title: Solid Lipid Nanoparticle assemblies (SLNas) for an anti-TB inhalation treatment-A Design of Experiments approach to investigate the influence of pre-freezing conditions on the powder respirability.
abstract: For direct intramacrophagic antitubercular therapy, pulmonary administration through Dry Powder Inhaler (DPI) devices is a reasonable option. For the achievement of efficacious aerosolisation, rifampicin-loaded Solid Lipid Nanoparticle assemblies (SLNas) were developed using the melt emulsifying technique followed by freeze-drying. Indeed, this drying method can cause freezing or drying stresses compromising powder respirability. It is the aim of this research to offer novel information regarding pre-freezing variables. These included type and concentration of cryoprotectants, pre-freezing temperature, and nanoparticle concentration in the suspension. In particular, the effects of such variables were observed at two main levels. First of all, on SLNas characteristics - i.e., size, polydispersity index, zeta-potential, circularity, density, and drug loading. Secondly, on powder respirability, taking into account aerodynamic diameter, emitted dose, and respirable fraction. Considering the complexity of the factors involved in a successful respirable powder, a Design of Experiments (DoE) approach was adopted as a statistical tool for evaluating the effect of pre-freezing conditions. Interestingly, the most favourable impact on powder respirability was exerted by quick-freezing combined with a certain grade of sample dilution before the pre-freezing step without the use of cryoprotectants. In such conditions, a very high SLNas respirable fraction (>50%) was achieved, along with acceptable yields in the final dry powder as well as a reduction of powder mass to be introduced into DPI capsules with benefits in terms of administered drug dose feasibility.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via G. Campi 103, 41125 Modena, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Maretti
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via G. Campi 103, 41125 Modena, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rustichelli
authors.affiliation: Department of Engineering Enzo Ferrari, University of Modena and Reggio Emilia, via P. Vivarelli 10, 41125 Modena, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Romagnoli
authors.affiliation: Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Anna Giulia
authors.initials: AG
authors.lastname: Balducci
authors.affiliation: Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Buttini
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via G. Campi 103, 41125 Modena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sacchetti
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via G. Campi 103, 41125 Modena, Italy.
authors.forename: Eliana
authors.initials: E
authors.lastname: Leo
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, via G. Campi 103, 41125 Modena, Italy. Electronic address: valentina.iannuccelli@unimore.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Iannuccelli
mesh_terms: D000280:Administration, Inhalation; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000737:chemistry*; D065546:Drug Liberation; D058995:Dry Powder Inhalers / Q000379:methods*; D005612:Freeze Drying / Q000379:methods; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry*; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D011208:Powders
chemical_list: D000995:Antitubercular Agents; D008055:Lipids; D011208:Powders
keywords: D-mannitol (PubChem CID: 6251); Freeze-drying; Inhalation; Methyl parahydroxybenzoate (PubChem CID: 7456); Rifampicin (PubChem CID: 5381226); Sodium taurocholate (PubChem CID: 23666345); Solid Lipid Nanoparticles; Statistical experimental design; Stearic acid (PubChem CID: 5281); Tuberculosis; d-(+)-trehalose (PubChem CID: 7427)