Manufacture, characterization, and pharmacodynamic evaluation of engineered ipratropium bromide particles.
OBJECTIVE
The intent of this research was to generate and characterize respirable particles of ipratropium bromide (IPB), a short-acting anticholinergic bronchodilator, to achieve demonstrable sustained-release properties. The value of a long-acting anticholinergic agent is evident in the use of tiotropium for the treatment of chronic obstructive pulmonary disease.


METHODS
Hollow, spherical particles of ipratropium bromide suitable for inhalation were generated using a spray-drying process and characterized by laser diffraction particle size analysis, scanning electron microscopy, dynamic vapor sorption, X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and dissolution testing. Experimental design techniques were used to identify critical process parameters and optimize the spray drying process. Pharmacodynamic studies were conducted to determine duration of effect.


RESULTS
Crystalline, stable, respirable particles with a range of dissolution profiles were manufactured by application of polylactic acid (PLA) coatings of 1, 5, 10, 15, 30, and 50% w/w. A novel, robust, modified Type IV dissolution method discriminated between formulations and guided their development. Preliminary studies in guinea pigs indicated an increased duration of bronchodilatory effect for 30% PLA-coated particles (56.3 min) particles compared with IPB powders alone (11.0 min).


CONCLUSIONS
Sustained-release respirable particles of ipratropium bromide were developed using a PLA spray coating approach and a trend for increased duration of effect was demonstrated in guinea pigs.
Taylor
Michael K
MK
GlaxoSmithKline, Research Triangle Park, NC 27709, USA. mkt5496@gsk.com
Hickey
Anthony J
AJ
VanOort
Michiel
M
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018680:Cholinergic Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005079:Excipients / Q000737:chemistry; D005260:Female; D006168:Guinea Pigs; D009241:Ipratropium / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D008855:Microscopy, Electron, Scanning; D015394:Molecular Structure; D010316:Particle Size; D011091:Polyesters; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry; D011208:Powders; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*; D013997:Time Factors; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
D000336:Aerosols; D001993:Bronchodilator Agents; D018680:Cholinergic Antagonists; D005079:Excipients; D011091:Polyesters; D011108:Polymers; D011208:Powders; D014867:Water; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D015060:1,2-Dipalmitoylphosphatidylcholine; D019344:Lactic Acid; C033616:poly(lactide); D009241:Ipratropium