title: Inclusion complexation of lorazepam with different cyclodextrins suitable for parenteral use.
abstract: The development of a parenteral lorazepam formulation, using cyclodextrins (CDs) as inclusion complexation agents, was investigated. CDs suitable for parenteral injection, i.e., hydroxypropyl-beta-cyclodextrin (HP-beta-CD), hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD), sulfobutylether-7-beta-cyclodextrin (SBE-7-beta-CD), and maltosyl-beta-cyclodextrin (malt-beta-CD) were studied for the possibility to increase the solubility of lorazepam. Lorazepam interacted with all tested CD derivatives and 1:1 complexes are formed. HP-beta-CD exerts the highest solubility improvement, reaching about 6 mg/ml lorazepam in 30% (w/v) CD solution. When using SBE-7-beta-CD or malt-beta-CD only half of that concentration can be dissolved. HP-gamma-CD interacts much less with lorazepam. Parenteral solutions with 4 mg/ml in 30% (w/v) HP-beta-CD solution, with 2 mg/ml in 30% (w/v) SBE-7-beta-CD, and with 2 mg/ml lorazepam in 15% (w/v) HP-beta-CD, were prepared. Sterile filtration of the formulation needs to be applied because of massive degradation of lorazepam during autoclaving. No precipitation is observed after dilution of the different formulations with (physiological) water or with 5% dextrose in water, which proves their suitability for administration with perfusions. The stability of the preparations was investigated in aqueous medium. During the first month, in all solutions more than 90% of lorazepam remained; after 3 months, less than 60% of lorazepam remained in the solutions with 15% (w/v) HP-beta-CD and around 65-70% in the solutions with 30% (w/v) of CDs. Because of this short stability time, the preparations need to be lyophilized.
authors.affiliation: Department of Pharmaceutical Technology and Physical Pharmacy, Vrije Universiteit Brussel-VUB, Brussels, Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Holvoet
authors.forename: Yvan
authors.initials: Y
authors.lastname: Vander Heyden
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Plaizier-Vercammen
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003505:Cyclodextrins / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004349:Drug Packaging / Q000379:methods / Q000592:standards; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007274:Injections, Intraperitoneal; D007552:Isotonic Solutions / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D008140:Lorazepam / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D008320:Maltose / Q000031:analogs & derivatives / Q000737:chemistry; D015203:Reproducibility of Results; D012995:Solubility; D013242:Sterilization / Q000379:methods; D047392:beta-Cyclodextrins / Q000737:chemistry; D047408:gamma-Cyclodextrins / Q000737:chemistry
chemical_list: D003505:Cyclodextrins; D003692:Delayed-Action Preparations; D005079:Excipients; D007552:Isotonic Solutions; D047392:beta-Cyclodextrins; D047408:gamma-Cyclodextrins; C479659:hydroxypropyl-gamma-cyclodextrin; C433303:maltosyl-cyclodextrin; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C093196:SBE4-beta-cyclodextrin; D008320:Maltose; D008140:Lorazepam