Effect of pulmonary surfactant and phospholipid hexadecanol tyloxapol on recombinant human-insulin absorption from intratracheally administered dry powders in diabetic rats.
The purpose of the present study was to evaluate the enhancement effect of the natural pulmonary surfactant (PS) or its artificial substitute, phospholipid hexadecanol tyloxapol (PHT) on the bioavailability and hypoglycemic activity of recombinant human insulin (rh-insulin) in a pulmonary delivery system. PS- or PHT-loaded insulin formulation was administered to streptozotocin induced diabetic rats, at doses of 5 U/kg, 10 U/kg and 20 U/kg insulin, respectively. The hypoglycemic effect caused by PS or PHT containing rh-insulin was analyzed and the area above the curves (AAC) of serum glucose levels versus time, the minimum glucose concentration (C(min)), the time to C(min) (T(min)) and the pharmacological availability (PA%) were derived from the serum glucose profiles. Results showed that PS and PHT caused significantly decrease in serum glucose levels. The decrease in plasma glucose levels continued for about 5 h after the nadir. The highest AAC value was obtained when 20 U/kg rh-insulin with PS or PHT as absorption enhancer was administered to rats. AAC(0-360 min) of PS- or PHT-loaded rh-insulin was 2-3 times as much as that without PS or PHT and PA% increased by 1.3-2 fold. Thus, the extent of oral absorption of insulin from PS- or PHT-loaded particles was significantly greater when compared with that without them. In addition, PHT as well as PS did not change the lactate dehydrogenase (LDH) activity, alkaline phosphatase (AKP) activity and N-acetyl-β-D-glucoaminidase (NAG) activity in bronch fluid which are sensitive indicators of acute toxicity to lung cells in bronchoalveolar lavage (BAL). It is concluded that PS and PHT is a promising absorption enhancer for pulmonary delivery systems of large molecule drugs as rh-insulin.
Center of Drug Metabolism and Pharmacokinetics, College of Pharmacy, China Pharmaceutical University, China.
Jianheng
J
Zheng
Ge
G
Zhang
Yang
Y
Lu
Fang
F
Fang
Jiake
J
He
Ning
N
Li
Amer
A
Talbi
Ying
Y
Zhang
Yue
Y
Tang
Jiabi
J
Zhu
Xijing
X
Chen
D000042:Absorption; D000118:Acetylglucosaminidase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002626:Chemistry, Pharmaceutical; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004333:Drug Administration Routes; D006801:Humans; D006836:Hydro-Lyases / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007328:Insulin / Q000235:genetics / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055370:Lung Injury / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011208:Powders / Q000737:chemistry; D011663:Pulmonary Surfactants / Q000737:chemistry*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D013501:Surface-Active Agents / Q000737:chemistry*; D013997:Time Factors; D014132:Trachea
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010743:Phospholipids; D011208:Powders; D011663:Pulmonary Surfactants; D011994:Recombinant Proteins; D013501:Surface-Active Agents; D011092:Polyethylene Glycols; D000469:Alkaline Phosphatase; D000118:Acetylglucosaminidase; D006836:Hydro-Lyases; C045581:lactate dehydratase; C016811:tyloxapol