Strategies in Lungs Delivery of Nanoparticles for Asthma & Related Disorders Md. Faiyazuddin 1,2 , Roop K. Khar 1 , A. Bhatnagar 3 , Farhan J. Ahmad 1 1 Department of Pharmaceutics, Jamia Hamdard, New Delhi, 2 Faculty of Pharmacy, Integral University, Lucknow, 3 Division of Nuclear Medicine, INMAS, Delhi, INDIA Introduction References Methods Results Results Conclusion In respiratory pharmaceutics, it is an open challenge to the scientists to cover all possible aspects in designing of stable particles. Particles less than 1 μm possess unique aerosol and deposition effects due to their increased surface for dissolution and improved fluidization for redispersion of drug, tailored release, decreased toxicity and deep targeting capabilities. Various drying operations have been reported in literatures utilized for nanoparticles, but none of them were found relevant as per pharmaceutical demand. The present investigations were undertaken to highlight the issue related to undesired particle growth and to optimize a robust drying method which deliver particles in submicron range. Commonly utilized drying methods like heat, freezing, vacuum, rotary and spray drying have been selected for this study to set their comparative distinction in controlling drug particle size using terbutaline sulfate (TBS) as a model drug. Formulation approaches in the development of stable submicron particles for effective lungs targeting by inhalation route are highlighted here. Also, the potential effect of drying and storage on particle performance is summarized. Also, submicron particles have been estimated in alveolar tissue and bronchioalveolar fluid by UHPLC-ESI-qTOF/MS. Drying methods evaluation 2.1. Effect of Nanosizing in particle formation For effective lungs deposition, the particle size must be in the range of 0.5–5 µm (Choi et al., 2010). Because of the cohesive nature and poor flow characteristics of existed aerosols, they are difficult to redisperse upon aerosolization with breath. Therefore techniques like simple stirring, ultrasonication, high- pressure homogenization, probe-sonication and nanoprecipitation were taken into account for the selection best nanosizing method in order to produce stable particles with least globular size. 2.2. Effect of Stabilizer in particle formation During particle formation the effect of type and surfactant concentration were also studied. In quest of an optimal stabilizer which hold particles stable, various stabilizers were investigated and studied for the particle aggregation behavior 2.3. Optimization of Drying technique Optimised formulations were exposed to various dryers and a comparative evaluation of drying method is set to see the real changes that have been occurred during the treatment. For this purpose, existing drying methods like hot plate, rotary evaporator, spray drying, vacuum drying and freeze drying were chosen to get particles below 1 μm. 2.4. Formulation characterization Formulation were characterized for Particle size distribution, TEM, SEM, Zeta potential, Polydispersity index, FTIR, DSC and PXRD. 2.5. Drug content and In Vitro aerosolization Drug content (DC) of TBS was calculated as follows: % DC = Recovered TBS mass /total mass of TBS × 100. Using ACI, powder blend was incorporated to each #3 cellulose capsule and aerosolized by means of Rotahaler ® . Contents were released and the system was vacuumed to produce air streams of 60 L min-1/5 sec. In all the cases the airflow was kept constant for a certain period of time so that a volume of 4L of air was used for each actuation. 3.1. Formulation Development • Simple stirring The influence of different surfactants on mean particle size of the drug using simple stirring method was assessed and various antisolvents (ACN, IPA & ethanol) with the varying ratio of surfactants (Tween 80, Pleuronic F68 & Leucine) were tried. In all batches, the best size (2.3 μm) was achieved in ACN using Pluronic F68 as a surfactant. • Ultrasonication & Homogenization Aggregated particles were obtained when acetone and IPA were used as antisolvent, however in contrary to previous ACN produced better size control. Formulation AA3 prepared with 10% Leucine was found best in achieving minimum particle size of 225.89 nm. As Leucine concentration increased from 5 to 10%, particle size decreased from 1421.20 to 225.89 nm. For nanosization, the particles were passed through different homogenization cycles (n=1 to 5; 10,000-15,000 psi pressure) and as number of homogenization cycle increased from 1-3, particle size also decreased from 278.70 nm to 187.44 nm. • Probe sonication & Nanoprecipitation As probe sonicator delivers high sonic energy to the suspension for faster breakdown of larger particles, best particles resulted in ACN with Pluronic F68 as a surfactant (186.1 nm). In antisolvent nanoprecipitation, least particle size values were obtained for formulations AG15 (Leucine: Pluronic F68:: 7.5: 2.5) and AG16 (Leucine: Pluronic F68:: 7.5: 05) with MPS of 95.86 nm and 89.65 nm, respectively (Fig. 1). 3.2. Optimisation of Drying technique Formulation AG16 yielded spray dried TBS submicron particles of 789.55 nm size (AS16) (Table 2, Fig 2d). AG16 was freeze by liquid nitrogen and the resulting powder was dried for 48 h in a freeze dryer. A combination of lactose (1.5%), sorbitol (0.5%), mannitol (2.0%) and leucine (0.5%) gave most effective amalgamation of cryoprotectants. SEM Images 3.3.2. FTIR FTIR spectrum for both Spray dried and freeze dried samples. The -NH< stretching absorption band appeared at 2987.53 (AS16) and 2975.96 cm-1 (AF16) suggesting that the polymer had no influence on the amino group. 3.3.3. DSC & PXRD DSC curve of plain TBS showed an endothermic peak at 279.4ºC. DSC study of freeze dried drug particles (AF 16 ) indicated the compatibility of excipients with TBS. DSC confirmed the physical state of TBS changed from crystalline to amorphous with reduced peaks on nanosizing. 3.5. In vitro aerosol behavior The results demonstrated higher retention of plain TBS in the application system. The particles mainly deposited in the throat and on stage 0 and 1 demonstrating the large particle size. Respiratory fraction and MMAD of plain TBS was found to be 15-17% and 5.52 μm respectively, inappropriate for the effective lung deposition In this study, the aerodynamic behavior of an inhalation dry powder was optimized by appropriately selecting powder composition and process intensifications. We confirmed that inter- particulate forces played a major role in the aerosilizaton properties of the powders and we reduced these forces by appropriately selecting excipients and production technology. Both spray dried and lyophilized submicron dry powders behave superior to others in order to achieve optimal lungs targeting. In respiratory pharmaceutics, this powder could incorporate small molecule drugs or biopharmaceuticals and be used to deliver these therapeutics to the lungs. 1. P. Couvreur, C. Vauthier. Poly-alkyl-cyano- acrylate nanoparticles as drug carrier: present state and perspectives. JCR (1991) 17, 187–198. 2. Md. Faiyazuddin, Niyaz Ahmad, Roop K. Khar, Aseem Bhatnagar, Farhan Jalees Ahmad. Stabilized terbutaline submicron particles for deep lungs deposition: Drug assay, pulmonokinetics and biodistribution by UHPLC/ESI-q-TOF-MS method. IJP, 434 (2012) 59– 69. Code Mean Particle Size (nm) Initial Freeze drying Spray drying Rotary evaporator AB 10 278.71 1305.77 1826.14 1950.91 AC 3 187.44 956.89 1244.65 1529.08 AD 1 186.15 911.37 1179.17 1345.71 AG 11 122.50 897.03 1018.94 1245.01 AG 15 95.86 620.81 993.04 1092.49 AG 16 89.65 612.22 789.55 1025.25 (a) (b) (c) FTIR and PXRD In Vitro Lungs Deposition
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Strategies in Lungs Delivery of Nanoparticles for Asthma & Related DisordersMd. Faiyazuddin1,2 , Roop K. Khar1, A. Bhatnagar3, Farhan J. Ahmad1
1Department of Pharmaceutics, Jamia Hamdard, New Delhi, 2Faculty of Pharmacy, Integral University, Lucknow, 3Division of Nuclear Medicine, INMAS, Delhi, INDIA
Introduction
References
Methods Results Results Conclusion
In respiratory pharmaceutics, it is an open challenge to the scientists to cover all possible aspects in designing of stable particles. Particles less than 1 μm possess unique aerosol and deposition effects due to their increased surface for dissolution and improved fluidization for redispersion of drug, tailored release, decreased toxicity and deep targeting capabilities. Various drying operations have been reported in literatures utilized for nanoparticles, but none of them were found relevant as per pharmaceutical demand. The present investigations were undertaken to highlight the issue related to undesired particle growth and to optimize a robust drying method which deliver particles in submicron range. Commonly utilized drying methods like heat, freezing, vacuum, rotary and spray drying have been selected for this study to set their comparative distinction in controlling drug particle size using terbutaline sulfate (TBS) as a model drug. Formulation approaches in the development of stable submicron particles for effective lungs targeting by inhalation route are highlighted here. Also, the potential effect of drying and storage on particle performance is summarized. Also, submicron particles have been estimated in alveolar tissue and bronchioalveolar fluid by UHPLC-ESI-qTOF/MS.
Drying methods evaluation
2.1. Effect of Nanosizing in particle formation For effective lungs deposition, the particle size must be in the range of 0.5–5 µm (Choi et al., 2010). Because of the cohesive nature and poor flow characteristics of existed aerosols, they are difficult to redisperse upon aerosolization with breath. Therefore techniques like simple stirring, ultrasonication, high-pressure homogenization, probe-sonication and nanoprecipitation were taken into account for the selection best nanosizing method in order to produce stable particles with least globular size.2.2. Effect of Stabilizer in particle formation During particle formation the effect of type and surfactant concentration were also studied. In quest of an optimal stabilizer which hold particles stable, various stabilizers were investigated and studied for the particle aggregation behavior2.3. Optimization of Drying techniqueOptimised formulations were exposed to various dryers and a comparative evaluation of drying method is set to see the real changes that have been occurred during the treatment. For this purpose, existing drying methods like hot plate, rotary evaporator, spray drying, vacuum drying and freeze drying were chosen to get particles below 1 μm. 2.4. Formulation characterizationFormulation were characterized for Particle size distribution, TEM, SEM, Zeta potential, Polydispersity index, FTIR, DSC and PXRD.2.5. Drug content and In Vitro aerosolizationDrug content (DC) of TBS was calculated as follows: % DC = Recovered TBS mass /total mass of TBS × 100.Using ACI, powder blend was incorporated to each #3 cellulose capsule and aerosolized by means of Rotahaler®. Contents were released and the system was vacuumed to produce air streams of 60 L min-1/5 sec. In all the cases the airflow was kept constant for a certain period of time so that a volume of 4L of air was used for each actuation.
3.1. Formulation Development•Simple stirringThe influence of different surfactants on mean particle size of the drug using simple stirring method was assessed and various antisolvents (ACN, IPA & ethanol) with the varying ratio of surfactants (Tween 80, Pleuronic F68 & Leucine) were tried. In all batches, the best size (2.3 μm) was achieved in ACN using Pluronic F68 as a surfactant.•Ultrasonication & HomogenizationAggregated particles were obtained when acetone and IPA were used as antisolvent, however in contrary to previous ACN produced better size control. Formulation AA3 prepared with 10% Leucine was found best in achieving minimum particle size of 225.89 nm. As Leucine concentration increased from 5 to 10%, particle size decreased from 1421.20 to 225.89 nm. For nanosization, the particles were passed through different homogenization cycles (n=1 to 5; 10,000-15,000 psi pressure) and as number of homogenization cycle increased from 1-3, particle size also decreased from 278.70 nm to 187.44 nm.•Probe sonication & NanoprecipitationAs probe sonicator delivers high sonic energy to the suspension for faster breakdown of larger particles, best particles resulted in ACN with Pluronic F68 as a surfactant (186.1 nm). In antisolvent nanoprecipitation, least particle size values were obtained for formulations AG15 (Leucine: Pluronic F68:: 7.5: 2.5) and AG16 (Leucine: Pluronic F68:: 7.5: 05) with MPS of 95.86 nm and 89.65 nm, respectively (Fig. 1). 3.2. Optimisation of Drying technique Formulation AG16 yielded spray dried TBS submicron particles of 789.55 nm size (AS16) (Table 2, Fig 2d). AG16 was freeze by liquid nitrogen and the resulting powder was dried for 48 h in a freeze dryer. A combination of lactose (1.5%), sorbitol (0.5%), mannitol (2.0%) and leucine (0.5%) gave most effective amalgamation of cryoprotectants.
SEM Images
3.3.2. FTIRFTIR spectrum for both Spray dried and freeze dried samples. The -NH< stretching absorption band appeared at 2987.53 (AS16) and 2975.96 cm-1 (AF16) suggesting that the polymer had no influence on the amino group. 3.3.3. DSC & PXRDDSC curve of plain TBS showed an endothermic peak at 279.4ºC. DSC study of freeze dried drug particles (AF16 ) indicated the compatibility of excipients with TBS. DSC confirmed the physical state of TBS changed from crystalline to amorphous with reduced peaks on nanosizing. 3.5. In vitro aerosol behavior The results demonstrated higher retention of plain TBS in the application system. The particles mainly deposited in the throat and on stage 0 and 1 demonstrating the large particle size. Respiratory fraction and MMAD of plain TBS was found to be 15-17% and 5.52 μm respectively, inappropriate for the effective lung deposition
In this study, the aerodynamic behavior of an inhalation dry powder was optimized by appropriately selecting powder composition and process intensifications. We confirmed that inter-particulate forces played a major role in the aerosilizaton properties of the powders and we reduced these forces by appropriately selecting excipients and production technology. Both spray dried and lyophilized submicron dry powders behave superior to others in order to achieve optimal lungs targeting. In respiratory pharmaceutics, this powder could incorporate small molecule drugs or biopharmaceuticals and be used to deliver these therapeutics to the lungs.
1. P. Couvreur, C. Vauthier. Poly-alkyl-cyano-acrylate nanoparticles as drug carrier: present state and perspectives. JCR (1991) 17, 187–198.2. Md. Faiyazuddin, Niyaz Ahmad, Roop K. Khar, Aseem Bhatnagar, Farhan Jalees Ahmad. Stabilized terbutaline submicron particles for deep lungs deposition: Drug assay, pulmonokinetics and biodistribution by UHPLC/ESI-q-TOF-MS method. IJP, 434 (2012) 59– 69.
Code Mean Particle Size (nm)Initial Freeze
dryingSpray drying
Rotary evaporator
AB10 278.71 1305.77 1826.14 1950.91
AC3 187.44 956.89 1244.65 1529.08
AD1 186.15 911.37 1179.17 1345.71
AG11 122.50 897.03 1018.94 1245.01
AG15 95.86 620.81 993.04 1092.49
AG16 89.65 612.22 789.55 1025.25
(a) (b) (c)
FTIR and PXRD
In Vitro Lungs Deposition
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