Inhalation delivery of proteins from ethanol suspensions.
To circumvent inherent problems associated with pulmonary administration of aqueous-solution and dry-powder protein drugs, inhalation delivery of proteins from their suspensions in absolute ethanol was explored both in vitro and in vivo. Protein suspensions in ethanol of up to 9% (wt/vol) were readily aerosolized with a commercial compressor nebulizer. Experiments with enzymic proteins revealed that nebulization caused no detectable loss of catalytic activity; furthermore, enzyme suspensions in anhydrous ethanol retained their full catalytic activity for at least 3 weeks at room temperature. With the use of Zn(2+)-insulin, conditions were elaborated that produced submicron protein particles in ethanol suspensions. The latter (insulin/EtOH) afforded respirable-size aerosol particles after nebulization. A 40-min exposure of laboratory rats to 10 mg/ml insulin/EtOH aerosols resulted in a 2-fold drop in the blood glucose level and a marked rise in the serum insulin level. The bioavailability based on estimated deposited lung dose of insulin delivered by inhalation of ethanol suspension aerosols was 33% (relative to an equivalent s.c. injection), i.e., comparable to those observed in rats after inhalation administration of dry powder and aqueous solutions of insulin. Inhalation of ethanol in a relevant amount/time frame resulted in no detectable acute toxic effects on rat lungs or airways, as reflected by the absence of statistically significant inflammatory or allergic responses, damage to the alveolar/capillary barrier, and lysed and/or damaged cells.
Choi
W S
WS
Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 01239, USA.
Murthy
G G
GG
Edwards
D A
DA
Langer
R
R
Klibanov
A M
AM
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001682:Biological Availability; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry* / Q000166:cytology; D002417:Cattle; D004355:Drug Stability; D000431:Ethanol / Q000633:toxicity; D005966:Glucuronidase / Q000032:analysis; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D007962:Leukocytes / Q000166:cytology; D008297:Male; D008657:Metabolic Clearance Rate; D009330:Nebulizers and Vaporizers; D011506:Proteins / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015032:Zinc
D000336:Aerosols; D007328:Insulin; D011506:Proteins; D000431:Ethanol; D007770:L-Lactate Dehydrogenase; D005966:Glucuronidase; D015032:Zinc