monobasic and dibasic), sodium chloride, calcium phosphate, calcium chloride and other physiologically acceptabl ⁇ salts.
- the first step in particulate production typically comprises feed stock preparation
- the selected drug is dissolved in water to produce a concentrated solution
- the drug may also be dispersed directly in the emulsion, particularly in the case of water insoluble agents
- the drug may be incorporated in the form of a solid particulate dispersion.
- concentration of th ⁇ drug used is dependent on the dose of drug required in th ⁇ final powder and the performance or efficiency of the nebulization d ⁇ vic ⁇
- co surfactants such as poloxamer 188 or span 80 may be added to this annex solution. Additionally, excipients such as sugars and starches can also be added.
- an oil in water emulsion is then formed in a separate vessel
- the oil ⁇ mployed is preferably a fluorocarbon (e.g., perfluorooctyl bromide, perfluorodecalm), which is emulsified using a surfactant such as a long chain saturated phospholipid
- a fluorocarbon e.g., perfluorooctyl bromide, perfluorodecalm
- a surfactant such as a long chain saturated phospholipid
- one gram of phospholipid may be homogenized in 150 g hot distilled water (e.g., 60°C) using a suitable high shear mechanical mixer (e.g., Ultra Turrax model T 25 mixer) at 8000 rpm for 2 to 5 minutes
- a suitable high shear mechanical mixer e.g., Ultra Turrax model T 25 mixer
- the resulting perfluorocarbon in-water emulsion is then processed using a high pressure homogemzer to reduc ⁇ th ⁇ particle size.
- the emulsion is process ⁇ d at 12,000 to 18,000 psi, 5 discrete passes and kept at 50 to 80°C.
- the two preparations will be miscible as the emulsion will preferably comprise an aqueous continuous phase.
- bioactive ag ⁇ nt is solubilized separately for the purposes of the instant discussion, it will be appreciated that, in other embodim ⁇ nts, th ⁇ bioactive agent may be solubilized (or dispersed) directly in the emulsion in such cases, th ⁇ bioactive emulsion is simply spray dried without combining a separate drug preparation.
- operating conditions such as inlet and outlet temperature, fe ⁇ d rate, atomization pressure, flow rate of the drying air, and nozzle configuration can be adjusted in accordance with the manufacturer's guidelines in order to produce th ⁇ required particle size and production yield of the resulting dry microstructures.
- Exemplary settings are as follows: an air inlet temperature between 60°C and 170°C; an air outlet between 40°C to 120°C, a feed rate between 3 ml to about 15 ml per minute, and an aspiration setting of 300 L/min and an atomization air flow rate between 1 ,200 to 2,800 L/hr.
- particulates or perforated microstructures useful in the present invention may be formed by lyophilization.
- lyophilization is a freeze drying process in which water is sublimed from th ⁇ composition after it is frozen
- biologicals and pharmaceuticals that are relatively unstable in an aqueous solution can b ⁇ d ⁇ d without ⁇ l ⁇ vat ⁇ d t ⁇ mperatures (thereby eliminating the adverse thermal effects), and then stored in a dry state where there are few stability problems.
- such techniques are particularly compatible with the incorporation of peptides, proteins, genetic material and other natural and synthetic macromolecules in particulates or perforated microstructures without compromising physiological activity.
- perforated microstructures or particles of the present invention may also be formed using a double emulsion method.
- the medicament is first disp ⁇ rs ⁇ d in a polym ⁇ r dissolved in an organic solvent (e g methylene chloride) by so cation or homogemzatio ⁇
- an organic solvent e g methylene chloride
- This primary ⁇ mulsio ⁇ is then stabilized by forming a multiple emulsion in a continuous aqueous phase containing an emulsifi ⁇ r such as polyvinylalcohol
- the organic solvent is th ⁇ n removed by evaporation or extraction using conventional techniques and apparatus.
- the resulting microspheres are washed, filtered and lyophilized p ⁇ or to dispersion into suspension medium in accordance with the pr ⁇ s ⁇ nt mv ⁇ ntion While particulate suspensions comprising a non liquid dispersed phase are particularly compatible with the pres ⁇ nt invention, it will be appreciat ⁇ d that, as discussed above, the stabilized dispersions may also comprise liquid in liquid colloidal systems, e.g. reverse emulsions and microemulsions. Those skilled in the art will appreciate that such systems are known in the art and stabilized dispersions compatible with the teachings herein may be provided without undue experimentation.
- any reverse emulsion or microemulsio ⁇ that is capable of being nebulized to provide a therapeutically effective aerosol for pulmonary administration is contemplat ⁇ d as being within the scope of the present invention.
- the emulsions will be water in fluorochemical emulsions That is, the s ⁇ l ⁇ cted reverse emulsion or microemulsio ⁇ will pref ⁇ rably comp ⁇ s ⁇ a fluorochemical disperse phase with the other phase being aqueous in nature.
- Exemplary reverse emulsions useful with the present invention are disclosed in U S Pat No 5,770,585, pending U S S 08/487,612 and pending U S S N.
- biocompatible nonaqueous compounds may be used as suspension mediums or as a continuous phase.
- Particularly pref ⁇ rred suspension media are compatibl ⁇ with us ⁇ in nebulizers That is, they will be able to form aerosols upon the application of energy thereto.
- the select ⁇ d suspension medium should be biocompatible d e relatively non toxic) and non reactive with resp ⁇ ct to the suspend ⁇ d p ⁇ rforat ⁇ d microstructures compnsing the bioactive agent
- Pref ⁇ rred embodiments comp ⁇ se suspension media sel ⁇ ct ⁇ d from the group consisting of fluorochemicals, fluorocarbons (including those substituted with other halogens), perfluorocarbons, fluorocarbo ⁇ /hydrocarbon diblocks, hydrocarbons, alcohols, ethers, or combinations thereof
- th ⁇ suspension medium may comprise a mixture of va ⁇ ous compounds selected to impart specific characte ⁇ stics.
- the perforated microstructures are pref ⁇ rably insoluble in th ⁇ susp ⁇ sion m ⁇ dium, th ⁇ r ⁇ by providing for stabilized medicament particles, and effectively protecting a selected bioactive agent from degradation, as might occur dunng prolonged storage in an aqueous solution.
- the sel ⁇ cted suspension medium is bacte ⁇ ostatic
- the susp ⁇ nsion formulation also protects the bioactive agent from degradation dunng the nebulization process.
- the suspension media may comprise any one of a number of different compounds including hydrocarbons, fluorocarbons or hydrocarbon/fluorocarbo ⁇ diblocks.
- the contemplated hydrocarbons or highly fluo ⁇ nated or p ⁇ rfluo ⁇ nat ⁇ d compounds may b ⁇ linear, branched or cyclic, saturated or unsaturated compounds
- Conventional structural derivatives of these fluorochemicals and hydrocarbons are also contemplated as being within the scope of the present invention as well
- Select ⁇ d embodiments compnsing thes ⁇ totally or partially fluonnated compounds may contain one or more hetero atoms and/or atoms of bromine or chlo ⁇ ne.
- thes ⁇ fluorochemicals compnse from 1 to 16 carbon atoms and include, but are not limited to, linear, cyclic or polycyclic perfluoroalkanes, b ⁇ s(perfluoroalkyl)alke ⁇ es, perfluoroethers, perfluoroammes, perfluoroalkyl bromides and perfluoroaikyl chlorides such as dichlorooctane
- Particularly preferred fluo ⁇ nat ⁇ d compounds for use in the suspension medium may comprise perfluorooctyl bromide C 8 F, 7 Br (PFOB or perflubron), dichlorofluorooctane C 9 F, s Cl2 and the hydrofluoroalkane perfluorooctyl ethane C 8 F, 7 C 2 H 5 (PFOE).
- the use of perfluorohexane or perfluorope ⁇ tane as the suspension medium is especially preferred.
- 1 bromo F butan ⁇ n C.F 9 Br 1 bromo F hexane
- n C 6 F, 3 Br 1 bromo F h ⁇ ptane
- Fluorocarbons, fluorocarbon hydrocarbon compounds and haloge ⁇ ated fluorochemicals containing other linkage groups, such as ⁇ st ⁇ rs, thio ⁇ thers and amines are also suitable for use as suspension media in the present invention
- CJ ⁇ CH ' CHCJJ,. (as for example
- fluorochemical hydrocarbon ether diblocks or tnblocks i.e. C-F 2 -..
- n - 2 10; m 2-16 or C 5 H 2p .
- perfluoroalkylat ⁇ d ethers or polyethers may be compatible with the claimed dispersions.
- Poiycyclic and cyclic fluorochemicals such as C, 0 F, 8 (F decalin or perfluorodecalm), perfluorop ⁇ rhydroph ⁇ nanthr ⁇ n ⁇ , p ⁇ rfluorot ⁇ tramethylcyclohexane (AP 144) and perfluoro ⁇ butyldecalm ar ⁇ also within th ⁇ scope of the invention.
- Additional useful fluorochemicals include perfluo ⁇ ated amm ⁇ s, such as F tripropylamine
- FPA F t ⁇ butylami ⁇ e
- FMOQ m ⁇ thyloctahydroquinolizine
- FMIQ F N methyl decahydroisoquinoline
- FHQ F N-m ⁇ thyldecahydroquinoline
- FCHP F-N-cycloh ⁇ xylpyrrolidme
- FC 75 or "FC 77”
- fluo ⁇ nated compounds include perfluoroph ⁇ nanthrene, perfluoromethyldecalin, perfluorodimethylethylcyclohexa ⁇ e, perfluorodimethyldecali ⁇ , perfluorodiethyldecalin, perfluoromethyladama ⁇ tane, perfluorodimethyladamantan ⁇ .
- Other cont ⁇ mplat ⁇ d fluorochemicals having nonfiuo ⁇ ne substituents, such as, perfluorooctyl hydnde, and similar compounds having different numbers of carbon atoms are also useful.
- fluorocarbons or classes of fluo ⁇ nated compounds, that may be useful as suspension media include, but are not limited to. fluoroheptane, fluorocycloheptane fluoromethylcycloheptane, fluorohexa ⁇ e, fluorocyclohexane, fluoropentane, fluorocycl ⁇ p ⁇ ntan ⁇ , fluorom ⁇ thylcyclopentane, fluorodim ⁇ thyicyclopentan ⁇ s, fluoromethylcyclobutane, fluorodimethylcyclobutane, fluorot ⁇ methylcyclobutane, fluorobutane, fluorocyclobutane, fluoropropane, fluoroethers, fluoropolyethers and fluorot ⁇ ethylamin ⁇ s.
- fluoroheptane fluorocycloheptane fluoromethylcycloheptane
- fluorohexa ⁇ e fluorocyclohexane
- the selected suspension medium will preferably have a vapor pressure less than about 5 atmospheres and more pref ⁇ rably less than about 2 atmosph ⁇ res Unless otherwise specified, all vapor pressures recited herein are measured at 25°C. In other embodiments, preferred suspension media compounds will have vapor pressures on the order of about 5 torr to about 760 torr, with more preferable compounds having vapor pressures on the order of from about 8 torr to about 600 torr, while still more preferable compounds will have vapor pressures on the order of from about 10 torr to about 350 torr.
- suspension media may be us ⁇ d in conjunction with compressed air nebulizers, ultrasonic nebulizers or with mechanical atomizers to provide effective ventilation therapy. Moreov ⁇ r, more volatile compounds may be mixed with lower vapor pressure components to provide suspension media having specified physical characte ⁇ stics sel ⁇ ct ⁇ d to further improve stability or enhance the bioavailability of th ⁇ dispersed bioactive agent.
- Other embodim ⁇ nts of th ⁇ present invention will comp ⁇ se suspension m ⁇ dia that boil at selected temperatures under ambient conditions (i.e. 1 atm).
- preferred embodim ⁇ nts will comp ⁇ se suspension media compounds that boil above 0°C, above 5°C, above 10°C, above 15°, or above 20°C
- the suspension media compound may boil at or above 25°C or at or above 30°C.
- the select ⁇ d suspension media compound may boil at or above human body temp ⁇ rature (i.e. 37°C), above 45°C, 55°C, 65°C, 75°C, 85°C or above 100°C.
- the stabilized susp ⁇ nsions or dispersions of the pres ⁇ nt invention may be prepared by dispersal of the microstructures in the sel ⁇ ct ⁇ d suspension medium which may then be placed in a container or reservoir.
- th ⁇ stabilized preparations of the pr ⁇ s ⁇ nt invention can be made by simply combining the components in sufficient quantity to produce the final desired dispersion concentration.
- the microstructures readily disperse without mechanical energy
- the application of mechanical en ⁇ rgy to aid in disp ⁇ rsion e.g with the aid of sonication
- the components may be mix ⁇ d by simple shaking or oth ⁇ r type of agitation The process is pref ⁇ rably carried out under anhydrous conditions to obviate any adverse effects of moisture on suspension stability Once formed, the dispersion has a reduced susceptibility to fiocculation and sedimentation
- compositions of the present invention can be included in the pharmaceutical compositions of the present invention.
- osmotic ag ⁇ nts stabilizers, chelators, buff ⁇ rs, viscosity modulators, salts, and sugars can be added to fine tune the stabilized dispersions for maximum life and ease of administration.
- Such components may be added directly to the suspension medium, ether phase of an emulsion or associated with, or incorporated in, dispersed particles or perforated microstructures.
- bioactive agent may be indicated for the treatment of mild, moderate or severe, acute or chronic symptoms or for prophylactic treatment Moreover, the bioactive agent may be administered to treat local or syst ⁇ mic conditions or disorders. It will be appreciated that, th ⁇ pr ⁇ cis ⁇ dos ⁇ admimst ⁇ r ⁇ d will d ⁇ p ⁇ nd on th ⁇ ag ⁇ and condition of the patient, the particular medicam ⁇ t us ⁇ d and th ⁇ frequency of administration, and will ultimately be at the discretion of the attendant physician. When combinations of bioactive agents are employ ⁇ d, th ⁇ dos ⁇ of ⁇ ach compon ⁇ nt of th ⁇ combination will generally be that employed for each component when used alone.
- the stabilized dispersions disclosed herein are preferably administered to the lung or pulmonary air passages of a patient via aerosolizatio ⁇ , such as with a nebulizer.
- Nebulizers are well known in th ⁇ art and could easily b ⁇ employed for administration of the claimed dispersions without undue exp ⁇ m ⁇ ntatio ⁇ .
- Breath activated nebulizers, as well as those compnsing other types of improvements which have been, or will be, d ⁇ v ⁇ lop ⁇ d are also compatible with th ⁇ stabilized dispersions and pr ⁇ s ⁇ nt invention and are contemplated as being with in the scope thereof.
- the stabilized dispersions disclosed herein will be administered to the lung or pulmonary air passag ⁇ s of a pati ⁇ nt via nebulization
- Nebulizers are well known in the art and could easily be employ ⁇ d for administration of the claimed dispersions without undue exp ⁇ m ⁇ ntation. Nebulizers work by forming aerosols, that is converting a bulk liquid into small droplets susp ⁇ nd ⁇ d in a breathable gas.
- the aerosolized medicament to be administered (preferably to the pulmonary air passages) will comp ⁇ se small droplets of suspension medium associated with relatively non porous particles, perforat ⁇ d microstructures, or disperse liquid phase compnsing a bioactive agent.
- the stabilized dispersions of the present invention will typically be placed in a fluid reservoir operably associated with a nebulizer
- the specific volumes of preparation provided, means of filling the reservoir, etc., will largely be depe ⁇ d ⁇ nt on th ⁇ selection of the individual nebulizer and is well within the purvi ⁇ w of th ⁇ skilled artisan
- the pr ⁇ s ⁇ nt invention is entirely compatible with single-dose nebulizers and multiple dose nebulizers.
- nebulizer ⁇ diat ⁇ d a ⁇ rosolization typically requires an input of en ⁇ rgy in order to produce the increased surface area of the droplets and, in some cases, to provide transportation of the atomized or aerosolized medicament.
- One common mod ⁇ of aerosolizatio ⁇ is forcing a stream of fluid to be ejected from a nozzle, whereby droplets are formed.
- additional energy is usually imparted to provide droplets that will be sufficiently small to be transport ⁇ d d ⁇ p into th ⁇ lungs.
- additional ⁇ nergy is needed, such as that provided by a high velocity gas stream or a piezoelectnc crystal.
- jet nebulizers Two popular types of nebulizers, jet nebulizers and ultrasonic nebulizers, rely on the afor ⁇ mention ⁇ d methods of applying additional en ⁇ rgy to the fluid during atomization
- the jet nebulizer is well known and in wid ⁇ spread use.
- compressed air is forced into a device containing a liquid to b ⁇ aerosolized, such as one of the susp ⁇ nsions of th ⁇ present invention. Th ⁇ compressed air draws the liquid through one or more small openings, thus generating the aerosol.
- the high velocity of the compress ⁇ d air provid ⁇ s sufficient ⁇ nergy to enable the fo ⁇ nation of droplets small enough for inhalation
- th ⁇ dropl ⁇ ts initially impact a baffle.
- the compressed air may b ⁇ saturated with the suspension medium. This would allow the aerosolized droplets to b ⁇ d ⁇ posit ⁇ d in the lung, possibly facilitating enha ⁇ c ⁇ d spreading of bioactive agent after initial deposition.
- Ultrasonic nebulizers do not require the us ⁇ of compressed air, and thus, may be similar to MDIs as to compactness and portability, though they operate under different physical p ⁇ nciples.
- Preferred ultrasonic nebulizers are those which are fairly small, portable, battery powered and capable of deliv ⁇ nng s ⁇ v ⁇ ral dos ⁇ s, ⁇ ach of which comprises a single bolus of aerosolized solution. Such nebulizers may be term ⁇ d single-bolus nebulizers.
- Most devices are manually actuated, but some devices exist which are breath actuated. Breath actuated devices work by releasing aerosol when the device senses the patient inhaling through a circuit. Breath actuated nebulizers may also be placed in line on a ventilator circuit to release aerosol into th ⁇ air flow which comp ⁇ s ⁇ s th ⁇ inspiration gas ⁇ s for a pati ⁇ nt
- the heart of most species of ultrasonic nebulizer is a transducer made from a piezo ⁇ lect ⁇ c crystal. When oscillating energy is applied to the piezoelectric crystal, it will vibrate at the same frequency as the applied energy which is preferably in the ultrasonic range. This motion, when transmitted into a liquid, provid ⁇ s the energy needed to aerosolize the liquid.
- the droplet size (count median diamet ⁇ r) form ⁇ d by this ⁇ thod is a function of th ⁇ excitation frequency, the density of the liquid, and the surface tension of the liquid, whereas the rate of atomization is a function of the viscosity, surface tension, and vapor pressure.
- nebulizer is the Respimat (Boeh ⁇ nger I ⁇ g ⁇ lh ⁇ im, G ⁇ rma ⁇ y) which is manually actuated, hand-held and battery operat ⁇ d Wh ⁇ n th ⁇ patient squeezes a t ⁇ gger on th ⁇ device, a droplet of solution (about 100 I) is met ⁇ red into a pi ⁇ zoelectric plate about 1 cm in diameter. When e ⁇ rgy is applied, the plate vibrates at about 10 MHz, resulting in the aerosolization of the solution which may then be inhaled by a patient.
- Respimat Boeh ⁇ nger I ⁇ g ⁇ lh ⁇ im, G ⁇ rma ⁇ y
- AeroDos ⁇ Another type of ultrasonic nebulizer is the AeroDos ⁇ (AeroGe ⁇ , Sunnyvale, CA) (DeYoung, "The AeroDose Multidose Inhaler Device Design and Delivery Characte ⁇ stics," Respiratory Drug Delivery VI, 1998, p 91 )
- the battery powered AeroDose operates by means of a plate containing several hundred holes which vibrates at ultrasonic frequ ⁇ nci ⁇ s. Wh ⁇ n the top of the device is press ⁇ d down, a m ⁇ t ⁇ nng pump delivers a dose of liquid from a multidose canister to the plate.
- the device is breath actuated, with aerosolization beginning when the device senses the inspiration of the patient
- the investigators for the AeroDos ⁇ report that they are able to achieve a median mass aerodynamic diamet ⁇ r of 1.9 to 2.0 m using this device.
- ultrasonic nebulization dewc ⁇ s may act by ultrasonic ⁇ n ⁇ rgy alone, or may use ultrasonic energy in combination with other methods of aerosolization such as forcing or drawing a liquid or suspension through a mate ⁇ al with very small openings. Yet, regardless of the type of nebulizer selected, th ⁇ stabilized dispersions of the present invention provide a significant advantage due to their relatively homogen ⁇ ous disp ⁇ rsion of the incorporated bioactive agent over a period of time.
- the homogen ⁇ ous disp ⁇ rsion of the incorporated particulates ensures that the amount of bioactive agent administered will be consistent no matter which fraction of the preparation in th ⁇ fluid reservoir is actually nebulized in ⁇ ach individual actuation of th ⁇ nebulizer Similarly, wh ⁇ n used for continuous administration over an exte ⁇ d ⁇ d period the stable, homogeneous dispersions of the present invention ensure that relatively constant levels of bioactive agent are delivered during each incremental period of time.
- nebulizers are only for ex ⁇ mplary purposes. As will be recogmz ⁇ d by o ⁇ skilled in the art, other types of nebulizers, whether currently known or later inv ⁇ nt ⁇ d, may also be used for administration of the stabilized dispersions of th ⁇ present invention.
- th ⁇ stabilized preparations for use in nebulizers of the present invention may be advantageously supplied to the physician or other health care professional, in a sterile, prepackaged or kit form More particularly, th ⁇ formulations may be supplied as stable, preformed dispersions ready for administration or, as separata ready to mix components. When provided in a ready to use form, the dispersions may be packaged in single use containers or reservoirs, as well as in multi use containers or reservoirs. In either case, the container or reservoir may be associated with the selected nebulizer and used as described herein.
- kits may contain a number of ready to mix, or prepackaged components that may be packaged individually so that the user can then select the desired compo ⁇ e ⁇ t(s) for the particular indication or use In this regard, the user may then substitute sel ⁇ cted components at will, or as indicated, during a particular course of treatment. It will also be appreciated that such kits may optionally include a nebulizer or that the preparation may be supplied in a disposable nebulizer
- Perforated microstructures comprising gentamicin sulfate were prepared by a spray drying technique using a B 191 Mini Spray Drier (Buchi, Flawil, Switzerland) under th ⁇ following conditions- aspiration- 100%, inlet temperature. 85° C; outlet temperature: 61 °C, feed pump: 10%, N 2 flow.
- the hollow nature of the microstructures was also enhanced by the incorporation of additional blowing agent. More particularly, the series of six micrographs labeled 1 A2 to 1 F2 show cross sections of fractured microstructures as rev ⁇ al ⁇ d by transmission electron microscopy (TEM). Each of these images was produced using the same microstructure preparation as was used to produce the corresponding SEM micrograph in th ⁇ left hand column. Both the hollow nature and wail thickness of th ⁇ resulting perforated microstructures appeared to be largely dependent on the concentration of the selected blowing agent. That is, the hollow nature of the preparation appeared to increase and the thickness of the particle wails appeared to decrease as the PFC/PC ratio mcreas ⁇ d.
- TEM transmission electron microscopy
- Figs. 1 A2 to 1 C2 substantially solid structures were obtained from formulations containing little or no fluorocarbon blowing ag ⁇ nt Conv ⁇ rs ⁇ ly, th ⁇ perforated microstructures produced using a relatively high PFC /PC ratio of approximately 45 (shown in Fig. 1 F2 proved to be ⁇ xtr ⁇ m ⁇ ly hollow with a relatively thin wall ranging from about 43.5 to 261 nm Both types of particles are compatible for use in the present invention.
- the feed solution was prepared by mixing two solutions A and B immediat ⁇ ly prior to spray drying.
- Solution A 20g of wat ⁇ r was used to dissolve 1 g of albuterol sulfate (Accurate Chemical, Westbury, NY) and 0 021 g of poloxam ⁇ r 188 NF grade (BASF, Mount Olive, NJ).
- Solutions A and B were combined and fed into the spray-dryer under the conditions described above.
- a free flowing whit ⁇ powd ⁇ r was collected at the cyclone separator
- the hollow porous albuterol sulfate particles had a volume-weighted mean aerodynamic diameter of 1.18 ⁇ 1 42 ⁇ m as determined by a time-of flight analytical method (Aerosizer, Amh ⁇ rst Proc ⁇ ss Instruments, Amherst, MA) Scanning electron microscopy (SEM) analysis showed the powd ⁇ rs to be sphe ⁇ cal and highly porous.
- the tap density of the powder was det ⁇ rmin ⁇ d to be less than 0 1 g/cm 3
- This foregoing ⁇ xampl ⁇ s ⁇ rv ⁇ s to illustrate the inherent diversity of th ⁇ pr ⁇ s ⁇ nt invention as a drug delivery platform capable of effectively incorporating any one of a number of pharmaceutical agents.
- the p ⁇ nciple is further illustrated in the next ⁇ xampl ⁇ .
- the hollow porous cromolyn sodium particles had a volume weight ⁇ d m ⁇ an a ⁇ rodynamic diam ⁇ t ⁇ r of 1 23 ⁇ 1 31 ⁇ m as determin ⁇ d by a tim ⁇ -of flight analytical method (Aerosizer, Amherst Process Instruments, Amherst, MA). As shown in Fig. 2, scanning electron microscopy (SEM) analysis showed th ⁇ powd ⁇ rs to be both hollow and porous. The tap density of the powder was determined to be less than 0.1 g/cm 3 .
- the emulsion was mixed for an additional p ⁇ nod of not less than 4 minutes
- the resulting coarse emulsion was th ⁇ n passed through a high pressure homogemzer (Avestin, Ottawa, Canada) at 18,000 psi for 5 passes This ⁇ muision was then us ⁇ d to form the feed stock which was spray dried as desc ⁇ b ⁇ d above
- a free flowing white powder was collected at the cyclone separator.
- the hollow porous BDP particles had a tap density of less than 0.1 g/cm 3 .
- TAA tnamci ⁇ olone aceto ⁇ ide
- Solution A 20g of water was used to dissolve 0.5gr of human pancreas DNase I (Calbiochem, San Diego CA) and 0 012g of poloxamer 188 NF grade (BASF, Mount Olive, NJ).
- Solution B A fluorocarbon-in-water emulsion stabilized by phospholipid was prepared in th ⁇ following way.
- Av ⁇ stin Ottawa, Canada
- Solutions A and B wore combin ⁇ d and fed into the spray dryer under the conditions described above.
- a fre ⁇ flowing pale yellow powder was collected at th ⁇ cyclone separator
- the hollow porous DNase I particles had a volume-weighted mean aerodynamic diameter of 1.29 ⁇ 1.40 ⁇ m as det ⁇ rmin ⁇ d by a time of flight analytical method (Aerosizer, Amherst Process Instruments, Amherst, MA) Scanning electron microscopy (SEM) analysis showed the powders to be both hollow and porous.
- the tap density of the powder was determined to be less than 0.1 g/cm 3 .
- the preparations of the pr ⁇ s ⁇ nt invention may be formulated to effectively incorporate larger, fragile molecules such as peptides, proteins and genetic mate ⁇ al.
- Poloxamer 188 (BASF, Mount Olive, NJ)
- solution 1 The ingredients of solution 1 were dissolved in warm water using a stir plate.
- the surfactants in solution 2 were dispers ⁇ d in water using a high shear mixer.
- the solutions were combined following emulsification and saturated with nitrogen prior to spray drying.
- the resulting dry, fre ⁇ flowing, hollow, sph ⁇ cal product had a m ⁇ a ⁇ particle diamet ⁇ r of 2.6 ⁇ 1 5 ⁇ m.
- the particles which may be used for the replac ⁇ ment or augmentation of lung surfactant, were spherical and porous as determined by SEM.
- blowing agents here nitrogen
- one of the primary advantages of the present invention is the ability to alter formation conditions so as to preserve biological activity (i.e. with proteins or lung surfactant) or produce microstructures having s ⁇ l ⁇ ct ⁇ d porosity.
- the resulting DPPC/HES dispersion was chilled in an ice bath Ampicillin (1.25 g) was added and allowed to mix for 1 minute (T
- a perforated microstructure powder comprising ampicillin was obtained by spray-drying (Buchi, 191 Mini Spray Dryer, Switzerland) the ampicillin containing emulsion at a rate of 5 5 ml/mm.
- the inlet and outlet temp ⁇ ratur ⁇ s of th ⁇ spray dryer were 90 C and 55 C respectively.
- the nebulization air and aspiration flows were 1 ,800 L/hr and 100% respectively.
- a free flowing white powder compnsing porous microspheres was obtained.
- th ⁇ neat and spray dried surfactant suspensions The main difference observed between th ⁇ neat and spray dried surfactant suspensions is the rate at which they adsorb to the bubble surface and thus lower th ⁇ tension.
- Th ⁇ spray dn ⁇ d materials required 6 cycles to achiev ⁇ low surface tension as compared with o ⁇ cycle for the Alveofact sample. Howev ⁇ r, the magnitude of th ⁇ t ⁇ sion at maximum, and minimum bubble diamet ⁇ r w ⁇ r ⁇ found to b ⁇ approximately the same.
- the tension decreas ⁇ d from 32 mN/m at maximum diameter to 4 mN/m at minimum in the first cycle
- a st ⁇ ady stat ⁇ oscillation was reached with a maximum t ⁇ nsion max 33 mN/m and a minimum t ⁇ nsion nn 0 to 1 mN/m.
- the tension decreased from 36 mN/m at maximum diameter to 16 mN/m at minimum in the first cycle.
- m consult and m ⁇ n were ⁇ respectively 36 and 2 mN/m.
- the resulting PFH in water emulsion was mixed with the Ultra Turrax) for a total of not less than 4 minutes.
- the insulin microstructure powder was obtained using a Buchi model 191 mini spray dryer (Buchi, Switzerland).
- the insulin containing emulsion was f ⁇ d at a rat ⁇ of 5 5 ml/mm.
- the inlet and outl ⁇ t temperatures of th ⁇ spray dryer were 80 C and 45 C respectively.
- the nebulization air and aspiration flows were 1,800 L/hr and 100% respectively.
- a free flowing, white powd ⁇ r compnsing porous microsph ⁇ r ⁇ s was obtained
- Th ⁇ activity of th ⁇ perflubron treated DNAse I to cleave th ⁇ phosphodi ⁇ st ⁇ r linkages of DNA was compared with an u ⁇ treat ⁇ d DNAse preparation. Se ⁇ al dilutions of a DNAse solution (1 mg/ml) was combined with 50 g DNA and dissolved in 500 L of a 10mM T ⁇ s HCI buffer (6 3 pH) which contained 0 15 mg/ml CaCl, and 8 77 mg/ml NaCI The samples were ⁇ placed on an orbital shaker and incubated at 37 C for 30 minutes.
- DPPC Dipalmitoylphosphatidylcholine
- NBD-PC nitrobenzoyldiol phosphatidylcholme
- HES Hydroxyethyl starch
- DPPC dipalmitoylphosphatidyl choline
- 75 ml deionized water were then add ⁇ d to the DPPC/NBD PC thin film.
- the surfactants and starch were then disp ⁇ rs ⁇ d in th ⁇ aqu ⁇ ous phas ⁇ using an
- PFH Perfluorohexane
- Aerosols were generated w th a DeVilbiss air jet nebulizer (DeVilbiss Co., Somerset, PA).
- the nebulizer was connected to an Andersen cascade impactor (Sierra And ⁇ rs ⁇ n 1 ACFM Nonviable Ambient Particle Sizing Sampler).
- Table III lists the characteristics of each cascade impactor stage, the inhalation behavior of the nebulized microshells and liposom ⁇ s
- the NBD PC mass distribution as a function of a ⁇ rody ⁇ amic diameter was calculated using calibration curves described by Gonda, et. al counter [Gonda, I., Kayes, J.B., Groom, C.V., and Fild ⁇ s, F.J.T.; Characterization of hydroscopic inhalation aerosols. In: Particle Size Analysis 1981
- Formulations described in Examples XVIII, XIX, XX and XXI comprising Cromolyn sodium were tested using commonly acc ⁇ pt ⁇ d pharmaceutical procedures. The m ⁇ thod utilized was compliant with th ⁇ United State
- Th ⁇ extraction from all the plates, induction port, and actuator were p ⁇ rf ormed in closed vials with 10 mL of a suitable solvent.
- the filter was installed but not assayed, because the polyacrylic binder interfered with the analysis
- Th ⁇ plates were extract ⁇ d with deionized water.
- Cromolyn sodium was quantitated by absorption spectroscopy (Beckman DU640 spectrophotom ⁇ t ⁇ r) relative to an external standard curve with the extraction solvent as the blank. Cromolyn sodium was quantitated using the absorption peak at 326 nm
- Throat deposition was defined as the mass of drug found in the induction port and on plates 0 and 1.
- the mean mass aerodynamic diameters (MMAD) and geometric standard diameters (GSD) were evaluated by fitting the experimental cumulative function with log normal distribution by using two param ⁇ t ⁇ r fitting routine. Th ⁇ results of such m ⁇ asur ⁇ ments ar ⁇ pr ⁇ s ⁇ nt ⁇ d in subsequent exampl ⁇ s.
- Th ⁇ impactor was disass ⁇ mbl ⁇ d and the plat ⁇ s of the impactor were extracted with water. Cromolyn sodium content was m ⁇ asured by UV adsorption at 326nm.
- the fine particle fraction is the ratio of particles deposited in stages 2 through 7 to those deposited in all stages of the impactor
- the fine particle mass is the weight of mate ⁇ al deposited in stages 2 through 7.
- the deep lung fraction is th ⁇ ratio of particles deposited in stages 5 through 7 of the impactor (which correlate to the alveoli) to thos ⁇ deposit ⁇ d in all stag ⁇ s.
- the de ⁇ p lung mass is th ⁇ weight of matenal deposited in stages 5 through 7. Table IV immediat ⁇ ly below provides a summary of the results.
- XIX Nebulization of Porous Particulate Structures Comprising Phospholipids and Cromolyn Sodium in Perfluorooctylethane using a Raindrop Nebulizer A quantity of lipid based microspheres containing 50% cromolyn sodium, as from Example V, w ⁇ ighing 40 mg was dispersed in 10 ml perfluorooctyl ⁇ tha ⁇ e (PFOE) by shaking, thereby forming a suspension. The suspension was nebulized until the fluorocarbon liquid was delivered or had evaporated using a Raindrop disposable nebulizer (Nell ⁇ or Pu ⁇ tan Benn ⁇ t) co ⁇ ect ⁇ d to a PulmoAide air compressor (DeVilbiss).
- PFOE perfluorooctyl ⁇ tha ⁇ e
- the amount of powder filled into the can was determined by the amount of drug required to provid ⁇ a desired th ⁇ rap ⁇ utic effect After this the can was crimp s ⁇ al ⁇ d using a DF31/50act 50ul valv ⁇ (Valois of Am ⁇ rica Gr ⁇ nwich, CT) and filled with HFA 134a propellant (DuPont, Wilmington DE) by overpressure through the stem Th ⁇ amount of propellant in the can was determined by weighing the can before and after the fill.
- the filled MDI was then used to compare the administration of cromolyn sodium using a met ⁇ r ⁇ d dos ⁇ inhaler and a n ⁇ ubulizer. More specifically, a cromolyn sodium preparation was nebulized and quantitated as descnbed in Example XVlll. The MDI was then associated with th ⁇ And ⁇ rs ⁇ n impactor and discharged For the test 5 shots w ⁇ re sent to waste and, 20 shots were made into the Andersen impactor. A compa ⁇ son of the Anders ⁇ n cascad ⁇ impactor results for th ⁇ nebulized cromolyn sodium and the cromolyn sodium administered by the MDI is shown in Fig. 3. As seen in the Figure, a significantly greater percentage of the nebulized drug is found on plates 5 7 showing the enhanced potential for systemic delivery via nebulization
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CA002304973A CA2304973C (en) | 1997-09-29 | 1998-09-29 | Stabilized preparations for use in nebulizers |
KR1020007003368A KR100599634B1 (en) | 1997-09-29 | 1998-09-29 | Stabilized preparations for use in nebulizers |
EP98954933A EP1019023B1 (en) | 1997-09-29 | 1998-09-29 | Stabilized preparations for use in nebulizers |
AT98954933T ATE239447T1 (en) | 1997-09-29 | 1998-09-29 | STABILIZED PREPARATIONS USABLE IN NEBULIZERS |
AU11857/99A AU750567B2 (en) | 1997-09-29 | 1998-09-29 | Stabilized preparations for use in nebulizers |
DE69814428T DE69814428T2 (en) | 1997-09-29 | 1998-09-29 | PREPARED, STABILIZED PREPARATIONS |
JP2000513558A JP2001517692A (en) | 1997-09-29 | 1998-09-29 | Stabilized preparation for use in a nebulizer |
US09/218,213 US6946117B1 (en) | 1997-09-29 | 1998-12-22 | Stabilized preparations for use in nebulizers |
JP2000556800A JP2003535017A (en) | 1998-06-29 | 1999-03-31 | Particulate delivery systems and methods of use |
EP99917320A EP1091755A1 (en) | 1998-06-29 | 1999-03-31 | Particulate delivery systems and methods of use |
KR1020007015026A KR100796220B1 (en) | 1998-06-29 | 1999-03-31 | Particulate delivery systems and methods of use |
CA002335940A CA2335940A1 (en) | 1998-06-29 | 1999-03-31 | Particulate delivery systems and methods of use |
AU35469/99A AU760537B2 (en) | 1998-06-29 | 1999-03-31 | Particulate delivery systems and methods of use |
US11/076,430 US20050207986A1 (en) | 1997-09-29 | 2005-03-09 | Stabilized preparations for use in nebulizers |
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US09/106,932 | 1998-06-29 | ||
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US09/133,848 | 1998-08-14 |
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US09/218,213 Continuation US6946117B1 (en) | 1997-09-29 | 1998-12-22 | Stabilized preparations for use in nebulizers |
US11/076,430 Continuation US20050207986A1 (en) | 1997-09-29 | 2005-03-09 | Stabilized preparations for use in nebulizers |
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US9421166B2 (en) | 2001-12-19 | 2016-08-23 | Novartis Ag | Pulmonary delivery of aminoglycoside |
US9554993B2 (en) | 1997-09-29 | 2017-01-31 | Novartis Ag | Pulmonary delivery particles comprising an active agent |
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US6503480B1 (en) | 1997-05-23 | 2003-01-07 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
US6254854B1 (en) | 1996-05-24 | 2001-07-03 | The Penn Research Foundation | Porous particles for deep lung delivery |
WO2000000215A1 (en) * | 1998-06-29 | 2000-01-06 | Inhale Therapeutic Systems, Inc. | Particulate delivery systems and methods of use |
US6630169B1 (en) | 1999-03-31 | 2003-10-07 | Nektar Therapeutics | Particulate delivery systems and methods of use |
EP1185248B1 (en) | 1999-06-09 | 2012-05-02 | Robert E. Sievers | Supercritical fluid-assisted nebulization and bubble drying |
US20020103165A1 (en) * | 2000-02-29 | 2002-08-01 | Alliance Pharmaceutical Corp., | Engineered spray-dried lipid-based microparticles for cellular targeting |
US7141236B2 (en) | 2000-07-28 | 2006-11-28 | Nektar Therapeutics | Methods and compositions for delivering macromolecules to or via the respiratory tract |
WO2003057593A1 (en) | 2001-12-21 | 2003-07-17 | Nektar Therapeutics | Capsule package with moisture barrier |
US8513204B2 (en) | 2004-06-21 | 2013-08-20 | Novartis Ag | Compositions comprising amphotericin B, mehods and systems |
AU2005258040A1 (en) | 2004-06-21 | 2006-01-05 | Novartis Ag | Compositions comprising amphotericin b |
EP2285345A1 (en) | 2008-05-15 | 2011-02-23 | Novartis AG | Pulmonary delivery of a fluoroquinolone |
US8974828B2 (en) | 2009-03-18 | 2015-03-10 | Incarda Therapeutics, Inc. | Unit doses, aerosols, kits, and methods for treating heart conditions by pulmonary administration |
EP3212212B1 (en) | 2014-10-31 | 2020-09-23 | Monash University | Powder formulation |
WO2016118625A1 (en) | 2015-01-20 | 2016-07-28 | Incarda Therapeutics, Inc. | Unit aerosol doses for anticoagulation |
GB2581301A (en) * | 2016-02-01 | 2020-08-12 | Incarda Therapeutics Inc | Combining electronic monitoring with inhaled pharmacological therapy to manage atrial arrhythmias including atrial fibrillation |
IL270407B2 (en) | 2017-05-10 | 2024-03-01 | Incarda Therapeutics Inc | Unit doses, aerosols, kits, and methods for treating heart conditions by pulmonary administration |
WO2018217800A1 (en) | 2017-05-22 | 2018-11-29 | Insmed Incorporated | Glycopeptide derivative compounds and uses thereof |
EP3768378A4 (en) | 2018-03-22 | 2021-11-17 | InCarda Therapeutics, Inc. | A novel method to slow ventricular rate |
US11007185B2 (en) | 2019-08-01 | 2021-05-18 | Incarda Therapeutics, Inc. | Antiarrhythmic formulation |
WO2022189662A1 (en) | 2021-03-12 | 2022-09-15 | Alvarius Pharmaceuticals Ltd. | Compositions and methods for treating addictions comprising 5-meo-dmt |
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US9554993B2 (en) | 1997-09-29 | 2017-01-31 | Novartis Ag | Pulmonary delivery particles comprising an active agent |
US8877162B2 (en) | 2000-05-10 | 2014-11-04 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery |
US9439862B2 (en) | 2000-05-10 | 2016-09-13 | Novartis Ag | Phospholipid-based powders for drug delivery |
US9421166B2 (en) | 2001-12-19 | 2016-08-23 | Novartis Ag | Pulmonary delivery of aminoglycoside |
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