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BACKGROUND: Astaxanthin (AST) is approved by the US Food and Drug Administration (FDA) as a safe dietary supplement for humans. As a potent lipid‐soluble keto‐carotenoid, it is widely used in food, cosmetics, and the pharmaceutical industry. However, its low solubility limits its powerful biological activity and its application in these fields. This study aims to develop a delivery system to address the low solubility and bioavailability of AST and to enhance its antioxidant capacity. RESULTS: Astaxanthin‐loaded composite micelles were successfully prepared via coaxial electrospray technology. Astaxanthin existed in the amorphous state in the electro‐sprayed formulation with an approximate particle size of 186.28 nm and with a polydispersity index of 0.243. In this delivery system, Soluplus and copovidone (PVPVA 64) were the main polymeric matrix for AST, which then released the drug upon contact with aqueous media, resulting in an overall increase in drug solubility and a release rate of 94.08%. Meanwhile, lecithin, and Polyethylene glycol‐grafted Chitosan (PEG‐g‐CS) could support the absorption of AST in the gastrointestinal tract, assisting transmembrane transport. The relative bioavailability reached about 308.33% and the reactive oxygen species (ROS) scavenging efficiency of the formulation was 44.10%, which was 1.57 times higher than that of free astaxanthin (28.10%) when both were at the same concentration level based on astaxanthin. CONCLUSION: Coaxial electrospray could be applied to prepare a composite micelles system for the delivery of poorly water‐soluble active ingredients in functional food, cosmetics, and medicine. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

This review provides an assessment of post-inhalation cough with therapeutic aerosols. Factors that increase cough may be mitigated through design of the drug, formulation, and device. The incidence of cough is typically less than 5% for drugs with a nominal dose less than 1 mg, including asthma and COPD therapeutics. Cough increases markedly as the dose approaches 100 mg. This is due to changes in the composition of epithelial lining fluid (e.g., increases in osmolality, proton concentration). Whether an individual exhibits cough depends on their degree of sensitization to mechanical and chemical stimuli. Hypersensitivity is increased when the drug, formulation or disease result in increases in lung inflammation. Cough related to changes in epithelial lining fluid composition can be limited by using insoluble neutral forms of drugs and excipients. Unlabelled Image [ABSTRACT FROM AUTHOR]

Delivery of drugs to the lungs via dry powder inhaler (DPI) is a promising approach for the treatment of both local pulmonary conditions and systemic diseases. Though DPIs are widely used for the pulmonary deposition of potent bronchodilators, anticholinergics, and corticosteroids, there is growing interest in the utilization of this delivery system for the administration of high drug doses to the lungs, as made evident by recent regulatory approvals for anti-microbial, anti-viral and osmotic agents. However, the formulation of high dose DPIs carries several challenges from both a physiological and physicochemical standpoint. This review describes the various formulation techniques utilized to overcome the barriers associated with the pulmonary delivery of high dose powders. [ABSTRACT FROM AUTHOR]

Stimuli responsive polyelectrolyte nanoparticles have been developed for chemo-photothermal destruction of breast cancer cells. This novel system, called layer by layer Lipo-graph (LBL Lipo-graph), is composed of alternate layers of graphene oxide (GO) and graphene oxide conjugated poly ( l -lysine) (GO-PLL) deposited on cationic liposomes encapsulating doxorubicin. Various concentrations of GO and GO-PLL were examined and the optimal LBL Lipo-graph was found to have a particle size of 267.9 ± 13 nm, zeta potential of +43.9 ± 6.9 mV and encapsulation efficiency of 86.4 ± 4.7%. The morphology of LBL Lipo-graph was examined by cryogenic-transmission electron microscopy (Cryo-TEM), atomic force microcopy (AFM) and scanning electron microscopy (SEM). The buildup of LBL Lipo-graph was confirmed via ultraviolet-visible (UV–Vis) spectrophotometry, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analysis. Infra-red (IR) response suggests that four layers are sufficient to induce a gel-to-liquid phase transition in response to near infra-red (NIR) laser irradiation. Light-matter interaction of LBL Lipo-graph was studied by calculating the absorption cross section in the frequency domain by utilizing Fourier analysis. Drug release assay indicates that the LBL Lipo-graph releases much faster in an acidic environment than a liposome control. A cytotoxicity assay was conducted to prove the efficacy of LBL Lipo-graph to destroy MD-MB-231 cells in response to NIR laser emission. Also, image stream flow cytometry and two photon microcopy provide supportive data for the potential application of LBL Lipo-graph for photothermal therapy. Study results suggest the novel dual-sensitive nanoparticles allow intracellular doxorubin delivery and respond to either acidic environments or NIR excitation. Statement of Significance Stimuli sensitive hybrid nanoparticles have been synthesized using a layer-by-layer technique and demonstrated for dual chemo-photothermal destruction of breast cancer cells. The hybrid nanoparticles are composed of alternating layers of graphene oxide and graphene oxide conjugated poly- l -lysine coating the surface of a thermosensitive cationic liposome containing doxorubicin as a core. Data suggests that the hybrid nanoparticles may offer many advantages for chemo-photothermal therapy. Advantages include a decrease of the initial burst release which may result in the reduction in systemic toxicity, increase in pH responsivity around the tumor environment and improved NIR light absorption. [ABSTRACT FROM AUTHOR]

Purpose: We tested the hypothesis that the increases in the porosity of the skin during iontophoresis would not significantly increase the transport of peptides due to the small size of electrically induced pores. To investigate this mechanistically, we used human epidermal membrane under constant voltage conditions, applying the Nernst–Planck equation to the transport of a small ionic solute, tetraethylammonium bromide (TEAB), and a model peptide, luteinizing hormone releasing hormone. Methods: Steady-state flux of the drugs was determined under passive conditions and also during iontophoresis using constant DC voltages applied across side-by-side diffusion cells. Electrical conductance measurements were used to monitor the porosity changes that occur during electrical field application. Results: Porosity increases observed in the membrane substantially increased the permeability enhancement of the small ionic solute TEAB. The permeability enhancement was well described by Nernst–Planck model predictions after porosity changes in the membrane were taken into account. Enhancement of luteinizing hormone releasing hormone under identical conditions was much less than TEAB. The porosity increases induced by iontophoresis had little or no effect on the permeability enhancement of the larger molecule. Conclusions: These findings closely parallel those reports that have found electrically induced pores to be significantly smaller than preexisting pores in the human epidermal membrane. The data obtained also support the view that iontophoresis-induced pores, alone, may provide limited benefit for macromolecule transport across the skin. [ABSTRACT FROM AUTHOR]

[Display omitted] • New chitosan-hyaluronic acid (CS-HA) core–shell nanoparticles (NPs) were developed. • The CS-HA NPs are the first sequential targeting delivery system of doxorubicin. • Mitotropic triphenylphosphonium-doxorubicin conjugate was synthesized. • The drug conjugate-loaded NPs were tested for sequential targeting of breast cancer. • In-vivo studies confirmed efficiency of CS-HA core–shell NPs for dual-stage delivery. Targeted therapy exploits cancerous niches' properties including acidic extracellular environment, hypoxic tumor core, and over expression of tumor-specific surface antigens. The present study aims to develop and evaluate a sequential targeted core–shell nanoparticulate (NPs) system for treatment of breast cancer. Sequential (double-stage) targeting was achieved at the cellular-level through employing the selective CD44- receptor binding hyaluronic acid (HA), followed by subcellular mitochondrial drug-delivery using the mitotropic triphenylphosphonium-conjugated doxorubicin (DOX-TPP+). NPs were prepared through incorporation of the electrostatic-complexes of DOX.HCl/DOX-TPP+ with tripolyphosphate (STPP-) into chitosan (CS) forming the core that was further coated with HA shell. Physicochemical characterization techniques namely; FTIR, DSC, DLS, morphological evaluation and spectroscopic assessments were implemented. Moreover, the drug entrapment efficiency (EE%), loading capacity (LC%), drug release profile and kinetics were investigated. Lastly, to validate the biological efficiency of the developed NPs, cytotoxic activity was evaluated as well as flow cytometric analyses to assess apoptosis induction and cell-cycle arrest were studied. Results showed that, the obtained core–shell NPs possessed a spherical shape with a mean size of 220–280 nm and attained high EE% and LC%. In-vitro cytotoxicity evaluations demonstrated successful apoptosis induction and cell-cycle abrogation. Moreover, in-vivo studies on Solid Ehrlich carcinoma (SEC)-bearing mice confirmed the efficient anticancer activity of the mitotropic DOX-TPP+-loaded NPs. Conclusively, the developed core–shell NPs proved efficient in sequential targeting of DOX to breast cancer. [ABSTRACT FROM AUTHOR]

Non-invasive delivery systems are desirable for routine administration of therapeutic protein and peptides. The large absorptive surface area of the lungs, thin alveolar epithelial barrier, and extensive vasculature makes the pulmonary route a promising option. For many years, drug delivery to the lungs has been achieved by nebulizers and metered dose inhalers. Two rapidly expanding fields of aerosol drug delivery are liquid-spray systems and dry-powder delivery systems. The selection of an aerosolization system for protein and peptide active compounds will be driven by several inter-related factors that include: physicochemical properties of the macromolecule, the principle of aerosolization of the device, and patient- and disease-related properties. Although novel liquid spray systems may have aerosol and delivery advantages over current inhalation aerosol technologies, rigorous scientific evaluation has not yet been performed due to the relatively recent introduction of these systems. Alternatively, dry-powder inhaler systems for protein and peptide therapeutics have undergone significantly more scientific evaluation. Dry-powder systems for protein and peptide therapeutics may have stability and sterility advantages. However, with currently used excipients and passive dispersion mechanisms, these devices are relatively inefficient. A convergence of improved particle manufacturing methods and technologies with active dispersion technologies may lead to more efficient delivery options. Alongside these delivery considerations, issues pertaining to economic viability, regulatory approval, and patient factors are equally important for selection of an appropriate delivery system. Thus, with our current understanding, there is no acceptable decision tree or algorithm that can be used to derive the most appropriate device technology for inhaled protein and peptide therapy. This review aims to provide guidance to select the best formulation alternative to deliver a candidate protein/peptide drug through the pulmonary route. [ABSTRACT FROM AUTHOR]

Nose-to-brain delivery has gained significant interest over the past several decades. This has resulted in numerous strategies described to improve the delivery of drugs to the brain directly through the olfactory epithelium of the nasal cavity. In some cases, intranasal administration may be more effective than other routes of administration in treating central nervous system and related disorders. Here, we briefly review the strategies that have been used to facilitate nose-to-brain delivery as well as approaches to block the delivery of drugs from the nose to the brain. Even though numerous strategies have already been used to increase nose-to-brain delivery, the research for strategies inhibitory of nose-to-brain delivery seems to be scarce. [ABSTRACT FROM AUTHOR]

Franz cell (FC) experiments in topical and transdermal drug development represent the gold standard in vitro method but require a relatively high quantity of human skin, are low-throughput, and are time-consuming to perform. To address these issues, we studied a micro-well plate-based screening method for permeability and retention that could enable the direct screening of large numbers of formulations simultaneously across human skin. Using freshly excised dermatomed human skin modified to reflect poor barrier function and a model hydrophilic compound, Sulforhodamine B (SRB), FC permeation and retention quantification was compared to the 96-well high-throughput system (HTS). The skin was analyzed using 2-photon microscopy to determine the drug distribution within the skin. A screen of 15 different formulations in triplicate in a single piece of human skin, using full factorial design was then conducted. Permeability of SRB across the skin as well as the drug distribution profile of SRB retained in the skin were similar for the FC and HTS system. The influence of different excipients on drug retention was observed in the full factorial formulation screen. The HTS method is promising for the investigation of large numbers of formulations and the influence of formulations changes in skin retention of drug. [ABSTRACT FROM AUTHOR]

High-speed laser imaging (HSLI) is the preferred technique to characterize the geometry of the plume in pressurized metered dose inhalers (pMDIs). However, current methods do not allow for simulation of inhalation airflow and do not use drug mass quantification to determine plume angles. To address these limitations, a Plume Induction Port Evaluator (PIPE) was designed to characterize the plume geometry based on mass deposition patterns. The method is easily adaptable to current pMDI characterization methodologies, uses similar calculations methods, and can be used under airflow. The effect of airflow and formulation on the plume geometry were evaluated using PIPE and HSLI. Deposition patterns in PIPE were highly reproducible and log-normal distributed. Mass Median Plume Angle (MMPA) was a new characterization parameter to describe the effective angle of the droplets deposited in the induction port. Plume angles determined by mass showed a significant decrease in size as ethanol increases which correlates to the decrease on vapor pressure in the formulation. Additionally, airflow significantly decreased the angle of the plumes when cascade impactor was operated under flow. PIPE is an alternative to laser-based characterization methods to evaluate the plume angle of pMDIs based on reliable drug quantification while simulating patient inhalation. [ABSTRACT FROM AUTHOR]

[Display omitted] The process of solids mixing is applied across a considerable range of industries. Pharmaceutical science is one of those industries that utilizes solids mixing extensively. Specifically, solids mixing as a key factor in the preparation of dry powder inhalers using the ordered mixing process will be discussed here. This review opens with a history of dry powder mixing theory, continues to ordered mixing in the preparation for dry powder inhalers, details key interparticulate interactions, explains formulation components for dry powder blends, and finally discusses different types of mixers used in the production of dry powder blends for inhalation. Lastly, the authors offer some suggestions for future work on this topic. [ABSTRACT FROM AUTHOR]

In this investigation, novel biodegradable physically crosslinked hydrogel microparticles were developed and evaluated in vitro as potential carriers for sustained pulmonary drug delivery. To facilitate sustained release in the lungs, aerosols must first navigate past efficient aerodynamic filtering to penetrate to the deep lung (requires small particle size) where they must then avoid rapid macrophage clearance (enhanced by large particle size). The strategy suggested in this study to solve this problem is to deliver drug-loaded hydrogel microparticles with aerodynamic characteristics allowing them to be respirable when dry but attain large swollen sizes once deposited on moist lung surfaces to reduce macrophage uptake rates. The microparticles are based on PEG graft copolymerized onto chitosan in combination with Pluronic® F-108 and were prepared via cryomilling. The synthesized polymers used in preparation of the microparticles were characterized using FTIR, EA, 2D-XRD, and differential scanning calorimetry (DSC). The microparticles size, morphology, moisture content, and biodegradation rates were investigated. Swelling studies and in vitro drug release profiles were determined. An aerosolization study was conducted and macrophage uptake rates were evaluated against controls. The microparticles showed a respirable fraction of approximately 15% when prepared as dry powders. Enzymatic degradation of microparticles started within the first hour and about 7–41% weights were remaining after 240 h. Microparticles showed sustained release up to 10 and 20 days in the presence and absence of lysozyme, respectively. Preliminary macrophage interaction studies indicate that the developed hydrogel microparticles significantly delayed phagocytosis and may have the potential for sustained drug delivery to the lung. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2343–2356, 2010 [ABSTRACT FROM AUTHOR]

A significant limitation of locally delivered treatments for chronic pulmonary infections is often the short residence time within the airways. Ciprofloxacin (CIP), for example, undergoes rapid absorption from the airway lumen. Previously, we demonstrated that the complexation of CIP with copper (CIP-Cu) reduces its apparent epithelial permeability and pulmonary absorption rate without affecting antimicrobial activity against Pseudomonas aeruginosa grown planktonically or as biofilms. This study aimed to evaluate the in vivo efficacy of CIP-Cu, prepared as a dry powder, in a chronic lung infection model. The powders were prepared by jet milling (CIP-HCl) and by spray drying (CIP-Cu). A bioluminescent strain of P. aeruginosa (PAO1::p16S lux) was used to prepare bacteria-loaded agar beads that were inoculated intratracheally to rats. The dynamics of the infection were monitored using luminometry. The bacteria/beads ratio was optimized to allow the highest luminescence signal and animal survival for 8 days. The efficacy of the treatment was evaluated by luminometry in addition to the end-point (Day 8) where colony counting was performed after lung harvesting. Luminescent P. aeruginosa entrapped in agar beads were useful to monitor the spatial development of the chronic lung infection in rats. The rats were treated with the dry powders in a nose-only inhalation exposure system (NOIES). CIP-Cu and CIP-HCl powders showed similar aerodynamic properties and comparable CIP lung deposition. However, treatment with CIP-Cu significantly (p < 0.01) reduced by 4-log the number of CFU of P. aeruginosa per lung in the chronic infection model, whereas CIP-HCl effect was not different from the untreated control group. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The objective of this work is to use phage display libraries as a screening tool to identify peptides that facilitate transport across the mucus barrier. Mucus is a complex selective barrier to particles and molecules, limiting penetration to the epithelial surface of mucosal tissues. In mucus-associated diseases such as cystic fibrosis (CF), mucus has increased viscoelasticity and a higher concentration of covalent and non-covalent physical entanglements compared to healthy tissues, which greatly hinders permeability and transport of drugs and particles across the mucosae for therapeutic delivery. Treatment of CF lung diseases and associated infections must overcome this abnormal mucosal barrier. Critical bottlenecks hindering effective drug penetration remain and while recent studies have shown hydrophilic, net-neutral charge polymers can improve the transport of nanoparticles and minimize interactions with mucus, there is a dearth of alternative carriers available. We hypothesized that the screening of a phage peptide library against a CF mucus model would lead to the identification of phage-displayed peptide sequences able to improve transport in mucus. These combinatorial libraries possess a large diversity of peptide-based formulations (108–109) to achieve unprecedented screening for potential mucus-penetrating peptides. Here, phage clones displaying discovered peptides were shown to have up to 2.6-fold enhanced diffusivity in the CF mucus model. In addition, we demonstrate reduced binding affinities to mucin compared to wild-type control. These findings suggest that phage display libraries can be used as a strategy to improve transmucosal delivery. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The number of biologics in the therapeutic development pipeline is increasing including those delivered though inhalation (Morales, 2017; Fathe, 2016). Biologics comprise a broad variety of complex macromolecules with unique physicochemical characteristics. These distinctive characteristics control their pharmacological mechanisms of action, stability, and ultimately affect their processing, formulation, and delivery requirements. This review systematically covers crucial aspects of biologic powders formulations and dry powder inhalers which need to be taken into consideration to establish the drug loading and the payload to be delivered to reach the desired clinical dose. [ABSTRACT FROM AUTHOR]

There is currently no in vitro technique for assessing plume geometry of nasal sprays under airflow conditions. However, a majority of FDA approved nasal products recommend that patients inhale during actuation. Therefore, a reproducible in vitro test that measures plume angles under physiologically relevant inhalation flow rates would be useful. The purpose of this study was to adapt the recently described Plume Induction Port Evaluator (PIPE) apparatus for nasal sprays under flow and correlate these with nasal cast deposition patterns. Mass Median Plume Angles (MMPAs) of four nasal spray formulations with increasing viscosities were determined using the PIPE apparatus in the absence and presence of airflow. MMPAs were then correlated to drug deposition within 3D printed nasal casts using airflow. We evaluated different inhalation instructions obtained from the package insert of nasal products. MMPAs significantly reduced (narrower angles) when using flow for the three formulations with the lowest viscosities. An increase in the turbinate deposition was observed in the nasal casts when just one of the nostrils was closed during inhalation, except by the highest viscosity formulation. The turbinate deposition numerically correlated with changes in the plume angles observed using PIPE. [ABSTRACT FROM AUTHOR]

• Around 40% of the formulation would be deposited in the alveolar membrane. • Inclusion of alginic acid confers mucoadhesive properties to the inhalatory system. • Plasmatic area under the curve is higher when the drug is combined with the polymer. • The developed material is not cytotoxic in the A-549 cell line even at high doses. • The interaction between the drug and polymer is reversible by ionic exchange. Hypertension is a chronic pathology where blood pressure levels are continuously high, causing cardiac, renal, cerebral, and vascular damage leading to early morbi-mortality. This illness is the main risk factor for cardiovascular diseases and the main cause of atrial fibrillation. Atenolol (AT) is a β-1 blocker drug useful for antihypertension and antiarrhythmic treatments. However, this drug possesses low oral bioavailability associated to its low permeability and extensive hepatic first-pass metabolism. To solve the conventional AT-administration problems, oral controlled-release and transdermal delivery have been reported. In this work, an alternative AT inhalatory system administered by nebulization is presented. This system is based on an ionic complex between acidic groups of alginic acid and cationic groups of AT (AA-AT), which was obtained by spray-drying. Pharmaceutical and biopharmaceutical properties for AA-AT inhalatory administration using a jet nebulizer were investigated. The aerodynamic performance (assayed at different cup-nebulizer loadings) of the nebulized system demonstrated that around 40% of the formulation would deposit in the respiratory membrane, with mass median aerodynamic diameters of 3.4–3.6 µm. The AT carried in the AA-AT system was released adequately by ionic exchange in saline solution by permeation through a cellulose membrane. The presence of AA as polyelectrolyte conferred mucoadhesive properties to the ionic complex. Even at high relative AA-AT concentrations, no cytotoxic effect was detected in A-549 cell line. Finally, the preliminary pharmacokinetic assay in the in vivo model confirmed that AT was absorbed from the lung to the systemic circulation, with a greater plasmatic AUC compared to the pure drug (around 50% higher). Then, the system and the nebulization administration demonstrated potential for drug cardiac targeting. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Gene therapy and more recently, gene editing is attractive via pulmonary delivery for enhanced regional targeting. However, processing of sensitive therapeutics into dry powders for inhalation can be problematic due to relatively stressful spraying or milling steps. Thin-film freeze-drying (TFFD) has attracted attention with its promising application in the production of DPI formulations possessing respirable particle size range (1–5 µm) particularly for thermally or shear sensitive therapeutics. In this study, gene editing dry powder formulations containing PEGylated chitosan/CRISPR-Cas9 nanocomplexes were prepared by TFFD. To evaluate stability during processing, nanocomplex size, zeta potential and transfection efficiency of reconstituted formulations were evaluated, and six potential DPI formulations were identified and characterized in terms of geometric particle size, powder surface morphology, and crystallinity. It was found that two formulations containing 3% mannitol with or without leucine were identified as suitable for inhalation with a desired aerodynamic performance. The flow rate dependency and inhaler dependency of these two formulations were also evaluated at different flow rates (60 L/min and 45 L/min) and different inhaler devices (RS01 DPI and HandiHaler) using NGI testing. This study demonstrated that TFFD processing of CRISPR-Cas9 polymer nanocomplexes resulted in a suitable dry powder for inhalation. [ABSTRACT FROM AUTHOR]

The performance of dry powder aerosols for the delivery of drugs to the lungs has been studied extensively in the last decade. The focus for different research groups has been on aspects of the powder formulation, which relate to solid state, surface and interfacial chemistry, bulk properties (static and dynamic) and measures of performance. The nature of studies in this field, tend to be complex and correlations between specific properties and performance seem to be rare. Consequently, the adoption of formulation approaches that on a predictive basis lead to desirable performance has been an elusive goal but one that many agree is worth striving towards. The purpose of this paper is to initiate a discussion of the use of a variety of techniques to elucidate dry particle behavior that might guide the data collection process. If the many researchers in this field can agree on this, or an alternative, guide then a database can be constructed that would allow predictive models to be developed. This is the first of two papers that discuss static and dynamic methods of characterizing dry powder inhaler formulations. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1282–1301, 2007 [ABSTRACT FROM AUTHOR]

Characteristics of particles included in dry powder inhalers is extended from our previous report (in this journal) to include properties related to their dynamic performance. The performance of dry powder aerosols for pulmonary delivery is known to depend on fluidization and dispersion which reflects particle interactions in static powder beds. Since the solid state, surface/interfacial chemistry and static bulk properties were assessed previously, it remains to describe dynamic performance with a view to interpreting the integrated database. These studies result in complex data matrices from which correlations between specific properties and performance may be deduced. Lactose particles were characterized in terms of their dynamic flow, powder and aerosol electrostatics, and aerodynamic performance with respect to albuterol aerosol dispersion. There were clear correlations between flow properties and aerosol dispersion that would allow selection of lactose particles for formulation. Moreover, these properties can be related to data reported earlier on the morphological and surface properties of the carrier lactose particles. The proposed series of analytical approaches to the evaluation of powders for inclusion in aerosol products has merit and may be the basis for screening and ultimately predicting particle performance with a view to formulation optimization. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1302–1319, 2007 [ABSTRACT FROM AUTHOR]