Respirable controlled release polymeric colloid (RCRPC) of bosentan for the management of pulmonary hypertension: in vitro aerosolization, histological examination and in vivo pulmonary absorption.
Bosentan is an endothelin receptor antagonist (ERA) prescribed for patients with pulmonary arterial hypertension (PAH). The oral delivery of bosentan possesses several drawbacks such as low bioavailability (about 50%), short duration of action, frequent administration, hepatotoxicity and systemic hypotension. The pulmonary administration would circumvent the pre-systemic metabolism thus improving the bioavailability and avoids the systemic adverse effects of oral bosentan. However, the short duration of action and the frequent administration are the major drawbacks of inhalation therapy. Thus, the aim of this work is to explore the potential of respirable controlled release polymeric colloid (RCRPC) for effective, safe and sustained pulmonary delivery of bosentan. Central composite design was adopted to study the influence of formulation and process variables on nanoparticles properties. The particle size, polydispersity index (PDI), entrapment efficiency (EE) and in vitro bosentan released were selected as dependent variables. The optimized RCRPC showed particle size of 420 nm, PDI of 0.39, EE of 60.5% and sustained release pattern where only 31.0% was released after 16 h. The in vitro nebulization of RCRPC indicated that PLGA nanoparticles could be incorporated into respirable nebulized droplets better than drug solution. Pharmacokinetics and histopathological examination were determined after intratracheal administration of the developed RCRPC to male albino rats compared to the oral bosentan suspension. Results revealed the great improvement of bioavailability (12.71 folds) and sustained vasodilation effect on the pulmonary blood vessels (more than 12 h). Bosentan-loaded RCRPC administered via the pulmonary route may therefore constitute an advance in the management of PAH.
a Department of Pharmaceutics and Industrial Pharmacy , Faculty of Pharmacy, Cairo University , Cairo , Egypt.
Lydia A
LA
Hanna
a Department of Pharmaceutics and Industrial Pharmacy , Faculty of Pharmacy, Cairo University , Cairo , Egypt.
Emad B
EB
Basalious
a Department of Pharmaceutics and Industrial Pharmacy , Faculty of Pharmacy, Cairo University , Cairo , Egypt.
Omaima N
ON
ELGazayerly
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D000077300:Bosentan; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D004339:Drug Compounding; D065546:Drug Liberation; D004355:Drug Stability; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D019344:Lactic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D010316:Particle Size; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011652:Pulmonary Circulation / Q000187:drug effects; D017208:Rats, Wistar; D065589:Respiratory Tract Absorption; D013449:Sulfonamides / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D000336:Aerosols; D000959:Antihypertensive Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000077300:Bosentan
Bosentan; intratracheal; nanoparticles; pulmonary delivery; respirable controlled release polymeric colloid