Aerodynamically light particles for pulmonary drug delivery

a technology of pulmonary drug delivery and aerodynamic light particles, which is applied in the direction of drug compositions, powder delivery, peptides, etc., can solve the problems of local toxic effects, poor control of the site, and excessive loss of inhaled

Inactive Publication Date: 2005-11-03
EDWARDS DAVID A +6
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, pulmonary drug delivery strategies present many difficulties for the delivery of macromolecules; these include protein denaturation during aerosolization, excessive loss of inhaled drug in the oropharyngeal cavity (often exceeding 80%), poor control over the site of deposition, irreproducibility of therapeutic results owing to variations in breathing patterns, the often too-rapid absorption of drug potentially resulting in local toxic effects, and phagocytosis by lung macrophages.
This is because particles of standard mass density (mass density near 1 g / cm3) and mean diameters greater than 5 μm are known to deposit excessively in the upper airways or in the inhaler device.
Slow release from a therapeutic aerosol can prolong the residence of an administered drug in the airways or acini, and diminish the rate of drug appearance in the bloodstream.
However, increasing the particle size also minimizes the probability of particles (possessing standard mass density) entering the airways and acini due to excessive deposition in the oropharyngeal or nasal regions.

Method used

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  • Aerodynamically light particles for pulmonary drug delivery
  • Aerodynamically light particles for pulmonary drug delivery
  • Aerodynamically light particles for pulmonary drug delivery

Examples

Experimental program
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example 1

Synthesis of Aerodynamically Light Poly[(p-carboxyphenoxy)-hexane anhydride] (“PCPH”) Particles

[0079] Aerodynamically light poly[(p-carboxyphenoxy)-hexane anhydride] (“PCPH”) particles were synthesized as follows. 100 mg PCPH (MW approximately 25,000) was dissolved in 3.0 mL methylene chloride. To this clear solution was added 5.0 mL 1% w / v aqueous polyvinyl alcohol (PVA, MW approximately 25,000, 88 mole % hydrolyzed) saturated with methylene chloride, and the mixture was vortexed (Vortex Genie 2, Fisher Scientific) at maximum speed for one minute. The resulting milky-white emulsion was poured into a beaker containing 95 mL 1% PVA and homogenized (Silverson Homogenizers) at 6000 RPM for one minute using a 0.75 inch tip. After homogenization, the mixture was stirred with a magnetic stirring bar and the methylene chloride quickly extracted from the polymer particles by adding 2 mL isopropyl alcohol. The mixture was stirred for 35 minutes to allow complete hardening of the micropartic...

example 2

Synthesis of PLAL-Lys and PLAL-Lys-Ala Polymeric and Copolymeric Particles

[0081] Aerodynamically Light PLAL-Lys Particles

[0082] PLAL-Lys particles were prepared by dissolving 50 mg of the graft copolymer in 0.5 ml dimethylsulfoxide, then adding 1.5 ml dichloromethane dropwise. The polymer solution is emulsified in 100 ml of 5% w / v polyvinyl alcohol solution (average molecular weight 25 KDa, 88% hydrolyzed) using a homogenizer (Silverson) at a speed of approximately 7500 rpm. The resulting dispersion was stirred using a magnetic stirrer for 1 hour. Following this period, the pH was brought to between 7.0 and 7.2 by addition of a 0.1 N NaOH solution. Stirring was continued for an additional 2 hours until the dichloromethane was completely evaporated and the particles hardened. The particles were then isolated by centrifugation at 4000 rpm (1600 g) for 10 minutes (Sorvall RC-5B). The supernatant was discarded and the precipitate washed three times with distilled water followed by cen...

example 3

Synthesis of Spray-Dried Particles

[0090] Aerodynamically Light Particles Containing Polymer and Drug Soluble in Common Solvent

[0091] Aerodynamicatiy light 50:50 PLGA particles were prepared by spray drying with testosterone encapsulated within the particles according to the following procedures. 2.0 g poly (D,L-lactic-co-glycolic acid) with a molar ratio of 50:50 (PLGA 50:50, Resomer RG503, B. I. Chemicals, Montvale, N.J.) and 0.50 g testosterone (Sigma Chemical Co., St. Louis, Mo.) were completely dissolved in 100 mL dichloromethane at room temperature. The mixture was subsequently spraydried through a 0.5 mm nozzle at a flow rate of 5 mL / min using a Buchi laboratory spray-drier (model 190, Buchi, Germany). The flow rate of compressed air was 700 nl / h. The inlet temperature was set to 30° C. and the outlet temperature to 25° C. The aspirator was set to achieve a vacuum of −20 to −25 bar. The yield was 51% and the mean particle size was approximately 5 μm. The particles were aerod...

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Abstract

Improved aerodynamically light particles for delivery to the pulmonary system, and methods for their preparation and administration are provided. In a preferred embodiment, the aerodynamically light particles are made of a biodegradable material and have a tap density less than 0.4 g / cm3 and a mass mean diameter between 5 μm and 30 μm. The particles may be formed of biodegradable materials such as biodegradable polymers. For example, the particles may be formed of a functionalized polyester graft copolymer consisting of a linear a-hydroxy-acid polyester backbone having at least one amino acid group incorporated herein and at least on poly(amino acid) side chain extending from an amino acid group in the polyester backbone. In one embodiment, aerodynamically light particles having a large mean diameter, for example greater than 5 μm, can be used for enhanced delivery of a therapeutic or diagnostic agent to the alveolar region of the lung. The aerodynamically light particles optionally can incorporate a therapeutic or diagnostic agent, and may be effectively aerosolized for administration to the respiratory tract to permit systemic or local delivery of a wide variety of incorporated agents.

Description

BACKGROUND OF THE INVENTION [0001] The present application relates generally to biodegradable particles of low density and large size for delivery to the pulmonary system. [0002] Biodegradable particles have been developed for the controlled-release and delivery of protein and peptide drugs. Langer, R., Science, 249: 1527-1533 (1990). Examples include the use of biodegradable particles for gene therapy (Mulligan, R. C. Science, 260: 926-932 (1993)) and for ‘single-shot’ immunization by vaccine delivery (Eldridge et al., Mol. Immunol., 28: 287-294 (1991)). [0003] Aerosols for the delivery of therapeutic agents to the respiratory tract have been developed. Adjei, A. and Garren, J. Pharm. Res. 7, 565-569 (1990); and Zanen, P. and Lamm, J.-W. J. Int. J. Pharm. 114, 111-115 (1995). The respiratory tract encompasses the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into the bronchi and bronchioli. The ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/00A61K9/14A61K9/16A61K31/57A61K38/28A61K47/34A61L9/04G06F7/00G06F17/30
CPCA61K9/0075A61K9/1647A61K9/1682G06F17/30595A61K38/28A61K47/34A61K31/57G06F16/284
Inventor EDWARDS, DAVID A.CAPONETTI, GIOVANNIAHRKACH, JEFFREY S.LOTAN, NOAHHANES, JUSTINBEN-JEBRIA, ABDELL AZIZLANGER, ROBERT S.
Owner EDWARDS DAVID A
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