According to the WHO global report 2014, tuberculosis (TB) remains one of the world’s deadliest communicable diseases, despite implementation of highly standard treatment regimen that has caused the number of cases began to decline from 1992. The current therapy following WHO guidelines involves three/four drug oral regimen (first-line drugs), long-term therapy (6/7 months), high and frequent doses so producing several side-effects, in particular hepatotoxicity (WHO, 2014). The long therapy, responsible for patient’s non-compliance that is the most common reason for treatment failure, is connected to Mycobacterium tuberculosis (Mtb) nature. Unlike most microbes, Mtb survives in AM phagosomes, has a slow growing and metabolism besides death, so that the drugs have to be taken for a long period. To overcome these drawbacks and improve treatment efficacy, the new strategies could involve vaccination (limited success), new drug development (no new drugs in the last 30 year) and new formulation design for old drugs. Among these, the shortest-term goal is represented by new technological approaches or Drug Delivery Systems (DDS). In this latter context, considering that 75-80% of TB cases remain localized in the lungs, pulmonary route appears the most logical route to reach promptly the primary infected site providing to reduced dose and dose frequency, treatment duration, TB dissemination in other organs risk of drug-resistant mutants and toxicity as well as improving patient’s compliance (Pham D-D., 2015). Among the portable inhalation devices, Dry Powder Inhaler (DPI) appears more advantageous than Metered Dose Inhaler (MDI), considering low water solubility of most anti-TB drugs, propellant absence and drug stability in its dry state (Hoppentocht, 2014). For an efficient drug delivery by DPI, several powder properties (particle microsize, irregular shape reducing particle contact area so favoring powder deaggragation, low tapped density, surface charge, weak adhesion between particles, good flowability) contribute to determining powder aerodynamic performance and, consequently, dose emission and dispersion, deposition onto alveolar epithelium, and phagocytosis by alveolar macrophages (Claus, 2014). Based on these assumptions, Solid Lipid Microparticles (SLM), constituted by a solid lipid core stabilized by a surfactant on their surface, are known to be biocompatible, biodegradable, physically stable, and obtainable by using low cost materials and eco-friendly processes without organic solvents. More, SLM are suitable to incorporate firmly high lipophilic drug loading levels, and they are not hygroscopic avoiding so powder flowability compromising. In a previous study, SLM loaded with rifampicin (RIF), a first-line anti-TB drug, were designed in a perspective of an inhaled therapy by means a DPI device and found capable of preserving drug antimicrobial activity and being taken up by murine macrophages cell lines (Maretti, 2014). The present research focused on the evaluation of both RIF stability during the production phases and the role of variables relating to freeze-drying process (freezing conditions, sample dilution, cryoprotectants) affecting the powder aerosolization. The freezing method can gave a significant effect on the ice structure affecting both water-vapor flow during the primary drying and the ice crystal size, so influencing the dry final product. Considering the complexity of the factors involved in a successful breathable powder, a statistical Design of Experiments (DOE) was adopted to study the critical variables that influence the final product.

Solid Lipid Microparticles for inhaled anti-TB therapy by DPI: influence of the production process on drug stability and powder breathability / Maretti, Eleonora; Sacchetti, Francesca; Romagnoli, Marcello; Balducci, Anna Giulia; Buttini, Francesca; Leo, Eliana Grazia; Iannuccelli, Valentina. - (2015), pp. 80-81. ((Intervento presentato al convegno 3rd International TB-Meeting Inhaled therapies for tuberculosis and other infectious diseases tenutosi a Parma, Italy nel 14-16 ottobre 2015.

Solid Lipid Microparticles for inhaled anti-TB therapy by DPI: influence of the production process on drug stability and powder breathability

MARETTI, ELEONORA;SACCHETTI, FRANCESCA;ROMAGNOLI, Marcello;LEO, Eliana Grazia;IANNUCCELLI, Valentina
2015

Abstract

According to the WHO global report 2014, tuberculosis (TB) remains one of the world’s deadliest communicable diseases, despite implementation of highly standard treatment regimen that has caused the number of cases began to decline from 1992. The current therapy following WHO guidelines involves three/four drug oral regimen (first-line drugs), long-term therapy (6/7 months), high and frequent doses so producing several side-effects, in particular hepatotoxicity (WHO, 2014). The long therapy, responsible for patient’s non-compliance that is the most common reason for treatment failure, is connected to Mycobacterium tuberculosis (Mtb) nature. Unlike most microbes, Mtb survives in AM phagosomes, has a slow growing and metabolism besides death, so that the drugs have to be taken for a long period. To overcome these drawbacks and improve treatment efficacy, the new strategies could involve vaccination (limited success), new drug development (no new drugs in the last 30 year) and new formulation design for old drugs. Among these, the shortest-term goal is represented by new technological approaches or Drug Delivery Systems (DDS). In this latter context, considering that 75-80% of TB cases remain localized in the lungs, pulmonary route appears the most logical route to reach promptly the primary infected site providing to reduced dose and dose frequency, treatment duration, TB dissemination in other organs risk of drug-resistant mutants and toxicity as well as improving patient’s compliance (Pham D-D., 2015). Among the portable inhalation devices, Dry Powder Inhaler (DPI) appears more advantageous than Metered Dose Inhaler (MDI), considering low water solubility of most anti-TB drugs, propellant absence and drug stability in its dry state (Hoppentocht, 2014). For an efficient drug delivery by DPI, several powder properties (particle microsize, irregular shape reducing particle contact area so favoring powder deaggragation, low tapped density, surface charge, weak adhesion between particles, good flowability) contribute to determining powder aerodynamic performance and, consequently, dose emission and dispersion, deposition onto alveolar epithelium, and phagocytosis by alveolar macrophages (Claus, 2014). Based on these assumptions, Solid Lipid Microparticles (SLM), constituted by a solid lipid core stabilized by a surfactant on their surface, are known to be biocompatible, biodegradable, physically stable, and obtainable by using low cost materials and eco-friendly processes without organic solvents. More, SLM are suitable to incorporate firmly high lipophilic drug loading levels, and they are not hygroscopic avoiding so powder flowability compromising. In a previous study, SLM loaded with rifampicin (RIF), a first-line anti-TB drug, were designed in a perspective of an inhaled therapy by means a DPI device and found capable of preserving drug antimicrobial activity and being taken up by murine macrophages cell lines (Maretti, 2014). The present research focused on the evaluation of both RIF stability during the production phases and the role of variables relating to freeze-drying process (freezing conditions, sample dilution, cryoprotectants) affecting the powder aerosolization. The freezing method can gave a significant effect on the ice structure affecting both water-vapor flow during the primary drying and the ice crystal size, so influencing the dry final product. Considering the complexity of the factors involved in a successful breathable powder, a statistical Design of Experiments (DOE) was adopted to study the critical variables that influence the final product.
3rd International TB-Meeting Inhaled therapies for tuberculosis and other infectious diseases
Parma, Italy
14-16 ottobre 2015
Maretti, Eleonora; Sacchetti, Francesca; Romagnoli, Marcello; Balducci, Anna Giulia; Buttini, Francesca; Leo, Eliana Grazia; Iannuccelli, Valentina
Solid Lipid Microparticles for inhaled anti-TB therapy by DPI: influence of the production process on drug stability and powder breathability / Maretti, Eleonora; Sacchetti, Francesca; Romagnoli, Marcello; Balducci, Anna Giulia; Buttini, Francesca; Leo, Eliana Grazia; Iannuccelli, Valentina. - (2015), pp. 80-81. ((Intervento presentato al convegno 3rd International TB-Meeting Inhaled therapies for tuberculosis and other infectious diseases tenutosi a Parma, Italy nel 14-16 ottobre 2015.
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