Hydroxyzine- and cetirizine-loaded liposomes: effect of duration of thin film hydration, freeze-thawing, and changing buffer pH on encapsulation and stability.
OBJECTIVE
To assess the effect of the duration of film hydration, freeze-thawing, and changing buffer pH on the extent of entrapment of hydroxyzine and cetirizine, H1-antihistamines with different polarity, into liposomes, and the stability of these liposomes.


METHODS
Multilamellar vesicles (MLV) were prepared by thin-lipid film hydration using L-alpha-phosphatidylcholine (PC) and buffer containing 80 mg hydroxyzine at pH 7. For MLV containing hydroxyzine, the liposomes were subjected to 1) hydration for 1 h, 24 h, or 48 h for the control batch, batch B, or batch D respectively; and 2) hydration for 1 h, 24 h, or 48 h with freeze-thawing for 5-cycles for batch A, batch C, or batch E, respectively. These formulations were stored at 10 +/- 2 degrees C and 37 +/- 0.1 degrees C. Small unilamellar vesicles (SUV) and MLV were prepared using L-alpha-phosphatidylcholine (PC), and buffer at pH 5.0, 5.5, 6.0, 6.5, and 7.0, containing 80 mg hydroxyzine or 82 mg cetirizine by the ethanol injection and thin-lipid film hydration methods, respectively. These formulations were stored at 10 +/- 2 degrees C. Liposomes were evaluated immediately after preparation and after storage by determining percent entrapment of hydroxyzine (PETH) or of cetirizine (PEC) and by observing changes in the physical appearance (PA). Particle size (PSA) of the liposomes freshly prepared at pH=6.5 was measured from transmission electron micrographs (TEM).


RESULTS
Increasing thin-film hydration time or repeated freeze-thawing did not affect the initial PETH or long-term stability of control, A, B, C, D, and E batches of MLV containing hydroxyzine stored at 10 +/- 2 degrees C. At 37 +/- 0.1 degrees C, PETH of all MLV batches decreased considerably after 1 month. This was more evident in batches B, C, and E exposed to freeze-thawing. The PETH of SUV increased markedly from 53.0% to 84.0% when the pH of the buffer was increased from 5.0 to 5.5. As pH increased from 6.0 to 7.0, PETH continued to increase from 84% to 94%. The initial PETH of MLV increased slightly from 82.0% to 94.0% as the buffer pH values increased from 5.0 to 7.0. There was no effect of pH on initial PEC, and stability of SUV or initial PEC of MLV, which ranged from 92% to 94%, as buffer pH values increased from 5.0 to 6.5. After storage at 10 +/- 2 degrees C PEC in MLV decreased from 94% to 74%.


CONCLUSIONS
The freeze-thawing processes had some effect on the stability of liposomes stored at temperatures higher than ambient temperature, 37 +/- 0.1 degrees C. The effect of changing the buffer pH from 5.5 to 7.0, and from 5.0 to 6.5 on initial PETH and PEC, respectively, was minimal. After 24 months at l0 +/- 2 degrees C, pH had no effects on PETH; however, PEC of MLV decreased.
Elzainy
Abeer A W
AA
Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.
Gu
Xiaochen
X
Simons
F Estelle R
FE
Simons
Keith J
KJ
D017332:Cetirizine / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004355:Drug Stability; D005615:Freezing; D006634:Histamine H1 Antagonists / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006919:Hydroxyzine / Q000737:chemistry*; D008081:Liposomes; D010713:Phosphatidylcholines / Q000737:chemistry; D013997:Time Factors
D006634:Histamine H1 Antagonists; D008081:Liposomes; D010713:Phosphatidylcholines; D006919:Hydroxyzine; D017332:Cetirizine