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Pharmaceutics, Volume 10, Issue 1 (March 2018)

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Editorial

Jump to: Research, Review

Open AccessEditorial Acknowledgement to Reviewers of Pharmaceutics in 2017
Pharmaceutics 2018, 10(1), 8; https://doi.org/10.3390/pharmaceutics10010008
Received: 11 January 2018 / Revised: 11 January 2018 / Accepted: 11 January 2018 / Published: 11 January 2018
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Abstract
Peer review is an essential part in the publication process, ensuring that Pharmaceutics maintains high quality standards for its published papers [...]
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Open AccessEditorial Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape—A Summary of This Indispensable Special Issue
Pharmaceutics 2018, 10(1), 13; https://doi.org/10.3390/pharmaceutics10010013
Received: 15 January 2018 / Revised: 15 January 2018 / Accepted: 15 January 2018 / Published: 16 January 2018
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Abstract
Canadian Pharmaceutical Scientists have a rich history of groundbreaking research in pharmacokinetics and drug metabolism undertaken primarily throughout its Pharmacy Faculties and within the Pharmaceutical and Biotechnology industry.[...] Full article

Research

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Open AccessFeature PaperArticle Prediction of Drug-Drug Interactions with Bupropion and Its Metabolites as CYP2D6 Inhibitors Using a Physiologically-Based Pharmacokinetic Model
Pharmaceutics 2018, 10(1), 1; https://doi.org/10.3390/pharmaceutics10010001
Received: 31 October 2017 / Revised: 5 December 2017 / Accepted: 19 December 2017 / Published: 21 December 2017
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Abstract
The potential of inhibitory metabolites of perpetrator drugs to contribute to drug-drug interactions (DDIs) is uncommon and underestimated. However, the occurrence of unexpected DDI suggests the potential contribution of metabolites to the observed DDI. The aim of this study was to develop a
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The potential of inhibitory metabolites of perpetrator drugs to contribute to drug-drug interactions (DDIs) is uncommon and underestimated. However, the occurrence of unexpected DDI suggests the potential contribution of metabolites to the observed DDI. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model for bupropion and its three primary metabolites—hydroxybupropion, threohydrobupropion and erythrohydrobupropion—based on a mixed “bottom-up” and “top-down” approach and to contribute to the understanding of the involvement and impact of inhibitory metabolites for DDIs observed in the clinic. PK profiles from clinical researches of different dosages were used to verify the bupropion model. Reasonable PK profiles of bupropion and its metabolites were captured in the PBPK model. Confidence in the DDI prediction involving bupropion and co-administered CYP2D6 substrates could be maximized. The predicted maximum concentration (Cmax) area under the concentration-time curve (AUC) values and Cmax and AUC ratios were consistent with clinically observed data. The addition of the inhibitory metabolites into the PBPK model resulted in a more accurate prediction of DDIs (AUC and Cmax ratio) than that which only considered parent drug (bupropion) P450 inhibition. The simulation suggests that bupropion and its metabolites contribute to the DDI between bupropion and CYP2D6 substrates. The inhibitory potency from strong to weak is hydroxybupropion, threohydrobupropion, erythrohydrobupropion, and bupropion, respectively. The present bupropion PBPK model can be useful for predicting inhibition from bupropion in other clinical studies. This study highlights the need for caution and dosage adjustment when combining bupropion with medications metabolized by CYP2D6. It also demonstrates the feasibility of applying the PBPK approach to predict the DDI potential of drugs undergoing complex metabolism, especially in the DDI involving inhibitory metabolites. Full article
(This article belongs to the Special Issue Preclinical Pharmacokinetics and Bioanalysis)
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Open AccessArticle Determination of Tangeretin in Rat Plasma: Assessment of Its Clearance and Absolute Oral Bioavailability
Pharmaceutics 2018, 10(1), 3; https://doi.org/10.3390/pharmaceutics10010003
Received: 6 November 2017 / Revised: 9 December 2017 / Accepted: 24 December 2017 / Published: 29 December 2017
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Abstract
Tangeretin (TAN) is a dietary polymethoxylated flavone that possesses a broad scope of pharmacological activities. A simple high-performance liquid chromatography (HPLC) method was developed and validated in this study to quantify TAN in plasma of Sprague-Dawley rats. The lower limit of quantification (LLOQ)
[...] Read more.
Tangeretin (TAN) is a dietary polymethoxylated flavone that possesses a broad scope of pharmacological activities. A simple high-performance liquid chromatography (HPLC) method was developed and validated in this study to quantify TAN in plasma of Sprague-Dawley rats. The lower limit of quantification (LLOQ) was 15 ng/mL; the intra- and inter-day assay variations expressed in the form of relative standard deviation (RSD) were all less than 10%; and the assay accuracy was within 100 ± 15%. Subsequently, pharmacokinetic profiles of TAN were explored and established. Upon single intravenous administration (10 mg/kg), TAN had rapid clearance (Cl = 94.1 ± 20.2 mL/min/kg) and moderate terminal elimination half-life (t1/2 λz = 166 ± 42 min). When TAN was given as a suspension (50 mg/kg), poor but erratic absolute oral bioavailability (mean value < 3.05%) was observed; however, when TAN was given in a solution prepared with randomly methylated-β-cyclodextrin (50 mg/kg), its plasma exposure was at least doubled (mean bioavailability: 6.02%). It was obvious that aqueous solubility hindered the oral absorption of TAN and acted as a barrier to its oral bioavailability. This study will facilitate further investigations on the medicinal potentials of TAN. Full article
(This article belongs to the Special Issue Preclinical Pharmacokinetics and Bioanalysis)
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Open AccessArticle Development and Validation of an UPLC-MS/MS Method for Pharmacokinetic Comparison of Five Alkaloids from JinQi Jiangtang Tablets and Its Monarch Drug Coptidis Rhizoma
Pharmaceutics 2018, 10(1), 4; https://doi.org/10.3390/pharmaceutics10010004
Received: 22 November 2017 / Revised: 18 December 2017 / Accepted: 21 December 2017 / Published: 29 December 2017
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Abstract
JinQi Jiangtang (JQJT) tablets, a Chinese patent medicine approved by the State Food and Drug Administration, are composed of Coptidis Rhizoma, Astragali Radix, and Lonicerae Japonicae Flos, and have a significant effect on diabetes. Coptidis Rhizoma is monarch drug in the prescription. The
[...] Read more.
JinQi Jiangtang (JQJT) tablets, a Chinese patent medicine approved by the State Food and Drug Administration, are composed of Coptidis Rhizoma, Astragali Radix, and Lonicerae Japonicae Flos, and have a significant effect on diabetes. Coptidis Rhizoma is monarch drug in the prescription. The aim of the present study was to investigate and compare the pharmacokinetics of multiple ingredients from JQJT tablets and Coptidis Rhizoma extract (CRE) following oral administration in rats. Five alkaloids: coptisine chloride, epiberberine chloride, berberine chloride, jatrorrhizine chloride, and palmatine chloride, were simultaneously determined in rat plasma using established and validated ultra-high performance liquid chromatography mass spectrometry (UPLC-MS/MS). Significant pharmacokinetic differences were observed for the five alkaloids after a single administration of CRE and JQJT tablets. Compared with CRE, the Cmax values of palmatine chloride and jatrorrhizine chloride were decreased significantly, the AUC0–t values of four alkaloids (all except jatrorrhizine chloride) were notably decreased, and the mean residence times of all five alkaloids were significantly decreased after administration of JQJT tablets. The results indicated that the absorption characteristics of the five alkaloids from Coptidis Rhizoma would be influenced by the compatibility of Astragali Radix or Lonicerae Japonicae Flos from JQJT tablets, such that absorption was inhibited and elimination was accelerated. In conclusion, the developed strategy was suitable for the comparison of five alkaloids from JinQi Jiangtang tablets and its monarch drug, which could be valuable for compatibility studies of traditional Chinese medicines. Full article
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Open AccessArticle Development of a Parenteral Formulation of NTS-Polyplex Nanoparticles for Clinical Purpose
Pharmaceutics 2018, 10(1), 5; https://doi.org/10.3390/pharmaceutics10010005
Received: 9 December 2017 / Revised: 23 December 2017 / Accepted: 2 January 2018 / Published: 3 January 2018
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Abstract
Neurotensin (NTS)-polyplex is a nanoparticle system for targeted gene delivery that holds great promise for treatment of Parkinson’s disease and various types of cancer. However, the high instability in aqueous suspension of NTS-polyplex nanoparticles is a major limitation for their widespread clinical use.
[...] Read more.
Neurotensin (NTS)-polyplex is a nanoparticle system for targeted gene delivery that holds great promise for treatment of Parkinson’s disease and various types of cancer. However, the high instability in aqueous suspension of NTS-polyplex nanoparticles is a major limitation for their widespread clinical use. To overcome this obstacle, we developed a clinical formulation and a lyophilization process for NTS-polyplex nanoparticles. The reconstituted samples were compared with fresh preparations by using transmission electron microscopy, dynamic light scattering, electrophoretic mobility, circular dichroism and transfection assays in vitro and in vivo. Our formulation was able to confer lyoprotection and stability to these nanoparticles. In addition, transmission electron microscopy (TEM) and size exclusion-high performance liquid chromatography (SEC-HPLC) using a radioactive tag revealed that the interaction of reconstituted nanoparticles with fetal bovine or human serum did not alter their biophysical features. Furthermore, the formulation and the lyophilization procedure guaranteed functional NTS-polyplex nanoparticles for at least six months of storage at 25 °C and 60% relative humidity. Our results offer a pharmaceutical guide for formulation and long-term storage of NTS-polyplex nanoparticles that could be applied to other polyplexes. Full article
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Open AccessArticle Regulation of Hepatic UGT2B15 by Methylation in Adults of Asian Descent
Pharmaceutics 2018, 10(1), 6; https://doi.org/10.3390/pharmaceutics10010006
Received: 12 December 2017 / Revised: 3 January 2018 / Accepted: 4 January 2018 / Published: 7 January 2018
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Abstract
The hepatic uridine 5′-diphosphate-glucuronosyl transferases (UGTs) are critical for detoxifying endo- and xenobiotics. Since UGTs are also dynamically responsive to endogenous and exogenous stimuli, we examined whether epigenetic DNA methylation can regulate hepatic UGT expression and differential effects of ethnicity, obesity, and sex.
[...] Read more.
The hepatic uridine 5′-diphosphate-glucuronosyl transferases (UGTs) are critical for detoxifying endo- and xenobiotics. Since UGTs are also dynamically responsive to endogenous and exogenous stimuli, we examined whether epigenetic DNA methylation can regulate hepatic UGT expression and differential effects of ethnicity, obesity, and sex. The methylation status of UGT isoforms was determined with Illumina Methylation 450 BeadChip arrays, with genotyping confirmed by sequencing and gene expression confirmed with quantitative reverse transcriptase polymerase chain reaction (q-RT-PCR). The UGT1A3 mRNA was 2-fold higher in females than males (p < 0.05), while UGT1A1 and UGT2B7 mRNA were significantly higher in Pacific Islanders than Caucasians (both p < 0.05). Differential mRNA or methylation did not occur with obesity. The methylation of the UGT2B15 locus cg09189601 in Caucasians was significantly lower than the highly methylated locus in Asians (p < 0.001). Three intergenic loci between UGT2B15 and 2B17 (cg07973162, cg10632656, and cg07952421) showed higher rates of methylation in Caucasians than in Asians (p < 0.001). Levels of UGT2B15 and UGT2B17 mRNA were significantly lower in Asians than Caucasians (p = 0.01 and p < 0.001, respectively). Genotyping and sequencing indicated that only UGT2B15 is regulated by methylation, and low UGT2B17 mRNA is due to a deletion genotype common to Asians. Epigenetic regulation of UGT2B15 may predispose Asians to altered drug and hormone metabolism and begin to explain the increased risks for adverse drug reactions and some cancers in this population. Full article
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Open AccessArticle Curcumin-Artemisinin Coamorphous Solid: Xenograft Model Preclinical Study
Pharmaceutics 2018, 10(1), 7; https://doi.org/10.3390/pharmaceutics10010007
Received: 29 November 2017 / Revised: 27 December 2017 / Accepted: 4 January 2018 / Published: 9 January 2018
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Abstract
Curcumin is a natural compound present in Indian spice turmeric. It has diverse pharmacological action but low oral solubility and bioavailability continue to limit its use as a drug. With the aim of improving the bioavailability of Curcumin (CUR), we evaluated Curcumin-Pyrogallol (CUR-PYR)
[...] Read more.
Curcumin is a natural compound present in Indian spice turmeric. It has diverse pharmacological action but low oral solubility and bioavailability continue to limit its use as a drug. With the aim of improving the bioavailability of Curcumin (CUR), we evaluated Curcumin-Pyrogallol (CUR-PYR) cocrystal and Curcumin-Artemisinin (CUR-ART) coamorphous solid. Both of these solid forms exhibited superior dissolution and pharmacokinetic behavior compared to pure CUR, which is practically insoluble in water. CUR-ART coamorphous solid showed two fold higher bioavailability than CUR-PYR cocrystal (at 200 mg/kg oral dose). Moreover, in simulated gastric and intestinal fluids (SGF and SIF), CUR-ART is stable up to 3 and 12 h, respectively. In addition, CUR-PYR and CUR-ART showed no adverse effects in toxicology studies (10 times higher dose at 2000 mg/kg). CUR-ART showed higher therapeutic effect and inhibited approximately 62% of tumor growth at 100 mg/kg oral dosage of CUR in xenograft models, which is equal to the positive control drug, doxorubicin (2 mg/kg) by i.v. administration. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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Open AccessArticle Is the Skin Absorption of Hydrocortisone Modified by the Variability in Dosing Topical Products?
Pharmaceutics 2018, 10(1), 9; https://doi.org/10.3390/pharmaceutics10010009
Received: 6 December 2017 / Revised: 5 January 2018 / Accepted: 8 January 2018 / Published: 12 January 2018
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Abstract
Fingertip units have been proposed as a tool to standardize topical therapy with semisolid formulations. However, no studies to date have characterized the variability in dosing by patients using this concept and whether this variability ultimately affects the topical absorption of drugs. This
[...] Read more.
Fingertip units have been proposed as a tool to standardize topical therapy with semisolid formulations. However, no studies to date have characterized the variability in dosing by patients using this concept and whether this variability ultimately affects the topical absorption of drugs. This work aimed to answer these two questions. A first study determined the dose measured, the area of spread and the area-normalized dose for a 1% hydrocortisone cream and ointment applied by members of the public using this dosing approach before and after brief counselling. Then, in vivo tape-stripping and in vitro permeation studies investigated whether the variability in the area-normalized dose altered the skin absorption of hydrocortisone. Participants applied greater doses and spread them over larger areas after a short counselling intervention leading to smaller area-normalized doses. In vivo hydrocortisone uptake by the stratum corneum was significantly greater for the higher normalized dose and the differences were further supported by the in vitro permeation studies. However, these differences were relatively small and not proportional to the increase in normalized dose. This work shows that, following brief advice, patients and carers can apply consistent and sufficient doses of corticosteroids whilst minimizing risks and variability in hydrocortisone absorption. Full article
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Open AccessArticle Solvation and Aggregation of Meta-Aminobenzoic Acid in Water: Density Functional Theory and Molecular Dynamics Study
Pharmaceutics 2018, 10(1), 12; https://doi.org/10.3390/pharmaceutics10010012
Received: 4 January 2018 / Revised: 18 January 2018 / Accepted: 19 January 2018 / Published: 23 January 2018
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Abstract
Meta-aminobenzoic acid, an important model system in the study of polymorphism and crystallization of active pharmaceutical ingredients, exist in water in both the nonionic (mABA) and zwitterionic (mABA±) forms. However, the constituent molecules of the polymorph that crystallizes from aqueous solutions
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Meta-aminobenzoic acid, an important model system in the study of polymorphism and crystallization of active pharmaceutical ingredients, exist in water in both the nonionic (mABA) and zwitterionic (mABA±) forms. However, the constituent molecules of the polymorph that crystallizes from aqueous solutions are zwitterionic. This study reports atomistic simulations of the events surrounding the early stage of crystal nucleation of meta-aminobenzoic acid from aqueous solutions. Ab initio molecular dynamics was used to simulate the hydration of mABA± and mABA and to quantify the interaction of these molecules with the surrounding water molecules. Density functional theory calculations were conducted to determine the low-lying energy conformers of meta-aminobenzoic acid dimers and to compute the Gibbs free energies in water of nonionic, (mABA)2, zwitterionic, (mABA±)2, and nonionic-zwitterionic, (mABA)(mABA±), species. Classical molecular dynamics simulations of mixed mABA–mABA± aqueous solutions were carried out to examine the aggregation of meta-aminobenzoic acid. According to these simulations, the selective crystallization of the polymorphs whose constituent molecules are zwitterionic is driven by the formation of zwitterionic dimers in solution, which are thermodynamically more stable than (mABA)2 and (mABA)(mABA±) pairs. This work represents a paradigm of the role of molecular processes during the early stages of crystal nucleation in affecting polymorph selection during crystallization from solution. Full article
(This article belongs to the Special Issue Pharmaceutical Crystallisation Science and Engineering)
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Open AccessArticle Development of a Region-Specific Physiologically Based Pharmacokinetic Brain Model to Assess Hippocampus and Frontal Cortex Pharmacokinetics
Pharmaceutics 2018, 10(1), 14; https://doi.org/10.3390/pharmaceutics10010014
Received: 2 January 2018 / Revised: 8 January 2018 / Accepted: 12 January 2018 / Published: 17 January 2018
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Abstract
Central nervous system drug discovery and development is hindered by the impermeable nature of the blood–brain barrier. Pharmacokinetic modeling can provide a novel approach to estimate CNS drug exposure; however, existing models do not predict temporal drug concentrations in distinct brain regions. A
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Central nervous system drug discovery and development is hindered by the impermeable nature of the blood–brain barrier. Pharmacokinetic modeling can provide a novel approach to estimate CNS drug exposure; however, existing models do not predict temporal drug concentrations in distinct brain regions. A rat CNS physiologically based pharmacokinetic (PBPK) model was developed, incorporating brain compartments for the frontal cortex (FC), hippocampus (HC), “rest-of-brain” (ROB), and cerebrospinal fluid (CSF). Model predictions of FC and HC Cmax, tmax and AUC were within 2-fold of that reported for carbamazepine and phenytoin. The inclusion of a 30% coefficient of variation on regional brain tissue volumes, to assess the uncertainty of regional brain compartments volumes on predicted concentrations, resulted in a minimal level of sensitivity of model predictions. This model was subsequently extended to predict human brain morphine concentrations, and predicted a ROB Cmax of 21.7 ± 6.41 ng/mL when compared to “better” (10.1 ng/mL) or “worse” (29.8 ng/mL) brain tissue regions with a FC Cmax of 62.12 ± 17.32 ng/mL and a HC Cmax of 182.2 ± 51.2 ng/mL. These results indicate that this simplified regional brain PBPK model is useful for forward prediction approaches in humans for estimating regional brain drug concentrations. Full article
(This article belongs to the Special Issue Preclinical Pharmacokinetics and Bioanalysis)
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Open AccessArticle Chitosan Gel to Treat Pressure Ulcers: A Clinical Pilot Study
Pharmaceutics 2018, 10(1), 15; https://doi.org/10.3390/pharmaceutics10010015
Received: 7 December 2017 / Revised: 10 January 2018 / Accepted: 14 January 2018 / Published: 17 January 2018
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Abstract
Chitosan is biopolymer with promising properties in wound healing. Chronic wounds represent a significant burden to both the patient and the medical system. Among chronic wounds, pressure ulcers are one of the most common types of complex wound. The efficacy and the tolerability
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Chitosan is biopolymer with promising properties in wound healing. Chronic wounds represent a significant burden to both the patient and the medical system. Among chronic wounds, pressure ulcers are one of the most common types of complex wound. The efficacy and the tolerability of chitosan gel formulation, prepared into the hospital pharmacy, in the treatment of pressure ulcers of moderate severity were evaluated. The endpoint of this phase II study was the reduction of the area of the lesion by at least 20% after four weeks of treatment. Thus, 20 adult volunteers with pressure ulcers within predetermined parameters were involved in a 30 days study. Dressing change was performed twice a week at outpatient clinic upon chronic wounds management. In the 90% of patients involved in the study, the treatment was effective, with a reduction of the area of the lesion and wound healing progress. The study demonstrated the efficacy of the gel formulation for treatment of pressure ulcers, also providing a strong reduction of patient management costs. Full article
(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)
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Open AccessArticle Preventing Crystal Agglomeration of Pharmaceutical Crystals Using Temperature Cycling and a Novel Membrane Crystallization Procedure for Seed Crystal Generation
Pharmaceutics 2018, 10(1), 17; https://doi.org/10.3390/pharmaceutics10010017
Received: 4 December 2017 / Revised: 16 January 2018 / Accepted: 18 January 2018 / Published: 24 January 2018
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Abstract
In this work, a novel membrane crystallization system was used to crystallize micro-sized seeds of piroxicam monohydrate by reverse antisolvent addition. Membrane crystallization seeds were compared with seeds produced by conventional antisolvent addition and polymorphic transformation of a fine powdered sample of piroxicam
[...] Read more.
In this work, a novel membrane crystallization system was used to crystallize micro-sized seeds of piroxicam monohydrate by reverse antisolvent addition. Membrane crystallization seeds were compared with seeds produced by conventional antisolvent addition and polymorphic transformation of a fine powdered sample of piroxicam form I in water. The membrane crystallization process allowed for a consistent production of pure monohydrate crystals with narrow size distribution and without significant agglomeration. The seeds were grown in 350 g of 20:80 w/w acetone-water mixture. Different seeding loads were tested and temperature cycling was applied in order to avoid agglomeration of the growing crystals during the process. Focused beam reflectance measurement (FBRM); and particle vision and measurement (PVM) were used to monitor crystal growth; nucleation and agglomeration during the seeded experiments. Furthermore; Raman spectroscopy was used to monitor solute concentration and estimate the overall yield of the process. Membrane crystallization was proved to be the most convenient and consistent method to produce seeds of highly agglomerating compounds; which can be grown via cooling crystallization and temperature cycling. Full article
(This article belongs to the Special Issue Pharmaceutical Crystallisation Science and Engineering)
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Open AccessArticle Minoxidil Skin Delivery from Nanoemulsion Formulations Containing Eucalyptol or Oleic Acid: Enhanced Diffusivity and Follicular Targeting
Pharmaceutics 2018, 10(1), 19; https://doi.org/10.3390/pharmaceutics10010019
Received: 9 December 2017 / Revised: 14 January 2018 / Accepted: 14 January 2018 / Published: 25 January 2018
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Abstract
In this work, we examined enhanced skin delivery of minoxidil applied in nanoemulsions incorporating skin penetration enhancers. Aliquots of fully characterized oil-in-water nanoemulsions (1 mL), containing minoxidil (2%) and the skin penetration enhancer oleic acid or eucalyptol as oil phases, were applied to
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In this work, we examined enhanced skin delivery of minoxidil applied in nanoemulsions incorporating skin penetration enhancers. Aliquots of fully characterized oil-in-water nanoemulsions (1 mL), containing minoxidil (2%) and the skin penetration enhancer oleic acid or eucalyptol as oil phases, were applied to full-thickness excised human skin in Franz diffusion cells, while aqueous solutions (1 mL) containing minoxidil were used as controls. Minoxidil in the stratum corneum (SC), hair follicles, deeper skin layers, and flux through the skin over 24 h was determined, as well as minoxidil solubility in the formulations and in the SC. The nanoemulsions significantly enhanced the permeation of minoxidil through skin compared with control solutions. The eucalyptol formulations (NE) promoted minoxidil retention in the SC and deeper skin layers more than did the oleic acid formulations, while the oleic acid formulations (NO) gave the greatest hair follicle penetration. Minoxidil maximum flux enhancement was associated with increases in both minoxidil SC solubility and skin diffusivity in both nanoemulsion systems. The mechanism of enhancement appeared to be driven largely by increased diffusivity, rather than increased partitioning into the stratum corneum, supporting the concept of enhanced fluidity and disruption of stratum corneum lipids. Full article
(This article belongs to the Special Issue Penetration Enhancement of Topical Formulations)
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Open AccessArticle Pharmacokinetics and Pharmacodynamics of (S)-Ketoprofen Co-Administered with Caffeine: A Preclinical Study in Arthritic Rats
Pharmaceutics 2018, 10(1), 20; https://doi.org/10.3390/pharmaceutics10010020
Received: 31 October 2017 / Revised: 16 January 2018 / Accepted: 23 January 2018 / Published: 26 January 2018
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Abstract
The purpose of the present study was to determine whether caffeine modifies the pharmacokinetics and pharmacodynamics of (S)-ketoprofen following oral administration in a gout-type pain model. 3.2 mg/kg of (S)-ketoprofen alone and combined with 17.8 mg/kg of caffeine were
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The purpose of the present study was to determine whether caffeine modifies the pharmacokinetics and pharmacodynamics of (S)-ketoprofen following oral administration in a gout-type pain model. 3.2 mg/kg of (S)-ketoprofen alone and combined with 17.8 mg/kg of caffeine were administered to Wistar rats and plasma levels were determined between 0.5 and 24.0 h. Additionally, antinociception was evaluated based on the protocol of the PIFIR (pain-induced functional impairment in the rat) model before blood sampling between 0.5 and 4.0 h. Significant differences in Cmax, AUC0-24, and AUC0-∞ values were observed with caffeine administration (p < 0.05). Also, significant differences in Emax, Tmax, and AUC0-4 values were determined when comparing the treatments with and without caffeine (p < 0.05). By relating the pharmacokinetic and pharmacodynamic data, a counter-clockwise hysteresis loop was observed regardless of the administration of caffeine. When the relationship between AUCe and AUCp was fitted to the sigmoidal Emax model, a satisfactory correlation was found (R2 > 0.99) as well as significant differences in Emax and EC50 values (p < 0.05). With caffeine, Emax and EC50 values changed by 489.5% and 695.4%, respectively. The combination studied represents a convenient alternative for the treatment of pain when considering the advantages offered by using drugs with different mechanisms of action. Full article
(This article belongs to the Special Issue Preclinical Pharmacokinetics and Bioanalysis)
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Open AccessArticle Feasibility of Using Gluconolactone, Trehalose and Hydroxy-Propyl Gamma Cyclodextrin to Enhance Bendroflumethiazide Dissolution Using Lyophilisation and Physical Mixing Techniques
Pharmaceutics 2018, 10(1), 22; https://doi.org/10.3390/pharmaceutics10010022
Received: 29 November 2017 / Revised: 22 January 2018 / Accepted: 24 January 2018 / Published: 1 February 2018
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Abstract
Purpose: Hydrophobic drugs are facing a major challenge in dissolution rate enhancement and solubility in aqueous solutions; therefore, a variety of methods have been used to improve dissolution rate and/or solubility of bendroflumethiazide as a model hydrophobic drug. Methods: In this study, two
[...] Read more.
Purpose: Hydrophobic drugs are facing a major challenge in dissolution rate enhancement and solubility in aqueous solutions; therefore, a variety of methods have been used to improve dissolution rate and/or solubility of bendroflumethiazide as a model hydrophobic drug. Methods: In this study, two main methods (physical mixing and lyophilisation) were used with gluconolactone, hydroxyl propyl γ-ccyclodextrin, and trehalose to explore this challenge. Bendroflumethiazide, practically insoluble in water, was mixed with one of the three excipients gluconolactone, hydroxyl propyl γ-cyclodextrin, and trehalose in three different ratios 1:1, 1:2, 1:5. To the best of our knowledge, the dissolution of the drug has not been previously enhanced by using either these methods or any of the used excipients. Samples containing drug and each of the excipients were characterized via dissolution testing, Fourier Transform infra-red spectroscopy, differential scanning calorimetry, and scanning electron microscopy. Results: The used methods showed a significant enhancement in dug dissolution rate; physical mixing significantly, p < 0.05, increased the percentage of the drug released with time; for example, bendroflumethiazide dissolution in distilled water was improved from less than 20% to 99.79% within 90 min for physically mixed drug-cyclodextrin 1:5. The lyophilisation process was enhanced and the drug dissolution rate and the highest drug dissolution was achieved for (drug-gluconolactone 1:1) with 98.98% drug release within 90 min. Conclusions: the physical mixing and freeze drying processes significantly increased the percentage of drug release with time. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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Open AccessArticle Chitosan Loaded into a Hydrogel Delivery System as a Strategy to Treat Vaginal Co-Infection
Pharmaceutics 2018, 10(1), 23; https://doi.org/10.3390/pharmaceutics10010023
Received: 22 December 2017 / Revised: 27 January 2018 / Accepted: 1 February 2018 / Published: 3 February 2018
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Abstract
Polymeric hydrogels are common dosage forms designed for the topical administration of antimicrobial drugs to treat vaginal infections. One of the major advantages of using chitosan in these formulations is related to the intrinsic and broad antimicrobial activity exerted on bacteria and fungi
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Polymeric hydrogels are common dosage forms designed for the topical administration of antimicrobial drugs to treat vaginal infections. One of the major advantages of using chitosan in these formulations is related to the intrinsic and broad antimicrobial activity exerted on bacteria and fungi by this natural polymer. Most vaginal yeast infections are caused by the pathogenic fungus Candida albicans. However, despite the anti-Candida activity towards and strains susceptibility to low molecular weight chitosan being documented, no information is available regarding the antimicrobial efficacy of mixed hydrogels in which chitosan is dispersed in a polymeric matrix. Therefore, the aim of the study is to evaluate the anti-Candida activity against eight different albicans and non-albicans strains of a mixed hydroxypropyl methylcellulose (HPMC)/chitosan hydrogel. Importantly, chitosan was dispersed in HPMC matrix either assembled in nanoparticles or in a monomolecular state to eventually correlate any variation in terms of rheological and mucoadhesive properties, as well as anti-Candida activity, with the chitosan form. Hydrogels containing 1% w/w chitosan, either as free polymer chain or assembled in nanoparticles, showed an improved mucoadhesiveness and an anti-Candida effect against all tested albicans and non-albicans strains. Overall, the results demonstrate the feasibility of preparing HPMC/CS mixed hydrogels intended for the prevention and treatment of Candida infections after vaginal administration. Full article
(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)
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Open AccessArticle Epinephrine in Anaphylaxis: Preclinical Study of Pharmacokinetics after Sublingual Administration of Taste-Masked Tablets for Potential Pediatric Use
Pharmaceutics 2018, 10(1), 24; https://doi.org/10.3390/pharmaceutics10010024
Received: 22 November 2017 / Revised: 19 December 2017 / Accepted: 12 January 2018 / Published: 11 February 2018
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Abstract
Epinephrine is a life-saving treatment in anaphylaxis. In community settings, a first-aid dose of epinephrine is injected from an auto-injector (EAI). Needle phobia highly contributes to EAI underuse, leading to fatalities—especially in children. A novel rapidly-disintegrating sublingual tablet (RDST) of epinephrine was developed
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Epinephrine is a life-saving treatment in anaphylaxis. In community settings, a first-aid dose of epinephrine is injected from an auto-injector (EAI). Needle phobia highly contributes to EAI underuse, leading to fatalities—especially in children. A novel rapidly-disintegrating sublingual tablet (RDST) of epinephrine was developed in our laboratory as a potential alternative dosage form. The aim of this study was to evaluate the sublingual bioavailability of epinephrine 30 mg as a potential pediatric dose incorporated in our novel taste-masked RDST in comparison with intramuscular (IM) epinephrine 0.15 mg from EAI, the recommended and only available dosage form for children in community settings. We studied the rate and extent of epinephrine absorption in our validated rabbit model (n = 5) using a cross-over design. The positive control was IM epinephrine 0.15 mg from an EpiPen Jr®. The negative control was a placebo RDST. Tablets were placed under the tongue for 2 min. Blood samples were collected at frequent intervals and epinephrine concentrations were measured using HPLC with electrochemical detection. The mean ± SEM maximum plasma concentration (Cmax) of 16.7 ± 1.9 ng/mL at peak time (Tmax) of 21 min after sublingual epinephrine 30 mg did not differ significantly (p > 0.05) from the Cmax of 18.8 ± 1.9 ng/mL at a Tmax of 36 min after IM epinephrine 0.15 mg. The Cmax of both doses was significantly higher than the Cmax of 7.5 ± 1.7 ng/mL of endogenous epinephrine after placebo. These taste-masked RDSTs containing a 30 mg dose of epinephrine have the potential to be used as an easy-to-carry, palatable, non-invasive treatment for anaphylactic episodes for children in community settings. Full article
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Open AccessArticle Pharmacokinetics and Scintigraphic Imaging of the Hypoxia-Imaging Agent [123I]IAZA in Healthy Adults Following Exercise-Based Cardiac Stress
Pharmaceutics 2018, 10(1), 25; https://doi.org/10.3390/pharmaceutics10010025
Received: 15 January 2018 / Revised: 16 February 2018 / Accepted: 16 February 2018 / Published: 22 February 2018
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Abstract
The objective of this work is to evaluate the potential effect of cardiac stress exercise on the accumulation of [123I]IAZA, a radiopharmaceutical used to image focal tissue hypoxia, in otherwise normal myocardium in healthy volunteers, and to determine the impact of
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The objective of this work is to evaluate the potential effect of cardiac stress exercise on the accumulation of [123I]IAZA, a radiopharmaceutical used to image focal tissue hypoxia, in otherwise normal myocardium in healthy volunteers, and to determine the impact of exercise on [123I]IAZA pharmacokinetics. The underlying goal is to establish a rational basis and a baseline for studies of focal myocardial hypoxia in cardiac patients using [123I]IAZA. Three healthy male volunteers ran the ‘Bruce’ treadmill protocol, a clinically-accepted protocol designed to expose myocardial ischemia in patients. The ‘Bruce’ criterion heart rate is 85% of [220–age]. Approximately one minute before reaching this level, [123I]IAZA (5.0 mCi/0.85 mg) was administered as a slow (1–3 min) single intravenous (i.v.) injection via an indwelling venous catheter. The volunteer continued running for an additional 1 min before being transferred to a gamma camera. Serum samples were collected from the arm contralateral to the administration site at pre-determined intervals from 1 min to 45 h post injection and were analyzed by radio HPLC. Pharmacokinetic (PK) parameters were derived for [123I]IAZA and total radioactivity (total[123I]) using compartmental and noncompartmental analyses. Whole-body planar scintigraphic images were acquired from 0.75 to 24 h after dosing. PK data and scintigraphic images were compared to previously published [123I]IAZA data from healthy volunteers rest. Following exercise stress, both [123I]IAZA and total[123I] exhibited bi-exponential decline profiles, with rapid distribution phases [half-lives (t1/2α) of 1.2 and 1.4 min, respectively], followed by slower elimination phases [t1/2β of 195 and 290 min, respectively]. Total body clearance (CLTB) and the steady state volume of distribution (Vss) were 0.647 L/kg and 185 mL/min, respectively, for [123I]IAZA and 0.785 L/kg and 135 mL/min, respectively, for total[123I]. The t1/2β, CLTB and Vss values were comparable to those reported previously for rested volunteers. The t1/2α was approximately 4-fold shorter for [123I]IAZA and approximately 3-fold shorter for total[123I] under exercise relative to rested subjects. The heart region was visualized in early whole body scintigraphic images, but later images showed no accumulated radioactivity in this region, and no differences from images reported for rested volunteers were apparent. Minimal uptake of radiotracer in myocardium and skeletal muscle was consistent with uptake in non-stressed myocardium. Whole-body scintigrams for [123I]IAZA in exercise-stressed healthy volunteers were indistinguishable from images of non-exercised volunteers. There was no evidence of hypoxia-dependent binding in exercised but otherwise healthy myocardium, supporting the conclusion that exercise stress at Bruce protocol intensity does not induce measurable myocardial hypoxia. Effects of exercise on PK parameters were minimal; specifically, the t1/2α was shortened, reflecting increased cardiac output associated with exercise. It is concluded that because [123I]IAZA was not metabolically bound in exercise-stressed myocardium, a stress test will not create elevated myocardial background that would mask regions of myocardial perfusion deficiency. [123I]IAZA would therefore be suitable for the detection of viable, hypoxic myocardium in patients undergoing stress-test-based diagnosis. Full article
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Open AccessArticle Design, Optimization and Characterization of a Transfersomal Gel Using Miconazole Nitrate for the Treatment of Candida Skin Infections
Pharmaceutics 2018, 10(1), 26; https://doi.org/10.3390/pharmaceutics10010026
Received: 19 January 2018 / Revised: 17 February 2018 / Accepted: 20 February 2018 / Published: 23 February 2018
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Abstract
Miconazole nitrate (MIC) is an antifungal drug used for treatment of superficial fungal infections. However, it has low skin permeability. Hence, the objective of this study was to prepare miconazole nitrate using Transfersomes to overcome the barrier function of the skin. MIC Transfersomes
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Miconazole nitrate (MIC) is an antifungal drug used for treatment of superficial fungal infections. However, it has low skin permeability. Hence, the objective of this study was to prepare miconazole nitrate using Transfersomes to overcome the barrier function of the skin. MIC Transfersomes were prepared using a thin lipid film hydration technique. The prepared Transfersomes were evaluated with respect to entrapment efficiency (EE%), particle size, and quantity of in vitro drug released to obtain an optimized formulation. The optimized formulation of MIC Transfersomes was incorporated into a Carbapol 934 gel base which was evaluated in comparison with a marketed product (Daktarin® cream 2%) for drug content, pH, spreadability, viscosity, in vitro permeation, and in vitro and in vivo antifungal activity. The prepared MIC Transfersomes had a high EE% ranging from (67.98 ± 0.66%) to (91.47 ± 1.85%), with small particle sizes ranging from (63.5 ± 0.604 nm) to (84.5 ± 0.684 nm). The in vitro release study suggested that there was an inverse relationship between EE% and in vitro release. The kinetic analysis of all release profiles was found to follow Higuchi’s diffusion model. All independent variables had a significant effect on the dependent variables (p-values < 0.05). The prepared MIC transfersomal gel showed higher antifungal activity than Daktarin® cream 2%. Therefore, miconazole nitrate in the form of Transfersomes has the ability to penetrate the skin, overcoming the stratum corneum barrier. Full article
(This article belongs to the Special Issue Lipid-Based Dosage Form)
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Open AccessArticle In Vitro Evaluation of Sunscreen Safety: Effects of the Vehicle and Repeated Applications on Skin Permeation from Topical Formulations
Pharmaceutics 2018, 10(1), 27; https://doi.org/10.3390/pharmaceutics10010027
Received: 16 December 2017 / Revised: 16 February 2018 / Accepted: 24 February 2018 / Published: 27 February 2018
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Abstract
The evaluation of UV-filter in vitro percutaneous absorption allows the estimation of the systemic exposure dose (SED) and the margin of safety (MoS) of sunscreen products. As both the vehicle and pattern of application may affect sunscreen safety and efficacy, we evaluated in
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The evaluation of UV-filter in vitro percutaneous absorption allows the estimation of the systemic exposure dose (SED) and the margin of safety (MoS) of sunscreen products. As both the vehicle and pattern of application may affect sunscreen safety and efficacy, we evaluated in vitro release and skin permeation of two widely used UV-filters, octylmethoxycinnamate (OMC) and butylmethoxydibenzoylmethane (BMBM) from topical formulations with different features (oil in water (O/W) emulsions with different viscosity, water in oil (W/O) emulsion, oils with different lipophilicity). To mimic in-use conditions, we carried out experiments repeating sunscreen application on the skin surface for three consecutive days. BMBM release from all these vehicles was very low, thus leading to poor skin permeation. The vehicle composition significantly affected OMC release and skin permeation, and slight increases of OMC permeation were observed after repeated applications. From skin permeation data, SED and MoS values of BMBM and OMC were calculated for all the investigated formulations after a single application and repeated applications. While MoS values of BMBM were always well beyond the accepted safety limit, the safety of sunscreen formulations containing OMC may depend on the vehicle composition and the application pattern. Full article
(This article belongs to the Special Issue Penetration Enhancement of Topical Formulations)
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Open AccessArticle Prediction of Phase Behavior of Spray-Dried Amorphous Solid Dispersions: Assessment of Thermodynamic Models, Standard Screening Methods and a Novel Atomization Screening Device with Regard to Prediction Accuracy
Pharmaceutics 2018, 10(1), 29; https://doi.org/10.3390/pharmaceutics10010029
Received: 11 February 2018 / Revised: 27 February 2018 / Accepted: 2 March 2018 / Published: 7 March 2018
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Abstract
The evaluation of drug–polymer miscibility in the early phase of drug development is essential to ensure successful amorphous solid dispersion (ASD) manufacturing. This work investigates the comparison of thermodynamic models, conventional experimental screening methods (solvent casting, quench cooling), and a novel atomization screening
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The evaluation of drug–polymer miscibility in the early phase of drug development is essential to ensure successful amorphous solid dispersion (ASD) manufacturing. This work investigates the comparison of thermodynamic models, conventional experimental screening methods (solvent casting, quench cooling), and a novel atomization screening device based on their ability to predict drug–polymer miscibility, solid state properties (Tg value and width), and adequate polymer selection during the development of spray-dried amorphous solid dispersions (SDASDs). Binary ASDs of four drugs and seven polymers were produced at 20:80, 40:60, 60:40, and 80:20 (w/w). Samples were systematically analyzed using modulated differential scanning calorimetry (mDSC) and X-ray powder diffraction (XRPD). Principal component analysis (PCA) was used to qualitatively assess the predictability of screening methods with regards to SDASD development. Poor correlation was found between theoretical models and experimentally-obtained results. Additionally, the limited ability of usual screening methods to predict the miscibility of SDASDs did not guarantee the appropriate selection of lead excipient for the manufacturing of robust SDASDs. Contrary to standard approaches, our novel screening device allowed the selection of optimal polymer and drug loading and established insight into the final properties and performance of SDASDs at an early stage, therefore enabling the optimization of the scaled-up late-stage development. Full article
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Open AccessArticle Rational Design, Synthesis and Evaluation of γ-CD-Containing Cross-Linked Polyvinyl Alcohol Hydrogel as a Prednisone Delivery Platform
Pharmaceutics 2018, 10(1), 30; https://doi.org/10.3390/pharmaceutics10010030
Received: 30 January 2018 / Revised: 1 March 2018 / Accepted: 4 March 2018 / Published: 7 March 2018
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Abstract
This study describes the in-silico rational design, synthesis and evaluation of cross-linked polyvinyl alcohol hydrogels containing γ-cyclodextrin (γ-CDHSAs) as platforms for the sustained release of prednisone (PDN). Through in-silico studies using semi-empirical quantum mechanical calculations, the effectiveness of 20 dicarboxylic acids to generate
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This study describes the in-silico rational design, synthesis and evaluation of cross-linked polyvinyl alcohol hydrogels containing γ-cyclodextrin (γ-CDHSAs) as platforms for the sustained release of prednisone (PDN). Through in-silico studies using semi-empirical quantum mechanical calculations, the effectiveness of 20 dicarboxylic acids to generate a specific cross-linked hydrogel capable of supporting different amounts of γ-cyclodextrin (γ-CD) was evaluated. According to the interaction energies calculated with the in-silico studies, the hydrogel made from PVA cross-linked with succinic acids (SA) was shown to be the best candidate for containing γ-CD. Later, molecular dynamics simulation studies were performed in order to evaluate the intermolecular interactions between PDN and three cross-linked hydrogel formulations with different proportions of γ-CD (2.44%, 4.76% and 9.1%). These three cross-linked hydrogels were synthesized and characterized. The loading and the subsequent release of PDN from the hydrogels were investigated. The in-silico and experimental results showed that the interaction between PDN and γ-CDHSA was mainly produced with the γ-CDs linked to the hydrogels. Thus, the unique structures and properties of γ-CDHSA demonstrated an interesting multiphasic profile that could be utilized as a promising drug carrier for controlled, sustained and localized release of PDN. Full article
(This article belongs to the Special Issue Smart Hydrogels for Drug Delivery)
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Open AccessArticle Absolute Oral Bioavailability of Creatine Monohydrate in Rats: Debunking a Myth
Pharmaceutics 2018, 10(1), 31; https://doi.org/10.3390/pharmaceutics10010031
Received: 8 November 2017 / Revised: 13 February 2018 / Accepted: 27 February 2018 / Published: 8 March 2018
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Abstract
Creatine is an ergogenic compound used by athletes to enhance performance. Supplementation with creatine monohydrate (CM) has been suggested for musculoskeletal and neurological disorders. Until now, little is known about its pharmacokinetic profile. Our objective was to determine the oral bioavailability of CM
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Creatine is an ergogenic compound used by athletes to enhance performance. Supplementation with creatine monohydrate (CM) has been suggested for musculoskeletal and neurological disorders. Until now, little is known about its pharmacokinetic profile. Our objective was to determine the oral bioavailability of CM and the influence of dose on oral absorption. Rats were dosed orally with low dose (10 mg/kg) or high dose (70 mg/kg) 13C-labeled CM. Blood samples were removed at various time points. Muscle and brain tissue were collected at the conclusion of the study. Plasma and tissue levels of 13C-labeled creatine were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Physiologically based pharmacokinetic (PBPK) models of CM were built using GastroPlus™. These models were used to predict the plasma concentration–time profiles of creatine hydrochloride (CHCL), which has improved aqueous solubility compared to CM. Absolute oral bioavailability for low dose CM was 53% while high dose CM was only 16%. The simulated Cmax of 70 mg/kg CHCL was around 35 μg/mL compared to 14 μg/mL for CM with a predicted oral bioavailability of 66% with CHCL compared to 17% with CM. Our results suggest that the oral bioavailability of CM is less than complete and subject to dose and that further examination of improved dosage formulations of creatine is warranted. Full article
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Open AccessArticle Citrate- and Succinate-Modified Carbonate Apatite Nanoparticles with Loaded Doxorubicin Exhibit Potent Anticancer Activity against Breast Cancer Cells
Pharmaceutics 2018, 10(1), 32; https://doi.org/10.3390/pharmaceutics10010032
Received: 7 February 2018 / Revised: 19 February 2018 / Accepted: 22 February 2018 / Published: 11 March 2018
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Abstract
Biodegradable inorganic apatite-based particle complex is popular for its pH-sensitivity at the endosomal acidic environment to facilitate drug release following cellular uptake. Despite being a powerful anticancer drug, doxorubicin shows severe off-target effects and therefore would need a carrier for the highest effectiveness.
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Biodegradable inorganic apatite-based particle complex is popular for its pH-sensitivity at the endosomal acidic environment to facilitate drug release following cellular uptake. Despite being a powerful anticancer drug, doxorubicin shows severe off-target effects and therefore would need a carrier for the highest effectiveness. We aimed to chemically modify carbonate apatite (CA) with Krebs cycle intermediates, such as citrate and succinate in order to control the growth of the resultant particles to more efficiently carry and transport the anticancer drug into the cancer cells. Citrate- or succinate-modified CA particles were synthesized with different concentrations of sodium citrate or sodium succinate, respectively, in the absence or presence of doxorubicin. The drug loading efficiency of the particles and their cellular uptake were observed by quantifying fluorescence intensity. The average diameter and surface charge of the particles were determined using Zetasizer. Cell viability was assessed by MTT assay. Citrate-modified carbonate apatite (CMCA) exhibited the highest (31.38%) binding affinity for doxorubicin and promoted rapid cellular uptake of the drug, leading to the half-maximal inhibitory concentration 1000 times less than that of the free drug in MCF-7 cells. Hence, CMCA nanoparticles with greater surface area enhance cytotoxicity in different breast cancer cells by enabling higher loading and more efficient cellular uptake of the drug. Full article
(This article belongs to the Special Issue Nanotechnology Advances in Cancer Treatment)
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Open AccessArticle Hyaluronic Acid Decorated Naringenin Nanoparticles: Appraisal of Chemopreventive and Curative Potential for Lung Cancer
Pharmaceutics 2018, 10(1), 33; https://doi.org/10.3390/pharmaceutics10010033
Received: 5 February 2018 / Revised: 25 February 2018 / Accepted: 5 March 2018 / Published: 12 March 2018
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Abstract
Lung carcinoma is the most common cancer in men and second in women (preceded by breast cancer) worldwide. Around 1 in 10 of all cancers diagnosed in men, lung cancer contributed to a total fraction of 20% cancer deaths. Naringenin (NAR) is well
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Lung carcinoma is the most common cancer in men and second in women (preceded by breast cancer) worldwide. Around 1 in 10 of all cancers diagnosed in men, lung cancer contributed to a total fraction of 20% cancer deaths. Naringenin (NAR) is well known for its chemopreventive properties since ancient times but lacks an appropriate delivery carrier. The objective of present study was to expand the functionality of naringenin loaded poly caprolactone (PCL) nanoparticles in terms of release, chemoprevention and therapeutics. Polymeric nanoparticles such as PCL lack target specificity; hence, surface modification was attempted using layer by layer technique (LBL) to achieve improved and desired delivery as well as target specificity. The designing of Hyaluronic acid (HA) decorated PCL nanoparticles were prepared by utilizing self-assembling LBL technique, where a polycationic layer of a polymer was used as a linker for modification between two polyanionic layers. Additionally, an attempt has been made to strengthen the therapeutic efficacy of PCL nanocarriers by active targeting and overcoming the extracellular matrix associated barriers of tumors using HA targeting cluster determinant 44 receptor (CD44). Cell cytotoxicity study on A549 cells and J774 macrophage cells depicted enhanced anticancer effect of NAR-HA@CH-PCL-NP with safe profile on macrophages. Uptake study on A549 cells advocated enhanced drug uptake by cancer cells. Cell cycle arrest analysis (A549 cell lines) demonstrated the superior cytotoxic effect and active targeting of NAR-HA@CH-PCL-NP. Further chemopreventive treatment with NAR-HA@CH-PCL-NP was found effective in tumor growth inhibitory effect against urethane-induced lung cancer in rat. In conclusion, developed formulation possesses a promising potential as a therapeutic and chemopreventive agent against urethane-induced lung carcinoma in albino wistar rats. Full article
(This article belongs to the Special Issue Nanotechnology Advances in Cancer Treatment)
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Open AccessArticle Orally Disintegrating Tablets Containing Melt Extruded Amorphous Solid Dispersion of Tacrolimus for Dissolution Enhancement
Pharmaceutics 2018, 10(1), 35; https://doi.org/10.3390/pharmaceutics10010035
Received: 9 February 2018 / Revised: 9 March 2018 / Accepted: 10 March 2018 / Published: 16 March 2018
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Abstract
In order to improve the aqueous solubility and dissolution of Tacrolimus (TAC), amorphous solid dispersions of TAC were prepared by hot melt extrusion with three hydrophilic polymers, Polyvinylpyrrolidone vinyl acetate (PVP VA64), Soluplus® and Hydroxypropyl Cellulose (HPC), at a drug loading of
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In order to improve the aqueous solubility and dissolution of Tacrolimus (TAC), amorphous solid dispersions of TAC were prepared by hot melt extrusion with three hydrophilic polymers, Polyvinylpyrrolidone vinyl acetate (PVP VA64), Soluplus® and Hydroxypropyl Cellulose (HPC), at a drug loading of 10% w/w. Molecular modeling was used to determine the miscibility of the drug with the carrier polymers by calculating the Hansen Solubility Parameters. Powder X-ray diffraction and differential scanning calorimetry (DSC) studies of powdered solid dispersions revealed the conversion of crystalline TAC to amorphous form. Fourier transform Infrared (FTIR) spectroscopy results indicated formation of hydrogen bond between TAC and polymers leading to stabilization of TAC in amorphous form. The extrudates were found to be stable under accelerated storage conditions for 3 months with no re-crystallization, indicating that hot melt extrusion is suitable for producing stable amorphous solid dispersions of TAC in PVP VA64, Soluplus® and HPC. Stable solid dispersions of amorphous TAC exhibited higher dissolution rate, with the solid dispersions releasing more than 80% drug in 15 min compared to the crystalline drug giving 5% drug release in two hours. These stable solid dispersions were incorporated into orally-disintegrating tablets in which the solid dispersion retained its solubility, dissolution and stability advantage. Full article
(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)
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Open AccessReview GE11 Peptide as an Active Targeting Agent in Antitumor Therapy: A Minireview
Pharmaceutics 2018, 10(1), 2; https://doi.org/10.3390/pharmaceutics10010002
Received: 29 October 2017 / Revised: 6 December 2017 / Accepted: 11 December 2017 / Published: 22 December 2017
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Abstract
A lot of solid tumors are characterized by uncontrolled signal transduction triggered by receptors related to cellular growth. The targeting of these cell receptors with antitumor drugs is essential to improve chemotherapy efficacy. This can be achieved by conjugation of an active targeting
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A lot of solid tumors are characterized by uncontrolled signal transduction triggered by receptors related to cellular growth. The targeting of these cell receptors with antitumor drugs is essential to improve chemotherapy efficacy. This can be achieved by conjugation of an active targeting agent to the polymer portion of a colloidal drug delivery system loaded with an antitumor drug. The goal of this minireview is to report and discuss some recent results in epidermal growth factor receptor targeting by the GE11 peptide combined with colloidal drug delivery systems as smart carriers for antitumor drugs. The minireview chapters will focus on explaining and discussing: (i) Epidermal growth factor receptor (EGFR) structures and functions; (ii) GE11 structure and biologic activity; (iii) examples of GE11 conjugation and GE11-conjugated drug delivery systems. The rationale is to contribute in gathering information on the topic of active targeting to tumors. A case study is introduced, involving research on tumor cell targeting by the GE11 peptide combined with polymer nanoparticles. Full article
(This article belongs to the Special Issue Nanotechnology Advances in Cancer Treatment)
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Open AccessReview Ophthalmic Drug Delivery Systems for Antibiotherapy—A Review
Pharmaceutics 2018, 10(1), 10; https://doi.org/10.3390/pharmaceutics10010010
Received: 13 November 2017 / Revised: 4 January 2018 / Accepted: 9 January 2018 / Published: 13 January 2018
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Abstract
The last fifty years, ophthalmic drug delivery research has made much progress, challenging scientists about the advantages and limitations of this drug delivery approach. Topical eye drops are the most commonly used formulation in ocular drug delivery. Despite the good tolerance for patients,
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The last fifty years, ophthalmic drug delivery research has made much progress, challenging scientists about the advantages and limitations of this drug delivery approach. Topical eye drops are the most commonly used formulation in ocular drug delivery. Despite the good tolerance for patients, this topical administration is only focus on the anterior ocular diseases and had a high precorneal loss of drugs due to the tears production and ocular barriers. Antibiotics are popularly used in solution or in ointment for the ophthalmic route. However, their local bioavailability needs to be improved in order to decrease the frequency of administrations and the side effects and to increase their therapeutic efficiency. For this purpose, sustained release forms for ophthalmic delivery of antibiotics were developed. This review briefly describes the ocular administration with the ocular barriers and the currently topical forms. It focuses on experimental results to bypass the limitations of ocular antibiotic delivery with new ocular technology as colloidal and in situ gelling systems or with the improvement of existing forms as implants and contact lenses. Nanotechnology is presently a promising drug delivery way to provide protection of antibiotics and improve pathway through ocular barriers and deliver drugs to specific target sites. Full article
(This article belongs to the Special Issue Advanced Ocular Drug Delivery)
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Open AccessReview Application of Nanoparticle Technologies in the Combat against Anti-Microbial Resistance
Pharmaceutics 2018, 10(1), 11; https://doi.org/10.3390/pharmaceutics10010011
Received: 29 November 2017 / Revised: 8 January 2018 / Accepted: 10 January 2018 / Published: 14 January 2018
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Abstract
Anti-microbial resistance is a growing problem that has impacted the world and brought about the beginning of the end for the old generation of antibiotics. Increasingly, more antibiotics are being prescribed unnecessarily and this reckless practice has resulted in increased resistance towards these
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Anti-microbial resistance is a growing problem that has impacted the world and brought about the beginning of the end for the old generation of antibiotics. Increasingly, more antibiotics are being prescribed unnecessarily and this reckless practice has resulted in increased resistance towards these drugs, rendering them useless against infection. Nanotechnology presents a potential answer to anti-microbial resistance, which could stimulate innovation and create a new generation of antibiotic treatments for future medicines. Preserving existing antibiotic activity through novel formulation into or onto nanotechnologies can increase clinical longevity of action against infection. Additionally, the unique physiochemical properties of nanoparticles can provide new anti-bacterial modes of action which can also be explored. Simply concentrating on antibiotic prescribing habits will not resolve the issue but rather mitigate it. Thus, new scientific approaches through the development of novel antibiotics and formulations is required in order to employ a new generation of therapies to combat anti-microbial resistance. Full article
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Open AccessReview A Review on Recent Advances in Stabilizing Peptides/Proteins upon Fabrication in Hydrogels from Biodegradable Polymers
Pharmaceutics 2018, 10(1), 16; https://doi.org/10.3390/pharmaceutics10010016
Received: 26 October 2017 / Revised: 6 January 2018 / Accepted: 16 January 2018 / Published: 18 January 2018
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Abstract
Hydrogels evolved as an outstanding carrier material for local and controlled drug delivery that tend to overcome the shortcomings of old conventional dosage forms for small drugs (NSAIDS) and large peptides and proteins. The aqueous swellable and crosslinked polymeric network structure of hydrogels
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Hydrogels evolved as an outstanding carrier material for local and controlled drug delivery that tend to overcome the shortcomings of old conventional dosage forms for small drugs (NSAIDS) and large peptides and proteins. The aqueous swellable and crosslinked polymeric network structure of hydrogels is composed of various natural, synthetic and semisynthetic biodegradable polymers. Hydrogels have remarkable properties of functionality, reversibility, sterilizability, and biocompatibility. All these dynamic properties of hydrogels have increased the interest in their use as a carrier for peptides and proteins to be released slowly in a sustained manner. Peptide and proteins are remarkable therapeutic agents in today’s world that allow the treatment of severe, chronic and life-threatening diseases, such as diabetes, rheumatoid arthritis, hepatitis. Despite few limitations, hydrogels provide fine tuning of proteins and peptides delivery with enormous impact in clinical medicine. Novels drug delivery systems composed of smart peptides and molecules have the ability to drive self-assembly and form hydrogels at physiological pH. These hydrogels are significantly important for biological and medical fields. The primary objective of this article is to review current issues concerned with the therapeutic peptides and proteins and impact of remarkable properties of hydrogels on these therapeutic agents. Different routes for pharmaceutical peptides and proteins and superiority over other drugs candidates are presented. Recent advances based on various approaches like self-assembly of peptides and small molecules to form novel hydrogels are also discussed. The article will also review the literature concerning the classification of hydrogels on a different basis, polymers used, “release mechanisms” their physical and chemical characteristics and diverse applications. Full article
(This article belongs to the Special Issue Protein Therapeutics)
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Open AccessReview Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs
Pharmaceutics 2018, 10(1), 18; https://doi.org/10.3390/pharmaceutics10010018
Received: 29 November 2017 / Revised: 2 January 2018 / Accepted: 10 January 2018 / Published: 25 January 2018
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Abstract
Cocrystals can be used as an alternative approach based on crystal engineering to enhance specific physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs) when the approaches to salt or polymorph formation do not meet the expected targets. In this article, an overview
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Cocrystals can be used as an alternative approach based on crystal engineering to enhance specific physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs) when the approaches to salt or polymorph formation do not meet the expected targets. In this article, an overview of pharmaceutical cocrystals will be presented, with an emphasis on the intermolecular interactions in cocrystals and the methods for their preparation. Furthermore, cocrystals of direct pharmaceutical interest, along with their in vitro properties and available in vivo data and characterization techniques are discussed, highlighting the potential of cocrystals as an attractive route for drug development. Full article
(This article belongs to the Special Issue Pharmaceutical Crystallisation Science and Engineering)
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Open AccessReview Extended Duration Vascular Endothelial Growth Factor Inhibition in the Eye: Failures, Successes, and Future Possibilities
Pharmaceutics 2018, 10(1), 21; https://doi.org/10.3390/pharmaceutics10010021
Received: 17 December 2017 / Revised: 15 January 2018 / Accepted: 23 January 2018 / Published: 27 January 2018
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Abstract
Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of neovascularization and edema from several common chorioretinal vascular conditions. The intravitreally injected drugs (aflibercept, bevacizumab, conbercept, pegaptanib, and ranibizumab) used to treat these conditions improve the visual acuity and macular
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Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of neovascularization and edema from several common chorioretinal vascular conditions. The intravitreally injected drugs (aflibercept, bevacizumab, conbercept, pegaptanib, and ranibizumab) used to treat these conditions improve the visual acuity and macular morphology in most patients. Monthly or bimonthly injections were administered in the phase III pivotal trials but physicians usually individualize therapy with pro re nata (PRN) or treat and extend regimens. Despite these lower frequency treatment regimens, frequent injections and clinic visits are still needed to produce satisfactory outcomes. Newly developed drugs and refillable reservoirs with favorable pharmacokinetic profiles may extend durations of action and require fewer office visits. However, we have learned from previous experiences that the longer durations of action seen in strategically designed phase III trials often do not translate to less frequent injections in real-life clinical practice. Unfortunately, long-acting therapies that produce soluble VEGF receptors (encapsulated cell technology and adenovirus injected DNA) have failed in phase II trials. The development of longer duration therapies remains a difficult and frustrating process, and frequent drug injections are likely to remain the standard-of-care for years to come. Full article
(This article belongs to the Special Issue Advanced Ocular Drug Delivery)
Open AccessReview Ocular Drug Delivery Barriers—Role of Nanocarriers in the Treatment of Anterior Segment Ocular Diseases
Pharmaceutics 2018, 10(1), 28; https://doi.org/10.3390/pharmaceutics10010028
Received: 22 December 2017 / Revised: 12 February 2018 / Accepted: 23 February 2018 / Published: 27 February 2018
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Abstract
Ocular drug delivery is challenging due to the presence of anatomical and physiological barriers. These barriers can affect drug entry into the eye following multiple routes of administration (e.g., topical, systemic, and injectable). Topical administration in the form of eye drops is preferred
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Ocular drug delivery is challenging due to the presence of anatomical and physiological barriers. These barriers can affect drug entry into the eye following multiple routes of administration (e.g., topical, systemic, and injectable). Topical administration in the form of eye drops is preferred for treating anterior segment diseases, as it is convenient and provides local delivery of drugs. Major concerns with topical delivery include poor drug absorption and low bioavailability. To improve the bioavailability of topically administered drugs, novel drug delivery systems are being investigated. Nanocarrier delivery systems demonstrate enhanced drug permeation and prolonged drug release. This review provides an overview of ocular barriers to anterior segment delivery, along with ways to overcome these barriers using nanocarrier systems. The disposition of nanocarriers following topical administration, their safety, toxicity and clinical trials involving nanocarrier systems are also discussed. Full article
(This article belongs to the Special Issue Advanced Ocular Drug Delivery)
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Open AccessReview Surface-Modified Nanocarriers for Nose-to-Brain Delivery: From Bioadhesion to Targeting
Pharmaceutics 2018, 10(1), 34; https://doi.org/10.3390/pharmaceutics10010034
Received: 8 February 2018 / Revised: 10 March 2018 / Accepted: 12 March 2018 / Published: 15 March 2018
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Abstract
In the field of nasal drug delivery, nose-to-brain delivery is among the most fascinating applications, directly targeting the central nervous system, bypassing the blood brain barrier. Its benefits include dose lowering and direct brain distribution of potent drugs, ultimately reducing systemic side effects.
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In the field of nasal drug delivery, nose-to-brain delivery is among the most fascinating applications, directly targeting the central nervous system, bypassing the blood brain barrier. Its benefits include dose lowering and direct brain distribution of potent drugs, ultimately reducing systemic side effects. Recently, nasal administration of insulin showed promising results in clinical trials for the treatment of Alzheimer’s disease. Nanomedicines could further contribute to making nose-to-brain delivery a reality. While not disregarding the need for devices enabling a formulation deposition in the nose’s upper part, surface modification of nanomedicines appears the key strategy to optimize drug delivery from the nasal cavity to the brain. In this review, nanomedicine delivery based on particle engineering exploiting surface electrostatic charges, mucoadhesive polymers, or chemical moieties targeting the nasal epithelium will be discussed and critically evaluated in relation to nose-to-brain delivery. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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Open AccessReview Evidence of Drug–Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update
Pharmaceutics 2018, 10(1), 36; https://doi.org/10.3390/pharmaceutics10010036
Received: 13 February 2018 / Revised: 13 March 2018 / Accepted: 16 March 2018 / Published: 20 March 2018
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Abstract
The long-term use of prescription and over-the-counter drugs can induce subclinical and clinically relevant micronutrient deficiencies, which may develop gradually over months or even years. Given the large number of medications currently available, the number of research studies examining potential drug–nutrient interactions is
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The long-term use of prescription and over-the-counter drugs can induce subclinical and clinically relevant micronutrient deficiencies, which may develop gradually over months or even years. Given the large number of medications currently available, the number of research studies examining potential drug–nutrient interactions is quite limited. A comprehensive, updated review of the potential drug–nutrient interactions with chronic use of the most often prescribed medications for commonly diagnosed conditions among the general U.S. adult population is presented. For the majority of the interactions described in this paper, more high-quality intervention trials are needed to better understand their clinical importance and potential consequences. A number of these studies have identified potential risk factors that may make certain populations more susceptible, but guidelines on how to best manage and/or prevent drug-induced nutrient inadequacies are lacking. Although widespread supplementation is not currently recommended, it is important to ensure at-risk patients reach their recommended intakes for vitamins and minerals. In conjunction with an overall healthy diet, appropriate dietary supplementation may be a practical and efficacious way to maintain or improve micronutrient status in patients at risk of deficiencies, such as those taking medications known to compromise nutritional status. The summary evidence presented in this review will help inform future research efforts and, ultimately, guide recommendations for patient care. Full article
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