Rapid-onset intranasal delivery of metoclopramide hydrochloride. Part I. Influence of formulation variables on drug absorption in anesthetized rats.
Intranasal (IN) administration is a promising approach for rapid-onset delivery of medications and to circumvent their first-pass elimination when taken orally. Metoclopramide (MCP) is a potent antiemetic, effective even for preventing emesis induced by cancer chemotherapy. The feasibility of developing an efficacious intranasal formulation of metoclopramide has been undertaken in this study. The nasal absorption of MCP was studied in anesthetized rats over 60min using the in vivo in situ technique. The influence of several formulation variables, vis., pH and the addition of preservative, viscosity and absorption enhancing agents on the nasal MCP absorption was examined. The data obtained showed that MCP was well absorbed nasally where almost 90% of the drug was absorbed after 60min from the rat nasal cavity. The MCP absorption was pH-dependant such that the apparent first-order rate constant of absorption (K(app)) was almost tripled when the pH of the solution was increased from 5 to 8. However, deviation from the classical pH-partition theory was observed pointing to the role of aqueous pore pathway in MCP nasal absorption. The K(app) was significantly increased (P<0.05) by incorporation of 0.01% of the preservative benzalkonium chloride. Conversely, increasing the solution viscosity by the use of hydroxylpropyl methylcellulose adversely affected the rate of absorption. The use of enhancers namely sodium deoxycholate, sodium cholate, chitosan low and high molecular weight, protamine sulphate and poly-l-arginine resulted in significant increase in MCP absorption. The highest promoting effect was observed with the bile salt sodium deoxycholate where about 92% of the drug was absorbed in 25min from the rat nasal cavity and the K(app) showed more than two-fold increase as compared to control (from 0.0452 to 0.1017min(-1)).
Zaki
N M
NM
Department of Pharmaceutics, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, Egypt. anm1998@lycos.com
Awad
G A S
GA
Mortada
N D
ND
Abd ElHady
S S
SS
D000042:Absorption / Q000187:drug effects; D000281:Administration, Intranasal; D000758:Anesthesia; D000818:Animals; D000932:Antiemetics / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D001548:Benzalkonium Compounds / Q000008:administration & dosage / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D008297:Male; D008747:Methylcellulose / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D008787:Metoclopramide / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism; D011310:Preservatives, Pharmaceutical / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D014783:Viscosity
D000932:Antiemetics; D001548:Benzalkonium Compounds; D011310:Preservatives, Pharmaceutical; D003840:Deoxycholic Acid; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D008787:Metoclopramide