US20080230053A1 - Pulse drug nebulization systems, formulations therefore, and methods of use - Google Patents

Pulse drug nebulization systems, formulations therefore, and methods of use Download PDF

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Publication number
US20080230053A1
US20080230053A1 US11/855,870 US85587007A US2008230053A1 US 20080230053 A1 US20080230053 A1 US 20080230053A1 US 85587007 A US85587007 A US 85587007A US 2008230053 A1 US2008230053 A1 US 2008230053A1
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Prior art keywords
oil
drug
pulmonary
nebulizing
composition
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US11/855,870
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English (en)
Inventor
Edward R. Kraft
Perenlei Enkhbaatar
Daniel L. Traber
Gabriela A. Kulp
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University of Texas System
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University of Texas System
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Priority to US11/855,870 priority Critical patent/US20080230053A1/en
Publication of US20080230053A1 publication Critical patent/US20080230053A1/en
Assigned to BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM reassignment BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ENKHBAATAR, PERENLEI, TRABER, DANIEL L., KRAFT, EDWARD R., KULP, GABRIELA A.
Priority to US13/423,044 priority patent/US8776786B2/en
Priority to US14/330,200 priority patent/US20150034077A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/002—Details of inhalators; Constructional features thereof with air flow regulating means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/06—Sprayers or atomisers specially adapted for therapeutic purposes of the injector type
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/04—Sprayers or atomisers specially adapted for therapeutic purposes operated by the vapour pressure of the liquid to be sprayed or atomised
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0021—Mouthpieces therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/08—Inhaling devices inserted into the nose
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/02—Spray pistols; Apparatus for discharge
    • B05B7/06—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane
    • B05B7/062—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane with only one liquid outlet and at least one gas outlet
    • B05B7/066—Spray pistols; Apparatus for discharge with at least one outlet orifice surrounding another approximately in the same plane with only one liquid outlet and at least one gas outlet with an inner liquid outlet surrounded by at least one annular gas outlet
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/02—Spray pistols; Apparatus for discharge
    • B05B7/08—Spray pistols; Apparatus for discharge with separate outlet orifices, e.g. to form parallel jets, i.e. the axis of the jets being parallel, to form intersecting jets, i.e. the axis of the jets converging but not necessarily intersecting at a point
    • B05B7/0892—Spray pistols; Apparatus for discharge with separate outlet orifices, e.g. to form parallel jets, i.e. the axis of the jets being parallel, to form intersecting jets, i.e. the axis of the jets converging but not necessarily intersecting at a point the outlet orifices for jets constituted by a liquid or a mixture containing a liquid being disposed on a circle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. mouth-to-mouth respiration; Tracheal tubes
    • A61M16/06—Respiratory or anaesthetic masks
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/0007—Special media to be introduced, removed or treated introduced into the body
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00—Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/02—Spray pistols; Apparatus for discharge
    • B05B7/08—Spray pistols; Apparatus for discharge with separate outlet orifices, e.g. to form parallel jets, i.e. the axis of the jets being parallel, to form intersecting jets, i.e. the axis of the jets converging but not necessarily intersecting at a point
    • B05B7/0876—Spray pistols; Apparatus for discharge with separate outlet orifices, e.g. to form parallel jets, i.e. the axis of the jets being parallel, to form intersecting jets, i.e. the axis of the jets converging but not necessarily intersecting at a point to form parallel jets constituted by a liquid or a mixture containing a liquid

Definitions

  • ROS reactive oxygen species
  • tocopherols are redox agents which act under certain circumstances as antioxidants. In acting as an antioxidant, tocopherols presumably prevent the formation of toxic oxidation products, such as perioxidation products formed from unsaturated fatty acids. Further, it has recently been discovered that individual members in the class of tocopherols may exhibit different biological properties from one another despite their structural similarity. Some investigators, for example, believe that ⁇ -tocopherol, unlike ⁇ -tocopherol, acts in vivo as a trap for membrane-soluble electrophilic nitrogen oxides and other electrophilic mutagens [Christen, S., et al. Proc. Natl. Acad. Sci. 94: 3217-3222 (1997].
  • Vitamin E is remarkably safe, and falls within a class of compounds that are “generally regarded as safe” or “GRAS”. Vitamin E is available in several forms that present varied activities between them. Whereas alpha-tocopherol has been widely investigated for therapeutic uses, until recently gamma-tocopherol (a form of “des-methyl tocopherol”) has received much less attention in science. However, gamma-tocopherol presents a variety of beneficial advantages over alpha-tocopherol in various considerations. In one particular regard, gamma-tocopherol has been characterized to exhibit much more potent anti-oxidant qualities, resulting in a unique anti-inflammatory activity not shared with the alpha-tocopherol.
  • GRAS general regarded as safe
  • the present invention meets these needs by providing novel, pharmaceutical compositions of tocopherols, such as gamma tocopherol, and tocopherol derivatives which are demonstrated herein to protect animals from cytotoxic injury and death, pulmonary injury, as well as other injuries and disease conditions, including inflammatory diseases, as well as methods and systems for delivering these compositions by way of nebulizing such water-insoluble drug formulations.
  • tocopherols such as gamma tocopherol, and tocopherol derivatives which are demonstrated herein to protect animals from cytotoxic injury and death, pulmonary injury, as well as other injuries and disease conditions, including inflammatory diseases, as well as methods and systems for delivering these compositions by way of nebulizing such water-insoluble drug formulations.
  • a pulmonary drug delivery system capable of nebulizing a composition comprising a water-insoluble or substantially water-insoluble drug and a fatty acid or lipid
  • the system comprises a reservoir for containing the drug composition; a reservoir for containing a propellant gas; a mechanical control valve capable of regulating the flow of the propellant gas and the drug composition; and a nebulizing nozzle adapted to receive both the drug composition and the propellant gas, wherein the nebulizing nozzle can produce aerosol droplets having a particle size ranging from about 2 ⁇ m to about 12 ⁇ m in median mass aerodynamic size.
  • formulations for nebulization of water-insoluble drugs are provided.
  • a non-aqueous medicinal aerosol composition comprising a therapeutically effective amount of an inhibitor of c-GMP-specific phosphodiesterase (PDE) type IV or type V, or a derivative, metabolite, solvate, prodrug, or polymorph thereof, and a lipid or fatty acid.
  • PDE c-GMP-specific phosphodiesterase
  • a drug nebulizing apparatus adapted for pulmonary inhalation and delivery of aerosolized medicaments into a mammalian patient
  • the apparatus comprises a reservoir containing a drug formulation and a nebulizing nozzle adapted to be fit to a breathing circuit and further attached to a face mask, wherein the nebulizing nozzle produces aerosolized droplets sized for pulmonary, inhaled drug delivery of the drug formulation, and wherein the nebulizing nozzle comprises a fluid micro-tube with an air delivery tube capable of nebulizing a fluid from the micro-tube into droplets into droplets sized for inhaled drug delivery.
  • a face mask for use in a pressurized drug delivery system
  • the face mask comprising an at least partially deformable body having a surface for placement against a face of a patient and a nose bridge section formed in an upper section of the body, a vent to the atmosphere outside of the face mask, and a connector integral to a portion of the mask, the connector defining a fluid pathway into an interior portion of the face mask and constructed to receive, under pressure, an aerosolized drug composition.
  • the face mask may be coupled to a nebulizer drug delivery system for delivering an aerosolized drug through the face mask.
  • the body of the face mask may include a bottommost surface for contacting the face when the face mask is applied against the face and the body at least partially deforms.
  • the pH of the tocopherol compositions in particular the gamma tocopherol composition, is in the range from about 2 to about 9, while in other embodiments, the pH may be in the range from about 3 to about 8.
  • the pH of the pharmaceutical composition may be adjusted to a physiologically compatible range.
  • the pH of the pharmaceutical compositions described herein may be in the range from about 3.0 to about 7.5.
  • the pharmaceutical compositions of the present invention may have a pH in the range from about 3.5 to about 7.5.
  • storage of the gamma tocopherol pharmaceutical composition is about three months, and the storage temperature is in the range from about 15° C. to about 30° C., and more preferably in the range from about 20° C. to about 25° C.
  • storage of the gamma tocopherol pharmaceutical composition is about six months, and the storage temperature is in the range from about 15° C. to about 30° C., and more preferably in the range from about 20° C. to about 25° C.
  • storage of the gamma tocopherol pharmaceutical composition is about twelve months, and the storage temperature is in the range from about 15° C. to about 30° C., and more preferably in the range from about 20° C. to about 25° C.
  • FIG. 1A illustrates a cross-sectional view of a micro-channel nebulizing nozzle in accordance with an aspect of the present disclosure.
  • FIG. 7A illustrates the effect of alpha- and gamma-tocopherol on pulmonary gas exchange evaluated by measuring the PaO 2 /FiO 2 ratio.
  • FIG. 7C illustrates the effect of alpha- and gamma-tocopherol as delivered via the nebulizers of the present disclosure on the pulmonary vascular permeability of a shunt fraction of animals tested, as evaluated by measuring the pulmonary shunt fraction (Qs/Qt) over time.
  • FIG. 7D illustrates the effect of formulations administered in accordance with the present disclosure on peak airway pressures over time.
  • FIG. 8 illustrates nebulized fatty acid droplets generated using systems and methods of the present disclosure, impacted on a counting slide.
  • FIG. 9 illustrates the exemplary gamma-tocopherol concentration in lung tissue.
  • composition refers to a formulation of a compound and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefore.
  • phrases “pharmaceutically acceptable carrier, diluent or excipient” as used herein includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • the dose administered to an animal should be sufficient to prevent the targeted disease or disorder, e.g., cancer, delay its onset, slow its progression, or treat the disease or disorder (e.g., reverse or negate the condition).
  • dosage will depend upon a variety of factors including the strength of the particular composition employed, as well as the age, species, condition, and body weight of the animal.
  • the size of the dose will also be determined by the route, timing, and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular composition and the desired physiological effect.
  • Bioactive agent refers to any amino acid, peptide, protein, or antibody, natural or synthetic, which exhibits a therapeutically useful effect.
  • tocopherol includes all such natural and synthetic tocopherol or Vitamin E compounds having the general structure as shown below, including all 10 isomers (five tocopherols ( ⁇ -, ⁇ -, ⁇ -, ⁇ 2 -) and five tocotrienols ( ⁇ / ⁇ 1 -, ⁇ / ⁇ -, ⁇ -, ⁇ -, ⁇ -), as well as combinations thereof, including but not limited to ⁇ -tocopherol (alpha tocopherol)(2,5,7,8-tetramethyl-2-(4′,8′,12′-trimethyldecyl)-6-chromanole), ⁇ -tocopherol (beta-tocopherol), ⁇ -tocopherol (gamma tocopherol), ⁇ -tocopherol (delta tocopherol), and ⁇ 2 -tocopherol, as well as the d, l and dl [also referred to equivalently as the (+), ( ⁇ ), and (
  • any of the above groups that contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the compounds of this invention include all stereochemical isomers and mixtures thereof arising from the substitution of these compounds.
  • % when used without qualification (as with w/v, v/v, or w/w) means % weight-in-volume for solutions of solids in liquids (w/v), % weight-in-volume for solutions of gases in liquids (w/v), % volume-in-volume for solutions of liquids in liquids (v/v) and weight-in-weight for mixtures of solids and semisolids (w/w), such as described in Remington's Pharmaceutical Sciences [Troy, David B., Ed.; Lippincott, Williams and Wilkins; 21st Edition, (2005)].
  • patient and “subject”, as used herein, are used interchangeably and refer generally to a mammal, and more particularly to human, ape, monkey, rat, pig, dog, rabbit, cat, cow, horse, mouse, sheep and goat.
  • lung surfaces or membranes described and referenced in accordance with this disclosure refer to those of a mammal, preferably a human or an animal test subject, such as a sheep.
  • particle size or “droplet size” is used in the context of the present disclosure to refer to the average diameter of particles, e.g., drug, lipid vesicles, in a suspension, and is defined herein as the “Mass Median Aerodynamic Diameter” (MMAD) which is referenced from an equivalent aqueous solution with a density of 1.0 g/ml. As the fluid density decreases the real droplet diameter/volume increases and conversely. Lung deposition of a particle or droplet is primarily dependent on the MMAD of the individual particle or droplet.
  • MMAD Mass Median Aerodynamic Diameter
  • drug as used in conjunction with the present disclosure means any compound which is biologically active, e.g., exhibits or is capable of exhibiting a therapeutic or prophylactic effect in vivo, or a biological effect in vitro.
  • annular intermediate space Intermediate between the outer gas-delivery tube 12 and the inner microtube 14 is an annular intermediate space, which serves to convey the nebulizing carrier gas via gas entry port 5 through the nebulizer needle from the distal to the proximal end, whereupon it acts to nebulize the liquid within inner microtube 14 into an aerosol having an aerosolized particle size ranging from about 1 mm to about 10 mm.
  • the particle size may be controlled by the spatial relationship of tubes 12 and 14 to each other, and the flow rate of the carrier gas.
  • outer tube 12 and the inner microtube 14 are illustrated to be substantially cylindrical in shape, those of skill in the art will appreciate that they can also be of any appropriate shape, providing such shape provides the same advantageous flow rates and particle sizes as the illustrated arrangement. Additionally, while the nebulizer 10 is illustrated to comprise inner and outer tubes which are substantially blunt at the proximal end 11 of the assembly, it is equally acceptable for either outer tube 12 , inner microtube 14 , or both to have an outer lip comprising an annular bevel (not shown), the angle of such a bevel ranging from about 5° to about 88°.
  • FIG. 2A illustrates a cross-sectional view of the proximal end 11 of nebulizer fluid nozzle assembly 10 .
  • the spacing between the outer surface of inner-microtube 14 and the interior surface of outer gas-delivery tube 12 has a diameter d 3 , and this has a value proportional to the outer diameter D 1 of inner-microtube 14 .
  • the intermediate air space 16 between the two tubes 12 and 14 may generally be described to be the free air opening value, the value of which is the internal diameter of the outer gas-delivery tube, D 2 , minus the total outside diameter of the inner microchannel delivery tube, D 1 .
  • Such aerosol droplet particle sizes include about 3 ⁇ m, about 4 ⁇ m, about 5 ⁇ m, about 6 ⁇ m, about 7 ⁇ m, about 8 ⁇ m, about 9 ⁇ m, about 10 ⁇ m, about 11 ⁇ m, about 12 ⁇ m, about 13 ⁇ m, about 14 ⁇ m, about 15 ⁇ m, about 16 ⁇ m, about 17 ⁇ m, about 18 ⁇ m, about 19 ⁇ m, and about 20 ⁇ m, as well as ranges between any two of these values, such as from about 4 ⁇ m to about 11 ⁇ m.
  • nebulizing nozzle 70 comprises a plurality of individual micro-channel nozzles 74 a - 74 f within a larger mass air channel/annular intermediate space 76 within outer air-delivery tube 72 .
  • the plurality of individual micro-channel nozzles 74 is preferably arranged around a central, longitudinal axis 75 extending through outer tube 72 .
  • the plurality of individual micro-channel nozzles 74 can range from about 2 to about 12 nozzles, including 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 individual nozzles.
  • the devices described and illustrated in FIG. 4 may be readily manufactured from existing technologies and electronic control configurations.
  • the system uses existing signal generations from the various mechanical ventilation devices as the controller for the nebulizing device.
  • the entire device simply adapts with the existing mechanical ventilating equipment.
  • a portable handheld nebulizing or inhaler device 50 is illustrated generally in FIG. 5 , comprising a lower equalization chamber portion 43 and an upper pressure vessel portion 35 , wherein the inhaler device 50 is capable of delivering metered doses of a medicament to a patient.
  • the medicinal formulation 38 comprising the medicament such as described in more detail below, is retained within a bladder 37 , separated from the propellant gas 36 contained within a pressure vessel 35 .
  • the medicinal composition within bladder 37 is not emulsified with the propellant gas 36 , thus allowing many different propellant gases to be used in this configuration including those gasses that may be difficult or impossible to solubilize with the drug formulation.
  • the formulations and devices described herein can provide for medicinal droplets that do not substantially evaporate.
  • a mist of persistent and size stable droplets containing medicine can be generated into a large vessel.
  • droplets in the 2-5 ⁇ m are well known to be the optimum size for pulmonary drug delivery and are well known to stay suspended in air with only minor movement of air currents within the vessel.
  • an environment of medicinal droplets is produced in a space and remains suspended and persist as a stable aerosol in the air within the environment until inhaled.
  • the method described would be suitable for passive inhaled drug delivery for one or more persons. More particularly, the embodiment would provide for drug delivery for many persons as in a mass casualty situation where a medicinal nebulizer could be shared with one or more persons. This embodiment would be useful to minimize equipment and personnel for mass inhalation pulmonary drug delivery.
  • the devices and methods described herein may be useful in industrial applications where the generation of an aerosol from a viscose fluid or emulsion is required. These applications shall include pharmaceutical manufacture, oil micro-droplet lubrication and fuel injection.
  • the micro-channel nebulizer systems described above may be adapted for continuous or semi-continuous nebulization and delivery of inspirable droplets via a semi-closed face mask breathing circuit 62.
  • the drug is contained in a flexible membrane within a pressurized housing, which allows for the nebulizer to operate in various positions unaffected by gravity.
  • Humidified air is provided by a separate standard mask humidifier which is existing equipment for face mask delivery of oxygen.
  • the mask and lipid nebulizer is intended to be adaptable to existing equipment.
  • Another spring loaded blow-off valve 47 regulates the pressure in medicament reservoir 49 . Excess pressure, as regulated by blow-off valve 47 , is vented through a port 48 . The pressure in the reservoir exerts pressure through ports 53 on the medicament bladder 37 and forces the medicine in the bladder 38 into the micro-channel liquid delivery tube 9 .
  • compositions may be comprised of a drug itself or any mixture of a biologically active substance with a solvent, and oil, a gelling agent, a carrier or adjuvant, emulsifier, one or more different drugs, polymers, excipients, coatings and combinations thereof.
  • the drug(s) or substances can be combined with any combination of pharmaceutically acceptable components to be delivered to the cellular surfaces within the pulmonary system by the method described herein, e.g., pulmonary drug delivery.
  • the drug(s) does not have to be dissolved in a drug delivery medium solvent but can be suspended or emulsified in a solvent or medium.
  • the delivery medium can take the form of an aqueous mixture, oil, or an organic liquid.
  • the delivery media solution can also comprise microspheres or nanospheres of biologically active substances.
  • compositions of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically acceptable salt as used herein is meant to refer to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well-known in the art. For example, P. H. Stahl, et al. describe pharmaceutically acceptable salts in detail in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley VCH, Zunch, Switzerland: 2002).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the present invention or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, flimarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate,
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl
  • salts of compounds which may be used in formulations and systems described herein may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal for example, sodium, potassium or lithium
  • alkaline earth metal for example calcium or magnesium
  • the present invention uses (1) a novel nebulizing nozzle configuration that requires limited energy from a compressed gas to cause droplet nebulization from a mass fluid into droplets of a suitable size; and (2) a drug carrier(s) that is based on essential fatty acid oils, lipids, gelled aqueous solutions, emulsions, or combinations thereof that are harmlessly absorbed by the lung tissues and are metabolized or expired.
  • Suitable vitamins for use herein include but are not limited to Vitamin A, Vitamin B (including Vitamin B 12 ), Vitamin C, Vitamin D, Vitamin E, Vitamin K3 (menadione; 1,4-dehydro-1,4-dioxo-2-methyl-naphthalene, MNQ), retinol, riboflavin, niacin, ascorbic acid, ⁇ -carotene, and Coenzyme Q, including various derivatives of Coenzyme Q having various isoprenoid side chains, including but not limited to QH, QH 2 , Q 3 and Q 10 .
  • Tocopherols suitable for use in accordance with these aspects of the present disclosure may be obtained from plants, such as by extracted from plants using known procedures, or prepared synthetically using known organic synthetic methods, all of which are in accordance with the present disclosure. Additionally, and as suggested above, any of the forms or isomers of tocopherols and their derivatives, eg. esters may be used according to the present invention.
  • gamma-tocopherol can be used as such, or in the form of its esters such as gamma-tocopherol acetate, linoleate, nicotinate or hemi succinate-ester, many of which are available commercially or through known synthetic routes.
  • compositions may comprise antianginal and/or antihypertensive drugs or biologically active agents which are insoluble or substantially insoluble in water, or exhibit poor water solubility (e.g., less than about 5 mg/mL).
  • Compounds of these types suitable for use herein include inhibitors of cAMP (3′,5′-cyclic adenosine monophosphate), cGMP (3′,5′-cyclic guanosine monophosphate), inhibitors of cGMP-specific phosphodiesterase type IV (PDE IV), inhibitors of c-GMP-specific phosphodiesterase type V (PDE V), drugs that may exhibit anti-anginal effects, including drugs which exhibit therapeutic effects on angina pectoris, and compounds which can enhance the natriuretic effect of atrial natriuretic peptide (ANP).
  • cAMP 3′,5′-cyclic adenosine monophosphate
  • cGMP 3′,5′-cyclic guanosine monophosphate
  • PDE IV inhibitors of cGMP-specific phosphodiesterase type IV
  • PDE V inhibitors of c-GMP-specific phosphodiesterase type V
  • drugs that may exhibit anti-anginal effects including drugs which exhibit
  • the drug is sildenafil.
  • Such drugs may be used in a therapeutically effective amount ranging from about 1 mg/kg/d to about 1,000 mg/kg/d, as well as therapeutically effective amounts within this range.
  • Selected naturally-occurring fats and oils suitable for use in formulations of the present disclosure include, but are not limited to, the following compounds: Adansonla Digitata Oil; Apricot ( Prunus armeniaca ) Kernel Oil; Argania Spinosa Oil; Argemone Mexicana Oil; avocado ( Persea gratissima ) Oil; Babassu ( Orbignya olelfera ) Oil; Balm Mint ( Melissa officinalis ) Seed Oil; Bitter Almond ( Prunus amygdalus amara ) Oil; Bitter Cherry ( Prunus cerasus ) Oil; Black Currant ( Ribes nigrum ) Oil; Borage ( Borago officinalis ) Seed Oil; Brazil ( Bertholletia excelsa ) Nut Oil; Burdock ( Arctium lappa ) Seed Oil; Butter; C12-18 Acid Triglyceride; Calophyllum Tacamahaca Oil; Camellia Kissi Oil; Cam
  • the formulation composition comprises Linseed Oil, which is also known as flaxseed oil, as well as fatty acids found therein, including but not limited to linolenic acid (LA), linoleic acid, oleic acid, stearic acid, palmitic acid, alpha-linolenic acid (LNA), and gamma-linolenic acid (GLA), any of which may be saturated or unsaturated as appropriate.
  • the formulations may also comprise hylauronic acid in an amount suitable to minimize water from transpiring across the droplets formed by the nebulizer.
  • compositions of the present invention may further optionally comprise preservatives.
  • preservative is intended to mean a compound used to prevent the growth of microorganisms. Such preservatives may be used in the tocopherol and gamma tocopherol pharmaceutical compositions described herein at typical concentrations in accordance with current pharmaceutical practices as described. [see: The United States Pharmacopeia - National Formulary, 29th Edition, (2006) Rockville, Md.; and, Remington's Pharmaceutical Sciences, 21st Edition, Troy, D B, Ed. Lippincott, Williams and Wilkins; (2005)].
  • binding materials e.g., block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones and styrene-butadiene copolymers
  • colorants including but not limited to FD & C yellow # 6, FD & C red # 40, FD & C blue # 2, and FD & C violet # 1, as well as any other appropriate dye or combination of dyes
  • UV inhibitors to inhibit UV decomposition or isomerization of the therapeutic compositions.
  • compositions described and disclosed herein including but not limited to coatings, stabilizers, emulsifiers, and the like, such as those described in “ The Handbook of Pharmaceutical Manufacturing Formulations ” [Niazi, S. K., CRC Press (2004)].
  • one or more surface active agents may be added to the formulation compositions as appropriate.
  • incorporation of a compatible surfactant can improve the stability of the instant respiratory dispersions, increase pulmonary deposition and facilitate the preparation of the suspension.
  • the density of the particle or structural matrix may be adjusted to approximate the density of the surrounding medium and further stabilize the dispersion.
  • surfactant Any suitable surface active agent (surfactant) may be used in the context of the present invention, provided that the surfactant is preferably physiologically acceptable.
  • Physiologically acceptable surfactants are generally known in the art and include various detergents and phospholipids, as discussed in more detail below.
  • the surfactant is a phospholipid including, but not limited to, an extract of a natural surfactant such as any number of known pulmonary surfactants, including bovine- and calf-lung surfactant extracts, an egg phospholipid, a vegetable oil phospholipid such as a soybean phospholipid, or phosphatidylcholine.
  • the surfactant suitable for use with the therapeutic compositions of the present disclosure is an extract of a natural surfactant, an egg phospholipid, or combinations thereof. More preferably, the compositions may any one or more of a number of biocompatible materials as surfactants, such as surfactants comprising phospholipids.
  • preferred surfactants include but are not limited to those surfactants that are substantially insoluble in the medium, nonfluorinated, and selected from the group consisting of saturated and unsaturated lipids, especially those that are obtained or extracted from natural sources, nonionic 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) fluorinated surfactants are compatible with the teachings herein and may be used to provide the desired stabilized therapeutic preparations.
  • Exemplary phospholipids useful in the disclosed stabilized preparations of the present invention comprise egg phosphatidylcholine, dilauroylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidyl-choline, disteroylphosphatidylcholine, short-chain phosphatidylcholines, phosphatidylethanolamine, dioleylphosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, glyco lipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids bearing polymer chains such as polyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone; lipids bearing sulfonated mono-, di-, and polysaccharides; fatty acids such as palmitic acid, stea
  • biologically-compatible surfactants comprising phospholipids
  • biologically-compatible surfactants include those surfactants that are extracts of natural surfactants, in particular pulmonary surfactants, and synthetic synthesized mixtures of pulmonary surfactants in order to mimic natural lung surfactant.
  • sorbitan esters including sorbitan trioleate (SPANTM 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.
  • SPANTM 85 sorbitan trioleate
  • SPANTM 85 sorbitan sesquioleate
  • sorbitan monooleate sorbitan monooleate
  • sorbitan monolaurate polyoxyethylene (20) sorbitan monolaurate
  • polyoxyethylene (20) sorbitan monolaurate polyoxyethylene (20) sorbitan monolaurate
  • polyoxyethylene (20) sorbitan monooleate oleyl polyoxyethylene (2) ether
  • surfactants including those not listed above, may optionally be used in conjunction with the present invention.
  • the optimum surfactant, or combination thereof, for a given application can readily be determined by empirical studies that do not require undue experimentation.
  • 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. the aqueous hypophase in the lung).
  • the instant formulations and compositions of the therapeutic compositions comprising tocopherols such as gamma-tocopherol may comprise varying levels of surfactant.
  • the compositions and formulations described herein which include one or more surfactants will preferably comprise greater than about 0.1%, about 1%, about 5%, about 10%, about 15%, about 18%, or even about 20% w/w % surfactant.
  • the therapeutic compositions and formulations described herein may comprise greater than about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% w/w surfactant.
  • the present invention employs a novel composition comprising one or more lipids associated with at least one drug.
  • a lipid as referred to herein is a substance that is characteristically insoluble in water and extractable with an organic solvent.
  • Lipids include, for example, the substances comprising the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which are well known to those of skill in the art which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.
  • compounds other than those specifically described herein that are understood by one of skill in the art as lipids are also encompassed by the compositions and methods of the present invention.
  • a lipid for use with the present disclosure may be naturally occurring or synthetic (i.e., designed or produced by man).
  • a lipid is typically a biological substance.
  • Biological lipids are well known in the art, and include for example and without limitation, neutral fats, phospholipids, phosphoglycerides, steroids, terpenes, lysolipids, glycosphingolipids, glycolipids, sulphatides, lipids with ether and ester-linked fatty acids and polymerizable lipids, and combinations thereof.
  • a preferred range is from about 14 to about 24 carbon atoms in the chain portion of the fatty acid, with about 16 to about 18 carbon atoms being particularly preferred in certain embodiments.
  • the fatty acid carbon chain may comprise an odd number of carbon atoms, however, an even number of carbon atoms in the chain may be preferred in certain embodiments.
  • a fatty acid comprising only single bonds in its carbon chain is called saturated, while a fatty acid comprising at least one double bond in its chain is called unsaturated.
  • Specific fatty acids include, but are not limited to, linoleic acid, oleic acid, palmitic acid, linolenic acid, stearic acid, lauric acid, myristic acid, arachidic acid, palmitoleic acid, arachidonic acid ricinoleic acid, tuberculosteric acid, lactobacillic acid.
  • An acidic group of one or more fatty acids is covalently bonded to one or more hydroxyl groups of a glycerol.
  • a phopholipid may, of course, comprise further chemical groups, such as for example, an alcohol attached to the phosphate group.
  • alcohol groups include serine, ethanolamine, choline, glycerol and inositol.
  • specific phosphoglycerides include a phosphatidyl serine, a phosphatidyl ethanolamine, a phosphatidyl choline, a phosphatidyl glycerol or a phosphatidyl inositol.
  • Other phospholipids include a phosphatidic acid or a diacetyl phosphate.
  • a steroid is a four-membered ring system derivative of a phenanthrene.
  • Steroids often possess regulatory functions in cells, tissues and organisms, and include, for example, hormones and related compounds in the progestagen (e.g., progesterone), glucocoricoid (e.g., cortisol), mineralocorticoid (e.g., aldosterone), androgen (e.g., testosterone) and estrogen (e.g., estrone) families.
  • progestagen e.g., progesterone
  • glucocoricoid e.g., cortisol
  • mineralocorticoid e.g., aldosterone
  • androgen e.g., testosterone
  • estrogen e.g., estrone
  • Cholesterol is another example of a steroid, and generally serves structural rather than regulatory functions.
  • Vitamin D is another example of a sterol, and is involved in calcium ab
  • a terpene is a lipid comprising one or more five carbon isoprene groups.
  • Terpenes have various biological functions, and include, for example and without limitation, vitamin A, coenyzme Q and carotenoids (e.g., lycopene and 1-carotene).
  • a lipid component of a composition in accordance with the present disclosure may be uncharged or primarily uncharged.
  • a lipid component of a composition comprises one or more neutral lipids.
  • a lipid component of a composition may be substantially free of anionic and cationic lipids, such as certain phospholipids (e.g., phosphatidyl choline) and cholesterol.
  • a lipid component of an uncharged or primarily uncharged lipid composition comprises about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 95%, about 96%, about 97%, about 98%, about 99% or 100% lipids without a charge, substantially uncharged lipid(s), and/or a lipid mixture with equal numbers of positive and negative charges.
  • Lipids can be obtained from natural sources, commercial sources or chemically synthesized, as would be known to one of ordinary skill in the art.
  • phospholipids can be from natural sources, such as egg or soybean phosphatidylcholine, brain phosphatidic acid, brain or plant phosphatidylinositol, heart cardiolipin and plant or bacterial phosphatidylethanolamine.
  • lipids suitable for use according to the present invention can be obtained from commercial sources.
  • dimyristyl phosphatidylcholine can be obtained from Sigma Chemical Co.
  • dicetyl phosphate (“DCP”) may be obtained from K & K Laboratories (Plainview, N.Y.); cholesterol (“Chol”) may be obtained from Calbiochem-Behring; dimyristyl phosphatidylglycerol (“DMPG”) and other lipids known to those of skill in the art may be obtained from Avanti Polar Lipids, Inc. (Birmingham, Ala.).
  • stock solutions of lipids in chloroform or chloroform/methanol can be stored at about ⁇ 20° C.
  • chloroform is used as the only solvent since it is more readily evaporated than methanol, allowing for more expedient lipid recovery.
  • the drugs may be associated with one or more lipids, instead of or in addition to, the fatty-acid.
  • a drug associated with a lipid may be dispersed in a solution containing a lipid, dissolved with a lipid, emulsified with a lipid, mixed with a lipid, combined with a lipid, covalently bonded to a lipid, contained as a suspension in a lipid, contained or complexed with a micelle or liposome, or otherwise associated with a lipid or lipid structure.
  • a lipid or lipid/chimeric polypeptide associated composition of the present invention is not limited to any particular structure.
  • a fatty acid- or lipid-containing composition may comprise about 1%, about 2%, about 3%, about 4% about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%
  • a lipid composition may comprise about 10% to about 20% neutral lipids, and about 13% to about 84% of a tocopherol such as gamma-tocopherol, and about 1% cholesterol.
  • lipid compositions of the present invention may comprise any of the lipids, lipid types or other components in any combination or percentage range.
  • compositions according to the invention may also contain a “gelling agent” in combination with the drug or biologically active agent and lipid.
  • the gelling agent may be selected from the group including but not limited to hydroxyethyl cellulose (HEC), hydroxymethylcellulose (HMC), Natrasol®, pectines, agar, alginic acid and its salts, guar gum, pectin, polyvinyl alcohol, polyethylene oxide, cellulose and its derivatives, propylene carbonate, polyethylene glycol, hexylene glycol sodium carboxymethylcellulose, polyacrylates, polyoxyethylene-polyoxypropylene block copolymers, pluronics, wood wax alcohols, tyloxapol (a nonionic surfactant oligomer), proteins and sugars.
  • HEC hydroxyethyl cellulose
  • HMC hydroxymethylcellulose
  • Natrasol® Natrasol®
  • pectines agar
  • alginic acid and its salts guar gum
  • the formulations of water-insoluble and substantially water-insoluble compounds may be used, in combination with the nebulizer systems described herein, in order to administer a therapeutically effective amount of one or more drugs or biological agents as an aerosolized mixture.
  • the formulations comprising one or more water-insoluble compounds and a lipid can be administered using a nebulizer as described herein for the treatment of one or more pulmonary diseases.
  • Pulmonary diseases and disorders which may be treatable using the compositions, formulations, methods, and apparatus/systems of the present disclosure include but are not limited to asthma; alpha-1 antitrypsin deficiency (AAT Deficiency); dust-related pulmonary and lung diseases and disorders, including asbestosis; avian flu; bronchitis, including acute bronchitis; bronchiectasis; bronchopulmonary dysplasia (BPD); chronic cough; chronic obstructive pulmonary diseases and disorders; the common cold; chronic obstructive pulmonary disorder (COPD); croup; cystic fibrosis (CF); emphysema; farmer's lung; influenza; hantavirus; rhinitis (hay fever); histoplasmosis; interstitial lung disease; legionellosis (Legionnaire's disease); lung cancer (including both small cell, large cell and mixed small cell/large cell carcinoma); lung damage resultant from inhalation of smoke and heat; inflammation and lung damage resultant
  • Table 2 demonstrates the fluid delivery rates of various viscosity fluids though various fluid delivery tubes 14 ( FIG. 1A-1C ) at various fluid pressures.
  • the actual fluid flow rate is related to the delivery tube internal diameter size however, the amount of fluid flowing through a given fluid opening is also influenced by the resistance offered by the surfaces of the delivery tube 14 in contact with the fluid as well as the surface tension of the fluid to be delivered and may not be linier in function. Configurations are based on the nozzle configurations described in Table 1, above.
  • Table 2 demonstrates the measured air flow of selected micro-channel nozzle configurations whereby a selected fluid nozzle 14 is surrounded by an air delivery tube 12 .
  • Nebulizing air in this example is delivered at about 50 psi.
  • the free air space 16 surrounding the fluid delivery tube 14 enclosed by the air delivery tube 12 provides for the calculated “SQ inch Neb Free Air Opening”.
  • the actual nebulized air flow rate “Neb Air Flow cc/sec” is related to the free air opening size however, the amount of air flowing through a given free air space is also influenced by the resistance offered by the surfaces of the delivery tubes 14 and 12 in contact with the air and may not be linier in function.
  • Nebulizing air pressures, fluid pressures, micro-channel fluid tube size and the viscosity of the fluid to be nebulized are selected from a range of components of fluid delivery tubes 1 and air delivery tubes 2 to achieve the preferred air and fluid flow rates and the nebulized droplet size within the preferred air volume to viscous liquid volume ratio of less than about 60, 000:1.
  • an efferent lymph vessel from the caudal mediastinal lymph node was cannulated (Silastic catheter 0.025-in ID, 0.047-in OD; Dow Corning, Midland, Mich.) according to a modification of the technique described by Staub and colleagues [Staub, N., et al., J. Surg. Res ., Vol. 19, pp. 315-320 (1975); Traber, D., et al., J. Appl. Physiol ., Vol. 54, pp. 1167-1171 (1983)].
  • 1 gram mixed tocopherols 1000 mg DecanoxTM MTS-90G (94 mg/g alpha tocopherol, 15 mg/g beta-tocopherol, 604 mg/g gamma-tocopherol, 201 mg/g delta tocopherol for a total of 914 mg/g total mixed tocopherols), purchased from Daniels Midland Co., Decatur, Ill.] was added to 11 grams of linseed oil (flax oil) and mixed for 3 hours to make an 8.3% (w/w) solution of tocopherol in linseed oil before starting the nebulization, using a nebulizer as described with the present disclosure.
  • Nebulization was started 1 hour after the combined burn and smoke inhalation injury, and repeated every 12 h.
  • Burn and smoke inhalation injury The protocol followed was similar to that described in the art [Kimura, R., et al., J. Appl. Physiol ., Vol. 64(3): pp. 1107-1113 (1988); Enkhbaatar, P., et al., Am. J. Physiol. Regul. Integr. Comp. Physiol ., Vol. 285(2): pp. R366-R372 (2003)].
  • a modified bee smoker was filled with 50 g burning cotton toweling and was connected to the tracheostomy tube via a modified endothoracheal tube containing an indwelling thermistor from a Swan-Ganz catheter. During the insufflation procedures, the temperature of the smoke did not exceed 40° C. The sheep were insufflated with a total of 48 breaths of cotton smoke. After smoke insufflation, another 20% total body surface area, third-degree burn, was made on the contralateral flank.
  • Resuscitation protocol The protocol for subject resuscitation has been described previously in the art [id.]. Briefly, immediately following the injury, anesthesia was discontinued and the animals were allowed to awaken and were mechanically ventilated with a Servo ventilator (model 900C, Simens-Elena, Solna, Sweden) throughout the next 48 h experimental period. Ventilation was performed with a positive end-expiratory pressure (PEEP) of 5 cm H 2 O and a tidal volume of 15 mL/kg. The respiratory rate was set to maintain normocapnia.
  • PEEP positive end-expiratory pressure
  • B&S Concurrent cutaneous burn and smoke inhalation
  • inflammatory blood cells neutrophil granulocytes
  • neutrophil granulocytes infiltrate the lung tissues causing edema, swelling and additional tissue damage from products of the inflammatory cells.
  • Neutrophil infiltrate is an integral part of the formation or obstructive airway cast formation following inhalation injury.
  • Obstructive airway casts is the major cause of pulmonary obstruction following inhalation injury. Pulmonary obstruction reduces the flow of air in and out of the lung and is the primary cause of death following inhalation injury.
  • Pulmonary administration by nebulization of flax seed oil did not interfere with gas exchange or other pulmonary function when administered at a rate of ⁇ 0.5 cc per hour in uninjured sham animals.
  • All (6/6) saline nebulized control animals ( FIG. 7A ) deteriorated into respiratory distress (ARDS defined as a blood PO 2 ratio to inspired O 2 concentration of ⁇ 200; PO 2 :FiO 2 or P/F Ratio ⁇ 200) within 24 hours of the combined burn and smoke inhalation injury. None (0/4) of the animals receiving nebulized flax oil with 8.3% mixed tocopherols administered at 0.3 to 0.5 cc/hour deteriorated into ARDS. All physiological parameters ( FIGS. 7A-D ) were significantly improved in the insufflated flax oil/tocopherol group as compared with the saline nebulization group.
  • the novel, viscous lipid formulation nebulization nozzle and control system described herein was adapted to a Siemans® 900c servo ventilator (Siemans-Elema AB, Sweden), as shown and discussed generally in relation to FIGS. 1-6B , above.
  • the nebulizing nozzle FIG. 1B
  • calibrated blood counting slides were waved through the ventilator inspiratory airflow containing nebulized flax oil formulations allowing droplets to impact onto the slide.
  • IL GEM Premier 3000 Blood Gas Analyzer GMI, Minnesota
  • PaO 2 /F i O 2 ratio was measured to help assess pulmonary gas exchange.
  • the pulmonary microvascular fluid flux was evaluated by measuring the lung lymph flow. Sheep were sacrificed under deep halothane anesthesia 48 hr after injury. The right lung was then removed, and a 1-cm-thick section was taken from the middle of the lower lobe, injected with 10% formalin, and immersed in formalin.
  • Four tissue samples were taken at predetermined sites for histological examination. Fixed samples were embedded in paraffin, sectioned at 4 ⁇ m, and stained with hematoxylin and eosin.
  • a pathologist without knowledge of the group assignments evaluated the lung histology. Levels of airway obstruction were obtained with a standardized protocol. Fifteen bronchi were investigated, and the percentage of area obstructed by the cast was estimated (0%-100%). The remaining lower one-half of the right lower lobe was used for the determination of bloodless wet-to-dry weight ratio. Pulmonary shunt fraction (Qs/Qt) was calculated using standard equations.
  • the intensity of PAR staining of individual sections was determined by a blinded experimenter according to a semiquantitative PAR-positivity score from 1-10. (1: no staining, 2: light cytoplasmic staining, 3: few positive nuclei, 4: light nuclear staining in approximately 10% of cells, 5: light nuclear staining in approximately 25% of cells, 6: light nuclear staining in approximately 50% of cells, 7: strong nuclear staining in approximately 50% of cells, 8: approximately 75% of the nuclei are positive, 9: approximately 90% of the nuclei are positive, 10: few negative cells).
  • the threshold amplifications (Ct) for each dilution, and reaction efficiencies were determined for each analyte using Rotor-GeneTM software (Corbett Research).
  • the copy numbers were normalized between samples using GAPDH copy numbers obtained by determination of GAPDH copy number using an external standard constructed from the v-erb gene. All results were expressed as copy numbers per ⁇ g of total RNA.
  • Table 6 shows a comparison of effects of FO or ⁇ -T+FO nebulization on pulmonary gas exchange (PaO 2 /FiO 2 ratio and Qs/Qt) and pulmonary transvascular fluid flux (lung lymph flow).
  • PaO 2 /FiO 2 ratio ( FIG. 10A ) was markedly decreased in animals that were nebulized with saline (injured) as compared with sham animals (uninjured). Nebulization of ⁇ -T+FO attenuated the decrease in this variable. Statistically significant differences were observed at 24, 30, 36, 42 and 48 hr compared with the saline group and at 30, 36, and 42 hr compared with FO group. An increase in pulmonary shunt fraction ( FIG. 10B ) seen in the saline group was significantly attenuated by FO nebulization at 48 hr and ⁇ -T+FO nebulization at 36, 42 and 48 hr after the combined injury.
  • Lung lymph flow a characteristic of pulmonary transvascular fluid flux, was markedly increased in injured, saline nebulized animals compared with the sham group ( FIG. 11 ).
  • the lymph flow began to increase 12 hr after the insult and a peak was observed at 42 hr.
  • nebulization of ⁇ -T+FO reversed this increase in pulmonary transvascular fluid flux and significant differences were observed between ⁇ -T+FO and Saline groups at 18, 24, 30, 36, 42 and 48 hr, and ⁇ -T+FO and FO groups at 24 and 48 hr after the combined injury.
  • the airway obstruction score revealed a significant increase in mean obstruction of bronchi ( FIG. 12B ) in the saline group as compared with the sham group. Treatment with ⁇ -T+FO nebulization significantly reduced the obstruction score.
  • FIG. 13A illustrates the effect of ⁇ -T+FO nebulization on malondialdehyde concentration which is an index of lipid peroxidation (ROS) in lung tissue.
  • ROS lipid peroxidation
  • 3-Nitrotyrosine is a marker of nitrosative stress, resulting from reactive nitrogen species (RNS) such as peroxynitrite. Burn and smoke injury caused a marked increase in lung 3-nitrotyrosine 48 h after the insults. ⁇ -T+FO nebulization significantly prevented the increase in 3-nitrotyrosine ( FIG. 13B ).
  • RNS reactive nitrogen species
  • FIGS. 14A-14B After burn and smoke injury, there was a marked increase in poly (ADP-ribose) reactivity in the Saline and FO groups ( FIGS. 14A-14B ). Treatment with ⁇ -T+FO nebulization prevented this increase in activity ( FIG. 14A ).
  • FIG. 14B shows the PAR-positivity score graph which quantified the degree of poly (ADP-ribose) histochemical stain. Burn and smoke injury caused a significant increase in lung poly (ADP-ribose) polymerase activity. However, ⁇ -T+FO nebulization significantly prevented the increase in lung poly (ADP-ribose) polymerase activity.
  • IL-8 and IL-6 mRNA were measured in lung tissue ( FIG. 15 ). Burn and smoke injury caused a marked increase in lung IL-8 and IL-6 mRNA 48 hr after the insults. ⁇ -T+FO nebulization prevented the increase in IL-8 and IL-6 mRNA ( FIG. 15 ).

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US11497867B2 (en) 2016-12-09 2022-11-15 Trudell Medical International Smart nebulizer
US11511296B2 (en) * 2017-02-21 2022-11-29 Metabar Technology Oy Nozzle, nozzle arrangement and liquid distribution system
US11666801B2 (en) 2018-01-04 2023-06-06 Trudell Medical International Smart oscillating positive expiratory pressure device
US11964185B2 (en) 2018-01-04 2024-04-23 Trudell Medical International Smart oscillating positive expiratory pressure device
US11712175B2 (en) 2019-08-27 2023-08-01 Trudell Medical International Smart oscillating positive expiratory pressure device with feedback indicia
JP7329862B2 (ja) 2021-02-09 2023-08-21 株式会社フラックス 水素ガス送出装置
JP2022121758A (ja) * 2021-02-09 2022-08-22 株式会社フラックス 水素ガス送出装置及び水素ガス送出方法
WO2023227088A1 (fr) * 2022-05-26 2023-11-30 杭州堃博生物科技有限公司 Cathéter d'intervention, dispositif d'intervention, système d'administration de médicament par atomisation, méthode de commande, méthode d'atomisation et système et méthode de pulvérisation de milieu de traitement

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US8776786B2 (en) 2014-07-15

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