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Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties.
Int J Pharm. 2012 May 30; 428(1-2):103-13.IJ

Abstract

The purpose of this study was to produce a dry powder for inhalation (DPI) of a poorly soluble active ingredient (itraconazole: ITZ) that would present an improved dissolution rate and enhanced solubility with good aerosolization properties. Solid dispersions of amorphous ITZ, mannitol and, when applicable, D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) were produced by spray-drying hydro-alcoholic solutions in which all agents were dissolved. These dry formulations were characterized in terms of their aerosol performances and their dissolution, solubility and physical properties. Modulate differential scanning calorimetry and X-ray powder diffraction analyses showed that ITZ recovered from the different spray-dried solutions was in an amorphous state and that mannitol was crystalline. The inlet drying temperature and, indirectly, the outlet temperature selected during the spray-drying were critical parameters. The outlet temperature should be below the ITZ glass transition temperature to avoid severe particle agglomeration. The formation of a solid dispersion between amorphous ITZ and mannitol allowed the dry powder to be produced with an improved dissolution rate, greater saturation solubility than bulk ITZ and good aerosol properties. The use of a polymeric surfactant (such as TPGS) was beneficial in terms of dissolution rate acceleration and solubility enhancement, but it also reduced aerosol performance. For example, significant dissolution rate acceleration (f(2)<50) and greater saturation solubility were obtained when introducing 1% (w/w) TPGS (mean dissolution time dropped from 50.4 min to 36.9 min and saturation solubility increased from 20 ± 3 ng/ml to 46 ± 2 ng/ml). However, the fine particle fraction dropped from 47 ± 2% to 37.2 ± 0.4%. This study showed that mannitol solid dispersions may provide an effective formulation type for producing DPIs of poorly soluble active ingredients, as exemplified by ITZ.

Authors+Show Affiliations

Laboratoire de Pharmacie Galénique et de Biopharmacie, Université Libre de Bruxelles, Brussels, Belgium. cduret@ulb.ac.beNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

22414388

Citation

Duret, Christophe, et al. "Solid Dispersions of Itraconazole for Inhalation With Enhanced Dissolution, Solubility and Dispersion Properties." International Journal of Pharmaceutics, vol. 428, no. 1-2, 2012, pp. 103-13.
Duret C, Wauthoz N, Sebti T, et al. Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties. Int J Pharm. 2012;428(1-2):103-13.
Duret, C., Wauthoz, N., Sebti, T., Vanderbist, F., & Amighi, K. (2012). Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties. International Journal of Pharmaceutics, 428(1-2), 103-13. https://doi.org/10.1016/j.ijpharm.2012.03.002
Duret C, et al. Solid Dispersions of Itraconazole for Inhalation With Enhanced Dissolution, Solubility and Dispersion Properties. Int J Pharm. 2012 May 30;428(1-2):103-13. PubMed PMID: 22414388.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties. AU - Duret,Christophe, AU - Wauthoz,Nathalie, AU - Sebti,Thami, AU - Vanderbist,Francis, AU - Amighi,Karim, Y1 - 2012/03/10/ PY - 2012/01/05/received PY - 2012/03/04/revised PY - 2012/03/05/accepted PY - 2012/3/15/entrez PY - 2012/3/15/pubmed PY - 2012/9/28/medline SP - 103 EP - 13 JF - International journal of pharmaceutics JO - Int J Pharm VL - 428 IS - 1-2 N2 - The purpose of this study was to produce a dry powder for inhalation (DPI) of a poorly soluble active ingredient (itraconazole: ITZ) that would present an improved dissolution rate and enhanced solubility with good aerosolization properties. Solid dispersions of amorphous ITZ, mannitol and, when applicable, D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) were produced by spray-drying hydro-alcoholic solutions in which all agents were dissolved. These dry formulations were characterized in terms of their aerosol performances and their dissolution, solubility and physical properties. Modulate differential scanning calorimetry and X-ray powder diffraction analyses showed that ITZ recovered from the different spray-dried solutions was in an amorphous state and that mannitol was crystalline. The inlet drying temperature and, indirectly, the outlet temperature selected during the spray-drying were critical parameters. The outlet temperature should be below the ITZ glass transition temperature to avoid severe particle agglomeration. The formation of a solid dispersion between amorphous ITZ and mannitol allowed the dry powder to be produced with an improved dissolution rate, greater saturation solubility than bulk ITZ and good aerosol properties. The use of a polymeric surfactant (such as TPGS) was beneficial in terms of dissolution rate acceleration and solubility enhancement, but it also reduced aerosol performance. For example, significant dissolution rate acceleration (f(2)<50) and greater saturation solubility were obtained when introducing 1% (w/w) TPGS (mean dissolution time dropped from 50.4 min to 36.9 min and saturation solubility increased from 20 ± 3 ng/ml to 46 ± 2 ng/ml). However, the fine particle fraction dropped from 47 ± 2% to 37.2 ± 0.4%. This study showed that mannitol solid dispersions may provide an effective formulation type for producing DPIs of poorly soluble active ingredients, as exemplified by ITZ. SN - 1873-3476 UR - https://www.unboundmedicine.com/medline/citation/22414388/Solid_dispersions_of_itraconazole_for_inhalation_with_enhanced_dissolution_solubility_and_dispersion_properties_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(12)00201-3 DB - PRIME DP - Unbound Medicine ER -