WO2010019467A1 - Système et procédé de délivrance d'un médicament à petites particules à l'aide d'un mélange hypoxique d'hélium et d'oxygène - Google Patents

Système et procédé de délivrance d'un médicament à petites particules à l'aide d'un mélange hypoxique d'hélium et d'oxygène Download PDF

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Publication number
WO2010019467A1
WO2010019467A1 PCT/US2009/053126 US2009053126W WO2010019467A1 WO 2010019467 A1 WO2010019467 A1 WO 2010019467A1 US 2009053126 W US2009053126 W US 2009053126W WO 2010019467 A1 WO2010019467 A1 WO 2010019467A1
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WIPO (PCT)
Prior art keywords
drug
carrier gas
patient
helium
heliox
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PCT/US2009/053126
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English (en)
Inventor
Stephan C. F. Gamard
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Praxair Technology, Inc.
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Publication of WO2010019467A1 publication Critical patent/WO2010019467A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]

Definitions

  • the present invention relates to a drug delivery via inhalation and more particularly, to a system and method for using a hypoxic mix of helium and oxygen as a carrier of small particle size drugs to achieve a better drug deposition profile in lungs of a patient.
  • Drug delivery via inhalation has the potential to provide numerous medical benefits due to the large surface area of the lung as well as the excellent blood supply to the lungs and transfer mechanisms of such inhaled drugs into the blood stream of a patient.
  • Drug introduction via the lungs is generally achieved with relatively low enzymatic activity compared to drug ingestion via the oral route and often provides a quick acting means of drug administration.
  • drug delivery via inhalation to the lungs of a patient also allows for adsorption of even macro-sized molecules including various peptides and proteins and has been shown to work for drugs with limited or no oral bioavailability.
  • the challenges associated with drug delivery via inhalation include developing safe and effective delivery methods and devices as well as understanding and resolving various toxicology or pathology issues raised by adsorption of the drug in the lung tissue.
  • Heliox is a gas mixture of helium and oxygen and is commonly used in hospital respiratory applications, both in the emergency and intensive care units. Although drug delivery via inhalation using Heliox has been suggested in many prior art publications, there are few safe and effective devices or means to deliver Heliox gas to the patient on the market today. Thus, delivery of drugs via inhalation using Heliox or a helium- based carrier gas is not well understood. [0005] When looking at the physics of drug delivery in the respiratory tract of a patient, the first gas characteristic to examine is the Reynolds number of the carrier gas.
  • This non-dimensionalized Reynolds number reflects on the smoothness of the carrier gas flow where the higher the Reynolds number is the more propensity for turbulent flow of the carrier gas and drug particles within the patient's airway.
  • a typical Reynolds number during inhalation with room air is around 2,200. Switching from room air to a He/02 blend of about 80% helium and 20% oxygen (Heliox 80/20) lessens the Reynolds number to about 700, making the flow smoother and more laminar.
  • a typical Reynolds number during inhalation with a He/C> 2 blend of about 90% helium and 10% oxygen (Heliox 90/10) further reduces the Reynolds number by an additional 27% to about 500.
  • the present invention may be characterized as a method and system for small particle size drug delivery via inhalation using a hypoxic mix of helium and oxygen to achieve an improved drug deposition profile in lungs of a patient.
  • the combination of high concentrations of helium and small drug particle sizes provides a synergistic deposition benefit.
  • the present invention may also be characterized as a method and system for optimizing small particle size drug delivery via the respiratory tract of a patient using a hypoxic mix of helium and oxygen and actively controlling the drag particle size, the helium concentration of the carrier gas, the inspiration flow rate, the carrier gas temperature, and the inspiratory period during drug inhalation.
  • Fig. 1 is a table that shows the relative stopping distances of various sizes of drug particles in different helium-based carrier gases expressed as a percentage increase or decrease relative to the stopping distances of the same size drug particle transported in a carrier gas of room air;
  • Fig. 2 is a graph that depicts the drug particle deposition profiles in a helium-based carrier gas compared to the drug particle deposition in air as a function of carrier gas density for different drug particle sizes both with and without a Cunningham slip factor adjustment;
  • Fig. 3 is a graph that depicts the drug particle deposition for different inspiration flow rates for an air-based carrier gas and helium carrier gas and different drug particle sizes;
  • Fig. 4 is a table that presents data collected during an drug particle inhalation experiment and shows the fractional depositions of inhaled particles in various locations of the test subjects;
  • Fig. 5 is a table that presents data collected during a drug particle inhalation experiment and shows the peripheral to inner lung ratio of particles deposited in the lungs of the various test subjects.
  • Heliox therapy is optimized with high helium content. Indeed, the lower density of the helium gas compared to air or nitrogen tends to reduce the work of breathing by most patients. Using Heliox also increases convective flows into the peripheral lung of the patient which promotes increased diffusional flows, thus leading to more effective gas exchange.
  • Heliox has a similar ability to carry a medicinal aerosol as air or oxygen since the effect of gas density on aerodynamic force will be minimal for drug aerosols having particle sizes typical for inhalation drug delivery.
  • the increased momentum associated with the Heliox flows will therefore effectively drive the aerolized drug particles deeper into the lung.
  • Scintigraphy studies have confirmed that aerosol drug deposition in the peripheral lung increases proportionally with decreased resistance.
  • Exercise studies have demonstrated that subjects breathe at higher rates and with higher tidal volumes when inhaling Heliox gas as opposed to air, which under ideal drug delivery conditions would allow for more drugs to be delivered to the lungs as well.
  • Drug particles introduced to a patient via inhalation can deposit in a patient's airways in three manners, namely: (i) impaction (where the momentum of the particle is too large to follow the directional changes in the flow patterns within the patient's airway); (ii) gravitation (where the weight of the particle causes the drug particle to deposit on a surface in the patient's airway); or (iii) diffusion (where the Brownian random chaotic motions of the drug particle allows it to collide with a surface of the patient's airway).
  • Deposition by means of impaction is usually the dominant deposition mode for large drug particles or drug particles carried in relatively fast flows as may typically occur in the upper airways and entrance to the lungs.
  • Deposition by means of gravitation is the dominate deposition mode for smaller drug particles and or drug particles present deeper into the patient's lungs.
  • the relative deposition patterns or profiles were modeled by ascertaining the stopping distances of a given drug particle based on its aerodynamic diameter of the drug particle and the carrier gas mix in which it is immersed. The larger the stopping distances of a given drug particle, the more likely the drug particle is to deposit by impaction with a surface in the patient's airways.
  • the modeling of the Impaction based Stopping Distance is a product of the Relaxation Time and Gas Velocity, where the Relaxation Time is expressed as: ⁇ - p > ' d ⁇ ' > C °, where p p is the drug particle density; dp is the drug particle diameter; ⁇ is the gas mix's viscosity; and C c is the Cunningham slip factor.
  • the modeling of the Gravitation based Stopping Distance is a product of the Settling Velocity and Residence Time, where the Residence Time is calculated by dividing the airway length by the average velocity of the carrier gas in the airway and where the Settling Velocity is expressed as: where p p is the drug particle density; d p is the drug particle diameter; ⁇ is the gas mix's viscosity; Cc is the Cunningham slip factor; and g is the gravitational constant.
  • the modeling of the Diffusion based Stopping Distance is the root mean square of the Displacement during the Residence Time, where the Residence Time is calculated by dividing the airway length by the average velocity of the carrier gas in the airway and where the Displacement is the product of Residence Time and Diffusion Coefficient.
  • the Diffusion Coefficient is preferably expressed as: where d p is the drug particle diameter; ⁇ is the gas mix's viscosity; Cc is the Cunningham slip factor; 7 is the temperature of the carrier gas mix; and Na is the Avogadro number.
  • the Cunningham slip factor was estimated to be a constant value of 1.0.
  • the various stopping distances of drug particles ranging from about 0.5 microns in diameter to about 10 microns in diameter when transported in a carrier gas comprised of Heliox 70/30 ranges from a 6.02% improvement in stopping distance for drug particle sizes of 0.5 microns in diameter to a 7.18% reduction in stopping distance for drug particle sizes of 10 microns in diameter.
  • the various stopping distances of drug particles ranging from about 0.5 microns in diameter to about 10 microns in diameter when transported in a carrier gas comprised of Heliox 80/20 ranges from a 11.08% improvement in stopping distance for drug particle sizes of 0.5 microns in diameter to a 6.55% reduced stopping distance for drug particle sizes of 10 microns in diameter.
  • the stopping distances range from a 14.48% improvement in stopping distance for drug particle sizes of 0.5 microns in diameter to a 6.18% reduced stopping distance for drug particle sizes of 10 microns in diameter.
  • the stopping distances range from an 18.83% improvement in stopping distance for drug particle sizes of 0.5 microns in diameter to a 5.75% reduced stopping distance for drug particle sizes of 10 microns in diameter.
  • the stopping distances range from a 33.32% improvement in stopping distance for drug particle sizes of 0.5 microns in diameter to a 4.51% reduced stopping distance for drug particle sizes of 10 microns in diameter.
  • the improvement in stopping distances when compared to a carrier gas of room air is evident in the model for drug particle sizes up to about 3 microns in diameter.
  • the stopping distance is reduced with a helium-based gas carrier compared to the stopping distance when the drug particle is carried in room air.
  • the reduced stopping distance in Heliox or helium gas carrier diminishes the chance for early deposition in the mouth, throat, and upper airways.
  • This reduced stopping distance is relatively insensitive to the Heliox mix, since the difference in stopping distances between drug particles in Heliox 70/30 carrier gas and drug particles in Heliox 90/10 carrier gas is relatively small.
  • a Heliox 90/10 carrier gas mix provides larger stopping distances, or better chances for ultimate deposition in the deep lung. In this case, stopping distance improvements are shown with the Heliox 90/10 carrier gas offering a 7.44% improvement over room air for particles of about 1 micron in diameter compared to a stopping distance disadvantage of about 0.10% with a carrier gas of Heliox 70/30.
  • the benefits of using Heliox or helium-based carrier gases is even more pronounced with an improvement of almost 20% in the ascertained stopping distances compared to the stopping distances achieved with similar sized drug particles in room air.
  • the Impaction based Stopping Distance, Gravitational based Stopping Distance, and Diffusion based Stopping Distance are all directly proportional to the Cunningham slip factor, C c .
  • the Cunningham slip factor is a type of drag coefficient that reflects the added drag surrounding the drug particle by the fluid in which it is traveling. It is usually very close to 1.0, but would be expected to increase for very small drug particles on the nanoscale or where the drug particle size approaches the carrier gas particle size.
  • the Cunningham slip factor, C c is calculated as:
  • the present invention is based, in part on the discovery that the Cunningham slip factor is unexpectedly responsive to the composition of the carrier gas mix.
  • a 2 micron diameter drug particle exhibits a Cunningham slip factor (C c ) from about 1.0799 in room air to about 1.2324 in 100% helium gas.
  • C c Cunningham slip factor
  • the beneficial effects in terms of stopping distances and deposition of drug particles in the lungs of a patient when using Heliox as the carrier gas is attributable to the effect of the Cunningham slip factor for such Heliox blends.
  • the beneficial effects are even more evident when the Heliox carrier gas is a hypoxic helium blend (i.e. oxygen concentration of less than or equal to about 15%) for small drug particle sizes.
  • a computational fluid dynamics (CFD) simulation of the various drug particle deposition profiles in the lungs was performed for different carrier gas compositions including room air, Heliox 70/30, Heliox 80/20, and Heliox 90/10 and with two different drug particle sizes including 2 micron diameter and 5 micron diameter.
  • the CFD simulations modeled a steady flow rate only and looked at the deposition of the drug particles in a fixed geometry representing portions of a patient's airway. The simulations were first run without accounting for the change in the Cunningham slip factor effect due to the carrier gas properties. Additional simulations were then performed with correcting or accounting for the change in the Cunningham slip factor effect due to the carrier gas properties. Data for the different CFD simulations are presented in Table 2.
  • Table 2 shows the relative improvement in deposition for the different CFD simulations run with various Heliox based carrier gases and particle sizes compared to similar particle sizes with a carrier gas of room air. The data presented in Table 2 are divided into the pre-correction simulations where the Cunningham slip factor is not taken into account and the post-correction simulations where the Cunningham slip factor is taken into account thus compensating for the effect of the carrier gas properties. [0031] As can be seen in Table 2, there is a notable improvement in drug particle deposition attributable into the lungs to the Cunningham slip factor for a carrier gas of Heliox 90/10 than the other Heliox based carrier gases.
  • the CFD simulations show that there is 5.6% increase for Heliox 90/10 over room air for drug particles having a 2 micron particle diameter. This modeled improvement is significantly better than the 0.5% increase that was theoretically proposed from the data of Fig. 1 where the Cunningham slip factor was treated as a constant.
  • the CFD simulations further show that there is also a greater than 3% increase or improvement in lung deposition effectiveness for 5 micron diameter drug particles entrained in a carrier gas comprised of Heliox 90/10 over that of same particles entrained in a carrier gas of room air.
  • the theoretical calculations shown in Fig. 1 predicted a 1% decrease in lung deposition effectiveness.
  • the CFD simulations confirmed that the use of helium-based carrier gas for inhalation based drug delivery provides a more diffuse or evenly spread particle deposition pattern in the lungs.
  • Additional CFD simulations were performed using different inspiration flow rates in a carrier gas composition of 100% helium and in a carrier gas of standard room air with 2 micron diameter mono-dispersed spherical particles as well as 5 micron diameter mono-dispersed spherical particles.
  • the selected carrier gas flow rates for air and helium include: (i) 0.23 liters per second which represents the average human ventilation rate during rest periods; (ii) 0.5 liters per second which represents a typical flow rate from a Metered Dose Inhaler (MDI); and (iii) 1.2 liters per second which represents a typical flow rate from a Dry- Powder Inhaler (DPI).
  • MDI Metered Dose Inhaler
  • DPI Dry- Powder Inhaler
  • the tracheal deposition in general, occurred at the end of the endotracheal tube and was attributed to turbulence, which would be expected due to the higher Reynolds number of an air-based carrier gas compared to a He/C> 2 or Heliox based carrier gas.
  • a statistically significant fractional deposition of the inhaled aerosol was observed in the lungs of the test subjects exposed to 5 ⁇ m particles delivered with He/02 as the carrier gas when compared to the test subjects exposed to similar particle sizes carried in air media.
  • P/I peripheral to inner lung
  • ROI regions of interest
  • Fractional depositions of inhaled particles are summarized in Fig. 4 for the 2 ⁇ m and 5 ⁇ m particle size exposures. Analysis for differences in fractional deposition for air versus He/02 at both 2 ⁇ m and 5 ⁇ m particle size identified several statistically significant differences. There was increased deposition in the lung, when using HeO2 as the carrier media when compared to air media. In addition, tracheal deposition was statistically greater with air than He/0 2 in the 5 ⁇ m particle size simulations.
  • peripheral to inner lung (P/I) values a comparison of the peripheral (primarily small airways and alveoli) regions versus the central (primarily bronchi and conducting airways, but also including overlying alveoli and small airways) regions of the lung was calculated from the average count density for the anterior left and right lung and posterior left and right lung and are presented in Fig. 5.
  • Differences in tracheal deposition of particles were statistically significantly greater with air than HeZO 2 . A review of the data indicated the presence of increased concentrations of particles in the trachea, at or near the location of the end of the endotracheal tube.
  • the present invention thus provides various methods and systems for small particle size drug delivery via inhalation using a hypoxic mix of helium and oxygen. Improvement in drug particle deposition profile in the lungs of a patient is attained by actively controlling the drug particle size, the helium concentration of the carrier gas, the inspiration flow rate, the carrier gas temperature, and the inspiratory period during drug inhalation. Numerous modifications, changes, and variations of the present methods and systems will be apparent to a person skilled in the art and it is to be understood that such modifications, changes, and variations are to be included within the purview of this application.

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Abstract

La présente invention concerne un procédé et un système de délivrance de médicament à petite taille de particules par inhalation en utilisant un mélange hypoxique d'hélium et d'oxygène. Des améliorations du profil de dépôt des particules médicamenteuses dans les poumons d'un patient sont obtenues grâce à un contrôle actif de la taille des particules du médicament, de la concentration en hélium du gaz vecteur, du débit d'inspiration, de la température du gaz vecteur, et de la période d'inspiration pendant l'inhalation du médicament.
PCT/US2009/053126 2008-08-12 2009-08-07 Système et procédé de délivrance d'un médicament à petites particules à l'aide d'un mélange hypoxique d'hélium et d'oxygène WO2010019467A1 (fr)

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US61/088,175 2008-08-12

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003049791A1 (fr) * 2001-12-05 2003-06-19 Nupharmx, Llc Dispositif medical et methode permettant l'inhalation d'un medicament en aerosol avec de l'heliox

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003049791A1 (fr) * 2001-12-05 2003-06-19 Nupharmx, Llc Dispositif medical et methode permettant l'inhalation d'un medicament en aerosol avec de l'heliox

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANDERSON M ET AL: "Deposition in asthmatics of particles inhaled in air or in helium-oxygen", AMERICAN REVIEW OF RESPIRATORY DISEASES, NEW YORK, NY, vol. 147, no. 3, 1 March 1993 (1993-03-01), pages 524 - 528, XP009124312, ISSN: 0003-0805 *
DARQUENNE CHANTAL ET AL: "Aerosol deposition in the human respiratory tract breathing air and 80:20 heliox", JOURNAL OF AEROSOL MEDICINE, MARY ANN LIEBERT, INC., NEW YORK, US, vol. 17, no. 3, 22 October 2004 (2004-10-22), pages 278 - 285, XP009124344, ISSN: 0894-2684 *
SVARTENGREN M ET AL: "Human lung deposition of particles suspended in air or in helium/oxygen mixture", EXPERIMENTAL LUNG RESEARCH,, vol. 15, no. 4, 1 July 1989 (1989-07-01), pages 575 - 585, XP009124347, ISSN: 0190-2148 *
SWIFT D L ET AL: "Pulmonary penetration and deposition of aerosols in different gases: Fluid flow effects", ANNALS OF OCCUPATIONL HYGIENE, PERGAMON PRESS, OXFORD, GB, vol. 26, no. 1-4, 1 January 1982 (1982-01-01), pages 109 - 117, XP009124357, ISSN: 0003-4878 *

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