title: Evaluation of highly branched cyclic dextrin in inhalable particles of combined antibiotics for the pulmonary delivery of anti-tuberculosis drugs.
abstract: This work aims to identify a suitable formulation for the pulmonary delivery of combinations of inhalational drugs using highly branched cyclic dextrin (HBCD) macromolecules. We compared the effectiveness between powders prepared from HBCD with those prepared from five alternative excipients (lactose, maltose, sucrose, β-cyclodextrin and methyl β-cyclodextrin) in the pulmonary delivery of a single-dosage form of two anti-tuberculosis drugs (isoniazid and rifampicin). Fine particles of untreated active pharmaceutical ingredients (APIs) and combination products using excipients were prepared by spray drying. Rifampicin, a hydrophobic compound, was dissolved in ethanol, whereas isoniazid, a hydrophilic compound combined with either HBCD or an alternative excipient was dissolved in water. This was followed by the preparation of the spray-dried particle formulations (SDPs). The SDPs were characterised in terms of particle size, surface morphology, drug content, specific surface area, powder X-ray diffraction and inhalational properties. The addition of either an excipient or HBCD decreased API particle sizes, producing submicron-size particles. Surface morphology examination using scanning electron microscopy revealed API SDPs to be cylindrical and non-wrinkled. However, API-excipient SDPs were wrinkled and rough. Only HBCD SDPs were porous and non-aggregating, thereby suggesting superior aerodynamic properties and suitability for pulmonary delivery of these particles. HBCD formulations had the highest drug content in terms of both isoniazid (97.5%) and rifampicin (92.3%). Larger surface areas were obtained for SDPs of HBCD than those of other sugars. Regarding inhalational properties, HBCD formulations had higher emitted dose and fine-particle fractions than formulations of all other sugars tested. Our results confirm the feasibility of the formulation of hydrophilic and hydrophobic drug substances into a single-dosage preparation for pulmonary delivery using HBCD as an excipient.
authors.affiliation: Laboratory of Formulation Design and Pharmaceutical Technology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. Electronic address: kadota@gly.oups.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kadota
authors.affiliation: Laboratory of Formulation Design and Pharmaceutical Technology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Senda
authors.affiliation: Laboratory of Formulation Design and Pharmaceutical Technology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tagishi
authors.affiliation: Laboratory of Formulation Design and Pharmaceutical Technology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. Electronic address: shogo205@yahoo.com.
authors.forename: John Oluwasogo
authors.initials: JO
authors.lastname: Ayorinde
authors.affiliation: Laboratory of Formulation Design and Pharmaceutical Technology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. Electronic address: ytozuka@gly.oups.ac.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tozuka
mesh_terms: D000280:Administration, Inhalation; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D003912:Dextrins / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D004338:Drug Combinations; D015195:Drug Design; D005079:Excipients / Q000737:chemistry; D007538:Isoniazid / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008168:Lung / Q000378:metabolism*; D008962:Models, Theoretical; D010316:Particle Size; D016062:Porosity; D012293:Rifampin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013499:Surface Properties
chemical_list: D000904:Antibiotics, Antitubercular; D003912:Dextrins; D004337:Drug Carriers; D004338:Drug Combinations; D005079:Excipients; D007538:Isoniazid; D012293:Rifampin
keywords: Dry powder inhalers; Highly branched polymer; Isoniazid; Porous particles; Rifampicin; Spray-drying; Sugars