title: Three double-blind, randomized trials evaluating the safety and tolerance of different formulations of the saponin adjuvant QS-21.
abstract: The effects of the adjuvant QS-21 in various formulations on immediate pain on injection after intramuscular injection were evaluated in three Phase I clinical trials in healthy adults. Each trial was designed as a double-blind, randomized, four-way or five-way cross-over study with each subject acting as his/her own control. In the first trial, four formulations designed to evaluate the effect of QS-21 or pH (over a range of 6--7.2) were evaluated: phosphate-buffered saline at pH 6.0 or 7.2, and 50 microg of QS-21 in phosphate-buffered saline at pH 6.0 or 7.2. Thirty-three volunteers received each of the four intramuscular injections in random order separated by approximately 1 week. The volunteers assessed the immediate injection pain from 0 to 10 (none to most pain). The data indicate that the presence of QS-21, but not pH, is associated with transient injection site pain. The second trial, which utilized the same design as the first trial, evaluated formulations of QS-21 in various excipients. Fifteen volunteers received phosphate-buffered saline, QS-21/PBS, QS-21/aluminum hydroxide, and QS-21/4 mg/ml of polysorbate 80. Polysorbate 80, but not aluminum hydroxide, reduced the mean pain score compared to QS-21/PBS. The third trial evaluated formulations of QS-21 in additional excipients. Fifteen volunteers received aluminum hydroxide (without QS-21), QS-21/PBS, QS-21/0.72% benzyl alcohol, QS-21/30 mg/ml of hydroxypropyl-beta-cyclodextrin, and QS-21/8-mg/ml of polysorbate 80. Benzyl alcohol, cyclodextrin, and the higher concentration of polysorbate 80 reduced the pain scores associated with QS-21. Hence, QS-21 is associated with injection pain in simple buffer formulations, but it is possible to improve the acceptability of QS-21-containing formulations through reformulation with certain excipients.
authors: Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical Center, Worcester, MA 01605, USA.
authors: D C
authors: DC
authors: Waite
authors: E W
authors: EW
authors: Jacobson
authors: F A
authors: FA
authors: Ennis
authors: R
authors: R
authors: Edelman
authors: B
authors: B
authors: White
authors: R
authors: R
authors: Kammer
authors: C
authors: C
authors: Anderson
authors: C R
authors: CR
authors: Kensil
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects*; D000293:Adolescent; D000328:Adult; D000536:Aluminum Hydroxide / Q000008:administration & dosage; D019905:Benzyl Alcohol / Q000008:administration & dosage; D018592:Cross-Over Studies; D003505:Cyclodextrins / Q000008:administration & dosage; D004311:Double-Blind Method; D004361:Drug Tolerance; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007273:Injections, Intramuscular; D008875:Middle Aged; D010146:Pain / Q000209:etiology / Q000517:prevention & control; D011136:Polysorbates / Q000008:administration & dosage; D012449:Safety; D012503:Saponins / Q000008:administration & dosage* / Q000009:adverse effects*; D047392:beta-Cyclodextrins
chemical_list: D000276:Adjuvants, Immunologic; D003505:Cyclodextrins; D011136:Polysorbates; D012503:Saponins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000536:Aluminum Hydroxide; C078785:saponin QA-21V1; D019905:Benzyl Alcohol