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Pharmaceutics, Volume 5, Issue 1 (March 2013), Pages 1-219

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Research

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Open AccessArticle Efavirenz Dissolution Enhancement I: Co-Micronization
Pharmaceutics 2013, 5(1), 1-22; doi:10.3390/pharmaceutics5010001
Received: 23 August 2012 / Revised: 8 November 2012 / Accepted: 3 December 2012 / Published: 20 December 2012
Cited by 16 | PDF Full-text (777 KB) | HTML Full-text | XML Full-text
Abstract
AIDS constitutes one of the most serious infectious diseases, representing a major public health priority. Efavirenz (EFV), one of the most widely used drugs for this pathology, belongs to the Class II of the Biopharmaceutics Classification System for drugs with very poor water
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AIDS constitutes one of the most serious infectious diseases, representing a major public health priority. Efavirenz (EFV), one of the most widely used drugs for this pathology, belongs to the Class II of the Biopharmaceutics Classification System for drugs with very poor water solubility. To improve EFV’s dissolution profile, changes can be made to the physical properties of the drug that do not lead to any accompanying molecular modifications. Therefore, the study objective was to develop and characterize systems with efavirenz able to improve its dissolution, which were co-processed with sodium lauryl sulfate (SLS) and polyvinylpyrrolidone (PVP). The technique used was co-micronization. Three different drug:excipient ratios were tested for each of the two carriers. The drug dispersion dissolution results showed significant improvement for all the co-processed samples in comparison to non-processed material and corresponding physical mixtures. The dissolution profiles obtained for dispersion with co-micronized SLS samples proved superior to those of co-micronized PVP, with the proportion (1:0.25) proving the optimal mixture. The improvements may be explained by the hypothesis that formation of a hydrophilic layer on the surface of the micronized drug increases the wettability of the system formed, corroborated by characterization results indicating no loss of crystallinity and an absence of interaction at the molecular level. Full article
Open AccessArticle Organic Nitrate Maintains Bone Marrow Blood Perfusion in Ovariectomized Female Rats: A Dynamic, Contrast-Enhanced Magnetic Resonance Imaging (MRI) Study
Pharmaceutics 2013, 5(1), 23-35; doi:10.3390/pharmaceutics5010023
Received: 9 July 2012 / Revised: 14 December 2012 / Accepted: 17 December 2012 / Published: 21 December 2012
Cited by 3 | PDF Full-text (926 KB) | HTML Full-text | XML Full-text
Abstract
This study investigated the effects of nitrate on bone mineral density (BMD) and bone marrow perfusion in ovariectomized (OVX) female rats, and also the effects of nitrate on in vitro osteoblastic activity and osteoclastic differentiation of murine monocyte/ macrophage RAW 264.7 cells. Female
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This study investigated the effects of nitrate on bone mineral density (BMD) and bone marrow perfusion in ovariectomized (OVX) female rats, and also the effects of nitrate on in vitro osteoblastic activity and osteoclastic differentiation of murine monocyte/ macrophage RAW 264.7 cells. Female Sprague–Dawley rats were divided into OVX + nitrate group (isosorbide-5-mononitrate, ISM, 150 mg/kg/ day b.i.d), OVX + vehicle group, and control group. Lumbar spine CT bone densitometry and perfusion MRI were performed on the rats at baseline and week 8 post-OVX. The OVX rats’ BMD decreased by 22.5% ± 5.7% at week 8 (p < 0.001); while the OVX + ISM rats’ BMD decreased by 13.1% ± 2.7% (p < 0.001). The BMD loss difference between the two groups of rats was significant (p = 0.018). The OVX rats’ lumbar vertebral perfusion MRI maximum enhancement (Emax) decreased by 10.3% ± 5.0% at week 8 (p < 0.005), while in OVX + ISM rats, the Emax increased by 5.5% ± 6.9% (p > 0.05). The proliferation of osteoblast-like UMR-106 cells increased significantly with ISM treatment at 0.78 µM to 50 μM. Treatment of UMR-106 cells with ISM also stimulated the BrdU uptake. After the RAW 264.7 cells were co-treated with osteoclastogenesis inducer RANKL and 6.25 μM ~ 100 μM of ISM for 3 days, a trend of dose-dependent increase of osteoclast number was noted. Full article
(This article belongs to the Special Issue DCE-MRI in Preclinical Imaging)
Open AccessArticle Correlating Physicochemical Properties of Boronic Acid-Chitosan Conjugates to Glucose Adsorption Sensitivity
Pharmaceutics 2013, 5(1), 69-80; doi:10.3390/pharmaceutics5010069
Received: 28 August 2012 / Revised: 10 December 2012 / Accepted: 18 December 2012 / Published: 27 December 2012
Cited by 3 | PDF Full-text (1110 KB) | HTML Full-text | XML Full-text
Abstract
Phenyl boronic acid (PBA), which is known to interact with glucose, was covalently bonded to chitosan by direct reductive N-alkylation of chitosan with 4-formylphenylboronic acid (4-FPBA). Evidence of PBA bonding on chitosan was assessed by FTIR, ToF-SIMS, SEM, DSC and glucose adsorption
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Phenyl boronic acid (PBA), which is known to interact with glucose, was covalently bonded to chitosan by direct reductive N-alkylation of chitosan with 4-formylphenylboronic acid (4-FPBA). Evidence of PBA bonding on chitosan was assessed by FTIR, ToF-SIMS, SEM, DSC and glucose adsorption sensitivity measurements. FTIR spectra showed strong signals at 1560 and 630 cm−1 indicating the formation of p-substituted benzene. Similarly, ToF-SIMS analyses on the conjugates registered fragments of boron ion (B) at 11.0 m/z whose intensity increased in proportion to 4-FPBA loading. The degree to which PBA was bonded to chitosan was related to the 4-FPBA load used in the reaction (termed F1 through to F6 with increasing 4-FPBA load). Glucose adsorption sensitivity to PBA-bonded chitosan was directly related to the amount of PBA functionality within the conjugates and the physical nature of the matrices (porous or crystalline). Topographic analysis by SEM revealed that PBA-chitosan conjugates F1, F2 and F3 have porous matrices and their sensitivity to glucose adsorption was directly proportional to the degree of PBA substitution onto chitosan. Conversely, conjugates F4, F5 and F6 appeared crystalline under SEM and glucose adsorption sensitivity decreased in proportion to amount of PBA bonded to chitosan. The crystalline nature of the conjugates was confirmed by DSC, where the exothermic event related to the melting of the bonded PBA moiety, occurred at 338 °C. Thus, decreased sensitivity to glucose adsorption by the conjugates can be ascribed to the crystallinity imparted by increased content of the bonded PBA moiety, providing an optimal loading of PBA in terms of maximizing response to glucose. Full article
(This article belongs to the Special Issue Drug Delivery Using Nanotechnology)
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Open AccessArticle Pharmacokinetic Evaluation of a DSPE-PEG2000 Micellar Formulation of Ridaforolimus in Rat
Pharmaceutics 2013, 5(1), 81-93; doi:10.3390/pharmaceutics5010081
Received: 13 November 2012 / Revised: 20 December 2012 / Accepted: 21 December 2012 / Published: 27 December 2012
Cited by 3 | PDF Full-text (470 KB) | HTML Full-text | XML Full-text
Abstract
The rapamycin analog, ridaforolimus, has demonstrated potent anti-proliferative effects in cancer treatment, and it currently is being evaluated in a range of clinical cancer studies. Ridaforolimus is an extremely lipophilic compound with limited aqueous solubility, which may benefit from formulation with polymeric micelles.
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The rapamycin analog, ridaforolimus, has demonstrated potent anti-proliferative effects in cancer treatment, and it currently is being evaluated in a range of clinical cancer studies. Ridaforolimus is an extremely lipophilic compound with limited aqueous solubility, which may benefit from formulation with polymeric micelles. Herein, we report the encapsulation of ridaforolimus in 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000) (DSPE-PEG2000) via a solvent extraction technique. Micelle loading greatly improved the solubility of ridaforolimus by approximately 40 times from 200 μg/mL to 8.9 mg/mL. The diameters of the drug-loaded micelles were 33 ± 15 nm indicating they are of appropriate size to accumulate within the tumor site via the enhanced permeability and retention (EPR) effect. The DSPE-PEG2000 micelle formulation was dosed intravenously to rats at 10 mg/kg and compared to a control of ridaforolimus in ethanol/PEG 400. The micelle significantly increased the half-life of ridaforolimus by 170% and decreased the clearance by 58%, which is consistent with improved retention of the drug in the plasma by the micelle formulation. Full article
(This article belongs to the Special Issue Micellar Drug Delivery)
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Open AccessArticle Safety Monitoring in Clinical Trials
Pharmaceutics 2013, 5(1), 94-106; doi:10.3390/pharmaceutics5010094
Received: 6 November 2012 / Revised: 9 January 2013 / Accepted: 10 January 2013 / Published: 17 January 2013
Cited by 4 | PDF Full-text (442 KB) | HTML Full-text | XML Full-text
Abstract
Monitoring patient safety during clinical trials is a critical component throughout the drug development life-cycle. Pharmaceutical sponsors must work proactively and collaboratively with all stakeholders to ensure a systematic approach to safety monitoring. The regulatory landscape has evolved with increased requirements for risk
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Monitoring patient safety during clinical trials is a critical component throughout the drug development life-cycle. Pharmaceutical sponsors must work proactively and collaboratively with all stakeholders to ensure a systematic approach to safety monitoring. The regulatory landscape has evolved with increased requirements for risk management plans, risk evaluation and minimization strategies. As the industry transitions from passive to active safety surveillance activities, there will be greater demand for more comprehensive and innovative approaches that apply quantitative methods to accumulating data from all sources, ranging from the discovery and preclinical through clinical and post-approval stages. Statistical methods, especially those based on the Bayesian framework, are important tools to help provide objectivity and rigor to the safety monitoring process. Full article
(This article belongs to the Special Issue Drug Safety and Pharmacovigilance)
Open AccessCommunication Steroid Nanocrystals Prepared Using the Nano Spray Dryer B-90
Pharmaceutics 2013, 5(1), 107-114; doi:10.3390/pharmaceutics5010107
Received: 10 October 2012 / Revised: 15 January 2013 / Accepted: 21 January 2013 / Published: 25 January 2013
Cited by 10 | PDF Full-text (438 KB) | HTML Full-text | XML Full-text
Abstract
The Nano Spray Dryer B-90 offers a new, simple, and alternative approach for the production of drug nanocrystals. In this study, the preparation of steroid nanocrystals using the Nano Spray Dryer B-90 was demonstrated. The particle size was controlled by selecting the mesh
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The Nano Spray Dryer B-90 offers a new, simple, and alternative approach for the production of drug nanocrystals. In this study, the preparation of steroid nanocrystals using the Nano Spray Dryer B-90 was demonstrated. The particle size was controlled by selecting the mesh aperture size. Submicrometer steroid particles in powder form were successfully obtained. These nanoparticles were confirmed to have a crystal structure using powder X-ray diffraction pattern analysis. Since drug nanocrystals have recently been considered as a novel type of drug formulation for drug delivery systems, this study will be useful for nano-medical applications. Full article
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Open AccessArticle Analytical Electron Microscopy for Characterization of Fluid or Semi-Solid Multiphase Systems Containing Nanoparticulate Material
Pharmaceutics 2013, 5(1), 115-126; doi:10.3390/pharmaceutics5010115
Received: 13 September 2012 / Revised: 28 January 2013 / Accepted: 30 January 2013 / Published: 5 February 2013
Cited by 3 | PDF Full-text (2452 KB) | HTML Full-text | XML Full-text
Abstract
The analysis of nanomaterials in pharmaceutical or cosmetic preparations is an important aspect both in formulation development and quality control of marketed products. Despite the increased popularity of nanoparticulate compounds especially in dermal preparations such as emulsions, methods and protocols of analysis for
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The analysis of nanomaterials in pharmaceutical or cosmetic preparations is an important aspect both in formulation development and quality control of marketed products. Despite the increased popularity of nanoparticulate compounds especially in dermal preparations such as emulsions, methods and protocols of analysis for the characterization of such systems are scarce. This work combines an original sample preparation procedure along with different methods of analytical electron microscopy for the comprehensive analysis of fluid or semi-solid dermal preparations containing nanoparticulate material. Energy-filtered transmission electron microscopy, energy-dispersive X-ray spectroscopy, electron energy loss spectroscopy and high resolution imaging were performed on model emulsions and a marketed product to reveal different structural aspects of both the emulsion bulk phase and incorporated nanosized material. An innovative analytical approach for the determination of the physical stability of the emulsion under investigation is presented. Advantages and limitations of the employed analytical imaging techniques are highlighted. Full article
(This article belongs to the Special Issue Drug Delivery Using Nanotechnology)
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Open AccessArticle Drug Adverse Event Detection in Health Plan Data Using the Gamma Poisson Shrinker and Comparison to the Tree-based Scan Statistic
Pharmaceutics 2013, 5(1), 179-200; doi:10.3390/pharmaceutics5010179
Received: 6 November 2012 / Revised: 1 March 2013 / Accepted: 4 March 2013 / Published: 14 March 2013
Cited by 1 | PDF Full-text (262 KB) | HTML Full-text | XML Full-text
Abstract
Background: Drug adverse event (AE) signal detection using the Gamma Poisson Shrinker (GPS) is commonly applied in spontaneous reporting. AE signal detection using large observational health plan databases can expand medication safety surveillance. Methods: Using data from nine health plans, we conducted a
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Background: Drug adverse event (AE) signal detection using the Gamma Poisson Shrinker (GPS) is commonly applied in spontaneous reporting. AE signal detection using large observational health plan databases can expand medication safety surveillance. Methods: Using data from nine health plans, we conducted a pilot study to evaluate the implementation and findings of the GPS approach for two antifungal drugs, terbinafine and itraconazole, and two diabetes drugs, pioglitazone and rosiglitazone. We evaluated 1676 diagnosis codes grouped into 183 different clinical concepts and four levels of granularity. Several signaling thresholds were assessed. GPS results were compared to findings from a companion study using the identical analytic dataset but an alternative statistical method—the tree-based scan statistic (TreeScan). Results: We identified 71 statistical signals across two signaling thresholds and two methods, including closely-related signals of overlapping diagnosis definitions. Initial review found that most signals represented known adverse drug reactions or confounding. About 31% of signals met the highest signaling threshold. Conclusions: The GPS method was successfully applied to observational health plan data in a distributed data environment as a drug safety data mining method. There was substantial concordance between the GPS and TreeScan approaches. Key method implementation decisions relate to defining exposures and outcomes and informed choice of signaling thresholds. Full article
(This article belongs to the Special Issue Drug Safety and Pharmacovigilance)

Review

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Open AccessReview Protein Adsorption Patterns and Analysis on IV Nanoemulsions—The Key Factor Determining the Organ Distribution
Pharmaceutics 2013, 5(1), 36-68; doi:10.3390/pharmaceutics5010036
Received: 1 November 2012 / Revised: 30 November 2012 / Accepted: 4 December 2012 / Published: 21 December 2012
Cited by 11 | PDF Full-text (1293 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Intravenous nanoemulsions have been on the market for parenteral nutrition since the 1950s; meanwhile, they have also been used successfully for IV drug delivery. To be well tolerable, the emulsions should avoid uptake by the MPS cells of the body; for drug delivery,
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Intravenous nanoemulsions have been on the market for parenteral nutrition since the 1950s; meanwhile, they have also been used successfully for IV drug delivery. To be well tolerable, the emulsions should avoid uptake by the MPS cells of the body; for drug delivery, they should be target-specific. The organ distribution is determined by the proteins adsorbing them after injection from the blood (protein adsorption pattern), typically analyzed by two-dimensional polyacrylamide gel electrophoresis, 2-D PAGE. The article reviews the 2-D PAGE method, the analytical problems to be faced and the knowledge available on how the composition of emulsions affects the protein adsorption patterns, e.g., the composition of the oil phase, stabilizer layer and drug incorporation into the interface or oil core. Data were re-evaluated and compared, and the implications for the in vivo distribution are discussed. Major results are that the interfacial composition of the stabilizer layer is the main determining factor and that this composition can be modulated by simple processes. Drug incorporation affects the pattern depending on the localization of the drug (oil core versus interface). The data situation regarding in vivo effects is very limited; mainly, it has to be referred to in the in vivo data of polymeric nanoparticles. As a conclusion, determination of the protein adsorption patterns can accelerate IV nanoemulsion formulation development regarding optimized organ distribution and related pharmacokinetics. Full article
(This article belongs to the Special Issue Drug Delivery Using Nanotechnology)
Open AccessReview From Molecular to Nanotechnology Strategies for Delivery of Neurotrophins: Emphasis on Brain-Derived Neurotrophic Factor (BDNF)
Pharmaceutics 2013, 5(1), 127-167; doi:10.3390/pharmaceutics5010127
Received: 13 November 2012 / Revised: 30 January 2013 / Accepted: 5 February 2013 / Published: 8 February 2013
Cited by 26 | PDF Full-text (809 KB) | HTML Full-text | XML Full-text
Abstract
Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been
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Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF), which is the most abundant neurotrophin in the mammalian central nervous system (CNS). Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted. Full article
(This article belongs to the Special Issue Drug Delivery Using Nanotechnology)
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Open AccessReview Exploring Polymeric Micelles for Improved Delivery of Anticancer Agents: Recent Developments in Preclinical Studies
Pharmaceutics 2013, 5(1), 201-219; doi:10.3390/pharmaceutics5010201
Received: 21 December 2012 / Revised: 28 February 2013 / Accepted: 13 March 2013 / Published: 22 March 2013
Cited by 22 | PDF Full-text (269 KB) | HTML Full-text | XML Full-text
Abstract
As versatile drug delivery systems, polymeric micelles have demonstrated particular strength in solubilizing hydrophobic anticancer drugs while eliminating the use of toxic organic solvents and surfactants. However, the true promise of polymeric micelles as drug carriers for cancer therapy resides in their potential
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As versatile drug delivery systems, polymeric micelles have demonstrated particular strength in solubilizing hydrophobic anticancer drugs while eliminating the use of toxic organic solvents and surfactants. However, the true promise of polymeric micelles as drug carriers for cancer therapy resides in their potential ability to preferentially elevate drug exposure in the tumor and achieve enhanced anticancer efficacy, which still remains to be fully exploited. Here, we review various micellar constructs that exhibit the enhanced permeation and retention effect in the tumor, the targeting ligands that potentiate the anticancer efficacy of micellar drugs, and the polyplex micelle systems suitable for the delivery of plasmid DNA and small interference RNA. Together, these preclinical studies in animal models help us further explore polymeric micelles as emerging drug carriers for targeted cancer therapy. Full article
(This article belongs to the Special Issue Micellar Drug Delivery)

Other

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Open AccessCommentary Vaccine Safety Surveillance Systems: Critical Elements and Lessons Learned in the Development of the US Vaccine Safety Datalink’s Rapid Cycle Analysis Capabilities
Pharmaceutics 2013, 5(1), 168-178; doi:10.3390/pharmaceutics5010168
Received: 31 December 2012 / Revised: 16 February 2013 / Accepted: 18 February 2013 / Published: 12 March 2013
Cited by 2 | PDF Full-text (165 KB) | HTML Full-text | XML Full-text
Abstract
Since the late 1990s, there have been tremendous strides made in improving the capacity for carrying out routine active surveillance of new vaccines in the United States. These strides have led to new surveillance systems that are now in place. Some of the
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Since the late 1990s, there have been tremendous strides made in improving the capacity for carrying out routine active surveillance of new vaccines in the United States. These strides have led to new surveillance systems that are now in place. Some of the critical elements that are part of successful vaccine or drug safety surveillance systems include their use of (i) longitudinal data from a discrete enumerated population base, (ii) frequent, routine transfers of small amounts of data that are easy to collect and collate, (iii) avoidance of mission creep, (iv) statistical capabilities, (v) creation of an “industrialized process” approach and (vi) political safe harbor. Full article
(This article belongs to the Special Issue Drug Safety and Pharmacovigilance)

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