Metered-dose Inhaler Formulations Research Articles

In Vitro Evaluation of Colistin Conjugated with Chitosan-Capped Gold Nanoparticles as a Possible Formulation Applied in a Metered-Dose Inhaler.

Inhaled colistin is used to treat pneumonia and respiratory infections through nebulization or dry powder inhalers. Nevertheless, the development of a metered-dose inhaler (MDI) for colistin, which could enhance patient convenience and treatment efficacy, has not yet been developed. Colistin is known for its ability to induce cellular toxicity. Gold nanoparticles (AuNPs) can potentially mitigate colistin toxicity. Therefore, this study aimed to evaluate the antimicrobial effectiveness of colistin conjugated with chitosan-capped gold nanoparticles (Col-CS-AuNPs) and their potential formulation for use with MDIs to deliver the aerosol directly to the deep lung. Fourier-transform infrared spectroscopy, nuclear magnetic resonance, and elemental analysis were used to characterize the synthesized Col-CS-AuNPs. Drug release profiles fitted with the most suitable release kinetic model were evaluated. An MDI formulation containing 100 µg of colistin per puff was prepared. The aerosol properties used to determine the MDI performance included the fine particle fraction, mass median aerodynamic diameter, and geometric standard deviation, which were evaluated using the Andersen Cascade Impactor. The delivered dose uniformity was also determined. The antimicrobial efficacy of the Col-CS-AuNP formulation in the MDI was assessed. The chitosan-capped gold nanoparticles (CS-AuNPs) and Col-CS-AuNPs had particle sizes of 44.34 ± 1.02 and 174.50 ± 4.46 nm, respectively. CS-AuNPs effectively entrapped 76.4% of colistin. Col-CS-AuNPs exhibited an initial burst release of up to 60% colistin within the first 6 h. The release mechanism was accurately described by the Korsmeyer-Peppas model, with an R2 > 0.95. The aerosol properties of the Col-CS-AuNP formulation in the MDI revealed a high fine particle fraction of 61.08%, mass median aerodynamic diameter of 2.34 µm, and geometric standard deviation of 0.21, with a delivered dose uniformity within 75-125% of the labeled claim. The Col-CS-AuNP MDI formulation completely killed Escherichia coli at 5× and 10× minimum inhibitory concentrations after 6 and 12 h of incubation, respectively. The toxicity of CS-AuNP and Col-CS-AuNP MDI formulations in upper and lower respiratory tract cell lines was lower than that of free colistin. The stability of the Col-CS-AuNP MDI formulation was maintained for at least 3 months. The Col-CS-AuNP MDI formulation effectively eradicated bacteria over a 12-h period, showing promise for advancing lung infection treatments.

Canister valve and actuator deposition in metered dose inhalers formulated with low-GWP propellants

A challenge in pressurised metered-dose inhaler (pMDI) formulation design is management of adhesion of the drug to the canister wall, valve and actuator internal components and surfaces. Wall-material interactions differ between transparent vials used for visual inspection and metal canister pMDI systems. This is of particular concern for low greenhouse warming potential (GWP) formulations where propellant chemistry and solubility with many drugs are not well understood. In this study, we demonstrate a novel application of X-ray fluorescence spectroscopy using synchrotron radiation to assay the contents of surrogate solution and suspension pMDI formulations of potassium iodide and barium sulphate in propellants HFA134a, HFA152a and HFO1234ze(E) using aluminium canisters and standard components. Preliminary results indicate that through unit life drug distribution in the canister valve closure region and actuator can vary significantly with new propellants. For solution formulations HFO1234ze(E) propellant shows the greatest increase in local deposition inside the canister valve closure region as compared to HFA134a and HFA152a, with correspondingly reduced actuator deposition. This is likely driven by chemistry changes. For suspension formulations HFA152a shows the greatest differences, due to its low specific gravity. These changes must be taken into consideration in the development of products utilising low-GWP propellants.

Molecular Dynamic Simulation Approach to Predict the Compatibility of Formulation Components of Salbutamol Sulfate Metered Dose Inhaler Free off Ethanol

More than 50 years since the first introduction of metered dose inhaler (MDI) by Riker laboratories 1956. The major development in MDI manufacturing was the transformation from chloroflouro carbon (CFC) to hydroflouro alkane (HFA) which required a new engineering design to the MDI components and reformulation of existing MDI to fit the new propellant. Evolution of MDI formulation was challenging due to the low solubility profile of most excipients in HFA propellants and the limitation of generally recognized as safe (GRAS) excipients that could be delivered to the lung. The main purpose of this study was to develop a new salbutamol sulfate (SS) MDI using PEG400(1%) w/w as suitable alternative co-solvents to ethanol (10%)w/w. PVP-k30(0.001-0.0001%) w/w and Brij72(0.001-0.005-0.01%) were used separately as suggested stabilizer. In silico molecular dynamic (MD) simulation was carried out to investigate the compatibility of new excipients with SS and PEG400 before adding the HFA134a. Differential scanning calorimeter(DSC) was also run to evaluate the compatibility between formulations components that passed the visual observation test. Content per actuation was also used to estimate the developing formulation at accelerated stability conditions (40°C/75%RH).(N=10). MD simulation results demonstrated the compatibility of PVP-k30(0.0001%) w/w with other formulation's components before adding HFA134a propellant(small or negative value for and ). MD simulation results were also confirmed by DSC thermograms which indicate the compatibility between PVP-k30 based formulation due to a small change in endothermic maximum melting point compared with Brij 72 based formulation.Content per actuation of PVP-k30(0.0001%)w/w based formulation passed the accelerated stability test and there is a significant effect of stabilizer type and concentration on the emitted dose (p-value >0.05). This work confirms that MD simulations could save time and reduce the cost of experiments during the early stage of reformulation process of MDI.

Transport and deposition of beclomethasone dipropionate drug aerosols with varying ethanol concentration in severe asthmatic subjects

This study aims to assess the effects of varying an ethanol co-solvent on the deposition of drug particles in severe asthmatic subjects with distinct airway structures and lung functions using computational fluid dynamics. The subjects were selected from two quantitative computed tomography imaging-based severe asthmatic clusters, differentiated by airway constriction in the left lower lobe. Drug aerosols were assumed to be generated from a pressurized metered-dose inhaler (MDI). The aerosolized droplet sizes were varied by increasing the ethanol co-solvent concentration in the MDI solution. The MDI formulation consists of 1,1,2,2-tetrafluoroethane (HFA-134a), ethanol, and beclomethasone dipropionate (BDP) as the active pharmaceutical ingredient. Since HFA-134a and ethanol are volatile, both substances evaporate rapidly under ambient conditions and trigger condensation of water vapor, increasing the size of aerosols that are predominantly composed of water and BDP. The average deposition fraction in intra-thoracic airways for severe asthmatic subjects with (or without) airway constriction increased from 37%±12 to 53.2%±9.4 (or from 20.7%± 4.6 to 34.7%±6.6) when the ethanol concentration was increased from 1 to 10%wt/wt. However, when the ethanol concentration was further increased from 10 to 20%wt/wt, the deposition fraction decreased. This indicates the importance of selecting appropriate co-solvent amounts during drug formulation development for the treatment of patients with narrowed airway disease. For severe asthmatic subjects with airway narrowing, the inhaled aerosol may benefit from a low hygroscopic effect by reducing ethanol concentration to penetrate the peripheral region effectively. These results could potentially inform the selection of co-solvent amounts for inhalation therapies in a cluster-specific manner.

Targeted delivery of ursolic acid and oleanolic acid to lungs in the form of an inhaler for the management of tuberculosis: Pharmacokinetic and toxicity assessment.

Ursolic acid (UA) and oleanolic acid (OA) are triterpenoids. They are used to treat numerous diseases, including tuberculosis. Combinations of these drugs provide new insight into the management of tuberculosis. The major obstacle is the effective delivery of these drugs to the lungs, which are mainly affected due to M. tuberculosis. A metered-dose inhaler (MDI) was developed to address this issue containing UA and OA, followed by in-vitro and in-vivo evaluation. In the present study, MDI formulation was prepared by incorporating UA and OA at the dose level of 120 μg/ml in each actuation. In-vitro evaluation of this MDI formulation was performed to ensure its suitability to deliver UA and OA preciously. With prior approval of IAEC, a pharmacokinetic and acute inhalation toxicity study was conducted using MDI on Wistar rats. The pharmacokinetic study showed an increased biological half-life of UA (9.23±0.104 h) and OA (8.93±0.166 h) in combination therapy. In-vivo toxicity study demonstrated no adverse effects on body weight and vital organs in the treatment group compared with the control group. Histopathology examination of these essential organs showed no abnormalities. Mild alternation in the biochemical and hematological parameters was observed. However, these alterations did not affect the overall health of the animals. The present study documents a detailed study for the safety and pharmacokinetics of UA and OA in-vivo for their advanced application in tuberculosis disease.

Development of an ethanol-free salbutamol sulfate metered-dose inhaler: Application of molecular dynamic simulation-based prediction of intermolecular interaction

IntroductionMore than fifty years after the commercialization of the Ventolin metered-dose inhaler (MDI), its constituent active ingredient, salbutamol sulfate (SS), remains the most prescribed short-acting beta agonist for the first-line treatment of acute asthma attacks and the metered-dose inhaler remains its primary dosage form. The first generation of Ventolin MDI was developed at a time when environmental and regulatory concerns were less stringent than today. The MDI industry is now on the verge of a second major reformulation effort in response to environmental concerns. This paper serves to illustrate how modern computational modeling of molecular interactions can aid the reformulation process. By way of a case study, computational modeling was performed to compare poly(ethylene glycol) 400 (PEG400) and, separately, isopropyl myristate (IPM) as substitutes for the ethanol used in some generic salbutamol sulfate suspension-based hydrofluoroalkane MDIs. MethodsPEG400 and IPM were investigated as potential alternative cosolvents to ethanol in HFA134a-based SS suspension MDI formulations. Density functional theory (DFT) molecular dynamics simulations were used to evaluate the compatibility of the candidate cosolvents with the formulation's components. Corresponding physical formulations were filled into polyethylene terephthalate (PET) and, separately, aluminium canisters. In-vitro pharmaceutical product performance and macroscopic visual appearance were assessed and compared to the results of the simulation studies. ResultsThe simulation studies indicated that PEG400 would be a good candidate as a replacement for ethanol whereas IPM would not. The in-vitro and visual assessments support the predicted outcome of the simulation studies. ConclusionThis work suggests that molecular dynamics simulations may provide a useful tool to aid the selection of compatible excipients when reformulating MDI suspension-based products, thereby reducing the time and cost associated with manufacturing and testing of physical samples.

Effect of MDI Actuation Timing on Inhalation Dosimetry in a Human Respiratory Tract Model.

Accurate knowledge of the delivery of locally acting drug products, such as metered-dose inhaler (MDI) formulations, to large and small airways is essential to develop reliable in vitro/in vivo correlations (IVIVCs). However, challenges exist in modeling MDI delivery, due to the highly transient multiscale spray formation, the large variability in actuation–inhalation coordination, and the complex lung networks. The objective of this study was to develop/validate a computational MDI-releasing-delivery model and to evaluate the device actuation effects on the dose distribution with the newly developed model. An integrated MDI–mouth–lung (G9) geometry was developed. An albuterol MDI with the chlorofluorocarbon propellant was simulated with polydisperse aerosol size distribution measured by laser light scatter and aerosol discharge velocity derived from measurements taken while using a phase Doppler anemometry. The highly transient, multiscale airflow and droplet dynamics were simulated by using large eddy simulation (LES) and Lagrangian tracking with sufficiently fine computation mesh. A high-speed camera imaging of the MDI plume formation was conducted and compared with LES predictions. The aerosol discharge velocity at the MDI orifice was reversely determined to be 40 m/s based on the phase Doppler anemometry (PDA) measurements at two different locations from the mouthpiece. The LES-predicted instantaneous vortex structures and corresponding spray clouds resembled each other. There are three phases of the MDI plume evolution (discharging, dispersion, and dispensing), each with distinct features regardless of the actuation time. Good agreement was achieved between the predicted and measured doses in both the device, mouth–throat, and lung. Concerning the device–patient coordination, delayed MDI actuation increased drug deposition in the mouth and reduced drug delivery to the lung. Firing MDI before inhalation was found to increase drug loss in the device; however, it also reduced mouth–throat loss and increased lung doses in both the central and peripheral regions.

Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension.

Treprostinil palmitil (TP) is a prodrug of treprostinil (TRE), a pulmonary vasodilator that has been previously formulated for inhaled administration via a nebulizer. TP demonstrates a sustained presence in the lungs with reduced systemic exposure and prolonged inhibition of hypoxia-induced pulmonary vasoconstriction in vivo. Here, we report on re-formulation efforts to develop a more convenient solution-based metered-dose inhaler (MDI) formulation of TP, a treprostinil palmitil inhalation aerosol (TPIA) that matches the pharmacokinetic (PK) and efficacy profile of a nebulized TP formulation, treprostinil palmitil inhalation suspension (TPIS). MDI canisters were manufactured using a two-stage filling method. Aerosol performance, formulation solubility, and chemical stability assays were utilized for in vitro evaluation. For in vivo studies, TPIA formulations were delivered to rodents using an inhalation tower modified for MDI delivery. Using an iterative process involving evaluation of formulation performance in vitro (TP and excipient solubility, chemical stability, physical stability, and aerosol properties) and confirmatory testing in vivo (rat PK and efficacy, guinea pig cough), a promising formulation was identified. The optimized formulation, TPIA-W, demonstrates uniform in vitro drug delivery, a PK profile suitable for a once-daily administration, efficacy lasting at least 12 h in a hypoxic challenge model, and a significantly higher cough threshold than the parent drug treprostinil.

Development of an inhalation exposure system of a pressurized metered-dose inhaler (pMDI) formulation for small experimental animals

Development of an inhalation exposure system of a pressurized metered-dose inhaler (pMDI) formulation for small experimental animals

Evaluation of Valved Holding Chambers Simulating Repurposing Use of Ciclesonide Metered-dose Inhaler by Patients with Pneumonia

Achieving appropriate inhalation in patients with coronavirus disease 2019 (COVID-19) is a common challenge in the use of repurposed metered-dose inhaler (MDI) formulations. The purpose of this study was to evaluate the effect of five valved holding chambers (VHCs) on the inhalation of ciclesonide from Alvesco MDI. The aerodynamic particle size distribution of ciclesonide discharged from Alvesco MDI was evaluated using a Next Generation Impactor in the presence and absence of VHCs. The use of VHCs retained or slightly increased the amount of ciclesonide in the fine particle diameter range (aerodynamic particle size below 3 μm) (FPD) and reduced the amount at the induction port after coordinated inhalation. However, the use of VHC reduced the FPD of the formulation by increasing the time between the MDI discharge and the pump suction by various degrees among the five VHCs. These results indicated that use of the VHCs and minimizing the inhalation delay time should ensure sufficient inhalation of ciclesonide particles.

Relationship Between Geometric and Aerodynamic Particle Size Distributions in the Formulation of Solution and Suspension Metered-Dose Inhalers.

The relationship between the geometric particle size distribution (GPSD) and the aerodynamic particle size distribution (APSD) of commercial solution and suspension metered-dose inhaler (MDI) formulations was assessed to clarify the use of GPSD to estimate the APSD. The size distribution of particles discharged from four suspension and four solution MDIs was measured using the Inas®100 light-scattering spectrometer and a Next Generation Impactor. The conversion factor was calculated by measuring the GPSD and APSD of MDIs. The morphology and physical properties of MDIs were studied using scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). Six of the eight MDIs showed similar conversion factor profiles, irrespective of their composition and formulation types. Applying the conversion factor obtained from one of the six MDIs resulted in a particle size distribution comparable to each APSD except for some formulations. The two other solution MDIs, which contained citric acid, had much higher and variable conversion factors. SEM images and DSC scans of the solids obtained by nebulization of the solutions containing beclomethasone and/or citric acid showed the formation of a paste-like amorphous solid. These results indicated that APSD of solution and suspension MDIs that form rigid particles may be estimated by using the conversion factor and GPSD. Contrarily, the estimation is more difficult in formulations that tend to lose the particle structure during the measurement.

Development of an Aerosol Dose Collection Apparatus for In Vitro Dissolution Measurements of Orally Inhaled Drug Products

The aim of the study was to develop a robust and standardized in vitro dissolution methodology for orally inhaled drug products (OIDPs). An aerosol dose collection (ADC) system was designed to uniformly deposit the whole impactor stage mass (ISM) over a large filter area for dissolution testing. All dissolution tests were performed under sink conditions in a sodium phosphate buffered saline solution containing 0.2%w/w sodium dodecyl sulphate. An adapted USP Apparatus V, Paddle over Disk (POD), was used throughout the study. The dissolution characteristics of the ISM dose of a commercial metered-dose inhaler (MDI) and a range of dry powder inhaler (DPI) formulations containing inhaled corticosteroids were tested. The uniform distribution of the validated ISM dose considerably reduced drug loading effects on the dissolution profiles for both MDI and DPI formulations. The improvement in the robustness and discriminatory capability of the technique enabled characterization of dissolution rate differences between inhaler platforms and between different DPI product strengths containing fluticasone propionate. A good correlation between in vivo mean absorption time and in vitro dissolution half-life was found for a range of the inhaled corticosteroids. The ADC system and the reproducible in vitro POD dissolution measurements provided a quantitative-based approach for measuring the relationship between the influence of device and the dispersion characteristics on the aerosol dissolution of low solubility compounds. The in vitro dissolution method could potentially be applied as a dissolution methodology for compendial, quality control release testing, and during development of both branded orally inhaled drug products and their generic counterparts.

Preparation of Spray-Dried Nanoparticles for Efficient Drug Delivery to the Lungs.

The use of nanoparticulate systems for pulmonary drug delivery offers a number of advantages including significantly improved delivery efficiency to deep lung and the improved bioavailability. The traditional nanoparticle manufacturing process such as ball/jet milling often yields large aggregates, which could detrimentally inhibit the effective delivery of drug particles to the lower respiratory tract. Here we report an alternative technique of spray-drying the microemulsions to produce nanoparticles (<100nm) that can be dispersed homogenously in the propellant to form an extremely stable pressurized metered-dose inhaler (pMDI) formulations. Such nanoparticulate formulations provide an ideal tool for pulmonary drug delivery.

In-vitro and in-vivo respiratory deposition of a developed metered dose inhaler formulation of an anti-migraine drug

Enhancement of zolmitriptan bioavailability through development of micronized zolmitriptan pressurized metered dose inhaler (MDI) as an alternative to its traditional drug delivery systems. A reversed phase HPLC method for zolmitriptan determination was developed and evaluated. Micronized zolmitriptan MDI formulations were prepared using two different propellants. The prepared formulations were evaluated for mean shot weight, drug content, and leakage rate in addition to in-vitro deposition using next generation impactor where mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), fine particle dose, fine particle fraction (FPF), emitted dose (ED), and dispersibility were determined. The selected formulation was evaluated for in-vivo bronchial absorption in rats. The physicochemical characters of the prepared formulations were found to be dependent mainly on the vapor pressure of the used propellant. MDI formulation prepared with HFA 134a propellant was found to have the lowest MMAD (3.47 ± 0.65) with GSD of 2.3 ± 0.4. It also had the highest FPF (41.9), ED (89.26 ± 2.35) with dispersibility of 46.9%. This formulation, when applied to rats, resulted in faster Tmax (27 ± 5 min) with higher Cmax (1236 ± 116 ng/mL) and AUC(0-12) (3375 ± 482 ng/mL·h) over the oral tablet. Its relative bioavailability was 72.7% which was 1.25 times higher than the oral tablet relative bioavailability. Zolmitriptan MDI formulation was developed using micronized zolmitriptan powder without further modification or particle engineering. The developed formulation using HFA 134a propellant could be favorable alternative, with enhanced bioavailability, to zolmitriptan oral tablet for acute migraine treatment.

Pharmacokinetics and safety of a single dose of the novel LAMA/LABA fixed-dose combination of glycopyrronium/formoterol fumarate dihydrate metered dose inhaler, formulated using co-suspension delivery technology, in Japanese healthy subjects

BackgroundChronic obstructive pulmonary disease (COPD) causes significant mortality in Japan. GFF MDI is a long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination of glycopyrronium (GP) and formoterol fumarate dihydrate (FF), delivered by a metered dose inhaler (MDI) using co-suspension delivery technology, for the long-term maintenance treatment of COPD. MethodsThis randomized, Phase I, single-dose, four-treatment, four-period, crossover study (NCT02196714) examined the pharmacokinetic (PK) and safety profile of two doses of GFF MDI (28.8 μg/10 μg and 14.4 μg/10 μg) and two doses of GP MDI (28.8 μg and 14.4 μg), both formulated using co-suspension delivery technology, in healthy Japanese subjects (18–45 years of age). PK parameters included area under the curve (AUC) from 0 to 12 h (AUC0–12), AUC from 0 to the time of the last measurable plasma concentration, maximum observed plasma concentration (Cmax), and time to Cmax. Safety was monitored throughout the study. ResultsPlasma GP profiles were comparable between GFF MDI and GP MDI formulations containing the same GP dose. Increases in GP AUC0–12 and Cmax were generally dose proportional from 14.4 to 28.8 μg after administration of either formulation. ConclusionsThe addition of FF 10 μg to GP MDI 28.8 μg or 14.4 μg in a fixed-dose combination did not appreciably alter the PK of GP, nor did an increase in GP dose from 14.4 μg to 28.8 μg in a fixed-dose combination with FF 10 μg appreciably alter the PK of formoterol. Both formulations of GFF MDI and GP MDI were well tolerated in healthy Japanese subjects. Data from this study support further evaluation of GFF MDI in Japanese patients with COPD.

Effects of Formulation Variables on Lung Dosimetry of Albuterol Sulfate Suspension and Beclomethasone Dipropionate Solution Metered Dose Inhalers

The performance of pressurized metered dose inhalers (MDIs) is affected by formulation and device variables that impact delivered dose, aerodynamic particle size distribution, and consequently lung deposition and therapeutic effect. Specific formulation variables of relevance to two commercially available products-Proventil® HFA [albuterol sulfate (AS) suspension] and Qvar® [beclomethasone dipropionate (BDP) solution]-were evaluated to determine their influence on key performance attributes measured experimentally with in vitro cascade impaction studies. These commercial MDIs, utilized as model systems, provided mid-points for a design of experiments (DoE) plan to manufacture multiple suspension and solution MDI formulations. The experimental results were utilized as input variables in a computational dosimetry model to predict the effects of MDI formulation variables on lung deposition. For the BDP solution DoE MDIs, increased concentrations of surfactant oleic acid (0-2% w/w) increased lung deposition from 24 to 46%, whereas changes in concentration of the cosolvent ethanol (7-9% w/w) had no effect on lung deposition. For the AS suspension DoE MDIs, changes in oleic acid concentration (0.005-0.25% w/w) did not have significant effects on lung deposition, whereas lung deposition decreased from 48 to 26% as ethanol concentration increased from 2 to 20% w/w, and changes in micronized drug volumetric median particle size distribution (X50, 1.4-2.5μm) increased deposition in the tracheobronchial airways from 5 to 11%. A direct correlation was observed between fine particle fraction and predicted lung deposition. These results demonstrate the value of using dosimetry models to further explore relationships between performance variables and lung deposition.

Immunoglobulin G particles manufacturing by spray drying process for pressurised metered dose inhaler formulations

The objective of this work is to show the feasibility of manufacturing from a spray drying process particles containing immunoglobulin G capable of being administered by inhalation via a pressurized metered dose inhaler. Spray drying were made from aqueous solutions containing IgG and two types of excipients, mannitol and trehalose, with two ratios: 25% w/w and 75%w/w. The physicochemical and aerodynamic properties of the powders obtained were characterized just after manufacturing and after 1 month of storage at 40°C/75% RH according to criteria defined as needed to satisfy an inhaled formulation with a pressurized metered dose inhaler. Maintain of the biological activity and the structure of IgG after atomization was also tested by slot blot and circular dichroism. All spray-dried powders presented a median diameter lower than 5μm. The powders atomized with trehalose showed a solid state more stable than those atomized with mannitol. All atomized powders were in the form of wrinkled particles regardless the nature and the ratios of excipients. The results showed that the aerosolisation properties were compliant with the target, independently of the excipient used at a ratio of 25% w/w IgG-excipient. Moreover, the addition of excipient during the atomization process the denaturation of IgG was limited. This study showed that the use of trehalose as excipient could satisfy the requirements of an inhaled formulation with a pressurized metered dose inhaler.

Influence of Formulation Factors on the Aerosol Performance of Suspension and Solution Metered Dose Inhalers: A Systematic Approach.

Metered dose inhalers (MDIs) are complex drug-device combination products widely used to treat pulmonary disorders. The efficacy, driven by aerosol performance of the products, depends on a multitude of factors including, but not limited to, the physicochemical properties of drug and nature and amount of excipient(s). Under the quality by design (QbD) paradigm, systematic investigations are necessary to understand how changes in critical quality attributes (CQAs) of formulation, device, and manufacturing process influence key product performance parameters, such as delivered dose (DD) and fine particle dose (FPD). The purpose of this work is to provide a better understanding of the effects of different levels of excipients and drug particle size distribution on the aerosol performance of MDI products, while using two fundamentally different MDI products as relevant model systems, Proventil® HFA (albuterol sulfate suspension) and Qvar® (beclomethasone dipropionate solution). These MDI products, as model systems, provided mid-points around which a design of experiments (DOE), consisting of 22 suspension and 9 solution MDI formulations, were defined and manufactured. The DOE included formulations factors with varying ethanol (2 to 20% w/w and 7 to 9% w/w for the suspension and solution, respectively) and oleic acid concentrations (0.005 to 0.25% w/w and 0 to 2% w/w for the suspension and solution, respectively) and drug volumetric median particle size distribution (PSD D50, 1.4 to 2.5μm for the suspension). The MDI formulations were analyzed using compendial methods to elucidate the effect of these formulation variables (ethanol, oleic acid, and PSD D50) on DD and FPD. The outcomes of this study allowed defining design spaces for the formulation factors, such that DD and FPD would remain within specific pre-defined requirements. The systematic approach utilized in this work can contribute as a QbD tool to evaluate the extent to which the formulation factors govern the aerosol performance of MDI drug products, helping to design MDI formulations with desired product performance parameters.

TPP-dendrimer nanocarriers for siRNA delivery to the pulmonary epithelium and their dry powder and metered-dose inhaler formulations

The regulation of genes utilizing the RNA interference (RNAi) mechanism via the delivery of synthetic siRNA has great potential in the treatment of a variety of lung diseases. However, the delivery of siRNA to the lungs is challenging due to the poor bioavailability of siRNA when delivered intraveneously, and difficulty in formulating and maintaining the activity of free siRNA when delivered directly to the lungs using inhalation devices. The use of non-viral vectors such as cationic dendrimers can help enhance the stability of siRNA and its delivery to the cell cytosol. Therefore, in this work, we investigate the ability of a triphenylphosphonium (TPP) modified generation 4 poly(amidoamine) (PAMAM) dendrimer (G4NH2-TPP) to enhance the in vitro transfection efficiency of siRNA in a model of the pulmonary epithelium and their aerosol formulations in pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). Complexes of siRNA and G4NH2-TPP were prepared with varying TPP densities and increasing N/P ratios. The complexation efficiency was modulated by the presence of the TPP on the dendrimer surface, allowing for a looser complexation compared to unmodified dendrimer as determined by gel electrophoresis and polyanion competition assay. An increase in TPP density and N/P ratio led to an increase in the in vitro gene knockdown of stably green fluorescent protein (eGFP) expressing lung alveolar epithelial (A549) cells. G4NH2-12TPP dendriplexes (G4NH2 PAMAM dendrimers containing 12 TPP molecules on the surface complexed with siRNA) at N/P ratio 30 showed the highest in vitro gene knockdown efficiency. To assess the potential of TPP-dendriplexes for pulmonary use, we also developed micron particle technologies for both pMDIs and DPIs and determined their aerosol characteristics utilizing an Andersen Cascade Impactor (ACI). Mannitol microparticles encapsulating 12TPP-dendriplexes were shown to be effective in producing aerosols suitable for deep lung deposition for both pMDI formulations (fine particle fraction of 50–53%) and DPI formulations (fine particle fraction of 39%) with no impact on the in vitro gene knockdown efficiency of the siRNA. This work demonstrates the potential benefits of utilizing TPP-conjugated dendrimers in the formation of dendriplexes for siRNA delivery to the pulmonary epithelium and their aerosol formulation for local delivery to the lungs using portable inhalers.

What are the effects of salbutamol on gameto-maternal interaction? – New insights by cutting edge imaging technologies

More than fifty years after the commercialization of the Ventolin metered-dose inhaler (MDI), its constituent active ingredient, salbutamol sulfate (SS), remains the most prescribed short-acting beta agonist for the first-line treatment of acute asthma attacks and the metered-dose inhaler remains its primary dosage form. The first generation of Ventolin MDI was developed at a time when environmental and regulatory concerns were less stringent than today. The MDI industry is now on the verge of a second major reformulation effort in response to environmental concerns. This paper serves to illustrate how modern computational modeling of molecular interactions can aid the reformulation process. By way of a case study, computational modeling was performed to compare poly(ethylene glycol) 400 (PEG400) and, separately, isopropyl myristate (IPM) as substitutes for the ethanol used in some generic salbutamol sulfate suspension-based hydrofluoroalkane MDIs.PEG400 and IPM were investigated as potential alternative cosolvents to ethanol in HFA134a-based SS suspension MDI formulations. Density functional theory (DFT) molecular dynamics simulations were used to evaluate the compatibility of the candidate cosolvents with the formulation's components. Corresponding physical formulations were filled into polyethylene terephthalate (PET) and, separately, aluminium canisters. In-vitro pharmaceutical product performance and macroscopic visual appearance were assessed and compared to the results of the simulation studies.The simulation studies indicated that PEG400 would be a good candidate as a replacement for ethanol whereas IPM would not. The in-vitro and visual assessments support the predicted outcome of the simulation studies.This work suggests that molecular dynamics simulations may provide a useful tool to aid the selection of compatible excipients when reformulating MDI suspension-based products, thereby reducing the time and cost associated with manufacturing and testing of physical samples.