title: In-situ-micronization of disodium cromoglycate for pulmonary delivery.
abstract: Drug particle properties are critical for the therapeutic efficiency of a drug delivered to the lung. Jet-milling, a commonly used technique for micronization of drugs, has several disadvantages such as a non-homogeneous particle size distribution, and unnatural, thermodynamically activated particle surfaces causing high agglomeration. For pulmonary use in a dry powder inhaler, in addition to a small particle size, good de-agglomeration behaviour is required. In this study disodium cromoglycate is prepared in situ in a respirable particle size by a controlled crystallization technique. First the drug is dissolved in water (4%) and precipitated by a solvent change method in the presence of a cellulose ether (hydroxypropylmethylcellulose) as a stabilizing hydrocolloid. By rapidly pouring isopropyl alcohol into the drug solution in a 1:8 (v/v) ratio, the previously molecularly dispersed drug is associated to small particles and stabilized against crystal growth in the presence of the hydrophilic polymer. This dispersion was spray-dried. The mean particle size of the drug was around 3.5 microm and consequently was in the respirable range. The in-situ-micronized drug powder was tested for its aerodynamic behaviour and compared with jet-milled drug powder and with commercial products using the Spinhaler, the Cyclohaler, and the FlowCaps-Inhaler as model devices. The fine particle fraction (FPF) (<5 microm) was increased from 7% for the jet-milled drug to approximately 75% for the in-situ-micronized drug when the pure drug powder was dispersed without any device. Delivery of the engineered particles via the Spinhaler, the FlowCaps-Inhaler and the Cyclohaler increased the FPF from 11 to 46%, 19 to 51%, and 8 to 40%, respectively.
authors.affiliation: Department of Pharmaceutics and Biopharmaceutics, Christian Albrecht University Kiel, Kiel, Germany. steckel@pharmazie.uni-kiel.de
authors.forename: Hartwig
authors.initials: H
authors.lastname: Steckel
authors.forename: Norbert
authors.initials: N
authors.lastname: Rasenack
authors.forename: Bernd W
authors.initials: BW
authors.lastname: Müller
mesh_terms: D000280:Administration, Inhalation; D018927:Anti-Asthmatic Agents / Q000737:chemistry*; D004205:Cromolyn Sodium / Q000737:chemistry*; D003460:Crystallization; D004339:Drug Compounding; D016503:Drug Delivery Systems; D008855:Microscopy, Electron, Scanning; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D011208:Powders / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D018927:Anti-Asthmatic Agents; D011208:Powders; D004205:Cromolyn Sodium