title: In vitro evaluation of the effect of cyclodextrin complexation on pulmonary deposition of a peptide, cyclosporin A.
abstract: The effect of hydroxypropyl-alpha-cyclodextrin (HP-alpha-CD) complexation on in vitro pulmonary deposition of a cyclic peptide cyclosporin A (CsA) was studied. In addition, the effect of storage (32 days, 40 degrees C, 75% RH) on CsA/HP-alpha-CD complexes was studied. The complexation of CsA with CDs was evaluated by a phase-solubility method. Solid CsA/HP-alpha-CD complexes were prepared by freeze drying. Three inhalation formulations were prepared: CsA/lactose reference formulation (LF) (drug:carrier 1:364, w/w), CsA/HP-alpha-CD complex formulation (CDF) (drug:CD 1:269, w/w) and CsA/HP-alpha-CD complex/lactose formulation (CDLF) (complex:carrier 100:114, w/w). The inhalation studies were performed in vitro using Andersen Sampler (Ph. Eur.) and Taifun multi-dose dry powder inhalers (DPIs). Before the storage, the respirable fraction value (RF%) of CsA was 19.8+/-0.7%, 33.0+/-7.0% and 34.6+/-1.1% (mean+/-S.D., n=4 x 20) with LF, CDF and CDLF, respectively. When exposed to moisture (storage in a permeable polystyrene tube), the RF% values of CsA from formulations containing CsA/HP-alpha-CD complexes were lower than before the storage. However, when stored in the Taifun DPI, the RF% value of CsA from any of the formulations did not decrease. In conclusion, an acceptable RF% value of a peptide CsA from freeze-dried, simply micronized CsA/HP-alpha-CD complex powder was achieved before and after storage in the DPI.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. laura.matilainen@uku.fi
authors.forename: L
authors.initials: L
authors.lastname: Matilainen
authors.forename: K
authors.initials: K
authors.lastname: Järvinen
authors.forename: T
authors.initials: T
authors.lastname: Toropainen
authors.forename: E
authors.initials: E
authors.lastname: Näsi
authors.forename: S
authors.initials: S
authors.lastname: Auriola
authors.forename: T
authors.initials: T
authors.lastname: Järvinen
authors.forename: P
authors.initials: P
authors.lastname: Jarho
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000465:Algorithms; D001249:Asthma / Q000188:drug therapy; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D006084:Graft Rejection / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D008168:Lung / Q000378:metabolism*; D016040:Lung Transplantation; D010316:Particle Size; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D047391:alpha-Cyclodextrins / Q000737:chemistry*
chemical_list: D000336:Aerosols; D007166:Immunosuppressive Agents; D047391:alpha-Cyclodextrins; C479658:hydroxypropyl-alpha-cyclodextrin; D016572:Cyclosporine