International Journal of Pharmaceutics (v.514, #2)

Use of similarity scoring in the development of oral solid dosage forms by Ana P. Ferreira; Dolapo Olusanmi; Omar Sprockel; Admassu Abebe; Faranak Nikfar; Mike Tobyn (335-340).
Display OmittedIn the oral solid dosage form space, material physical properties have a strong impact on the behaviour of the formulation during processing. The ability to identify materials with similar characteristics (and thus expected to exhibit similar behaviour) within the company’s portfolio can help accelerate drug development by enabling early assessment and prediction of potential challenges associated with the powder properties of a new active pharmaceutical ingredient. Such developments will aid the production of robust dosage forms, in an efficient manner.Similarity scoring metrics are widely used in a number of scientific fields. This study proposes a practical implementation of this methodology within pharmaceutical development. The developed similarity metrics is based on the Mahalanobis distance. Scanning electron microscopy was used to confirm morphological similarity between the reference material and the closest matches identified by the metrics proposed. The results show that the metrics proposed are able to successfully identify material with similar physical properties.
Keywords: Solid oral dosage form; Quality by design; Robustness; Similarity scoring; Surrogate; Knowledge management;

Effect of the deformability of guest particles on the tensile strength of tablets from interactive mixtures by Sharad Mangal; Satu Lakio; Thomas Gengenbach; Ian Larson; David A.V. Morton (341-352).
Display OmittedIn this study, we investigated the influence of deformability of specifically-engineered guest particles on the tensile strength of tablets of interactive mixtures. The binder polyvinylpyrrolidone (PVP) of different molecular weights were spray dried with l-leucine to create guest particle formulations. The guest particle formulations were characterized by their particle size, surface l-leucine concentration and glass transition temperature (Tg). These spray-dried particles were then blended with paracetamol to form interactive mixtures, which were compacted into tablets and tablet tensile strength and elastic recovery were determined. The guest particles had particle diameters in the range of 1–10 μm, and surfaces that were l-leucine enriched. The Tg of guest particle formulations increased with increasing molecular weight of the PVP. All the guest particle formulations formed an observed homogeneous interactive mixture with paracetamol. The tensile strength of the tablets of interactive mixtures increased with decreasing Tg of the guest particles. In these interactive mixtures, higher tensile strength was also associated with lower tablet elastic recovery. The elastic recovery of the tablets showed a correlation with the elastic recovery of the tablets of guest particles. Thus, our results indicated that the deformability of guest particles dictates the tensile strength of the tablets of these interactive mixtures.
Keywords: Paracetamol; Tabletting; Binder; l-Leucine; Spray drying; Polyvinylpyrrolidone; Elasticity; Interactive mixing; Host particles;

Impact of PAMAM delivery systems on signal transduction pathways in vivo: Modulation of ERK1/2 and p38 MAP kinase signaling in the normal and diabetic kidney by Saghir Akhtar; Bashayer Al-Zaid; Ahmed Z. El-Hashim; Bindu Chandrasekhar; Sreeja Attur; Ibrahim F. Benter (353-363).
Display OmittedThe in vivo impact of two generation 6 cationic polyamidoamine (PAMAM) dendrimers on cellular signaling via extracellular-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK), as well as their relationship to epidermal growth factor receptor (EGFR), were studied in the normal and/or diabetic rat kidney. A single 10 mg/kg/i.p administration of Polyfect (PF; with an intact branching architecture) or Superfect (SF; with a fragmented branching architecture) modulated renal ERK1/2 and p38 MAPK phosphorylation in a dendrimer-specific and animal model-dependent manner. AG1478 treatment (a selective EGFR inhibitor) confirmed that renal ERK1/2 and p38 MAPK signaling was downstream of EGFR. Surprisingly, both PAMAMs induced hyperphosphorylation of ERK1/2 and p38 MAPK (at 1 or 5 mg/kg) despite inhibiting EGFR phosphorylation in the diabetic kidney. PAMAMs did not alter renal morphology but their effects on p38 MAPK and EGFR phosphorylation were reversed by ex vivo treatment of kidneys with the anti-oxidant, Tempol. Thus, PAMAMs can intrinsically modulate signaling of mitogen-activated protein kinases (MAPKs) depending on the type of dendrimer (fragmented vs intact branching architecture) and animal model (normal vs diabetic) used and likely occurs via an EGFR-independent and oxidative-stress dependent mechanism. These findings might have important toxicological implications for PAMAM-based delivery systems.
Keywords: PAMAM; Dendrimer delivery system; ERK1/2; p38 MAPK; EGFR; Toxicity; Polyfect; Superfect;

Pre-absorption physicochemical compatibility assessment of 8-drug metabolic cocktail by Ching Kim Tye; Zhanbin Wang; Randy C. Dockens; Blisse Vakkalagadda; Chunlei Wang; Yingru Zhang; Ching Chiang Su; Michael J. Hageman (364-373).
Display OmittedA comprehensive 8-drug metabolic cocktail was designed to simultaneously target 6 Cytochrome P450 enzymes and 2 membrane transporters. This study aimed to assess the pre-absorption risk of this new metabolic cocktail which contained metoprolol, caffeine, midazolam, pravastatin, flurbiprofen, omeprazole, digoxin and montelukast. This paper describes a systematic approach to understand whether the co-administration of the 8 selected drug products, i.e., the physical mixing of these products in the human gastro-intestinal environment, will create any issue that may interfere with the individual drug dissolution which in turns modify the total amount or timing of their availability for absorption. The evaluation consisted of two steps. An initial evaluation was based on theoretical understanding of the physicochemical properties of the drugs and the gastro intestinal environment, followed by in vitro dissolution tests. The results indicated that the designer 8-drug cocktail has acceptable pre-absorption compatibility when dosed simultaneously, and recommended the progression of the cocktail into clinical validation study.
Keywords: Metabolic cocktail; Co-administration; Physicochemical interaction;

From single excipients to dual excipient platforms in dry powder inhaler products by Jagdeep Shur; Robert Price; David Lewis; Paul M. Young; Grahame Woollam; Dilraj Singh; Stephen Edge (374-383).
Recent years have seen a marked diversification of excipient based formulation strategies used for the development and commercialisation of dry powder inhaler (DPI) products. These innovative approaches not only provide benefits to patients and health care professionals through the availability of a wider range of therapeutic DPI products, but, importantly, also allow formulators to exploit the potential opportunities that excipients provide for the development of DPIs. Whilst many DPI products have, and continue to be developed using a single formulation excipient, the commercialisation of DPI products which contain the two excipients lactose monohydrate and magnesium stearate, namely the ‘dual excipient platform’ has recently been achieved. This article provides an overview of the background and current status of the development of such ‘dual excipient platform’ based DPI products.
Keywords: Dry powder inhaler; Excipients; Formulation; Inhalation;

A dry powder combination of pyrazinoic acid and its n-propyl ester for aerosol administration to animals by P.G. Durham; E.F. Young; M.S. Braunstein; J.T. Welch; A.J. Hickey (384-391).
Display OmittedCombining the advantage of higher efficacy due to local pulmonary administration of pyrazinoic acid (POA) and potent effect of pyrazinoic acid ester (PAE) delivered as an aerosol would aid in tuberculosis therapy. A combination spray dried dry powder, composed of POA, PAE (n-propyl POA), maltodextrin and leucine, was prepared for aerosol delivery to animals. Solid-state characteristics of morphology (scanning electron microscopy) crystallinity (X-ray powder diffraction), thermal properties (thermogravimetric analysis and differential scanning calorimetry) and moisture content (Karl Fisher) were evaluated. Particle size distributions, by volume (laser diffraction) for the dispersed powder and by mass (inertial impaction) were determined. Efficient delivery of the powder to a nose only animal exposure chamber employed a novel rotating brush/micro-fan apparatus. Spherical, crystalline particles were prepared. The volume median diameter, ∼1.5 μm, was smaller than the mass median aerodynamic diameter, ∼3.0 μm, indicating modest aggregation. Drug content variations were observed across the particle size distribution and may be explained by PAE evaporative losses. Delivery to the nose-only exposure chamber indicated that boluses could be administered at approximately 3 min intervals to avoid aerosol accumulation and effect uniform dose delivery with successive doses suitable for future pharmacokinetic and pharmacodynamic studies.
Keywords: Aerosol; Lungs; Tuberculosis; Pyrazinoic acid; n-Propyl pyrazinoic acid; Spray drying; Powder dispersion apparatus; Nose-only exposure chamber;

The development of a single-use, capsule-free multi-breath tobramycin dry powder inhaler for the treatment of cystic fibrosis by Bing Zhu; Matteo Padroni; Gaia Colombo; Gary Phillips; John Crapper; Paul M. Young; Daniela Traini (392-398).
Display OmittedThe aerosol performance and delivery characteristics of tobramycin for the treatment of respiratory infection were evaluated using the Orbital™, a multi-breath, high dose, dry powder inhaler (DPI). Micronised tobramycin was prepared and tested in the Orbital and in the commercially available TOBI Podhaler (Novartis AG). Furthermore, the TOBI Podhaler formulation containing tobramycin as Pulmospheres was tested in both the commercial Podhaler device (T-326) and Orbital for comparison. By varying the puck geometry of the Orbital, it was possible to deliver equivalent doses of micronised tobramycin (114.09 ± 5.86 mg) to that of the Podhaler Pulmosphere product (116.01 ± 2.59 mg) over 4 sequential simulated breaths (60 L min−1 for 4 s) without the need for multiple capsules. In general, the aerosol performance of the micronised tobramycin from the Orbital was higher than the T-326 Podhaler device, with fine particle fraction (FPF) of 44.99% ± 1.09% and 37.03% ± 0.86%, respectively. When testing the Pulmosphere powder in the two devices, the T-326 had marginally better performance with a FPF of 68.77% ± 2.10% compared to 61.30% ± 3.45%. This is to be expected since the TOBI Podhaler and Pulmosphere are an optimised powder and device combination. The Orbital was shown to be capable of delivering high efficiency, high dose antibiotic therapy for inhalation without the need for the use of multiple capsules as used in current devices. This approach may pave the way for a number of antibiotic therapies and medicaments where high dose respiratory deposition is required.
Keywords: Orbital; High dose dry powder inhaler; Tobramycin; Crystalline;

Investigation of the enhanced antimicrobial activity of combination dry powder inhaler formulations of lactoferrin by Lindsay J. Marshall; Wilson Oguejiofor; Robert Price; Jagdeep Shur (399-406).
Display OmittedThe airways of most people with cystic fibrosis are colonized with biofilms of the Gram-negative, opportunistic pathogen Pseudomonas aeruginosa. Delivery of antibiotics directly to the lung in the form of dry powder aerosols offers the potential to achieve high local concentrations directly to the biofilms. Unfortunately, current aerosolised antibiotic regimes are unable to efficiently eradicate these biofilms from the airways. We investigated the ability of the innate antimicrobial, lactoferrin, to enhance the activity of two aminoglycoside antibiotics (tobramycin and gentamicin) against biofilms of P. aeruginosa strain PAO1. Biofilms were prepared in 96 well polystyrene plates. Combinations of the antibiotics and various lactoferrin preparations were spray dried. The bacterial cell viability of the various spray dried combinations was determined. Iron-free lactoferrin (apo lactoferrin) induced a 3-log reduction in the killing of planktonic cell by the aminoglycoside antibiotics (p < 0.01) and also reduced both the formation and persistence of P. aeruginosa biofilms (p < 0.01). Combinations of lactoferrin and an aminoglycoside displays potential as an effective new therapeutic strategy in the treatment of P. aeruginosa biofilms infections such as those typical of the CF lungs.
Keywords: Antimicrobial protein; Spray drying; Pseudomonas aeruginosa; Cystic fibrosis; Biofilms; Dry powder inhalers;

Development of aqueous dispersions of Coenzyme Q10 for pulmonary delivery and the dynamics of active vibrating-mesh aerosolization by Thiago C. Carvalho; John P. McCook; Niven R. Narain; Jason T. McConville (407-419).
Display OmittedCoenzyme Q10 (CoQ10) is a poorly-water soluble compound that is being investigated for the treatment of carcinomas. The aim of this study was to investigate the feasibility of preparing phospholipid-stabilized dispersions of the anticancer agent for continuous pulmonary delivery using a vibrating-mesh nebulizer. We determined the physicochemical properties (drug particle size distribution in dispersion, zeta potential, surface tension, and rheology) and compared the aerosolization profiles (nebulization performance, aerodynamic drug deposition and total emitted dose) of dispersions of CoQ10 prepared with different phospholipids. The hydrodynamic sizes of the drug particles in dispersion were primarily in the submicron range, but formulations with drug particle sizes greater than the aperture size of the nebulizer presented superior aerosolization profiles. At high shear rates, certain formulations presented increased shear-thickening behavior, which was connected to a decrease in mass and drug output over time, and with decreased aerodynamic and geometric sizes. Other formulations presented shear-thinning behavior and showed similarly high drug depositions. In this investigation, we found that dispersed formulations of CoQ10 presented different in vitro performance for pulmonary delivery based on their rheological behavior. In conclusion, this characterization methodology provides an innovative approach to screen formulations of poorly-water soluble compounds for continuous (no clogging) active vibrating-mesh nebulization.
Keywords: Lung cancer; Nano-dispersion; Aerosol; Anticancer agents;

Exploring the impact of sample flowrate on in vitro measurements of metered dose inhaler performance by D.A. Lewis; H. O’Shea; T.K. Church; G. Brambilla; D. Traini; P.M. Young (420-427).
Display OmittedPharmacopoeial methods for measurement of the aerodynamic particle size distribution (APSD) of metered dose inhalers (MDIs) by cascade impaction specify a sampling flow rate of 28.3 L/min. However, there is little data within the literature to rationalize this figure, or to support its clinical relevance. In addition, the standard United States Pharmacopoeia Induction Port (USP IP) used for testing is known to inaccurately reflect deposition behavior in the upper airway, further compromising the relevance of testing, for product development.This article describes experimental studies of the effect of sampling flow rate on APSD data gathered using an Andersen Cascade Impactor (ACI). Tests were carried out using two different formulations to assess the influence of formulation composition. In addition, comparative testing with an Alberta Idealised Throat, in place of the USP IP, to ensure more realistic representation of the upper airway.The results show how measured APSD and fine particle dose, the dose than on the basis of size would be expected to deposit in the lung, vary as a function of test methodology, providing insight as to how the testing can be modified towards greater clinical relevance.
Keywords: Metered dose inhalers; Aerodynamic particle size distribution; Fine particle dose; Testing conditions; Cascade impactor; Alberta idealized throat;

Display OmittedThe ability of a range of hydrophilic nonionic cellulose ethers (CEs) (namely methylhydroxethylcellulose, hydroxypropylmethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose) to prepare stable nabumetone nanoparticles (<1000 nm, as measured by laser diffraction) using wet-bead milling has been investigated. Due to the limited range of CE molecular weights commercially available, the CEs were degraded using ultrasonication for varying lengths of time to yield CEs of lower molecular weight. Of the CEs tested, only hydroxyethylcellulose was found not to stabilise the production of nabumetone nanoparticles at any of the molecular weights tested, namely viscosity average molecular weights (M v) in the range of 236–33 kg/mol. All other CEs successfully stabilised nabumetone nanoparticles, with the lower molecular weight/viscosity polymers within a series being more likely to result in nanoparticle production than their higher molecular weight counterparts. Unfortunately due to the nature of the ultrasonication process, it was not possible to compare the size of nabumetone particles produced using polymers of identical M v. There was, however, enough similarity in the M v of the various polymers to draw the general conclusion that there was no strong correlation between the M v of the various polymers and their ability to produce nanoparticles. For example hydroxypropylcellulose of 112.2 kg/mol or less successfully produced nanoparticles while only ethylhydroxyethylcellulose and hydroxypropylmethyl polymers of 52 and 38.8 kg/mol or less produced nanoparticles. These results suggest that polymer molecular weight is not the only determinant of nanoparticle production and that structure of the polymer is at least as important as its molecular weight. In particular the hydrophobic nature of the CE was thought to be an important factor in the production of nabumetone nanoparticles: the more hydrophobic the polymer, the stronger its interaction with nabumetone and the greater its ability to produce nanoparticles. In this context HPC was the most hydrophobic polymer and HEC the least hydrophobic.
Keywords: Cellulose ethers; Nabumetone; Nanoparticle; Wet-bead milling; Molecular weight;

Powder dispersion mechanisms within a dry powder inhaler using microscale particle image velocimetry by Xiang Kou; Steven T. Wereley; Paul W.S. Heng; Lai Wah Chan; M. Teresa Carvajal (445-455).
Display OmittedThe goal of this work was to evaluate the ability of Particle Image Velocimetry (PIV) to visually assess dry powder dispersion within an inhaler. Herein, the study reports particle movement characterization of entrained low-micron particles within an inhaler to further scheme of potential mechanisms. Carrier based DPI formulations were prepared and placed in a transparent model Rotahaler® chamber for the aerosolization experiments. Then using the PIV, a high-speed camera, the dried powder dispersion was directly observed and analyzed for all, neat, binary and ternary systems. Powder dispersion mechanisms proposed include drag force, impact with obstacle and particle-particle collision; these different mechanisms depended on the powder flow properties. A revised ratio of aerodynamic response time (τA) to the mean time between collisions (τC) was found to be 6.8 indicating that particle collisions were of strong influence to particle dispersion. With image analysis techniques, visualization of particle flow pattern and collision regions was possible; suggesting that the various mechanisms proposed did govern the powder dispersion.
Keywords: DPI; Dispersion mechanism; Impact; Collision; Image analysis; PIV;

Acid-base interactions in amorphous solid dispersions of lumefantrine prepared by spray-drying and hot-melt extrusion using X-ray photoelectron spectroscopy by Yang Song; Dmitry Zemlyanov; Xin Chen; Ziyang Su; Haichen Nie; Joseph W. Lubach; Daniel Smith; Stephen Byrn; Rodolfo Pinal (456-464).
Display OmittedThis study investigates drug-excipient interactions in amorphous solid dispersions (ASDs) of the model basic compound lumefantrine (LMN), with five acidic polymers. X-ray photoelectron spectroscopy (XPS) was used to measure the extent of the protonation of the tertiary amine in LMN by the five acidic polymers. The extent/efficiency of protonation of the ASDs was assessed a function of polymer type, manufacturing process (hot-melt extrusion vs. spray drying), and drug loading (DL). The most strongly acidic polymer, polystyrene sulfonic acid (PSSA) was found to be the most efficient polymer in protonating LMN, independently of manufacturing method and DL. The rank order for the protonation extent of LMN by each polymer is roughtly the same for both manufacturing processes. However, protonation efficiency of polymers of similar acidic strength ranged from ∼0% to 75% (HPMCAS and Eudragit L100-55, respectively), suggesting an important role of molecular/mixing effects. For some polymers, including Eudragit L100 55 and HPMCP, spray-drying resulted in higher protonation efficiency compared to hot-melt extrusion. This result is attributable to a more favorable encounter between acid and base groups, when exposed to each other in solution phase. Increasing DL led to decreased protonation efficiency in most cases, particularly for polyacrylic acid, despite having the highest content of acidic groups per unit mass. These results indicate that the combined effects of acid strength and mixing phenomena regulate the efficiency of acid-base interactions in the ASDs.
Keywords: Lumefantrine; Amorphous; Solid dispersion; XPS; Spray-drying; Hot-melt extrusion; Ionic interaction; Salt; Acid-base;

Display OmittedThe respiratory route increasingly has been used for both local and systemic drug delivery. Although drug is absorbed rapidly after respiratory delivery, the role of lung surfactant in drug delivery is not well understood. The human lung contains only around 15 mL of surface lining fluid spread over ∼100 m2 surface. The fluid contains lung surfactant at a concentration of 8–24 mg/kg/body weight; the lung surfactant which is lipo-protein in nature can form different liquid crystalline nanostructures. After a brief overview of the anatomy of respiratory system, the review has focused on the current understanding of lung surface lining fluid, lung surfactants and their composition and possible self-assembled nanostructures. The role of lung surfactant in drug delivery and drug dissolution has been briefly considered.Lung surfactant may form different liquid crystalline phases which can have an active role in drug delivery. The hypotheses developed in this review focuses on the potential roles of surface epithelial fluid containing liquid crystalline nanostructures in defining the dissolution mechanism and rate. The hypotheses also focus an understanding how liquid crystalline nanostructures can be used to control dissolution rate and how the nanostructures might be changed to influence delivery and induce toxicity.
Keywords: Lung surfactant; Liquid crystal; Dissolution; Respiratory drug delivery; Absorption; Controlled release;