On the Feasibility of Rugose Lipid Microparticles in Pressurized Metered Dose Inhalers with Established and New Propellants.

Pressurized metered dose inhalers (pMDIs) require optimized formulations to provide stable, consistent lung delivery. This study investigates the feasibility of novel rugose lipid particles (RLPs) as potential drug carriers in pMDI formulations. The physical stability of RLPs was assessed in three different propellants: the established HFA-134a and HFA-227ea and the new low global-warming-potential (GWP) propellant HFO-1234ze. A feedstock containing DSPC and calcium chloride was prepared without pore forming agent to spray dry two RLP batches at inlet temperatures of 55 °C (RLP55) and 75 °C (RLP75). RLPs performance in pMDI formulations was compared to two reference samples that exhibit significantly different performance when suspended in propellants: well-established engineered porous particles and particles containing 80% trehalose and 20% leucine (80T20L). An accelerated stability study at 40 °C and relative humidity of 7% ± 5% was conducted over 3 months. At different time points, a shadowgraphic imaging technique was used to evaluate the colloidal stability of particles in pMDIs. Field emission electron microscopy with energy dispersive X-ray spectroscopy was used to evaluate the morphology and elemental composition of particles extracted from the pMDIs. After 2 weeks, all 80T20L formulations rapidly aggregated upon agitation and exhibited significantly inferior colloidal stability compared to the other samples. In comparison, both the RLP55 and RLP75 formulations, regardless of the propellant used, retained their rugose structure and demonstrated excellent suspension stability comparable with the engineered porous particles. The studied RLPs demonstrate great potential for use in pMDI formulations with HFA propellants and the next-generation low-GWP propellant HFO-1234ze.

Lipid-Based Self-Microemulsion of Niclosamide Achieved Enhanced Oral Delivery and Anti-Tumor Efficacy in Orthotopic Patient-Derived Xenograft of Hepatocellular Carcinoma in Mice.

Introduction: We previously identified niclosamide as a promising repurposed drug candidate for hepatocellular carcinoma (HCC) treatment. However, it is poorly water soluble, limiting its tissue bioavailability and clinical application. To overcome these challenges, we developed an orally bioavailable self-microemulsifying drug delivery system encapsulating niclosamide (Nic-SMEDDS). Methods: Nic-SMEDDS was synthesized and characterized for its physicochemical properties, in vivo pharmacokinetics and absorption mechanisms, and in vivo therapeutic efficacy in an orthotopic patient-derived xenograft (PDX)-HCC mouse model. Niclosamide ethanolamine salt (NEN), with superior water solubility, was used as a positive control. Results: Nic-SMEDDS (5.6% drug load) displayed favorable physicochemical properties and drug release profiles in vitro. In vivo, Nic-SMEDDS displayed prolonged retention time and plasma release profile compared to niclosamide or NEN. Oral administration of Nic-SMEDDS to non-tumor bearing mice improved niclosamide bioavailability and Cmax by 4.1- and 1.8-fold, respectively, compared to oral niclosamide. Cycloheximide pre-treatment blocked niclosamide absorption from orally administered Nic-SMEDDS, suggesting that its absorption was facilitated through the chylomicron pathway. Nic-SMEDDS (100 mg/kg, bid) showed greater anti-tumor efficacy compared to NEN (200 mg/kg, qd); this correlated with higher levels (p < 0.01) of niclosamide, increased caspase-3, and decreased Ki-67 in the harvested PDX tissues when Nic-SMEDDS was given. Biochemical analysis at the treatment end-point indicated that Nic-SMEDDS elevated lipid levels in treated mice. Conclusion: We successfully developed an orally bioavailable formulation of niclosamide, which significantly enhanced oral bioavailability and anti-tumor efficacy in an HCC PDX mouse model. Our data support its clinical translation for the treatment of solid tumors.

A comparative study on micelles, liposomes and solid lipid nanoparticles for paclitaxel delivery.

The purpose of this work was to compare the in vitro and in vivo characteristics of LDV-targeted lipid-based micelles, liposomes and solid lipid nanoparticles (SLN) to provide further insights into their therapeutic potential for clinical development. Micelles, liposomes and SLN were prepared using LDV peptide amphiphiles and palmitic acid-derived lipids using solvent evaporation, thin-film hydration and microfluidic mixing respectively. Nanocarriers were characterized for their physicochemical properties, paclitaxel loading efficiency, in vitro release behavior, stability in biological media as well as in vivo antitumor efficacy in melanoma xenograft model. TEM and DLS results confirmed the presence of paclitaxel-loaded nanosized micelles (6 to 12 nm), liposomes (123.31 ± 5.87 nm) and SLN (80.53 ± 5.37 nm). SLN demonstrated the slowest paclitaxel release rate and the highest stability in biological media compared to micelles and liposomes. Paclitaxel-loaded SLN demonstrated a statistically significant delay in tumor growth compared to mice treated with paclitaxel-loaded liposomes and paclitaxel-loaded micelles (p < 0.05). The results obtained in this study indicate the potential of SLN as drug delivery vehicles for anticancer therapy.

Inhalable microparticle platform based on a novel shell-forming lipid excipient and its feasibility for respirable delivery of biologics.

Administration of biologics such as proteins, vaccines, and phages via the respiratory route is becoming increasingly popular. Inhalable powder formulations for the successful delivery of biologics must first ensure both powder dispersibility and physicochemical stability. A lipid-based inhalable microparticle platform combining the stability advantages offered by dry powder formulations and high dispersibility afforded by a rugose morphology was spray dried and tested. A new simplified spray drying method requiring no organic solvents or complicated feedstock preparation processes was introduced for the manufacture of the microparticles. Trehalose was selected to form the amorphous particle core, because of its well-known ability to stabilize biologics, and also because of its ability to serve as a surrogate for small molecule actives. Phospholipid distearoyl phosphatidylcholine (DSPC), the lipid component in this formulation, was used as a shell former to improve powder dispersibility. Effectiveness of the lipid excipient in modifying trehalose particle morphology and enhancing powder dispersibility was evaluated at different lipid mass fractions (5%, 10%, 25%, 50%) and compared with that of several previously published shell-forming excipients at their effective mass fractions, i.e., 5% trileucine, 20% leucine, and 40% pullulan. A strong dependence of particle morphology on the lipid mass fraction was observed. Particles transitioned from typical smooth spherical trehalose particles without lipid to highly rugose microparticles at higher lipid mass fractions (>5%). In vitro aerosol performance testing demonstrated a significant improvement of powder dispersibility even at lipid mass fractions as low as 5%. Powder formulations with excellent aerosol performance comparable to those modified with leucine and trileucine were achieved at higher lipid mass fractions (>25%). A model biologic-containing formulation with 35% myoglobin, 35% glass stabilizer (trehalose), and 30% lipid shell former was shown to produce highly rugose particle structure as designed and excellent aerosol performance for efficient pulmonary delivery. A short-term stability at 40 °C proved that this protein-containing formulation had good thermal stability as designed. The results demonstrated great potential for the new lipid microparticle as a platform for the delivery of both small-molecule APIs and large-molecule biologics to the lung.

Spray Dried Rugose Lipid Particle Platform for Respiratory Drug Delivery.

PURPOSE: To develop a new lipid-based particle formulation platform for respiratory drug delivery applications. To find processing conditions for high surface rugosity and manufacturability. To assess the applicability of the new formulation method to different lipids. METHODS: A new spray drying method with a simplified aqueous suspension feedstock preparation process was developed for the manufacture of rugose lipid particles of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). A study covering a wide range of feedstock temperatures and outlet temperatures was conducted to optimize the processing conditions. Aerosol performance was characterized in vitro and in silico to assess the feasibility of their use in respiratory drug delivery applications. The applicability of the new spray drying method to longer-chain phospholipids with adjusted spray drying temperatures was also evaluated. RESULTS: Highly rugose DSPC lipid particles were produced via spray drying with good manufacturability. A feedstock temperature close to, and an outlet temperature lower than, the main phase transition were identified as critical in producing particles with highly rugose surface features. High emitted dose and total lung dose showed promising aerosol performance of the produced particles for use as a drug loading platform for respiratory drug delivery. Two types of longer-chain lipid particles with higher main phase transition temperatures, 1,2-diarachidoyl-sn-glycero-3-phosphocholine (DAPC) and 1,2-dibehenoyl-sn-glycero-3-phosphocholine (22:0 PC), yielded similar rugose morphologies when spray dried at correspondingly higher processing temperatures. CONCLUSIONS: Rugose lipid particles produced via spray drying from an aqueous suspension feedstock are promising as a formulation platform for respiratory drug delivery applications. The new technique can potentially produce rugose particles using various other lipids.

Trileucine as a dispersibility enhancer of spray-dried inhalable microparticles.

The formation of trileucine-containing spray-dried microparticles intended for pulmonary delivery was studied in depth. A single-particle method was employed to study the shell formation characteristics of trileucine in the presence of trehalose as a glass former, and an empirical correlation was proposed to predict the instance of shell formation. A droplet chain instrument was used to produce and collect monodisperse particles to examine morphology and calculate particle density for different levels of trileucine. It was observed that the addition of only 0.5 mg/mL (10% w/w) trileucine to a trehalose system could lower dried particle densities by approximately 1 g/cm3. In addition, a laboratory-scale spray dryer was used to produce batches of trileucine/trehalose powders in the respirable range. Raman spectroscopy demonstrated that both components were completely amorphous. Scanning electron microscopy and time-of-flight secondary ion mass spectrometry were used to study the particle morphologies and surface compositions. For all cases with trileucine, highly rugose particles with trileucine coverages of more than 60% by mass were observed with trileucine feed fractions of as little as 2% w/w. Moreover, it was seen that at lower trileucine content, smaller and larger particles of a polydisperse powder had slightly different surface compositions. The surface activity of trileucine was also modeled via a modified form of the diffusion equation inside an evaporating droplet that took into account initial surface adsorption and eventual surface desorption due to droplet shrinkage. Finally, using the Flory-Huggins theory, it was estimated that at room temperature, liquid-liquid phase separation would start when the trileucine reached an aqueous concentration of about 18 mg/mL. Besides the surface activity of trileucine, this low concentration was assumed to explain the substantial effect of trileucine on the morphology of spray-dried particles due to early phase separation. The methodology proposed in this study can be used in the rational design of trileucine-containing microparticles.

Formulation strategies for bacteriophages to target intracellular bacterial pathogens.

Bacteriophages (Phages) are antibacterial viruses that are unaffected by antibiotic drug resistance. Many Phase I and Phase II phage therapy clinical trials have shown acceptable safety profiles. However, none of the completed trials could yield data supporting the promising observations noted in the experimental phage therapy. These trials have mainly focused on phage suspensions without enough attention paid to the stability of phage during processing, storage, and administration. This is important because in vivo studies have shown that the effectiveness of phage therapy greatly depends on the ratio of phage to bacterial concentrations (multiplicity of infection) at the infection site. Additionally, bacteria can evade phages through the development of phage-resistance and intracellular residence. This review focuses on the use of phage therapy against bacteria that survive within the intracellular niches. Recent research on phage behavior reveals that some phage can directly interact with, get internalized into, and get transcytosed across mammalian cells, prompting further research on the governing mechanisms of these interactions and the feasibility of harnessing therapeutic phage to target intracellular bacteria. Advances to improve the capability of phage attacking intracellular bacteria using formulation approaches such as encapsulating/conjugating phages into/with vector carriers via liposomes, polymeric particles, inorganic nanoparticles, and cell penetrating peptides, are summarized. While promising progress has been achieved, research in this area is still in its infancy and warrants further attention.

On the particle formation of leucine in spray drying of inhalable microparticles.

The particle formation of L-leucine, a dispersibility-enhancing amino acid used in the spray drying of inhalable pharmaceutical aerosols, was extensively studied using three experimental methods, and the results were interpreted with the aid of theory. A comparative-kinetics electrodynamic balance was used to study the shell formation behavior in single evaporating microdroplets containing leucine and trehalose. Different concentration thresholds of solidification and shell formation were determined for trehalose and leucine, which were then used in the particle formation model to predict the properties of spray-dried particles. Furthermore, a droplet chain instrument was used to study the particle morphologies and particle densities that were not accessible in the single particle experiments. Lab-scale spray drying was also used to produce powders typical for actual pharmaceutical applications. Raman spectroscopy confirmed that a glass former, such as trehalose, can inhibit the crystallization of leucine. The surface compositions of these spray-dried powders were analyzed via time-of-flight secondary ion mass spectrometry. The leucine surface coverage in a polydisperse powder was determined to be a function of the particle size or the initial droplet diameter of each respective particle. This observation confirms the important role of leucine crystallization kinetics in its shell-forming capabilities. A critical supersaturation ratio of 3.5 was also calculated for leucine, at which it is assumed to instantaneously nucleate out of solution. This ratio was used as the threshold for the initiation of crystallization. Crystallinity predictions for the leucine-trehalose particles based on this supersaturation ratio were in good agreement with the solid-state characterizations obtained by Raman spectroscopy. This study improves the fundamental understanding of the particle formation process of leucine-containing formulations, which can apply to other crystallizing systems and potentially facilitate the rational design of such formulations with reduced experimental effort.

Multi-Solvent Microdroplet Evaporation: Modeling and Measurement of Spray-Drying Kinetics with Inhalable Pharmaceutics.

PURPOSE: Evaporation and particle formation from multi-solvent microdroplets containing solid excipients pertaining to spray-drying of therapeutic agents intended for lung delivery were studied. Various water and ethanol co-solvent systems containing a variety of actives and excipients (beclomethasone, budesonide, leucine, and trehalose) were considered. METHODS: Numerical methods were used to predict the droplet evaporation rates and internal solute transfers, and their results verified and compared with results from two separate experimental setups. In particular, an electrodynamic balance was used to measure the evaporation rates of multicomponent droplets and a monodisperse droplet chain setup collected dried microparticles for further analytical investigations and ultramicroscopy. RESULTS: The numerical results are used to explain the different particle morphologies dried from solutions at different co-solvent compositions. The obtained numerical data clearly show that the two parameters controlling the general morphology of a dried particle, namely the Péclet number and the degree of saturation, can change with time in a multi-solvent droplet. This fact complicates product development for such systems. However, this additional complexity vanishes at what we define as the iso-compositional point, which occurs when the solvent ratios and other composition-dependent properties of the droplet remain constant during evaporation, similar to the azeotrope of such systems during distillation. CONCLUSIONS: Numerical and experimental analysis of multi-solvent systems indicate that spray-drying near the iso-compositional ratio simplifies the design and process development of such systems.

Correction to: Multi-Solvent Microdroplet Evaporation: Modeling and Measurement of Spray-Drying Kinetics with Inhalable Pharmaceutics.

The Publisher regrets having introduced the following errors into the article when performing proof corrections.

Characterization of the suspension stability of pharmaceuticals using a shadowgraphic imaging method.

A new shadowgraphic imaging method and an associated instrument for analyzing the physical stability of pharmaceutical suspensions are introduced in this paper. The new suspension tester consists mainly of a high-resolution camera that takes sequential shadowgraphic images of emulsions or suspensions and a 2D collimated LED for simultaneous whole-sample illumination in bright field. A built-in ultrasonic bath provides controlled initial agitation to the samples of interest. Sequential images acquired by the experimental setup were used to derive normalized transmission profiles from which an instability index was developed for quantitative stability comparison between samples. Instrument performance was verified by measuring the stability of a series of oil-in-water emulsions prepared with surfactant mixtures of different ratios. The new instrument correctly determined the required hydrophilic-lipophilic balance for sunflower oil to be 7.0. The stability of a pressurized suspension of spray dried lipid (DSPC) particles was monitored for 5 days after propellant filling. Although stable for the first 24 h, the lipid suspension was found to decrease in stability from day 1 to day 4. Morphological and spectroscopic analysis revealed that the suspended DSPC particles had reformed into large thin sheets of lipid, thereby causing the gradual stability decrease during the aging study. The effects of initial agitation on the stability of suspensions were demonstrated by agitating a suspension of micronized fluticasone propionate in propellant using a wrist action shaker and an ultrasonic bath respectively. A significant improvement of suspension stability was achieved by replacing the wrist action shaker method with ultrasonic agitation. Simultaneous illumination of the complete suspension, a high image acquisition rate, and controlled initial agitation are features that make this new suspension tester a suitable and more reliable instrument for investigating the stability of pressurized pharmaceutical suspensions.

Correction to: Drug Delivery from an Innovative LAMA/LABA Co-suspension Delivery Technology Fixed-Dose Combination MDI: Evidence of Consistency, Robustness, and Reliability.

This article was originally published Online First without open access. After publication it was discovered that the author had ordered open access during the production process. The incorrect license was assigned to this paper due to a technical error.

Drug Delivery from an Innovative LAMA/LABA Co-suspension Delivery Technology Fixed-Dose Combination MDI: Evidence of Consistency, Robustness, and Reliability.

To ensure consistency of clinical outcomes, orally inhaled therapies must exhibit consistent delivered dose and aerosol properties at the time of manufacturing, throughout storage, and during various patient-use conditions. Achieving consistency across these scenarios has presented a significant challenge, especially for combination products that contain more than one drug. This study characterized the delivered dose and aerosol properties of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI; Bevespi Aerosphere™). GFF MDI, a fixed-dose combination (FDC) of a long-acting muscarinic antagonist, glycopyrrolate (18 µg, equivalent to glycopyrronium 14.4 µg), and a long-acting ß2-agonist, formoterol fumarate (9.6 µg; equivalent to formoterol fumarate dihydrate 10 µg), is formulated using innovative co-suspension delivery technology, which suspends micronized drug crystals with spray-dried phospholipid porous particles in hydrofluoroalkane propellant. In this study, delivered dose uniformity was assessed through the labeled number of doses, and aerosol properties, such as percent fine particle fraction (FPF) and mass median aerodynamic diameter, were determined by cascade impaction. GFF MDI achieved reproducible dose delivery and an FPF greater than 55%, whether formulated and delivered as a monocomponent or dual FDC. The performance of GFF MDI was maintained across various manufacturing batches, under extended storage, and with variations in flow rate. Furthermore, unlike a GFF drug crystal-only suspension, drug delivery remained consistent for GFF MDI when simulated patient-handling errors were applied, such as reduced shake energy and delays between shaking and actuation. These results demonstrate that co-suspension delivery technology overcomes well-known sources of variability in MDI drug delivery.

Macro-Raman spectroscopy for bulk composition and homogeneity analysis of multi-component pharmaceutical powders.

A new macro-Raman system equipped with a motorized translational sample stage and low-frequency shift capabilities was developed for bulk composition and homogeneity analysis of multi-component pharmaceutical powders. Different sampling methods including single spot and scanning measurement were compared. It was found that increasing sample volumes significantly improved the precision of quantitative composition analysis, especially for poorly mixed powders. The multi-pass cavity of the macro-Raman system increased effective sample volumes by 20 times from the sample volume defined by the collection optics, i.e., from 0.02µL to about 0.4µL. A stochastic model simulating the random sampling process of polydisperse microparticles was used to predict the sampling errors for a specific sample volume. Comparison of fluticasone propionate mass fractions of the commercial products Flixotide® 250 and Seretide® 500 simulated for different sampling volumes with experimentally measured compositions verified that the effective sample volume of a single point macro-Raman measurement in the multi-pass cavity of this instrument was between 0.3µL and 0.5µL. The macro-Raman system was also successfully used for blend uniformity analysis. It was concluded that demixing occurred in the binary mixture of l-leucine and d-mannitol from the observation that the sampling errors indicated by the standard deviations of measured leucine mass fractions increased during mixing, and the standard deviation values were all larger than the theoretical lower limit determined by the simulation. Since sample volume was shown to have a significant impact on measured homogeneity characteristics, it was concluded that powder homogeneity analysis results, i.e., the mean of individual test results and absolute and relative standard deviations, must be presented together with the effective sample volumes of the applied testing techniques for any measurement of powder homogeneity to be fully meaningful.

Quantitative Macro-Raman Spectroscopy on Microparticle-Based Pharmaceutical Dosage Forms.

Quantitative macro-Raman spectroscopy was applied to the analysis of the bulk composition of pharmaceutical drug powders. Powders were extracted from seven commercial lactose-carrier-based dry-powder inhalers: Flixotide 50, 100, 250, and 500 µg/dose (four concentrations of fluticasone propionate) and Seretide 100, 250, and 500 µg/dose (three concentrations of fluticasone propionate, each with 50 µg/dose salmeterol xinafoate ). Also, a carrier-free pressurized metered-dose inhaler of the same combination product, Seretide 50 (50 µg fluticasone propionate and 25 µg salmeterol xinafoate per dose) was tested. The applicability of a custom-designed dispersive macro-Raman instrument with a large sample volume of 0.16 µL was tested to determine the composition of the multicomponent powder samples. To quantify the error caused by sample heterogeneity, a Monte Carlo model was developed to predict the minimum sample volume required for representative sampling of potentially heterogeneous samples at the microscopic level, characterized by different particle-size distributions and compositions. Typical carrier-free respirable powder samples required a minimum sample volume on the order of 10(-4) µL to achieve representative sampling with less than 3% relative error. In contrast, dosage forms containing non-respirable carriers (e.g., lactose) required a sample volume on the order of 0.1 µL for representative measurements. Error analysis of the experimental results showed good agreement with the error predicted by the simulation.

Isothermal microcalorimetry of pressurized systems II: effect of excipient and water ingress on formulation stability of amorphous glycopyrrolate.

PURPOSE: Use isothermal microcalorimetry to directly evaluate the effects of excipients and water content to produce a stable amorphous glycopyrrolate pressurized metered dose inhaler (pMDI) formulation. METHODS: Amorphous glycopyrrolate particles with and without excipients (Distearoyl-sn-glycero-3-phosphatidylcholine (DSPC) or ß-cyclodextrin (ßCD)) were spray dried and cold filled along with HFA 134a into customized thermal activity monitor (TAM) measurement ampoules. When applicable, a known amount of water was also pipetted into the ampoule. Sample ampoules were hermetically sealed, equilibrated to 25°C and measured isothermally for at least 24 h using the TAM III (TA Instruments, Sollentuna, Sweden). RESULTS: Amorphous glycopyrrolate particles were highly unstable and crystallized rapidly when suspended in HFA 134a. Co-spray drying the glycopyrrolate with DSPC failed to mitigate this instability, but co-spray drying with ßCD protected the amorphous glycopyrrolate from crystallization, resulting in a stable formulation at low water contents (≤ 100 ppm). CONCLUSIONS: This study shows that isothermal microcalorimetry can easily differentiate between physically stable and unstable pMDI formulations of glycopyrrolate within a few hours. Furthermore, it allows rapid screening of various formulation factors (drug form, excipients, water ingress), which can greatly reduce the time required to develop marketable products with acceptable shelf life.

Low-frequency shift dispersive Raman spectroscopy for the analysis of respirable dosage forms.

A high performance Raman system equipped with a CCD (charged coupled device) sensor and recently developed optical filter technology is described. It provides high sensitivity, high resolution, and access to low-frequency vibrations enabling resolution of spectral features due to lattice vibrational modes and internal vibrational modes, greatly improving the ability to detect small changes due to variations in the three dimensional molecular arrangement, e.g., during loss of crystallinity. Applications to solid state analysis, such as solid phase identification and differentiation of glycopyrronium bromide and formoterol fumarate in pharmaceutical powders, and identification of active pharmaceutical ingredients, e.g., salmeterol xinafoate, fluticasone propionate, mometasone furoate, and salbutamol sulphate, as well as excipients, e.g., amino acids, in different formulations, are presented. For the first time, low-frequency shift Raman spectra of mannitol polymorphs were measured and used for solid phase identification. Unambiguous identification of two similar bronchodilator metered dose inhalers, Ventolin(®) HFA and Airomir(®), was accomplished. The low-frequency shift Raman signals can be used for the analysis of crystallinity of small samples (<5mg) of respiratory dosage forms in a multi-component formulation matrix containing less than 3% by weight of the component of interest.

Isothermal microcalorimetry of pressurized systems I: a rapid method to evaluate pressurized metered dose inhaler formulations.

PURPOSE: The techniques available to study formulation stability in pressurized metered dose inhalers (pMDIs) are limited, due to the challenging conditions of working with high pressure propellants. Isothermal microcalorimetry is a valuable tool used to screen and aid in formulation development of solid and solution drug formulations; however there are currently no available methods to evaluate pMDIs. In this paper, we have developed a method that allows measurement of such pressurized systems. METHODS: Samples were prepared by cold filling ampoules with propellant (HFA 134a) and drugs of interest. Ampoule caps were fitted with a specific O-ring, coated with paraffin and pre-conditioned prior to measurement. Samples were equilibrated at 25°C, placed in a Thermal Activity Monitor III (TAM III) system and measured isothermally at 25°C for a period of at least 24 h. RESULTS: Using well-defined procedures and ampoule preparation techniques we were able to safely contain the volatile propellant and acquire a stable measurement baseline. We were able to rapidly determine, within 6 h, the physical stability of amorphous and crystalline drug forms of beclomethasone dipropionate and formoterol fumarate dihydrate when formulated with HFA 134a. CONCLUSIONS: Isothermal microcalorimetry in pressurized HFA propellant systems was shown to be a rapid screening tool to evaluate pMDI formulation physical stability. This method can potentially be applied to study pMDI formulation factors to expedite product development.

Cosuspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers.

Engineered porous phospholipid microparticles with aerodynamic diameters in the respirable range of 1-2 µm were cosuspended in 1,1,1,2-tetrafluoroethane, a propellant, with microcrystals of glycopyrrolate, formoterol fumarate dihydrate, or Mometasone furoate-three drugs with different solubilities in the propellant, and different physical, chemical, and pharmacological attributes. The drug microcrystals were added individually, in pairs, or all three together to prepare different cosuspensions, contained in a pressurized metered dose inhaler (pMDI). The drug microcrystals irreversibly associated with the porous particles, and the resultant cosuspensions possessed greatly improved suspension stability compared with suspensions of drug microcrystals alone. In general, all cosuspensions showed efficient dose delivery of the drugs, with fine particle fractions of more than 60% for a wide range of doses, including those as low as 300 ng per inhaler actuation. In the cosuspension pMDIs, comparable fine particle fractions were delivered for all tested drugs, whether or not they were emitted from an inhaler containing one, two, or three drugs. We demonstrate that the cosuspension approach solves at least three long-standing problems in the clinical development of pMDI-based products: (1) dose and drug dependent delivery efficiency, (2) inability to formulate dose strengths below 1 µg to fully explore drug efficacy and safety, and (3) combination suspensions delivering a different fine particle fraction than individual drug suspensions.