Multimodal particle size distributions emitted from HFA-134a solution pressurized metered-dose inhalers

The purpose of this research was to investigate the measurement and in vitro delivery implications of multimodal distributions, occurring near or in the respirable range, emitted from pressurized metered-dose inhalers (pMDIs). Particle size distributions of solution pMDIs containing hydrofluoroalkane-134a (HFA-134a) and ethanol were evaluated using 2 complementary particle-sizing methods: laser diffraction (LD) and cascade impaction (CI). Solution pMDIs were formulated from mixtures of HFA-134a (50%–97.5% wt/wt) and ethanol. A range of propellant concentrations was selected for a range of vapor pressures. The fluorescent probe, Rhodamine B, was included for chemical analysis. The complementary nature of LD and CI allowed identification of 2 dominant particle size modes at 1 and 10 μm or greater. Increasing propellant concentrations resulted in increases in the proportion of the size distributions at the 1-μm mode and also reduced the particle size of the larger droplet population. Despite significant spatial differences and time scales of measurement between the particle-sizing techniques, the fine particle fractions obtained from LD and CI were practically identical. This was consistent with LD experiments, which showed that particle sizes did not decrease with increasing measurement distance, and may be explained by the absence of significant evaporation/disintegration of larger droplets. The fine particle fractions (FPFs) emitted from HFA-134a/ethanol solution pMDI can be predicted on the basis of formulation parameters and is independent of measurement technique. These results highlight the importance of presenting particle size distribution data from complementary particle size techniques.     

Factors Affecting the Stability and Performance of Ipratropium Bromide; Fenoterol Hydrobromide Pressurized-Metered Dose Inhalers

The aim of the study was to investigate the factors affecting the stability and performance of ipratropium bromide and fenoterol hydrobromide in a pressurized-metered dose inhaler (pMDI). A factorial design was applied to investigate the effects of three parameters (propellant, water, and ethanol) on the performance of 27 designed formulations of a solution-based pMDI. The formulations that contained a hydrofluoroalkane (HFA) propellant lower than 72% v/v and an ethanol concentration higher than 27% v/v remained as clear solutions. Nine formulations that contained the HFA propellant higher than 74% v/v precipitated. The results indicated that it was not only the HFA propellant content of the formulations that was related to the formulation instability but also ethanol content. Only six formulations from the 18 formulations, that did not precipitate, produced drug contents that were within the acceptable range (80–120%). These six formulations generated aerosols with mass median aerodynamic diameters (MMAD) of approximately 2 μm with a fine particle fraction (FPF; particle size, <6.4 μm) between 45% and 52%. The MMAD and FPF did not change significantly after 6 months of storage (P > 0.05).KEY WORDS: fenoterol hydrobromide, ipratropium bromide, pressurized metered dose inhaler, stability     

Effect of Particle Shape on Dry Particle Inhalation: Study of Flowability, Aerosolization, and Deposition Properties

The shape effects of dry particles on flowability, aerosolization, and deposition properties in inhalation drug delivery are studied. The properties are compared with similar size range particles of different shapes such as sphere, needle, cube, plate, and pollen. Flowability of the particles is characterized by Carr’s compressibility index and angle of slide (θ) method. The aerosolization and deposition properties of the particles are studied in vitro using an eight-stage Anderson cascade impactor with a Rotahaler®. Pollen-shaped particles are found to exhibit better flowability, higher emitted dose, and higher fine particle fraction than particles of other shapes in similar size range. They showed minimum θ of 35° and maximum emitted dose of 87% and fine particle fraction of 16%. The use of pollen-shaped particles can be a potential improvement in dry particle inhalation.     

Factors Influencing Aerodynamic Particle Size Distribution of Suspension Pressurized Metered Dose Inhalers

Pressurized metered dose inhalers (pMDIs) are frequently used for the treatment of asthma and chronic obstructive pulmonary disease. The aerodynamic particle size distribution (APSD) of the residual particles delivered from a pMDI plays a key role in determining the amount and region of drug deposition in the lung and thereby the efficacy of the inhaler. In this study, a simulation model that predicts the APSD of residual particles from suspension pMDIs was utilized to identify the primary determinants for APSD. These findings were then applied to better understand the effect of changing drug concentration and micronized drug size on experimentally observed APSDs determined through Andersen Cascade Impactor testing. The experimental formulations evaluated had micronized drug mass median aerodynamic diameters (MMAD) between 1.2 and 2.6 μm and drug concentrations ranging from 0.01 to 1% (w/w) with 8.5% (w/w) ethanol in 1,1,1,2-tetrafluoroethane (HFA-134a). It was determined that the drug concentration, micronized drug size, and initially atomized droplet distribution have a significant impact in modulating the proportion of atomized droplets that contain multiple suspended drug particles, which in turn increases the residual APSD. These factors were found to be predictive of the residual particle MMAD for experimental suspension HFA-134a formulations containing ethanol. The empirical algebraic model allows predicting the residual particle size for a variety of suspension formulations with an average error of 0.096 μm (standard deviation of 0.1 μm).KEY WORDS: aerodynamic particle size distribution (APSD), formulation, pressurized metered dose inhaler (pMDI), suspension     

Co-Spray Dried Mannitol/Poly(amidoamine)-Doxorubicin Dry-Powder Inhaler Formulations for Lung Adenocarcinoma: Morphology, <Emphasis Type="Italic">In Vitro</Emphasis> Evaluation,and Aerodynamic Performance

nhaled chemotherapeutics have emerged as a promising regimen to combat lung cancer as they maximize local drug concentration while significantly reduce systemic exposure. However, the poor lung/systemic safety profiles and lack of clinically efficient formulations restrict the applicability of inhaled chemotherapeutics. This work developed a dry-powder inhaler (DPI) formulation that dispersed a pH-responsive poly(amidoamine) dendrimer-doxorubicin conjugate (G4-12DOX) into mannitol microparticles. The dendrimer conjugate only releases cytotoxic agents in response to intracellular pH drop, leading to reduced systemic and local toxicity. This work investigated the effect of G4-12DOX content on the microparticle size and morphology, redispersibility, in vitro cytotoxicity, and aerosol properties of the formulations. The spray-dried G4-12DOX/mannitol microparticles showed smooth and spherical morphology with 1–4 μm in diameter. As the content of the G4-12DOX conjugate in the microparticles increased, the size, and degree of aggregation of microparticles increased dramatically. The G4-12DOX/mannitol microparticles were readily redispersed in the aqueous environment, reverting to nanoscale dendrimer conjugates to escape alveolar phagocytosis. All DPI formulations demonstrated the similar cytotoxicity as the original conjugate against a lung adenocarcinoma cell line. The emitted dose (ED) and fine particle fraction (FPF) of the DPI formulations decreased as the content of G4-12DOX increased, but EDs and FPFs of all formulations fell within the range of 85–60% and 60–40%, which were higher than those of commercial products (EDs = 40–60%; FPFs = 12–40%). Therefore, the spray-dried dendrimer/mannitol microparticle is an efficient and practical DPI formulation for direct delivery of large dose of chemotherapeutics to lung tumors.     

In vitro and in vivo evaluation of topical formulations of Spantide II

The purpose of this study was to develop and evaluate topical formulations of Spantide II, a neurokinin-1 receptor (NK-1R) antagonist, for the treatment of inflammatory skin disorders. Spantide II lotion and gel was formulated with and without n-methyl-2-pyrrolidone (NMP) as a penetration enhancer. The release of Spantide II from gels was evaluated using microporous polyethylene and polypropylene membranes in a Franz Diffusion cell setup. In vitro percutaneous absorption of Spantide II from lotion and gel formulations was evaluated using the above setup by replacing the membranes with hairless rat skin. The in vivo anti-inflammatory activity of Spantide II formulations was evaluated in an allergic contact dermatitis (ACD) mouse model. Among different gels studied, PF127 gel showed highest (70-fold) release of Spantide II compared with hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) gels. Lotion and gel formulations with or without NMP showed no detectable levels of Spantide II in the receiver compartment of the Franz diffusion cell until 24 hours. However, Spantide II showed significant retention in epidermis and dermis from lotion and gel formulations at 24 hours. The dermal levels increased ≈3.5- and 2-fold when the lotion and gel formulations contained NMP as compared with the formulation with no NMP (P<.05). The in vivo studies indicated that Spantide II formulations with NMP were effective in significantly reducing ACD response, similar to dexamethasone (0.5 mM). In conclusion, Spantide II was stable as a topical formulation and delivered to target skin tissue (epidermis and dermis) for the treatment of ACD. In addition this study supports the role of cutaneous neurosensory system in modulating inflammatory responses in the skin. Published: October 31, 2005     

Formulation of a dry powder influenza vaccine for nasal delivery

The purpose of this research was to prepare a dry powder vaccine formulation containing whole inactivated influenza virus (VIIV) and a mucoadhesive compound suitable for nasal delivery. Powders containing WIIV and either lactose or trehalose were produced by lyophilization. A micro-ball mill was used to reduce the lyophilized cake to sizes suitable for nasal delivery. Chitosan flakes were reduced in size using a cryo-milling technique. Milled powders were sieved between 45 and 125 μm aggregate sizes and characterized for particle size and distribution, morphology, and flow properties. Powders were blended in the micro-ball mill without the ball. Lyophilization followed by milling produced irregularly shaped, polydisperse particles with a median primary particle diameter of ≈21 μm and a yield of ≈37% of particles in the 45 to 125 μm particle size range. Flow properties of lactose and trehalose powders after lyophilization followed by milling and sieving were similar. Cryo-milling produced a small yield of particles in the desired size range (<10%). Lyophilization followed by milling and sieving produced particles suitable for nasal delivery with different physicochemical properties as a function of processing conditions and components of the formulation. Further optimization of particle size and morphology is required for these powders to be suitable for clinical evaluation. Published: March 10, 2006     

The Abbreviated Impactor Measurement (AIM) Concept: Part II—Influence of Evaporation of a Volatile Component—Evaluation with a “Droplet-Producing” Pressurized Metered Dose Inhaler (pMDI)-Based Formulation Containing Ethanol as Cosolvent

The abbreviated impactor measurement (AIM) concept is a potential solution to the labor-intensive full-resolution cascade impactor (CI) methodology for inhaler aerosol aerodynamic particle size measurement. In this validation study, the effect of increasing the internal dead volume on determined mass fractions relating to aerodynamic particle size was explored with two abbreviated impactors both based on the Andersen nonviable cascade impactor (ACI) operating principle (Copley fast screening Andersen impactor [C-FSA] and Trudell fast screening Andersen impactor [T-FSA]). A pressurized metered dose inhaler-delivered aerosol producing liquid ethanol droplets after propellant evaporation was chosen to characterize these systems. Measures of extrafine, fine, and coarse particle mass fractions from the abbreviated systems were compared with corresponding data obtained by a full-resolution ACI. The use of liquid ethanol-sensitive filter paper provided insight by rendering locations visible where partly evaporated droplets were still present when the “droplet-producing” aerosol was sampled. Extrafine particle fractions based on impactor-sized mass were near equivalent in the range 48.6% to 54%, comparing either abbreviated system with the benchmark ACI-measured data. The fine particle fraction of the impactor-sized mass determined by the T-FSA (94.4 ± 1.7%) was greater than using the C-FSA (90.5 ± 1.4%) and almost identical with the ACI-measured value (95.3 ± 0.4%). The improved agreement between T-FSA and ACI is likely the result of increasing the dead space between the entry to the induction port and the uppermost impaction stage, compared with that for the C-FSA. This dead space is needed to provide comparable conditions for ethanol evaporation in the uppermost parts of these impactors.     

Development of Spray Dried Liposomal Dry Powder Inhaler of Dapsone

This investigation was undertaken to evaluate practical feasibility of site specific pulmonary delivery of liposomal encapsulated Dapsone (DS) dry powder inhaler for prolonged drug retention in lungs as an effective alternative in prevention of Pneumocystis carinii pneumonia (PCP) associated with immunocompromised patients. DS encapsulated liposomes were prepared by thin film evaporation technique and resultant liposomal dispersion was passed through high pressure homogenizer. DS nano-liposomes (NLs) were separated by ultra centrifugation and characterized. NLs were dispersed in phosphate buffer saline (PBS) pH 7.4 containing different carriers like lactose, sucrose, and hydrolyzed gelatin, and 15% l-leucine as antiadherent. The resultant dispersion was spray dried and spray dried formulation were characterized to ascertain its performance. In vitro pulmonary deposition was assessed using Andersen Cascade Impactor as per USP. NLs were found to have average size of 137 ± 15 nm, 95.17 ± 3.43% drug entrapment, and zeta potential of 0.8314 ± 0.0827 mV. Hydrolyzed gelatin based formulation was found to have low density, good flowability, particle size of 7.9 ± 1.1 μm, maximum fine particle fraction (FPF) of 75.6 ± 1.6%, mean mass aerodynamic diameter (MMAD) 2.2 ± 0.1 μm, and geometric standard deviation (GSD) 2.3 ± 0.1. Developed formulations were found to have in vitro prolonged drug release up to 16 h, and obeys Higuchi's Controlled Release model. The investigation provides a practical approach for direct delivery of DS encapsulated in NLs for site specific controlled and prolonged release behavior at the site of action and hence, may play a promising role in prevention of PCP.     

Controlled Release of Oral Tetrahydrocurcumin from a Novel Self-Emulsifying Floating Drug Delivery System (SEFDDS)

The objectives of this study were to develop and evaluate a novel self-emulsifying floating drug delivery system (SEFDDS) that resulted in improved solubility, dissolution, and controlled release of the poorly water-soluble tetrahydrocurcumin (THC). The formulations of liquid self-emulsifying drug delivery system (SEDDS; mixtures of Labrasol, Cremophor EL, Capryol 90, Labrafac PG) were optimized by solubility assay and pseudo-ternary phase diagram analysis. The liquid SEDDS was mixed with adsorbent (silicon dioxide), glyceryl behenate, pregelatinized starch, sodium starch glycolate, and microcrystalline cellulose and transformed into pellets by the extrusion/spheronization technique. The resulting pellets with 22% liquid SEDDS had a uniform size and good self-emulsification property. The microemulsions in aqueous media of different self-emulsifying floating pellet formulations were in a particle size range of 25.9–32.5 nm. Use of different weight proportions of glyceryl behenate and sodium starch glycolate in pellet formulations had different effects on the floating abilities and in vitro drug release. The optimum formulation (F2) had a floating efficiency of 93% at 6 h and provided a controlled release of THC over an 8-h period. The release rate and extent of release of THC liquid SEDDS (80% within 2 h) and self-emulsifying floating pellet formulation (80% within 8 h) were significantly higher than that of unformulated THC (only 30% within 8 h). The pellet formulation was stable under intermediate and accelerated storage conditions for up to 6 months. Controlled release from this novel SEFDDS can be a useful alternative for the strategic development of oral solid lipid-based formulations.     

High-Speed Laser Image Analysis of Plume Angles for Pressurised Metered Dose Inhalers: The Effect of Nozzle Geometry

The aim of this study is to investigate aerosol plume geometries of pressurised metered dose inhalers (pMDIs) using a high-speed laser image system with different actuator nozzle materials and designs. Actuators made from aluminium, PET and PTFE were manufactured with four different nozzle designs: cone, flat, curved cone and curved flat. Plume angles and spans generated using the designed actuator nozzles with four solution-based pMDI formulations were imaged using Oxford Lasers EnVision system and analysed using EnVision Patternate software. Reduced plume angles for all actuator materials and nozzle designs were observed with pMDI formulations containing drug with high co-solvent concentration (ethanol) due to the reduced vapour pressure. Significantly higher plume angles were observed with the PTFE flat nozzle across all formulations, which could be a result of the nozzle geometry and material’s hydrophobicity. The plume geometry of pMDI aerosols can be influenced by the vapour pressure of the formulation, nozzle geometries and actuator material physiochemical properties.     

Aerodynamic particle size analysis of aerosols from pressurized metered-dose inhalers: Comparison of andersen 8-stage cascade impactor,next generation pharmaceutical impactor,and model 3321 aerodynamic particle sizer aerosol spectrometer

The purpose of this research was to compare three different methods for the aerodynamic assessment of (1) chloroflurocarbon (CFC)-fluticasone propionate (Flovent), (2) CFC-sodium cromoglycate (Intal), and (3) hydrofluoroalkane (HFA)-beclomethasone dipropionate (Qvar) delivered by pressurized metered dose inhaler. Particle size distributions were compared determining mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), and fine particle fraction <4.7 μm aerodynamic diameter (FPF_{<4.7 μm}). Next Generation Pharmaceutical Impactor (NGI)-size distributions for Flovent comprised finer particles than determined by Andersen 8-stage impactor (ACI) (MMAD=2.0±0.05 μm [NGI]; 2.8±0.07 μm [ACI]); however FPF_{<4.7 μm} by both impactors was in the narrow range 88% to 93%. Size distribution agreement for Intal was better (MMAD=4.3±0.19 μm (NGI), 4.2±0.13 μm (ACI), with FPF_{<4.7 μm} ranging from 52% to 60%. The Aerodynamic Particle Sizer (APS) undersized aerosols produced with either formulation (MMAD=1.8±0.07 μm and 3.2±0.02 μm for Flovent and Intal, respectively), but values of FPF_{<4.7 μm} from the single-stage impactor (SSI) located at the inlet to the APS (82.9%±2.1% [Flovent], 46.4%±2.4% [Intal]) were fairly close to corresponding data from the multi-stage impactors. APS-measured size distributions for Qvar (MMAD=1.0±0.03 μm; FPF_{<4.7 μm}=96.4% ±2.5%), were in fair agreement with both NGI (MMAD=0.9±0.03 μm; FPF_{<4.7 μm}=96.7%±0.7%), and ACI (MMAD=1.2±0.02 μm, FPF_{<4.7 μm}=98%±0.5%), but FPF_{<4.7 μm} from the SSI (67.1%±4.1%) was lower than expected, based on equivalent data obtained by the other techniques. Particle bounce, incomplete evaporation of volatile constituents and the presence of surfactant particles are factors that may be responsible for discrepancies between the techniques.     

In Vitro and In Vivo Performance of Dry Powder Inhalation Formulations: Comparison of Particles Prepared by Thin Film Freezing and Micronization

Recently, inhaled immunosuppressive agents have attracted increasing attention for maintenance therapy following lung transplantation. The rationale for this delivery approach includes a more targeted and localized delivery to the diseased site with reduced systemic exposure, potentially leading to decreased adverse side effects. In this study, the in vitro and in vivo performance of an amorphous formulation prepared by thin film freezing (TFF) and a crystalline micronized formulation produced by milling was compared for tacrolimus (TAC). Despite the relatively large geometric size, the TFF-processed formulation was capable of achieving deep lung delivery due to its low-density, highly porous, and brittle characteristics. When emitted from a Miat® monodose inhaler, TFF-processed TAC formulations exhibited a fine particle fraction (FPF) of 83.3% and a mass median aerodynamic diameter (MMAD) of 2.26 μm. Single-dose 24-h pharmacokinetic studies in rats demonstrated that the TAC formulation prepared by TFF exhibited higher pulmonary bioavailability with a prolonged retention time in the lung, possibly due to decreased clearance (e.g., macrophage phagocytosis), compared to the micronized TAC formulation. Additionally, TFF formulation generated a lower systemic TAC concentration with smaller variability than the micronized formulation following inhalation, potentially leading to reduced side effects related to the drug in systemic circulation.     

Physicochemical Characteristics, Cytotoxicity, and Antioxidant Activity of Three Lipid Nanoparticulate Formulations of Alpha-lipoic Acid

Exogenously supplied alpha-lipoic acid (LA) has proven to be effective as an antioxidant. In an effort to develop a water-soluble formulation for topical administration, LA was formulated in the form of solid lipid nanoparticles (SLN), nanostructure lipid carriers (NLC), and nanoemulsion (NE) and characterized in terms of physical and biological properties. Mean particle size of 113, 110, and 121 nm were obtained for NE, NLC, and SLN, respectively, with narrow size distribution. Zeta potential was approximately in the range of −25 to −40 mV. Disc and spherical structures of nanoparticles were observed by cryo-scanning electron microscopy. Entrapment efficiency of LA in three formulations was found to be more than 70%. After 120 days of storage at 25°C, physical stability of all formulations remained unchanged whereas the entrapment efficiency of SLN and NLC could be maintained, suggesting relative long-term stability. Prolonged release of LA formulation following the Higuchi model was found where a faster release was observed from NE compared with that of SLN and NLC. More than 80% of cell survivals were found up to 1 μM of LA concentrations. Antioxidant activity analysis demonstrated that all LA-loaded formulations expressed antioxidant activity at a similar magnitude as pure LA. These results suggest that chosen compositions of lipid nanoparticles play an important role on drug loading, stability, and biological activity of nanoparticles. Both SLN and NLC demonstrated their potential as alternative carriers for aqueous topical administration of LA.     

Emulsions of oil from Adenanthera pavonina L. seeds and their protective effect

In our previous study, we developed very stable formulations of submicron oil-in-water emulsions from Adenanthera pavonina L. (family Leguminosae, subfamily Mimosoideae) seed oil, stabilised with soybean lecithin (SPC). Continuing our research, we introduced an additional co-emulsifier, Tween 80, to those formulations in order to decrease the size of the emulsion particles and improve their stability. Formulations with a mean particle size ranging from 43.6 to 306.5 nm and a negative surface charge from −45.3 to −28.5 mV were obtained. Our stability experiments also revealed that most of the tested formulations had a very good degree of stability over a 3-month storage period, both at 4°C and at room temperature. Since many intravenous injectable drugs exhibit lytic activity against erythrocytes, we examined this activity for the emulsion form of cardol, a natural compound with already proven hemolytic properties. The incorporation of this agent into the emulsion caused an evident decrease in hemolytic activity (97–99%). This highly protective effect, observed against sheep erythrocytes, was independent of both the composition and the particle size of the emulsions used. Our studies suggest that nonionic surfactant/phospholipid-based emulsions containing this edible oil of A. pavonina L. may be useful as an alternative formulation matrix for pharmaceutical, nutritional or cosmetic applications of otherwise membrane-acting components.     

Determination of Reference Ultrasound Parameters for Model and Hydrofluoroalkane Propellants Using High-Resolution Ultrasonic Spectroscopy

The aim of this research was to determine the reference ultrasonic velocity (v) and attenuation coefficient (α) for 2H, 3H-perfluoropentane (HPFP), 1,1,1,2-tetrafluoroethane (HFA-134a) and 1,1,1,2,3,3,3-tetrafluoroethane (HFA-227) propellants, for the future purpose of characterising pressurised metered dose inhaler (pMDI) formulations using high-resolution ultrasonic spectroscopy (HRUS). Perfluoroheptane (PFH) was used as a reference material for HPFP. With its velocity and attenuation coefficient determined at 25 °C, HPFP was subsequently used as a reference for HFA-134a and HFA-227. It was found that there is a linear decline in ultrasonic velocity with an increase in temperature. As with HPFP, the ultrasonic velocity of HFA-134a and HFA-227 were successfully calculated at 25 °C. However, the difference in density and viscosity between reference and sample prevented accurate determination of reference attenuation coefficient for the hydrofluoroalkanes. With ultrasonic velocity alone, dispersion concentration and stability monitoring for experimental pMDI formulations is possible using HRUS. However, at this point in time measurement of particle size is not feasible.     

Effect of formulation pH and storage temperatures on the preservative efficacy of some gases used as propellants in cosmetic aerosols

The effects of changes in formulation pH and storage temperature on the preservative activities of some aerosol propellants—butane, carbon dioxide, dimethylether and their combinations were investigated. A preservative challenge test method was used to determine the survival rates of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus niger at formulation pH levels 5·80, 7·28 and 8·10 and storage temperatures of 20°, 30° and 40°C.
A significant decrease in the pH of formulations was observed with no corresponding changes in the antimicrobial effectiveness when carbon dioxide was incorporated. Alterations in the antimicrobial profiles of these propellants due to changes in formulation pH were dependent on the propellant and the species of the micro-organism, especially when single propellants were used. Results also showed that the propellants exert antimicrobial activities against the various organisms at the three storage temperatures but there were significantly greater inhibitory activities at 40°C. With a combination of 10% butane/dimethylether (1:2) and 10 bar carbon dioxide there were no differences in the degree of microbial inhibition at the various formulation pH levels and storage temperatures. In most cases, the organisms were completely inactivated within 24 h. These findings showed that the combination of butane/dimethylether with carbon dioxide could be used to protect against microbial contamination and spoilage of formulations of different pH levels as well as those meant for storage at different temperatures.     

Liposomal amikacin dry powder inhaler: Effect of fines on in vitro performance

The aim of the present investigation was to prepare and evaluate the influence of adding fines on the in vitro performance of liposomal amikacin dry powder inhaler (AMK LDPI) formulations. Liposomes composed of hydrogenated soyaphosphatidylcholine, cholesterol and saturated soyaphosphatidylglycerol (AMK 1), or stearylamine (AMK 2) were prepared by a reverse phase evaporation technique, extruded to reduce size and separated from unentrapped drug. Purified liposomal dispersion was subjected to lyophilization using optimized cryoprotectant to achieve maximum percentage drug retentio (PDR). Lactose carrier in varying mass ratios with or without addition of fines in different mixing sequences was used to formulate AMK LDPI formulations. AMK LDPI formulations were characterized for angle of repose, compressibility index, dispersibility index, scanning electron microscopy, and fine perticle fraction (FPF). PDR was found to be 97.6%±2.2% for AMK1 and 98.5%±1.9% for AMK2 using sucrose as optimized cryoprotectant in lipid:sucrose ratio of 1∶4. Lactose carrier containing 10% fines (wt/wt) was found to be the optimum blend at 1∶5 mass ratio of liposome:lactose. The addition of fines and the order of mixing of fines were found to influence the FPF with significantly different device fractions. FPF of AMK LDPI formulations using Rotahaler as the delivery device at 30, 60, and 90 L/min were found to be 21.85%±2.2% and 24.6%±2.4%, 25.9% ±1.8% and 29.2%±2.1%, and 29.5%±2.6% and 34.2%±2.0% for AMK1 and AMK2, respectively. From the studies performed in this investigation, it was observed that liposomal charge, addition of fines and order of mixing fines, has a significant effect (P<.05) on in vitro deposition of drug from LDPI formulation.     

Effect of interactive ternary mixtures on dispersion characteristics of ipratropium bromide in dry powder inhaler formulations

The purpose of this investigation was to evaluate the effect of mixing order and the influence of adding fines on in vitro performance of ipratropium bromide (ITB) dry powder inhaler formulations. Coarse lactose (CL) in varying mass ratio with or without addition of micronized lactose (ML) and ITB in different mixing sequences was used to formulate ternary mixtures. A binary mixture composed of CL and ITP served as control. The in vitro deposition of ITB from these formulations was measured using an Andersen cascade impactor (aerosolization at 39 L/min) employing a HandiHaler as the delivery device. It was observed that mixing order has a significant effect (P<.05) on in vitro deposition of ITB. Formulations with preblending of CL and ITB produced similar deposition profiles as the control, regardless of the added ML. In contrast, formulations without preblending resulted in significantly higher fine particle dose (FPD) as compared with the control. In addition, an increased quantity of ML generally resulted in an increase in drug deposition. The results show that the effect of ML on dispersion of ITB is highly dependent upon the mixing order. The evaluation of atomic force measurement (AFM) to forecast drug detachment and predict the aerodynamic characteristics resulted in similar attraction forces for the different pairs lactose/lactose (42.66±25.01 nN) and lactose/ITB (46.77±17.04 nN). Published: April 20, 2007     

Effects of Temperature and Humidity on Laser Diffraction Measurements to Jet Nebulizer and Comparison with NGI

Laser diffraction (LD) and next generation impactor (NGI) are commonly used for the evaluation of inhaled drug formulations. In this study, the effect of temperature and humidity on the assessment of the nebulizer particle size distribution (PSD) by LD was investigated, and the consistency between NGI and LD measurements was evaluated. There was an increase in particle size with higher temperature or lower humidity. The particle population with a diameter less than 1 μm was significant at a temperature of 5°C or at relative humidity >90%; however, the same particle population became undetectable when temperature increased to 39°C or at relative humidity of 30–45%. The results of the NGI and LD measurements of aerosol generated from three types of jet nebulizers were compared. A poor correlation between the NGI and LD measurements was observed for PARI LC (2.2 μm) (R ²?=?0.893) and PARI LC (2.9 μm) (R ²?=?0.878), while a relatively good correlation (R ²?=?0.977) was observed for the largest particle size nebulizer (PARI TIA (8.6 μm)). We conclude that the ambient environment and the nebulizer have significant impacts on the performance and consistency between these instruments. These factors should be controlled in the evaluation of inhaled aerosol drug formulations when these instruments are used individually or in combination.