EP1019020A1 - Stabilized bioactive preparations and methods of use - Google Patents

Stabilized bioactive preparations and methods of use

Info

Publication number
EP1019020A1
EP1019020A1 EP98950824A EP98950824A EP1019020A1 EP 1019020 A1 EP1019020 A1 EP 1019020A1 EP 98950824 A EP98950824 A EP 98950824A EP 98950824 A EP98950824 A EP 98950824A EP 1019020 A1 EP1019020 A1 EP 1019020A1
Authority
EP
European Patent Office
Prior art keywords
perforated microstructures
suspension medium
surfactant
dispersion
bioactive agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98950824A
Other languages
German (de)
English (en)
French (fr)
Inventor
Luis A. Dellamary
Thomas E. Tarara
Alexey Kabalnov
Jeffry G. Weers
Ernest G. Schutt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nektar Therapeutics
Original Assignee
Inhale Therapeutics Systems Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27369827&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1019020(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Inhale Therapeutics Systems Inc filed Critical Inhale Therapeutics Systems Inc
Publication of EP1019020A1 publication Critical patent/EP1019020A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
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    • 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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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
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    • 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
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    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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Definitions

  • the present invention generally relates to formulations and methods for the administration of bioactive agents to a patient in need thereof. More particularly, the present invention relates to methods, systems and compositions comprising relatively stable dispersions of perforated microstructures in a suspension medium that are preferably administered via liquid dose instillation both for topical delivery to the lung, and for delivery via the lung to the systemic circulation.
  • the efficacy of many pharmaceutical agents is predicated on their ability to proceed to the selected target sites and remain there in effective concentrations for sufficient pe ⁇ ods of time to accomplish the desired therapeutic or diagnostic purpose Difficulty in achieving efficacy may be exacerbated by the location and environment of the target site as well as by the inherent physical characteristics of the compound administered
  • drug delivery via routes that are subject to repeated drainage or flushing as part of the body's natural physiological functions offer significant impediments to the effective administration of pharmaceutical agents
  • delivery and retention problems are often encountered when administering compounds through the respiratory or gastrointestinal tracts
  • Repeated administration of fairiy large doses are often required to compensate for the amount of drug washed away and to maintain an effective dosing regimen when employing such routes.
  • the molecular properties of the pharmaceutical compound may impair the absorption through a given delivery route, thereby resulting in a substantial reduction in efficacy.
  • insoluble particulates are known to be subject to phagocytosis and pinocytosis, resulting in the accelerated removal of the compound from the target site
  • Such reductions in delivery and retention time complicate dosing regimes, waste pharmaceutical resources and generally reduce the overall efficacy of the administered drug.
  • fluorochemicais one class of delivery vehicles that has shown great promise when used for the administration of pharmaceutical agents.
  • fluorochemicais have found wide ranging application in the medical field as therapeutic and diagnostic agents.
  • the use of fluorochemicais to treat medical conditions is based, to a large extent, on the unique physical and chemical properties of these substances.
  • the relatively low reactivity of fluorochemicais allows them to be combined with a wide va ⁇ ety of compounds without altering the properties of the incorporated agent
  • This relative inactivity when coupled with other beneficial characteristics such as an ability to carry substantial amounts of oxygen, radioopaqueness for certain forms of radiation and low surface energies, have made fluorochemicais invaluable for a number of therapeutic and diagnostic applications.
  • liquid ventilation For all practical purposes, liquid ventilation became a viable technique when it was discovered that fluorochemicais could be used as the respiratory promoter.
  • Liquid breathing using oxygenated fluorochemicais has been explored for some time
  • an animal submerged in an oxygenated fluorochemical liquid may exchange oxygen and carbon dioxide normally when the lungs fill with the fluorochemical.
  • mammals can derive adequate oxygen for survival when submerged by breathing the oxygenated fluorochemical liquid.
  • total liquid ventilation may keep mammals alive for extended periods prior to returning them to conventional gas breathing.
  • TLV Total liquid ventilation
  • the subject is then connected to a liquid breathing system and tidal liquid volumes are delivered at a frequency depending on respiratory requirements while exhaled liquid is purged of CO, and oxygenated extracorporeally between the breaths. This often involves the use of specialized fluid handling equipment.
  • partial liquid ventilation involves the use of conventional mechanical ventilation in combination with pulmonary administration of a respiratory promoter capable of oxygenation.
  • a liquid, vaporous or gaseous respiratory promoter ⁇ .e. a fluorochemical
  • Respiratory gas exchange may then be maintained for the duration of the procedure by, for example, continuous positive pressure ventilation using a conventional open circuit gas ventilator Alternatively, gas exchange may be maintained through spontaneous respiration.
  • the introduced respiratory promoter or fluorochemical may be allowed to evaporate from the lung rather than being physically removed as in TLV.
  • liquid ventilation will be used in a generic sense and shall be defined as the introduction of any amount of respiratory promoter or fluorochemical into the lung, including the techniques of partial liquid ventilation, total liquid ventilation and liquid dose installation.
  • Use of liquid ventilation may provide significant medical benefits that are not available through the use of conventional mechanical ventilators employing a breathable gas.
  • the weight of the respiratory promoter opens alveoli with much lower ventilator pressure than is possible with gas.
  • liquid ventilation using fluorochemicais as the respiratory promoter has been shown to be effective in ⁇ nsing out congestive materials associated with respiratory distress syndrome.
  • fluorochemicais may be effective in the pulmonary delivery of bioactive agents in the form of liquid or solid particulates.
  • pulmonary delivery of bioactive agents using fluorochemical suspensions is described in Sekms et al., U.S. Patent No.
  • bioactive agents may preferably be delivered in conjunction with partial liquid ventilation or lavage Due to the physical characteristics of compatible respiratory promoters or fluorochemicais, the use of such techniques provides for improved dispersion of the incorporated agent in the lung thereby increasing uptake and increasing efficacy. Further, direct administration of the bioactive agent is particularly effective in the treatment of lung disease as poor vascular circulation of diseased portions of the lung reduces the efficacy of intravenous drug delivery.
  • fluorochemical pharmaceutical formulations administered to the lung could also prove useful in the treatment and/or diagnosis of disorders such as RDS, impaired pulmonary circulation, cystic fibrosis and lung cancer.
  • fluorochemicais could advantageously be used for the administration of compounds via other routes such as topical, oral (e.g. for administration to the gastrointestinal tract), i ⁇ trape ⁇ toneal, or ocular.
  • the use of fluorochemical suspensions may result in unreliable and irreproducible drug delivery due to the admimstraion of a non homogeneous dispersion or instability of the particulates in the fluorochemical phase
  • drug suspensions in liquid fluorochemicais comprise heterogeneous systems which usually require redispersio ⁇ prior to use Yet, because of factors such a patient compliance obtaining a relatively homogeneous distribution of the pharmaceutical compound is not always easy or successful.
  • prior art formulations comprising micronized particulates may be prone to aggregation of the particles which can result in inadequate delivery of the drug. Crystal growth of the suspensions via Ostwald ripening may also lead to particle size heterogeneity and can significantly reduce the shelf life of the formulation.
  • Another problem with conventional dispersions is particle coarsening. Coarsening may occur via several mechanisms such as flocculation, fusion, molecular diffusion, and coalescence.
  • the methods and associated compositions of the present invention provide, in a broad aspect, for the improved delivery of bioactive agents to selected physiological target sites using stabilized preparations.
  • the bioactive agents are in a form for administration to at least a portion of the pulmonary air passages of a patient via liquid dose instillation.
  • the present invention provides for the formation and use of stabilized dispersions and delivery systems 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 by flocculation, sedimentation or creaming.
  • the stabilized preparations of the present invention preferably comprise a suspension medium that further serves to reduce the rate of degradation with respect to the incorporated bioactive agent.
  • the suspension medium will comprise a fluori ⁇ ated compound, fluorochemical or fluorocarbon.
  • the stabilized dispersions of the present invention comprise a continues phase suspension medium having a plurality of perforated microstructures dispersed or suspended therein wherein the stabilized dispersions are capable of being administered to the lung of a patient in need thereof.
  • the disclosed preparations will preferably be administered at least a portion of the pulmonary air passages of a patient using liquid dose instillation (LDI).
  • LDI comprises the direct instillation or administration of a liquid preparation to the lungs.
  • LDI comprises instillation of a bioactive preparation to the pulmonary air passages using a pulmonary delivery conduit.
  • the preparation may be delivered to an intubated patient through an e ⁇ dotracheal tube, or to a free-breathing patient via bronchoscope, or may even be administered using standard tubing and/or a syringe.
  • the methods and systems disclosed herein may be used with both ventilated and nonventilated patients.
  • the present invention may be used in conjunction with liquid ventilation (e.g. both PLV and TLV).
  • the stabilized dispersions of the present invention may be administered by a variety of routes and methods, such as top-loading onto existing fluorochemical (i.e. in the lung), trickle-filling or lavage, dosages can be more effectively administered and controlled.
  • administration of bioactive agents in a fluorochemical as is contemplated herein, provides a relatively anhydrous environment wherein the physiological uptake of the drug may be dramatically increased
  • the stabilized preparations of the present invention provide these and other advantages through the use of particulate suspensions compnsing hollow and/or porous perforated microstructures that substantially reduce attractive molecular forces, such as van der Waals forces, which dominate p ⁇ or 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. reduce Hamaker constant differentials) and further stabilize the preparation The relatively homogeneous nature of these particulate dispersions or suspensions, inhibits detenoration thereby allowing for pharmaceutical preparations having enhanced stability.
  • dispersed perforated microstructures those skilled in the art will appreciate that they 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 comp ⁇ se 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 material or configuration may be used to form the microstructure matrix
  • the microstructure incorporates at least one surfactant.
  • this surfactant will comp ⁇ se a phospho pid or other surfactant approved for pulmonary use.
  • particularly preferred embodiments of the invention incorporate spray dried, 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 stabilized dispersions for the delivery of a bioactive agent compnsing a biocompatible 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
  • the suspension medium may be any liquid or compound that is in liquid form, under appropriate thermodynamic conditions, for formation of a compatible particulate dispersions.
  • 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.
  • particularly preferred suspension mediums comp ⁇ se fluorochemicais (e.g. perfluorocarbo ⁇ s or fluorocarbons) that are liquid at room temperature.
  • fluorochemicais e.g. perfluorocarbo ⁇ s or fluorocarbons
  • fluorochemicais have a proven history of safety and bioco patibility in the lung.
  • fluorochemicais do not negatively impact gas exchange.
  • fluorochemicais may be able to provide for the dispe ⁇ on of particles deeper into the lung, thereby improving systemic delivery.
  • fluorochemicais are also bacte ⁇ ostatic thereby decreasing the potential for microbial growth in compatible preparations.
  • the present invention provides for the use of a liquid fluorochemical in the manufacture of a stabilized dispersion for the pulmonary delivery of a bioactive agent whereby the stabilized dispersion is directly administered to at least a portion of the pulmonary air passages of a patient in need thereof, said stabilized dispersion compnsing a fluorochemical suspension medium having dispersed therein a plurality of perforated microstructures compnsing at least one bioactive agent wherein the suspension medium substantially permeates said perforated microstructures.
  • the present invention comprises 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 comprise perforated microstructures that allow for the perfusion or permeation of the selected suspension medium
  • preferred embodiments of the invention provide methods for forming a stabilized dispersion for direct pulmonary administration of a bioactive agent comprising the steps of: combining a plurality of perforated microstructures compnsing at least one bioactive agent with a predetermined volume of a biocompatible 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 stabilized 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.
  • the present invention further provides methods for stabilizing a dispersion by reducing attractive van der Waals forces comprising the steps of: providing a plurality of perforated microstructures, combining the perforated microstructures with a biocompatible suspension medium comprising at least one liquid 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 comprise 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 systems for the direct pulmonary administration of a bioactive agent to a patient compnsing- a fluid reservoir, a stable dispersion in said fluid reservoir wherein said stabilized dispersion compnses a biocompatible suspension medium having a plurality of perforated microstructures dispersed therein, said perforated microstructures compnsing at least one bioactive agent; and a pulmonary delivery conduit operably associated with said fluid reservoir wherein the delivery conduit is capable of administering the stabilized dispersion to at least a portion of the pulmonary air passages of a patient in need thereof.
  • pulmonary delivery conduit shall be construed in a broad sense to comprise any device or apparatus, or component thereof, that provides for the instillation or administration of a liquid in the lungs
  • a pulmonary delivery conduit or delivery conduit shall be held to mean any bore, lumen, catheter, tube, conduit, syringe, actuator, mouthpiece, endotracheal tube or hronchoscope that provides for the administration or instillation of the disclosed dispersions to at least a portion of the pulmonary air passages of a patient in need thereof.
  • the delivery conduit may or may not be associated with a liquid ventilator or gas ventilator
  • the delivery conduit shall comp ⁇ se an endotracheal tube or bronchoscope.
  • 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.
  • compatible bioactive agents those skilled in the art will appreciate that any therapeutic or diagnostic agent may be incorporated in the stabilized dispersions of the present invention.
  • the bioactive agent may be selected from the group consisting of antiallergics, bronchodilators, bronchoconst ⁇ ctors, pulmonary lung surfactants, analgesics, antibiotics, leukotnene inhibitors or antagonists, anticholinergics, mast cell inhibitors, a ⁇ tihistamines, antii ⁇ flammato ⁇ es, antmeoplastics, anesthetics, anti tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic mate ⁇ al, viral vectors, antisense agents, proteins, peptides and combinations thereof.
  • bioactive agents comprise compounds which are to be administered systemically (i e to the systemic circulation of a patient) such as peptides, proteins or polynucleotides
  • the bioactive agent may be incorporated, blended in, coated on or otherwise associated with the perforated microstructure.
  • the present invention provides methods for the delivery of one or more bioactive agents compnsing the steps of: providing a stabilized dispersion compnsing a biocompatible suspension medium having dispersed therein a plurality of perforated microstructures wherein said perforated microstructures comprise a bioactive agent, and admimstenng a therapeutically effective amount of said stabilized dispersion to at least a portion of the pulmonary passages of a patient in need thereof
  • the stabilized dispersions of the present invention are particularly suitable for the pulmonary administration of bioactive agents, they may also be used for the localized or systemic administration of compounds to any location of the body. Accordingly, it should be emphasized that, in preferred embodiments, the formulations may be administered using a number of different routes including, but not limited to, the gastrointestinal tract, the respiratory tract, topically, intramuscularly, intrape ⁇ toneally, nasally, vaginally, rectally, aurally, orally or ocularly.
  • the selected bioactive agent may be used as the sole structural component of the perforated microstructures
  • the perforated microstructures may comprise one or more components (i e structural materials, surfactants, excipients, etc ) in addition to the incorporated bioactive agents
  • the suspended perforated microstructures will comp ⁇ se 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 stabilized dispersions of the invention may optionally comp ⁇ se one or more additives to further enhance stability or increase biocompatibility
  • additives for example, various 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
  • 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
  • specific quantities, ratios, and types of agents can be determined empirically without undue expenmentation
  • Other objects, features and advantages of the present invention will be apparent to those skilled in the art from a consideration of the following detailed descnption of preferred exemplary embodiments thereof
  • the present invention provides methods and compositions that allow for the formation of stabilized suspensions that may advantageously be used for the delivery of bioactive agents
  • the enhanced stability of the suspensions is primarily 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, and 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 hollow and porous, almost honeycombed or foam like in appearance
  • the perforated microstructures comprise hollow, porous spray dried microspheres.
  • the terms "perforated microstructures” and “perforated microparticles” are used to describe porous products, preferably comprising a bioactive agent, distributed throughout the suspension medium in accordance with the teachings herein Accordingly, the subject terms may be used interchangeably throughout the instant specification unless the contextual setting indicates otherwise
  • the suspension medium i.e. propellant
  • the suspension medium is able to permeate the particles, thereby creating a "homodispersio ⁇ ", wherein both the continuous and dispersed phases are substantially indistinguishable. Since the defined or "virtual" particles (i e.
  • the stabilized suspensions of the present invention are compatible with inhalation therapies and may be used in conjunction with metered dose inhalers, dry powder inhalers and nebulizers
  • the disclosed perforated microstructures may be dispersed in a suitable suspension medium (e.g.
  • liquid dose instillation a stabilized dispersion to the lungs
  • the stabilized dispersions may be administered topically, subcutaneously intramuscularly, intrape ⁇ toneally, nasally, vaginally, rectally, orally or ocularly.
  • the dispersions of the present invention are designed not to increase repulsion between particles, but rather to decrease attractive forces.
  • the principal forces driving flocculation in nonaqueous media are van der Waals (VDW) attractive forces.
  • VDW forces are quantum mechanical in origin, and can be visualized as attractions between fluctuating dipoles (i.e. induced dipole induced 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 sums up The resulting force is of considerably longer range, and depends on the geometry of the interacting bodies.
  • V A the magnitude of the VDW potential
  • R 2 are the radii of spherical particles 1 and 2
  • the effective Hamaker constant is proportional to the difference in the pola ⁇ zabilities of the dispersed particles and the suspension medium:
  • a ej r ( S J ⁇ - SM ⁇ • s ⁇ A P ⁇ RT )Z
  • -4 and A PART are the Hamaker constants for the suspension medium and the particles, respectively
  • a and A PART become closer in magnitude
  • 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.
  • 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 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 expenmentation. 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 refractive index of the suspension medium will preferably be within about 0.5 of the refractive index associated with the perforated particles or microstructures. It will further be appreciated that 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. Given that lower refractive index differentials imply greater dispersion stability, particularly preferred embodiments comprise index differentials of less than about
  • the present invention provides for stabilized dispersions, at least in part, by immobilizing the bioactive agent(s) and excipients (including surfactants) within the structural matrix of the hollow, porous microstructures. Accordingly, preferred excipients useful in the present invention are substantially insoluble in the suspension medium.
  • 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.
  • insoluble excipients also reduces the potential for particle growth by Ostwald ripening.
  • 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 average volume of the bioactive agent/excipient shell or matrix (i e the volume of medium actually displaced by the perforated microstructure) comprises less than 70% of the average particle volume (or less than 70% of the virtual particle) More preferably, the volume of the microparticulate matrix comprises less than about 50%, 40%, and 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 a matrix or shell volumes typically cont ⁇ butes little to the virtual particle density which is overwhelmingly dictated by the suspension medium found therein. Of course, in selected embodiments the excipients 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 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 0.2 g/cm 3 of the selected suspension medium. In even more preferable embodiments 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 viscoelastic behavior. Rheological behavior of this type is counterproductive in the administration of bioactive agents.
  • 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.
  • the denved values are different. Accordingly, the maximum packing fraction is often considered to be an empirical parameter for a given system.
  • the porous structures of the present invention do not exhibit undesirable viscoelastic 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 the disclosed suspensions is thought to be due, at least in large part, to the relatively low VDW 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.
  • 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.
  • 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, more preferably 0.001 0.01.
  • Yet other preferred embodiments comprise stabilized suspensions having volume fractions from approximately 0.01 to approximately 0.1.
  • the perforated microstructures of the present invention may also be used to stabilize dilute suspensions of micronized bioactive agents.
  • the perforated microstructures may be added to increase the volume fraction of particles in the suspension, thereby increasing suspension stability to creaming or sedimentation.
  • the incorporated microstructures may also act in preventing close approach (aggregation) of the micronized drug particles. It should be appreciated that 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.
  • dispersions of the present invention are preferably stabilized.
  • stabilized dispersion will be held to mean any dispersion that resists aggregation, flocculation or creaming to the extent required to provide for the effective delivery of a bioactive agent
  • 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.
  • One relatively simple way to determine the creaming time of a preparation is to provide a particulate suspension is sealed glass vials
  • the vials are agitated or shaken to provide relatively homogeneous dispersions which are then set aside and observed using appropriate instrumentation or by eye
  • the time necessary for the suspended particulates to cream to 1 /2 the volume of the suspension medium (i.e to nse to the top half of the suspension medium) or to sediment within 1 /2 the volume (i e to settle in the bottom half of the medium) is then noted.
  • Suspension formulations having a creaming time greater than 1 minute are preferred and indicates suitable stability.
  • the stabilized dispersions comp ⁇ se creaming times of greater than about 2, 5, 10, 15, 20 or 30 minutes
  • the stabilized dispersions exhibit creaming times of greater than about 1, 1.5, 2, 2.5, 3, 4 or even 5 hours.
  • Substantially equivalent pe ⁇ ods for sedimentation times are similarly indicative of compatible dispersions Regardless of the ultimate composition or precise creaming time, the stabilized respiratory dispersions of the present invention comp ⁇ se a plurality of perforated microstructures or microparticulates that are dispersed or suspended in the suspension medium.
  • the perforated microstructures comprise a structural mat ⁇ x that exhibits, defines or comprises 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 characte ⁇ stics is contemplated as being within the scope of the invention Accordingly, while preferred embodiments can comp ⁇ se approximately microsphencal shapes, collapsed, deformed or fractured particulates are also compatible.
  • the mean geometnc particle size of the perforated microstructures is preferably about 0.5 50 m, more preferably 1 30 m
  • liquid dose instillation or administration of bioactive agents does not depend critically on the aerodynamic properties of the particle for efficient biodist ⁇ bution Rather, the unique wettability characteristics of the FC suspension medium and the homogeneous nature of the dispersion promotes efficient biodist ⁇ bution
  • there may be some advantage to using larger particles i e.
  • compositions and methods of the present invention may provide for the deep lung deposition of the bioactive particulates thereby countering, at least in part, the mucociliary escalator Accordingly, larger perforated microstructures having a geomet ⁇ c diameter of greater than approximately 5 m may prove to be particularly effective when administered ( ⁇ .e.
  • the perforated microstructures will comprise a powder of dry, hollow, porous microsphe ⁇ cal shells of approximately 1 to 30 m in diameter, with shell thicknesses of approximately 0 1 to approximately 0.5 m. It is a particular advantage of the present invention that the particulate concentration of the dispersions and structural matnx components can be adjusted to optimize the delivery characteristics of the selected particle size.
  • the porosity of the microstructures may play a significant part is 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) of the perforated microstructures may range from approximately 0 5% to approximately 80%.
  • the mean porosity will range from approximately 2% to approximately 40%. Based on selected production parameters, the mean porosity may be greater than approximately, 2%, 5%, 10%, 15%, 20%, 25% or 30% of the microstructure surface area In other embodiments, the mean porosity of the microstructures may be greater than about 40%, 50%, 60%, 70% or even
  • 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 In particularly preferred embodiments the mean pore size will be in the range of from about 50 nm to about 100 nm.
  • the composition of the defining structural matnx may compnse any one of a number of biocompatible mate ⁇ als It will be appreciated that, as used herein, the terms "structural matrix” or “microstructure matnx” are equivalent and shall be held to mean any solid mate ⁇ al 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 matnx composes a spray dried hollow porous microsphere incorporating at least one surfactant.
  • the particulate mate ⁇ al may be coated one or more times with polymers, surfactants or other compounds which aid suspension.
  • the perforated microstructures may be formed of any biocompatible mate ⁇ al that is relatively stable and preferably insoluble with respect to the selected suspension medium and can provide the necessary perforated configuration. While a wide variety of materials may be used to form the particles, in particularly preferred embodiments the structural matnx is associated with, or comprises, a surfactant such as phospho pid or fluo ⁇ ated surfactant. Although not required, the incorporation of a compatible surfactant can improve the stability of the respiratory dispersions, increase pulmonary deposition and facilitate the preparation of the suspension. Moreover, bv altering the components, the density of the structural matrix 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, the perforated microstructures preferably comprise at least one bioactive agent.
  • the 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.
  • surfactants while not necessary to practice the instant invention, may further increase dispersion stability, simplify formulation procedures or increase bioavailability upon administration.
  • MDIs surfactants further serve to lubricate the metering valve, thereby ensuring consistent reproducibility of valve actuation and accuracy of dose dispersed
  • combinations of 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.
  • associated with or comprise it is meant that the structural matrix 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 structural matrix and the suspension medium.
  • the surfactant may comprise a single compound or any combination of compounds, such as in the case of co surfactants.
  • Particularly preferred surfactants are substantially insoluble in the propellant, nonfluonnated, and selected from the group consisting of saturated and unsaturated lipids, nomonic detergents, nonionic block copolymers, ionic surfactants, and combinations of such agents. It should be emphasized that, in addition to the aforementioned surfactants, suitable (i.e.
  • biocompatible fluo ⁇ 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 structural matrix.
  • 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 16 C 22 ) saturated lipids and more preferably comprise phospholipids.
  • Exemplary phospholipids useful in the disclosed stabilized preparations compnse egg phosphatidylcholi ⁇ e, dilauroylphosphatidylcholine, dioleylphosphatidylchohne, dipalmitoylphosphatidyl-chohne, disteroylphosphatidylchohne, short chain phosphatidylcho nes, phosphatidylethanolamine, dioleylphosphatidyletha ⁇ olamine, phosphatidylse ⁇ ne, phosphatidylglycerol, phosphatidylinositol, glycolipids, ganglioside GM1 , sphmgomyelin, phosphatidic acid, cardiolipm; lipids bearing polymer chains such as polyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone; lipids bearing sulfonated mono , di , and polysacchandes; fatty
  • phospholipids and combinations of phospholipids and poloxamers are particularly suitable for use in the stabilized dispersions disclosed herein
  • Compatible nonionic detergents comprise, sorbitan esters including sorbitan tnoleate (Span" 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan 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 sorbitan tnoleate (Span" 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxy
  • Preferred block copolymers include diblock and t ⁇ block copolymers of polyoxyethylene and polyoxypropylene, including poloxamer 188 (PluromZ F 68), poloxa er 407 (Pluronic " F 127), and poloxamer 338 Ionic surfactants such as sodium sulfosuccmate, and fatty acid soaps may also be utilized.
  • the microstructures may comprise oleic acid or its alkali salt.
  • cationic surfactants or lipids are preferred especially in the case of delivery or RNA or DNA.
  • suitable cationic lipids include. DOTMA, N [1 (2,3 dioleyloxylpropyll N,N,N t ⁇ methylammonium chloride; DOTAP, 1 ,2 dioleyloxy 3 (tr ⁇ methylammon ⁇ o)propane; and DOTB, 1,2 d ⁇ oleyl-3 (4'-tr ⁇ methylammon ⁇ o)butanoyl-sn glycerol.
  • polycationic ammo acids such as polylysme, and polyargimne are also contemplated Those skilled in the art will further appreciate that a wide range of surfactants may optionally be used in conjunction with the present invention Moreover, the optimum surfactant or combination thereof for a given application can readily be determined by empirical studies that do not require undue experimentation. It will further be appreciated that the preferred insolubility of any incorporated surfactant in the suspension medium will dramatically decrease the associated surface activity. As such, it is arguable as to whether these materials have surfactant like character prior to contracting an aqueous bioactive surface (e.g.
  • 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 du ⁇ ng processing to form the structural matrix
  • the structural matrix of the perforated microstructures may compnse relatively high levels of surfactant
  • the perforated microstructures will preferably comprise greater than about 1 %, 5%, 10%, 15%, 18%, or even 20% w/w surfactant.
  • the perforated microstructures will comp ⁇ se greater than about 25%, 30%, 35%, 40%, 45%, or 50% w/w surfactant Still other exemplary embodiments will comp ⁇ se 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 compnse essentially 100% w/w of a surfactant such as a phospho pid. Those skilled in the art will appreciate that, in such cases, the balance of the structural matrix (where applicable) will preferably comp ⁇ se a bioactive agent or non surface active excipients or additives.
  • surfactant levels are preferably employed in perforated microstructures, they may be used to provide stabilized systems compnsing relatively nonporous, or substantially solid, particulates. That is, while preferred embodiments will compnse perforated microstructures or microspheres associated with high levels of surfactant, acceptable dispersions may be formed using relatively low porosity particulates of the same surfactant concentration (i e. greater than about 10% or 20% w/w) In this respect such embodiments are specifically contemplated as being within the scope of the present invention.
  • the structural matrix defining the perforated microstructure optionally compnses synthetic or natural polymers or combinations thereof.
  • useful polymers comp ⁇ se polylactides, polylactide glycolides, cyclodextnns, polyacrylates, methylcellulose, carboxymethylcellulose, polyvinyl alcohols, polyanhyd ⁇ des, polylactams, polyvinyl pyrrolidones, polysacchandes (dextrans, starches, chitin, chitosan, etc ), hyaluronic acid, proteins, (albumin, collagen, gelatin, etc )
  • the delivery profile of the respiratory dispersion may be tailored to optimize the effectiveness of the bioactive agent.
  • excipients may be desirable to add other excipients to an aerosol formulation to improve microsph ⁇ re rigidity, drug delivery and deposition, shelf life and patient acceptance.
  • excipients include, but are not limited to. coloring agents, taste masking agents, buffers, hygroscopic agents, antioxidants, and chemical stabilizers
  • va ⁇ ous excipients may be incorporated in, or added to, the particulate matrix to provide structure and form to the perforated microstructures (i e. microspheres)
  • excipients may include, but are not limited to, carbohydrates including monosaccha ⁇ des, disacchandes and polysacchandes.
  • monosacchandes such as dextrose (anhydrous and monohydrate), galactose, mannitol, D mannos ⁇ , sorbitol, sorbose and the like, disacchandes such as lactose, maltose, sucrose, trehalose, and the like, trisaccha ⁇ des such as raffinose and the like; and other carbohydrates such as starches (hydroxyethylstarch), cyclodextnns and maltodext ⁇ ns Ammo acids are also suitable excipients with glycine preferred. Mixtures of carbohydrates and ammo acids are further held to be within the scope of the present invention. The inclusion of both inorganic (e.g.
  • perforated microstructures that may comprise, or may be coated with, charged species that prolong residence time at the point of contact or enhance penetration through mucosae.
  • aniomc charges are known to favor mucoadhesion
  • 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, polylysine, polylactic acid and chitosan.
  • 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 presence or absence of a disease in a patient andlor in methods for treating a disease 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 treatment 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). However, in selected embodiments the particles or perforated microstructures may incorporate much less bioactive agent depending on the activity thereof.
  • 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 embodiments of the invention may comprise 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 matnx or particulate.
  • the precise amount of bioactive agent incorporated in the stabilized dispersions of the present invention is dependent upon the agent of choice, the volume of suspension media required to effectively distnbute the drug, 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 are suitable for pulmonary administration in conjunction with the teachings herein include any drug that may be presented in a form which is relatively insoluble in the selected medium and subject to pulmonary uptake in physiologically effective amounts.
  • Compatible bioactive agents may comp ⁇ se hydrophilic and pophilic respiratory agents, bronchodilators, pulmonary lung surfactants, antibiotics, antivirais, anti inflammato ⁇ es, steroids, antihistamintcs, histamine antagonists, leukotnene inhibitors or antagonists, anticholinergics, anti neoplasties, anesthetics, enzymes, lung surfactants, cardiovascular agents, genetic material including DNA and RNA, viral vectors, immunoactive agents, imaging agents, vaccines, immunosuppressive agents, peptides, proteins and combinations thereof.
  • bioactive agents for localized administration 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, i.e cromoglycate (e.g. the sodium salt), and albuterol (e g. the sulfate salt).
  • cromoglycate e.g. the sodium salt
  • albuterol e g. the sulfate salt
  • peptides and proteins are particularly preferred.
  • Exemplary medicaments or bioactive agents may be selected from, for example, analgesics, e g codeine, dihydromorphine, ergotamine, fenta ⁇ yl, or morphine, anginal preparations, e.g. diltiazem, mast cell inhibitors, ⁇ g cromolyn sodium; antiinfectives, e g. cephalosporins, macrolides, quinolines, penicillins, streptomycin, sulpho ⁇ amides, tetracycli ⁇ es and pentamidine, antihistammes, e.g. methapy ⁇ le ⁇ e, anti inflammato ⁇ es, e g.
  • analgesics e g codeine, dihydromorphine, ergotamine, fenta ⁇ yl, or morphine
  • anginal preparations e.g. diltiazem, mast cell inhibitors, ⁇ g cromolyn sodium
  • fluticasone propionat ⁇ beclomethason ⁇ dipropionate, flunisolide, budesonide, tnpedane, cortisone, pred ⁇ isone, predmsilone, dexamethasone, betamethasone, or t ⁇ arncinolone acetomde; antitussives, e.g. noscapine; bronchodilators, e g ephednne, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, salbutamol, albuterol, salmeterol, terbutalme, diuretics, e.g. amilonde, anticholinergics, e.g.
  • ipatropium ipatropium, atropine, or oxitropium
  • lung surfactants e.g Surfaxin, Exosurf, Survanta
  • xanthines e.g aminophyllme, theophylline, caffeine
  • therapeutic proteins and peptides e.g.
  • macrophage activation factors such as lymphokines and muramyl dipeptides, opioid peptides and neuropeptides such as enkaphalins, e ⁇ dorphins, remn inhibitors, cholecystokimns, growth hormones, leukotnene inhibitors, ⁇ antitrypsin, and the like.
  • RNA or DNA sequence may be incorporated in the disclosed dispersions as described herein.
  • Representative DNA plasmids include, but are not limited to pCMV ⁇ (available from Genzyme Corp, Framington, MA) and pCMV ⁇ gal (a CMV promotor linked to the E coli Lac Z gene, which codes for the enzyme ⁇ galactosidase)
  • the selected bioactive agent(s) may be associated 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 Similarly, the incorporated bioactive agent may be associated with the discontinuous phase of a reverse emulsion.
  • the structural matrix, perforated microstructure, relativ ⁇ ly non porous particle or discontinuous phase may comprise, incorporate, adsorb, absorb, be coated with, or be formed by the bioactive agent.
  • the medicaments may be used in the form of salts (e g. alkali metal or amine salts or as acid addition salts), or as esters, or as solvates (hydrates).
  • the form of the bioactive agents may be selected to optimize the activity and/or stability of the medicament and/or, to minimize the solubility of the medicament in the suspension medium
  • 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 individually in separate species that are combined in the suspension medium or continuous phase
  • two or more bioactive agents may be incorporated in a single feed stock preparation and spray d ⁇ ed to provide a single microstructure species comprising a plurality of medicaments
  • 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 delivery systems as described below
  • the perforated microstructures (with or without an associated medicament) may be combined with one or more conventionally micronized bioactive agents to provide the desired dispersion stability
  • bioactive agents may be incorporated in the disclosed stabilized dispersions Accordingly, the list of preferred bioactive agents above is exemplary only and not intended to be limiting. It will also be appreciated by those skilled in the art that, the proper amount of bioactive agent and the timing of the dosages may be determin ⁇ d for the formulations in accordance with already existing information and without undue expe ⁇ mentation
  • perforated microstructures of the present invention may be associated with, or incorporated in the perforated microstructures of the present invention Similarly, several techniques may be used to provide particulates having the desired morphology (e g a perforated or hollow/porous configuration) and density Among other methods, perforated microstructures compatible with the instant invention may be formed by techniques including lyophilization, spray drying, multiple emulsion, micronization, or crystallization It will further be appreciated that the basic concepts of many of these techniques are well known in the prior art and would not, in view of the teachings herein, require undue experimentation to adapt them so as to provide the desired perforated microstructures.
  • spray drying is a one step process that converts a liquid feed to a dried particulate form
  • spray drying has been used to provide powdered material for various administrative routes including inhalation See, for example, M Sacchetti and M M Van Oort in- Inhalation Aerosols. Physical and Biological Basis for Therapy, A.J. Hickey, ed Marcel Dekkar, New York, 1996, which is incorporated herein by reference
  • spray drying consists of bringing together 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 be 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 the dried product to a collector.
  • the spent air is then exhausted with the solvent.
  • apparatus may be used to provide the desired product. For example, commercial spray dryers manufactured by Buchi
  • these spray dryers and specifically their atomizers, may be modified or customized for specialized applications, e.g. the simultaneous spraying of two solutions using a double nozzle technique. More specifically, a water-m-oil emulsion can be atomized from one nozzle and a solution containing an anti adherent 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.
  • HPLC high pressure liquid chromatography
  • spray-dned particles While typical spray-dned particles are approximately spherical in shape, nearly uniform in size and frequently hollow, there may be some degree of irregularity in shape depending upon the incorporated medicament and the spray drying conditions. In many instances the dispersion stability of spray-dned microspheres appears to be more effective if an inflating agent (or blowing agent) is used in their production. Particularly preferred embodiments may comprise, an emulsion with the inflating agent as the disperse or continuous phase (the other phase being 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 5000 to 15,000 psi
  • a surfactant solution using, for instance, a commercially available microfluidizer at a pressure of about 5000 to 15,000 psi
  • This process forms an emulsion, preferably stabilized by an incorporated surfactant, typically compnsing submicro ⁇ droplets of water immiscible blowing agent dispersed in an aqueous continuous phase.
  • the formation of such dispersions using this and other techniques are common and well known to those in the art.
  • the blowing agent is preferably a fluonnated compound (e.g.
  • blowing agents include chloroform, Freons and hydrocarbons. Nitrogen gas and carbon dioxide are also contemplated as a suitable blowing agent.
  • the perforated microstructures are preferably formed using a blowing agent as described above, it will be appreciated that, in some instances, no blowing agent is required and an aqueous dispersion of the medicament and surfactant(s) are spray dried directly.
  • the formulation may be amenable to process conditions (e.g., elevated temperatures) that generally lead to the formation of hollow, relatively porous microparttcles.
  • the medicament may possess special physicochemical properties such as, high crystallinity, elevated melting temperature, surface 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 the blowing agent, its concentration in the feed stock (i.e. as an emulsion), and the spray drying conditions
  • the use of compounds, heretofore unappreciated as blowing agents may provide perforated microstructures having particularly desirable characteristics
  • fluonnated compounds having relatively high boiling points i e greater than about 60°C
  • fluonnated 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.
  • blowing agents with relatively low water solubility ( ⁇ 10 6 M) are preferred since they enable the production of stable emulsion dispersions with mean weighted particle diameters less than 0 3 ⁇ m
  • these blowing agents will preferably be incorporated in an emulsified feed stock prior to spray drying
  • this feed stock will also preferably compnse one or more bioactive agents, one or more surfactants, or one or more excipients.
  • combinations of the aforementioned components are also within the scope of the invention.
  • the spray dried perforated microstructures 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 caused by residual blowing agent
  • this retained fluonnated blowing agent may alter the surface characteristics of the perforated microstructures and further increase the stability of the respiratory dispersions.
  • the residual blowing agent can generally be removed relatively easily with a post-production evaporation step in a vacuum oven.
  • pores may be formed by spray drying a bioactive agent and an excipient that can be removed from the formed microspheres under a vacuum.
  • blowing agent concentrations in the feed stock are between 5% and 100% w/v, and more preferably between about 20% to 90% w/v In other embodiments blowing agent concentrations will preferably be greater than about 10%, 20%, 30%, 40% 50% or even 60% w/v.
  • feed stock emulsions may comprise 70%, 80%, 90% or even 95% w/v of the selected high boiling point compound.
  • another method of identifying the concentration of blowing agent used in the feed is to provide it as a ratio of the concentration of the blowing agent to that of the stabilizing surfactant (i e phospholipid) in the precursor emulsion
  • the ratio may be termed a perfluorocarbon/phosphatidylcholine ratio (or PFC/PC ratio). While phosphotidylcholme is a preferred surfactant, those skilled in the art will appreciate that other surfactants may provide acceptable emulsions and may be substituted therefore In any event, the PFC/PC ratio will typically range from about 1 to about
  • the ratio will generally be greater than about 5, 10, 20, 25, 30, 40 or even 50.
  • PFC/PC ratios typically lead to particulates exhibiting greater porosity.
  • altering the PFC/PC ratio in the feed stock emulsion may advantageously control the morphology of the resulting microstructures
  • the use of higher PFC/PC ratios tends to provide structures of a more hollow and porous nature. More particularly, those methods employing a PFC/PC ratio of greater than about 4 8 tended to provide structures that are particularly compatible with the dispersions disclosed herein.
  • the inflating agent can be any mat ⁇ al that will turn to a gas at some point during the spray drying or post production process.
  • Suitable agents include: 1 Dissolved low boiling (below 100 C) solvents with limited irascibility with aqueous solutions, such as methylene chloride, acetone and carbon disulfide used to saturate the solution at room temperature. 2. A gas, e.g. C0 2 or N 2 , used to saturate the solution at room temperature and elevated pressure (e.g. 3 bar). The droplets are then supersaturated with the gas at 1 atmosphere and 100 C.
  • Emulsions of immiscible low boiling (below 100 C) liquids such as Freon 1 13, perfluoropentane, perfluorohexane, perfluorobutane, pentane, butane, FC 1 1, FC 11 B1, FC 11 B2, FC 12B2, FC 21, FC-21 B1, FC 21 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 1 112, FC 1121 and FC-1 131.
  • Freon 1 13 perfluoropentane, perfluorohexane, perfluorobutane, pentane, butane, FC 1 1, FC 11 B1, FC 11 B2, FC 12B2, FC 21, FC-21 B1, FC 21 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
  • these lower boiling point inflating agents are typically added to the feed stock in quantities of about 1 % to 80% w/v of the surfactant solution Approximately 30% w/v inflating agent has been found to produce a spray dried powder that may be used to form the stabilized dispersions of the present invention. Regardless of which blowing agent is ultimately selected, it has been found that compatible perforated microstructures may be produced particularly efficiently using a Buchi mini spray drier (model B
  • the inlet temperature and the outlet temperature 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 the desired activity of the medicament.
  • the inlet and outlet temperatures are adjusted depending on the melting characteristics of the formulation components and the composition of the feed stock
  • the inlet temperature may thus be between 60°C and 170°C, with the outlet temperatures of about 40°C to 120°C depending on the composition of the feed and the desired particulate characteristics
  • these temperatures will be from 90°C to 120°C for the inlet and from 60°C to 90°C for the outlet.
  • the flow rate that is used in the spray drying equipment will generally be about 3 ml per minute to about 15 ml per minute.
  • the atomizer 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 empi ⁇ cal testing, with due reference to the examples that follow Of course, the conditions may be adjusted so as to preserve biological activity in larger molecules such as proteins or peptides.
  • Particularly preferred embodiments 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 comp ⁇ se an excipient comprising a hydrophilic moiety such as, for example, a carbohydrate (i.e. glucose, lactose, or starch) in addition to any selected surfactant.
  • starches and denvatized starches suitable for use in the present invention 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 isotonicity, 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 isotonicity, hyperosmola ⁇ ty, or hyposmola ⁇ ty
  • suitable salts include sodium phosphate (both monobasic and dibasic), sodium chlo ⁇ de, calcium phosphate, calcium chloride and other physiologically acceptable 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. It will also be appreciated that the drug may be incorporated in the form of a solid particulate dispersion
  • concentration of the drug used is dependent on the dose of drug required in the final powder and the performance of the MDI drug suspension (e g , fine particle dose).
  • cosurfactants such as poloxamer 188 or span 80 may be added to this annex solution.
  • an oil in water emulsion is then formed in a separate vessel
  • the oil employed is preferably a fluorocarbon (e.g., perfluorooctyl bromide, perfluorodecalin) which is emulsified using a surfactant such as a long chain saturated phospholipid.
  • a fluorocarbon e.g., perfluorooctyl bromide, perfluorodecalin
  • 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.
  • Typical 5 to 25 g of fluorocarbon is added dropwise to the dispersed surfactant solution while mixing.
  • the resulting perfluorocarbon in water emulsion is then processed using a high pressure homogemzer to reduce the particle size
  • the emulsion is processed at 12,000 to 18,000 psi for 5 discrete passes and kept at 50 to 80°C.
  • the drug solution and perfluorocarbon emulsion are then combined and fed into the spray dryer.
  • the two preparations will be miscible as the emulsion will preferably comprise an aqueous continuous phase.
  • the bioactive agent is solubi zed separately for the purposes of the instant discussion it will be appreciated that, in other embodiments, the bioactive agent may be solubilized (or dispersed) directly in the emulsion In such cases, the bioactive emulsion is simply spray dried without combining a separate drug preparation.
  • operating conditions such as inlet and outlet temperature, feed 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 the 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 100% and an atomization air flow rate between 1,200 to 2,800 L/hr.
  • the selection of appropriate apparatus and processing conditions are well within the purview of a skilled artisan in view of the teachings herein and may be accomplished without undue experimentation.
  • the use of these and substantially equivalent methods provide for the formation of hollow porous aerodynamically light microspheres with particle diameters appropriate for aerosol deposition into the lung.
  • the perforated microstructures of the present invention may be formed by lyophilization.
  • lyophilization is a freeze-drying process in which water is sublimed from the composition after it is frozen.
  • biologicals and pharmaceuticals that are relatively unstable in an aqueous solution can be d ⁇ ed without elevated temperatures (thereby eliminating the adverse thermal effects), and then stored in a dry state where there are few stability problems.
  • the perforated microstructures of the present invention may also be formed using a double emulsion method.
  • the double emulsion method the medicament is first dispersed in a polymer dissolved in an organic solvent (e g methylene chloride) by sonication or homogenization.
  • This primary emulsion is then stabilized by forming a multiple emulsion in a continuous aqueous phase containing an emulsifier such as polyvinylalcohol Evaporation or extraction using conventional techniques and apparatus then removes the organic solvent.
  • an emulsifier such as polyvinylalcohol Evaporation or extraction using conventional techniques and apparatus then removes the organic solvent.
  • the resulting microspheres are washed, filtered and dried pnor to combining them with an appropriate suspension medium in accordance with the present invention.
  • the selected suspension media used to provide the desired stabilized dispersion is preferably compatible with pulmonary administration.
  • the selected suspension medium should be biocompatible (i.e. relatively non toxic) and non reactive with respect to the suspended perforated microstructures comprising the bioactive agent
  • Preferred embodiments comp ⁇ se suspension media selected from the group consisting of fluorochemicais, fluorocarbons (including those substituted with other halogens), perfluorocarbo ⁇ s, fluorocarbon/hydrocarbon diblocks, hydrocarbons, alcohols, ethers, or combinations thereof
  • the suspension medium may comprise a mixture of various compounds selected to impart specific characteristics.
  • the perforated microstructures are preferably insoluble in the suspension medium, thereby 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 select ⁇ d suspension medium is bact ⁇ nostatic.
  • the suspension media may comprise any one of a number of different compounds including hydrocarbons, fluorocarbons or hydrocarbon/fluorocarbon diblocks
  • the contemplated hydrocarbons or highly fluonnated or perfluon ⁇ ated compounds may be linear, branched or cyclic, saturated or unsaturated compounds
  • Conventional structural de ⁇ vatives of these fluorochemicais and hydrocarbons are also contemplated as being within the scope of the present invention.
  • Selected embodiments comprising these totally or partially fluonnated compounds may contain one or more hetero atoms including bromine or chlorine.
  • these fluorochemicais comprise from 1 to 16 carbon atoms and include, but are not limited to, linear, cyclic or polycyclic perfluoroalkanes, b ⁇ s(perfluoroalkyl)alkenes, perfluoroethers, perfluoroamines, perfiuoroalkyl bromides and perfiuoroalkyl chlorides such as dichlorooctane.
  • Particularly preferred fluonnated compounds for use in the suspension medium may comprise perfluorooctyl bromide, C ⁇ F, 7 Br (PFOB or perflubron), dichlorofluorooctane C ⁇ F, 6 CI 2 , and the hydrofluoroalkane perfluorooctyl ethane C e F, 7 C 2 H 5 (PFOE).
  • the suspension medium will comp ⁇ se a compound (particularly a fluorochemical) having a positive spreading coefficient
  • Other useful preparations may comprise perfluorohexane or perfluoropentane as suspension media.
  • 1 bromo F butane n C 4 F g Br
  • 1 bromo F hexane n C 6 F, 3 Br
  • Fluorocarbons, fluorocarbon-hydrocarbo ⁇ compounds and halogenated fluorochemicais containing other linkage groups, such as esters, thioethers and amines are also suitable for use as suspension media in the present invention.
  • CH CHC m F 2m ,
  • F ⁇ 36E), and C B F, 3 CH CHC 6 F, 3 (F 6BE)) where n and m are the same or different and n and m are integers from about 2 to about 12 are compatible with teachings herein.
  • Polycyclic and cyclic fluorochemicais such as C, 0 F, 8 (F deca n or perfluorodecalin), perfluoroperhydrophenanthrene, perfluorotetramethylcyclohexane (AP-144) and perfluoro n butyldecalin are also within the scope of the invention
  • Additional useful fluorochemicais include perfluo ⁇ nated amines, such as F t ⁇ propylamine (“FTPA”) and F t ⁇ butylamine (“FTBA”).
  • FMOQ F 4-methyloctahydroqu ⁇ nol ⁇ z ⁇ ne
  • FMIQ F N-methyl- decahydroisoquinoline
  • FHQ F N methyldecahydroquinoline
  • FCHP F 2 butyltetrahydrofuran
  • Still other useful fluonnated compounds include perfluorophe ⁇ anthrene, p ⁇ rfluoromethyldecalin, perfluorodimethylethyicyclohexan ⁇ , perfluorodimethyldecalin, perfluorodiethyldecalin, perfluoromethyladamantane, perfluorodimethyiadamantane.
  • fluorochemicais having ⁇ onfluo ⁇ e substituents, such as, perfluorooctyl hydride, and similar compounds having different numbers of carbon atoms are also useful.
  • va ⁇ ously modified fluorochemicais are encompassed within the broad definition of fluorochemical as used in the instant application and suitable for use in the present invention.
  • fluorochemical as used in the instant application and suitable for use in the present invention.
  • each of the foregoing compounds may be used, alone or in combination with other compounds to form the stabilized dispersions of the present invention.
  • fluorocarbons or classes of fluonnated compounds, that may be useful as suspension media include, but are not limited to, fluoroheptane, fluorocycloheptane fluoromethylcycloheptane, fluorohexane.
  • fluorocyclohexane fluoropentane, fluorocyclopentane, fluoromethylcyclopentane, fluorodimethylcyclopentanes, fluoromethylcyclobutane, fluorodimethylcyclobutane, fluorot ⁇ methylcyclobutane, fluorobutane, fluorocyclobutane, fluoropropane, fluoroethers, fluoropolyethers and fluorot ⁇ ethylami ⁇ s
  • fluorocyclohexane fluoropentane, fluorocyclopentane, fluoromethylcyclopentane, fluorodimethylcyclopentanes, fluoromethylcyclobutane, fluorodimethylcyclobutane, fluorot ⁇ methylcyclobutane, fluorobutane, fluorocyclobutane, fluoropropane, fluoroethers, fluoropolyethers and fluorot ⁇ ethylami ⁇ s
  • the selected suspension medium will preferably have a vapor pressure less than about 5 atmospheres and more preferably less than about 2 atmospheres 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
  • Such suspension media may be used in conjunction with compressed air nebulizers, ultrasonic nebulizers or with mechanical atomizers to provide effective ventilation therapy.
  • more volatile compounds may be mixed with lower vapor pressure components to provide suspension media having specified physical charactenstics selected to further improve stability or enhance the bioavailability of the dispersed bioactive agent.
  • suspension media that boil at selected temperatures under ambient conditions d e. 1 atmosphere).
  • preferred embodiments will comprise 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 selected suspension media compound may boil at or above human body temperature (i.e. 37°C), above 45°C, 55°C, 65°C,
  • the stabilized suspensions or dispersions of the present invention may be prepared by dispersal of the microstructures in the selected suspension medium, which may then be placed in a container or reservoir
  • the stabilized preparations of the present 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 energy to aid in dispersion e.g. with the aid of sonication
  • the components may be mixed by simple shaking or other type of agitation The process is preferably earned out under anhydrous conditions to obviate any adverse effects of moisture on suspension stability. Once formed, the dispersion has a reduced susceptibility to flocculation and sedimentation.
  • osmotic agents 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 Considerations such as sterility, isotonicity, and biocompatibility may govern the use of conventional additives to the disclosed compositions.
  • the use of such agents will be understood to those of ordinary skill in the art and, the specific quantities, ratios, and types of agents can be determined empirically without undue expenmentation
  • the stabilized suspensions or dispersions of the present invention may be prepared by dispersal of the microstructures in the selected suspension medium that may then be placed in a container or reservoir.
  • the stabilized preparations of the present invention can be made by simply combining the components in sufficient quantity to produce the final desired dispersion concentration That is, the components of the preparations may be combined to provide a respiratory blend.
  • the microstructures readily disperse without mechanical energy, the application of mechanical energy (e.g. sonication) to the respiratory blend to mix the components or aid in their dispersion is contemplated.
  • the components may be mixed by simple shaking or other type of agitation
  • the process is preferably carried out under anhydrous conditions to obviate any adverse effects of moisture on suspension stability. Once formed, the dispersion has a reduced susceptibility to flocculation and sedimentation
  • the stabilized preparations 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, the formulations may be supplied as stable, preformed dispersions ready for administration or, as separate ready to mix components.
  • the dispersions When provided in a ready to use form, the dispersions may be packaged in single use containers or reservoirs (e.g. in glass vials comprising a few milliliters of the dispersion) or in multi use containers or reservoirs.
  • the stabilized preparations may then be formed at any time prior to use by simply combining the contents of the containers as directed.
  • kits may contain a number of ready to mix, or prepackaged dispersions in a single use form so that the user can readily select or modify the therapeutic regimen for the particular indication.
  • each of the containers may be fitted with a septum for direct removal of the dispersion or with appropriate tubing, cannulas, Luer fittings, etc. for association with a ventilator or endotracheal apparatus.
  • kits may optionally include a bronchoscope or endotracheal apparatus (or components thereof) for administration of the preparations.
  • bioactive agent may be indicated for the treatment of mild, moderate or severe, acute or chronic symptoms or for prophylactic treatment.
  • the bioactive agent may be administered to treat local or systemic conditions or disorders.
  • one particularly preferred embodiment comprises the systemic administration (e.g. delivery to the systemic circulation of a patient via the pulmonary air passages) of a bioactive agent
  • systemic administration e.g. delivery to the systemic circulation of a patient via the pulmonary air passages
  • the precise dose administered will depend on the age and condition of the patient, the particular medicament used and the frequency of administration and will ultimately be at the discretion of the attendant physician
  • the dose of each agent will generally be that employed for each agent when used alone.
  • the stabilized dispersions are preferably used in conjunction with partial liquid ventilation or total liquid ventilation.
  • the present invention may further comprise introducing a therapeutically beneficial amount of a physiologically acceptable gas (such as nitric oxide or oxygen) into the pharmaceutical microdisp ⁇ rsio ⁇ p ⁇ or to, du ⁇ ng or following administration.
  • a physiologically acceptable gas such as nitric oxide or oxygen
  • compositions of the present invention may be administered to the lung using a pulmonary delivery conduit.
  • pulmonary delivery conduit shall be construed in a broad sense to comprise any device or apparatus, or component thereof, that provides for the instillation or administration of a liquid in the lungs.
  • a pulmonary delivery conduit or delivery conduit shall be held to mean any bore, lumen, catheter, tube, conduit, syringe, actuator, mouthpiece, endotracheal tube or bronchoscope that provides for the administration or instillation of the disclosed dispersions to at least a portion of the pulmonary air passag ⁇ s of a patient in need thereof.
  • the delivery conduit may or may not be associated with a liquid ventilator or gas ventilator.
  • the delivery conduit shall comprise an endotracheal tube or bronchoscope.
  • liquid dose instillation preferably involves the instillation of the perforated microstructures in a suitable suspension medium to an mtubated patient through an endotracheal tube, or to a free breathing patient via bronchoscope
  • Other embodiments comprise the administration of the disclosed dispersions directly into the throat. That is, the formulations of the present invention may be "trickled" into the lungs of the patient as a bolus using standard tubing and/or a sy ⁇ nge.
  • the dispersions of the present invention may be administered to ventilated (e.g.
  • the methods and systems of the present invention may comprise the use or inclusion of a mechanical ventilator.
  • the stabilized dispersions of the present invention may also be used as a lavage agent to remove debris in the lung, or for diagnostic lavage procedures.
  • introduction of liquids, particularly fluorochemicais, into the lungs of a patient is well known and could be accomplished by a skilled artisan in possession of the instant specification without undue expe ⁇ m ⁇ ntation.
  • the disclosed dispersions are preferably administered directly to at least a portion of the pulmonary air passages of a mammal.
  • the terms "direct instillation” or “direct administration” shall be held to mean the introduction of a stabilized dispersion into the lung cavity of a mammal. That is, the dispersion will preferably be administered through the trachea of a patient and into the lungs as a liquid. While the dispersions may be administered in the form of an aerosol or nebulized liquid, they will preferably be introduced as a volume of a relatively free flowing liquid passing through a delivery conduit and into the pulmonary air passages.
  • the flow of the dispersion may be gravity assisted or may be afforded by induced pressure such as through a pump or the compression of a syringe plunger.
  • the amount of dispersion administered may be monitored by mechanical devices such as flow meters or by visual inspection
  • liquid ventilation involves the introduction of a respiratory promoter (typically a fluorochemical) to the lung for the promotion of physiological gas exchange.
  • a respiratory promoter typically a fluorochemical
  • the patient is preferably ventilated using a mechanical ventilator following pulmonary introduction of the liquid
  • the respiratory promoter may comprise a stabilized dispersion.
  • perforated microparticles comprising penicillin may be suspended in perfluorooctyl bromide to provide a stabilized dispersion that could be used for liquid ventilation. This dispersion could then be administered, at any volume up to functional residual capacity (FRC), to the lung of a patient as desenbed in U.S. Pat. Nos.
  • a concentrated, but relatively stable, dispersion could be packaged in a single dose configuration having a total volume on the order of a few milliliters or less. It will be appreciated that the relatively small volume could be administered directly to the lung However, in preferred embodiments this concentrated dispersion could be mixed with a larger volume of neat respiratory promoter (which may be the same or different as the suspension medium) p ⁇ or to introduction to the lung In still other embodiments the concentrated dispersion could be administered directly to the lung of a patient already containing respiratory promoter.
  • the bioactive agent suspension may be top loaded onto an existing volume of a fluorochemical.
  • the respiratory promoter and/or suspension medium will provide for the efficient dispersal and deposition of the bioactive perforated microspheres on the lung membrane. More specifically, by providing for the administration of bioactive agents in what can be a relatively anhydrous environment, ⁇ .e. in a fluorochemical, physiological uptake of the agent may be dramatically increased.
  • lung surfactants such as phospholipids
  • phospholipids As discussed more fully in Example XIV below the adsorption time for surfactant is exponentially decreased when it is brought into contact with a wetted surface (lung membrane) by a fluorochemical as opposed to an aqueous solution This is because adsorption of the surfactant from an anhydrous suspension medium into an aqueous environm ⁇ nt is th ⁇ rmodynamically very favorable.
  • particularly preferred embodiments of the present invention comp ⁇ se perforated microstructures associated with, or incorporating, natural or synthetic surfactants distributed in a fluorochemical suspension medium
  • the stabilized dispersions may be administered up to the functional residual capacity of the lungs of a patient
  • selected embodiments will comp ⁇ se the pulmonary administration of much smaller volumes (e.g. on the order of a milliliter or less).
  • the volume administered may be on the order of 1, 3, 5, 10, 20, 50, 100, 200 or 500 milliliters.
  • the liquid volume is less than 0.25 or 0.5 percent FRC
  • the liquid volume is 0.1 percent FRC or less
  • the wettabi ty and spreading characteristics of the suspension media will facilitate the even distribution of the bioactive agent in the lung
  • LDI treatment as disclosed herein represents a new alternative for critically ill patients on mechanical ventilators, and opens the door for treatment of less ill patients with bronchoscopic administration
  • the stabilized dispersions of the present invention are particularly suitable for the pulmonary administration of bioactive agents, they may also be used for the localized or systemic administration of compounds to any location of the body. Accordingly, it should be emphasized that, in preferred embodiments, the formulations may be administered using a number of different routes including, but not limited to, the gastrointestinal tract, the respiratory tract, topically, intramuscularly, intrape ⁇ toneally, nasally, vaginally, rectally, aurally, orally or ocular. More generally, the stabilized dispersions of the present invention may be used to deliver agents topically or by administration to a non pulmonary body cavity.
  • the body cavity is selected from the group consisting of the pentoneum, sinus cavity, rectum, urethra, gastrointestinal tract, nasal cavity, vagina, auditory meatus, oral cavity, buccal pouch and pleura
  • stabilized dispersions compnsing the appropriate bioactive agent e g. an antibiotic or an anti inflammatory
  • the appropriate bioactive agent e g. an antibiotic or an anti inflammatory
  • the dispersions of the pres ⁇ nt invention may be used to selectively deliver pharmaceutical compounds to the lining of the stomach for the treatment of H. pylon infections or other ulcer related disorders.
  • Perforated microstructures comprising gentamicin sulfate were prepared by a spray drying technique using a B 191 Mini Spray Drier (Buchi, Flawil, Switzerland) under the following conditions- aspiration: 100%, inlet temperature: 85°C, outlet temperature. 61 °C, feed pump 10%; N 2 flow. 2,800 L/hr. Variations in powder porosity were examined as a function of the blowing agent concentration.
  • Fluorocarbon m-water emulsions of perfluorooctyl bromide containing a 1.1 w/w ratio of phosphatidylchohne (PC), and gentamicin sulfate were prepared varying only the PFC/PC ratio 1 3 grams of hydrogenated egg phosphatidylchohne was dispersed in 25 mL deionized water using an Ultra-Turrax mixer
  • PFC/PC ratios For example, the formulation devoid of perfluorooctyl bromide produced microstructures that appeared to be highly agglomerated and readily adhered to the surface of the glass vial Similarly, smooth, spherically shaped microparticles were obtain ⁇ d wh ⁇ n relatively little (PFC/PC ratio - 1 .1 or 2.2) blowing agent was used. However, as the PFC/PC ratio increased, the particles showed dramatic increases in porosity and surface roughness.
  • both the hollow nature and wall thickness of the 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 walls appeared to decrease as the PFC/PC ratio increased.
  • Substantially non-porous, relatively solid structures were obtained from formulations containing little or no fluorocarbon blowing agent.
  • the perforated microstructures produced using a relatively high PFC /PC ratio of approximately 45 proved to be extremely 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.
  • Hollow porous albuterol sulfate particles were prepared by a spray drying technique with a B 191 Mini Spray-Drier (Buchi, Flawil, Switzerland) under the following spray conditions: aspiration: 100%, inlet temperature: 85°C; outlet t ⁇ mp ⁇ ratur ⁇ : 61 °C; f ⁇ ed pump- 10%; N 2 flow: 2,800 L/hr
  • the feed solution was prepared by mixing two solutions A and B immediately prior to spray drying.
  • Solution A 20g of water was used to dissolve 1 g of albuterol sulfate (Accurate Chemical, Westbury, NY) and 0.021 g of poloxamer 188 NF grade (BASF, Mount Olive, NJ).
  • Solution B' A fluorocarbon in water emulsion stabilized by phospholipid was prepared in the following manner.
  • the phospholipid 1 g EPC-100 3 (Lipoid KG, Ludwigshafen, Germany), was homogenized in 150g of hot deionized water (T - 50 to 60°C) using an Ultra Turrax mixer (model T 25) at 8000 rpm for 2 to
  • Solutions A and B were combined and fed into the spray-dryer under the conditions described above.
  • 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, Amherst Process Instruments, Amherst, MA). Scanning electron microscopy
  • Porous Particulate Microstructures Comprising Mixture of Long-Chai ⁇ /Short-Chai ⁇ Phospholipids and Albuterol Sulfate
  • a dispersion for spray drying was prepared as described in Example III above, with the difference that 1 g of DSPC was dispersed with 100 mg of a short chain phospholipid, dioctylphosphatidylcholine (DOPC) (Avanti Polar Lipids, Alabaster, Alabama).
  • DOPC dioctylphosphatidylcholine
  • the composition of the spray feed is shown in Table II immediat ⁇ ly below. The resulting yield was 50%
  • Perforated microstructures comprising cromolyn sodium were prepared by a spray drying technique with a B 191 Mini Spray Drier (Buchi, Flawil, Switzerland) und ⁇ r th ⁇ following spray conditions- aspiration
  • Solution A 20g of water was used to dissolve 1 g of cromolyn sodium (Sigma Chemical Co, St. Louis, MO) and 0 021 g of poloxamer 188 NF grade (BASF, Mount Olive, NJ).
  • the hollow porous cromolyn sodium particles had a volume weighted mean aerodynamic diameter of 1 23 ⁇ 1 31 ⁇ m as determined by a t ⁇ me-of-fl ⁇ ght 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 resulting coarse emulsion was then passed through a high pressure homogenizer (Avestin, Ottawa, Canada) at 18,000 psi for 5 passes. This emulsion was then used to form the feed stock that was spray dned as desc ⁇ bed 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 t ⁇ amcinolone acetomde
  • the feed stock was prepar ⁇ d by mixing 0 57g of lactose with a fluorocarbon in water emulsion immediately prior to spray drying.
  • the emulsion was prepared by the technique described below.
  • Solution B A fluorocarbon in water emulsion stabilized by phospholipid was prepared in th ⁇ following way.
  • the phospholipid 0.52g EPC 100 3 (Lipoid KG, Ludwigshafen, Germany), was homogenized in 87g of hot deionized water (T - 50 to 60°C) using an Ultra Turrax mixer (model T 25) at 8000 rpm for 2 to 5 minutes (T - 60-70°C). 13g of perflubron (Atochem, Pans, France) was added dropwise during mixing. After the fluorocarbon was added, the emulsion was mixed for at least 4 minutes. The resulting coarse emulsion was then passed through a high pressure homogenizer (Avestin, Ottawa, Canada) at 18,000 psi for 5 passes.
  • the hollow porous DNase I particles had a volume weighted mean aerodynamic diamet ⁇ r of 1.29 ⁇ 1 40 ⁇ m as d ⁇ t ⁇ 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 Th ⁇ tap density of the powder was determined to be less than 0.1 g/cm 3 .
  • the foregoing example further illustrates the extraordinary compatibility of the present invention with a variety of bioactive agents. That is, in addition to relatively small hardy compounds such as steroids, the preparations of the present invention may be foimulated to effectively incorporate larger, fragile molecul ⁇ s such as peptides, proteins and genetic mate ⁇ al.
  • Poloxamer 188 (BASF, Mount Olive, NJ)
  • the resulting dry, free flowing, hollow, spherical product had a mean particle diameter of 2 6 ⁇ 1.5 ⁇ m.
  • the particles which may be used for the replacement 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 selected porosity.
  • HES Hydroxyethyl starch
  • DPPC dipalmitoylphosphatidylcholme
  • HAS Hydroxy ⁇ thyl starch
  • DPPC dipalmitoylphosphatidylcholine
  • 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 fed at a rate of 5 5 ml/mm. The inlet and outlet temperatures of the spray dryer were 80 C and 45 C respectively. The nebuhzation air and aspiration flows were 1,800 L/hr and 100% respectively. A free flowing, white powder comprising porous microspheres was obtained.
  • Nitrobenzoyldiol Phosphatidylchohne (Avanti Polar Lipids, Alabaster, AL) 17.6% w/w Hydroxyethyl starch (Ajinomoto, Japan) 82.2% w/w Dipalmitoylphosphatidylcholine (Genzym ⁇ , Cambndg ⁇ , MA) Perfluorohexane (3M, St. Paul, MN) Deionized wat ⁇ r
  • DPPC Dipalmitoylphosphatidylcholine
  • NBD PC nitrobenzoyldiol phosphatidylchohne
  • HES Hydroxyethyl starch
  • DPPC dipalmitoylphosphatidyl choline
  • T 45 50 C
  • NBD PC/DPPC/HES dispersion was chilled in an ice bath.
  • Perfluorohexane PFH, 4.11 g
  • T 5 10 C
  • the samples were analyzed for their surface properties using the Pulsating Bubble Surfactomet ⁇ r at 37 C (model EC PBS B, Electronics, Amherst, NY) according to the manufacturers instructions
  • Surfactant solutions were allowed to adsorb at minimum bubble diameter for 10 seconds, and bubble cycling was performed in the automatic mode (20 cycl ⁇ s/minut ⁇ ) For each ⁇ xpe ⁇ m ⁇ nt, measurements were taken for approximately the first 10 cycles, then again at 2, 4, and 6 minutes
  • the main difference observ ⁇ d b ⁇ tw ⁇ n the neat and spray dried surfactant suspensions is the rate at which they adsorb to the bubble surface and thus lower the tension.
  • the spray dried mate ⁇ als required 6 cycles to achieve low surface tension as compared with one cycl ⁇ for th ⁇ Alv ⁇ ofact sample Howev ⁇ r, th ⁇ magnitude of th ⁇ tension at maximum, and minimum bubble diameter were found to be approximately the same.
  • th ⁇ t ⁇ nsion decreased from 32 mN/m at maximum diamet ⁇ r to 4 mN/m at minimum in the first cycle
  • a steady state oscillation was reached with a maximum tension m ⁇ 33 mN/m and a minimum tension mn 0 to 1 mN/m.
  • Stabilized dispersions formed according to the present invention provide for enhanced surfactant spreading at the pulmonary air/water interface.
  • the equilibrium surface tension of dimyristoylphosphatidylcholine is ca. 22 mN/m.
  • Aqueous based liposomes are adsorbed very slowly at the air/water interface as evidenced by the fact that, after 1800 seconds, the surface tension of an aqueous solution has not been significantly reduced.
  • the slow adsorption for liposomes is due to the slow molecular diffusion of DMPC through the water phase.
  • PFOB perflubron
  • Example XI The insulin formulation desc ⁇ bed in Example XI was administered via liquid dose instillation (0.86 IU in 4.5 mi/kg of perflubron) and intramuscular (IM) to fasting rabbits.
  • IM intramuscular
  • rabbits were anesthetized, intubated, placed on a respirator, and their lungs were instilled with ca. 4.5 ml/kg of perflubron.
  • the hollow porous microsphere formulation of insulin was then top-loaded in a minimal perflubron volume onto the existing perflubron in the lung, at a dose of 0.86 lU/kg.
  • Control animals were injected IM with a similar dose of insulin (Humulin R).
  • Plasma levels of insulin were determined by a radioimmunoassay method, and th ⁇ d ⁇ cr ⁇ ase in serum glucose levels were also determined. The results are shown in Tables HI and IV. Extremely fast uptake of insulin into the syst ⁇ mic circulation was obs ⁇ rv ⁇ d following LDI administration. The relative bioavailability was found to be 53%. Little differences were noted in glucose modulation between the IM and LDI groups. These results show the utility of LDI administration in the syst ⁇ mic delivery of bioactive agents.
  • mice Male Wistar rats (ca. 500 g) were inoculated intratracheally with 10 9 colony forming units of Streptococcus pneumomae
  • the model is an acute pneumonia model with 100% of untreat ⁇ d control animals dying within 4 days of inoculation. Animals receiving 10 mg of ampicillin intramuscularly one day after inoculation exhibited improved survival with 27% of the animals surviving to 10 days. Animals receiving 10 mg of ampicillin (prepared according to Example X) in 10 ml of perflubron via LDI administration exhibited a survival of 87%.
  • Ampicillin concentrations in lung tissue and serum were measured for the two treatm ⁇ nt groups in Exampl ⁇ XV by a bioassay m ⁇ thod.
  • 60 ⁇ l of lung tissue homogenate, or serum obtained from the rats at various points after dosing is placed on a ste ⁇ l ⁇ disk
  • the disk is then placed on an agar plate covered with S pneumomae and incubated for 24 hr.
  • Levels of antibiotic high enough to inhibit growth of S. pneumomae resulted in zones of growth inhibition around the disk The no growth zones were quantitated, and concentrations of antibiotic were calculated based on a standard curve.
  • Ampicillin pharmacokinetics in rat lung effect of mode of administration.
  • the present invention may be ⁇ mbodi ⁇ d in other specific forms without departing from the spint or central attributes thereof.
  • desc ⁇ ption of the present invention discloses only exemplary embodiments ther ⁇ of, it is to b ⁇ und ⁇ rstood that, oth ⁇ r va ⁇ ations are contemplated as being within the scope of the present invention. Accordingly, the present invention is not limited to the particular embodiments that have been desc ⁇ b ⁇ d in detail herein. Rather, ref ⁇ rence should be made to the appended claims as indicative of the scope and content of the invention.

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