Liquid crystalline pharmacogel based enhanced transdermal delivery of propranolol hydrochloride.
A novel pharmacogel was developed for the enhanced transdermal delivery of propranolol hydrochloride (PH). The synthesized prodrugs, propranolol palmitate hydrochloride (PPH) and propranolol stearate hydrochloride (PSH) self-assembled to form gel simply upon mixing alcoholic solution of prodrug with an aqueous solution in a specified ratio. By varying the ratio of prodrug, alcohol and water, three-component phase diagram was constructed which revealed isotropic-gel-vesicular dispersion regions, respectively concomitant to increasing the ratio of water. The gel phase is termed 'Pharmacogel' and exhibits birefringence under plane-polarized light corroborating the presence of lamellar liquid crystals. The pharmacogel by virtue of high chemical potential gradient and improved physicochemical properties showed the enhanced in-vitro skin permeation flux of 51.5+/-3.7 and 42.5+/-3.1 microg/cm(2)/h from PPH and PSH gel, respectively, as compared to 1.9+/-0.1 microg/cm(2)/h for control; and decrease in lag time (1.8 and 2.8 h for PPH and PSH gel, respectively) compared to control (7.6 h) was observed. The admixing of egg lecithin (EL) in increasing ratio concomitantly decreased the flux values to 31.7+/-2.1 microg/cm(2)/h (at a mole ratio of 50:50 PPH:EL) and increased the lag time. In the gel containing 50% EL, the addition of span 40 and cholesterol slightly reduced the permeation while sodium deoxycholate and Tween-80 improved it. The plasma drug levels following transdermal application of control were low (C(max)=23 ng/ml) while in PPH gel, it increased with time reaching C(max) of 94 ng/ml at 8 h post-application of PPH gel (C(max) of 75 ng/ml at 12 h post application of PL5 gel) and maintained for longer times. The AUC(0-32 h) for PPH gel was much higher (1968 ng h/ml) than control (AUC(0-18 h) was 239 ng h/ml), while EL mixed gel also showed better absorption (AUC(0-32 h) was 1707 ng h/ml). The gel formulations also caused less irritation than control, while mixed gel showed least irritation. This novel self-assembled pharmacogel providing high transdermal permeation with many variables to regulate the delivery is therefore having a great potential in percutaneous delivery.
Namdeo
Alok
A
Novel Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. H.S. Gour University, (M.P.) Sagar 470 003, India. jnarendr@yahoo.co.in
Jain
N
N
D000279:Administration, Cutaneous; D000818:Animals; D003460:Crystallization; D016503:Drug Delivery Systems; D005079:Excipients / Q000737:chemistry; D005782:Gels; D010539:Permeability; D010713:Phosphatidylcholines / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011433:Propranolol / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000378:metabolism*; D012996:Solutions; D013997:Time Factors
D005079:Excipients; D005782:Gels; D010713:Phosphatidylcholines; D011355:Prodrugs; D012996:Solutions; C401282:palmitoyl propranolol; C467718:propranolol stearate; D011433:Propranolol