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Pharmaceutics, Volume 10, Issue 4 (December 2018)

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Cover Story (view full-size image) The oral administration of clofazimine (CFZ), a WHO-recommended treatment for leprosy and [...] Read more.
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Open AccessArticle Choline-Amino Acid Ionic Liquids as Green Functional Excipients to Enhance Drug Solubility
Pharmaceutics 2018, 10(4), 288; https://doi.org/10.3390/pharmaceutics10040288
Received: 14 November 2018 / Revised: 12 December 2018 / Accepted: 15 December 2018 / Published: 19 December 2018
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Abstract
The development of effective forms to incorporate poorly soluble drugs into delivery systems remains a problem. Thus, it is important to find alternatives such as finding excipients that increase drug solubility. Ionic liquids (ILs), particularly choline-based ILs, have been studied as solubility enhancers
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The development of effective forms to incorporate poorly soluble drugs into delivery systems remains a problem. Thus, it is important to find alternatives such as finding excipients that increase drug solubility. Ionic liquids (ILs), particularly choline-based ILs, have been studied as solubility enhancers in drug delivery systems. Nonetheless, to acknowledge this property as a functionality, it needs to be proven at non-toxic concentrations. Hence, herein two choline-amino acid ILs were studied as functional excipients by evaluating their influence on the solubility of the poorly water-soluble ferulic acid and rutin, while considering their safety. The solubility of the drugs was always higher in the presence of the ILs than in water. Ionic liquids did not affect the radical scavenging activity of the drugs or the cell viability. Moreover, stable oil-in-water (O/W) emulsions were prepared containing each drug and the ILs, allowing a significantly higher drug loading. Globally, our results suggest that choline-based ILs may act as green functional excipients, since at non-toxic concentrations they considerably improve drug solubility/loading, without influencing the antioxidant activity of the drugs, the cell viability, or the stability of the formulations. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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Open AccessArticle Combined Approach of Cyclodextrin Complexationand Nanostructured Lipid Carriers for the Development of a Pediatric Liquid Oral Dosage Form of Hydrochlorothiazide
Pharmaceutics 2018, 10(4), 287; https://doi.org/10.3390/pharmaceutics10040287
Received: 26 November 2018 / Accepted: 17 December 2018 / Published: 19 December 2018
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Abstract
The development of specific and age-appropriate pediatric formulations is essential to assure that all children and their care-givers can easily access to safe and effective dosage forms. The need for developing specific pediatric medicinal products has been highlighted by the European Medicines Agency.
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The development of specific and age-appropriate pediatric formulations is essential to assure that all children and their care-givers can easily access to safe and effective dosage forms. The need for developing specific pediatric medicinal products has been highlighted by the European Medicines Agency. The aim of this study was to investigate the effectiveness of combining the advantages of both cyclodextrin (CD) complexation and loading into nanostructured lipid carriers (NLC), to obtain a liquid oral pediatric formulation of hydrochlorothiazide (HCT), endowed with safety, dosage accuracy, good stability and therapeutic efficacy. Equimolar drug combinations as physical mixture (P.M.) or coground product (GR) with hydroxypropyl-β-cyclodextrin (HPβCD) or sulfobutylether-β-cyclodextrin (SBEβCD) were loaded into NLC, then characterized for particle size, homogeneity, Zeta potential, entrapment efficiency, gastric and storage stability. The presence of HPβCD allowed higher entrapment efficacy than NLC loaded with the plain drug, and enabled, in the case of GR systems a complete and sustained drug release, attributable to the wetting and solubilising properties of HPβCD toward HCT. In vivo studies on rats proved the superior therapeutic effectiveness of HCT-in HPβCD-in NLC formulations compared to the corresponding free HCT-loaded NLC, thus confirming the successfulness of the proposed approach in the development of an efficacious liquid oral formulation of the drug. Full article
(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)
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Open AccessArticle Autologous Red Blood Cell Delivery of Betamethasone Phosphate Sodium for Long Anti-Inflammation
Pharmaceutics 2018, 10(4), 286; https://doi.org/10.3390/pharmaceutics10040286
Received: 24 November 2018 / Revised: 14 December 2018 / Accepted: 15 December 2018 / Published: 18 December 2018
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Abstract
Although glucocorticoids are highly effective in treating various types of inflammation such as skin disease, rheumatic disease, and allergic disease, their application have been seriously limited for their high incidence of side effects, particularly in long term treatment. To improve efficacy and reduce
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Although glucocorticoids are highly effective in treating various types of inflammation such as skin disease, rheumatic disease, and allergic disease, their application have been seriously limited for their high incidence of side effects, particularly in long term treatment. To improve efficacy and reduce side effects, we encapsulated betamethasone phosphate (BSP) into biocompatible red blood cells (RBCs) and explored its long acting-effect. BSP was loaded into rat autologous erythrocytes by hypotonic preswelling method, and the loading amount was about 2.5 mg/mL cells. In vitro, BSP loaded RBCs (BSP-RBCs) presented similar morphology, osmotic fragility to native RBCs (NRBCs). After the loading process, the loaded cells can maintain around 70% of Na+/K+-ATPase activity of natural cells. In vivo, a series of tests including survival, pharmacokinetics, and anti-inflammatory effect were carried out to examine the long-acting effect of BSP-RBCs. The results shown that the loaded cells could circulate in plasma for over nine days, the release of BSP can last for over seven days and the anti-inflammatory effect can still be observed on day 5 after injection. Totally, BSP-loaded autologous erythrocytes seem to be a promising sustained releasing delivery system with long anti-inflammatory effect. Full article
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Open AccessArticle Enhanced Dissolution and Oral Bioavailability of Cyclosporine A: Microspheres Based on αβ-Cyclodextrins Polymers
Pharmaceutics 2018, 10(4), 285; https://doi.org/10.3390/pharmaceutics10040285
Received: 16 November 2018 / Revised: 14 December 2018 / Accepted: 16 December 2018 / Published: 18 December 2018
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Abstract
Cyclosporine (CsA) has a selective property of suppressing various T-lymphocyte functions. This is of utmost importance in preventing allograft rejection by several organ transplantations, as well as in the treatment of systemic and local autoimmune disorders. However, the poor water solubility of CsA
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Cyclosporine (CsA) has a selective property of suppressing various T-lymphocyte functions. This is of utmost importance in preventing allograft rejection by several organ transplantations, as well as in the treatment of systemic and local autoimmune disorders. However, the poor water solubility of CsA can be a major hurdle for its absorption into the blood stream, which leads to low bioavailability and thus less efficacy. The aim of this study was to prepare, characterize, and evaluate in vitro as well as in vivo, the potential of the innovative CsA drug delivery system. The latter contains CsA in spherical amorphous solid dispersion (SASD) which is embedded in an original α-cyclodextrin and β-cyclodextrin polymer mixture (Poly-αβ-CD) as a multifunctional amorphous carrier. The new developed SASD formulation showed that CsA was molecularly dispersed in αβ-cyclodextrins in an amorphous form, as was confirmed by physicochemical characterization studies. Interestingly, the peptide secondary structure, and thus, the drug activity was not impacted by the preparation of SASD as was shown by circular dichroism. Furthermore, the in vitro CsA release profile kinetics was almost identical to the commercially available product Neoral®. This study presents the first in vivo proof-of-concept for a novel drug delivery system based on Poly-αβ-CD containing CsA, with SASD allowing for increased bioavailibility. The pharmacokinetic parameters of cyclosporine A from the spherical spray-dried dispersion formulation was demonstrated in a “rat” animal model. For comparison, the commercially available Neoral® was studied. Importantly, the pharmacokinetic parameters were improved by extending Tmax from 2 to 3 h after the oral administration in rats, and eventually preventing the enterohepatic circulation. All these results clearly demonstrate the improved pharmacokinetic parameters and enhanced bioavailability of CsA in the new developed drug delivery system. These data demonstrated the superiority of the newly developed Poly-αβ-CD formulation for oral administration of the poorly soluble CsA in vivo without altering its secondary structure. Poly-αβ-CD can be a very useful tool for the oral administration of poorly water-soluble drugs. Full article
(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)
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Open AccessArticle HSA—Coated Magnetic Nanoparticles for MRI-Guided Photodynamic Cancer Therapy
Pharmaceutics 2018, 10(4), 284; https://doi.org/10.3390/pharmaceutics10040284
Received: 5 November 2018 / Revised: 13 December 2018 / Accepted: 13 December 2018 / Published: 17 December 2018
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Abstract
Background: Photodynamic therapy (PDT) is a promising technique for cancer treatment; however, low tissue permeability for irradiating light and insufficient photosensitizer (PS) accumulation in tumors limit its clinical potential. Nanoparticles are engineered to improve selective drug delivery to tumor sites, but its accumulation
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Background: Photodynamic therapy (PDT) is a promising technique for cancer treatment; however, low tissue permeability for irradiating light and insufficient photosensitizer (PS) accumulation in tumors limit its clinical potential. Nanoparticles are engineered to improve selective drug delivery to tumor sites, but its accumulation is highly variable between tumors and patients. Identifying PS accumulation peak in a personalized manner is crucial for therapeutic outcome. Magnetic nanoparticles (MNPs) provide opportunity for tracking drug accumulation in dynamics using non-invasive magnetic resonance imaging (MRI). The purpose of the study was to evaluate MNP loaded with PS as a theranostic tool for treating cancer in mice xenograft colon cancer models. Methods: MNPs coated with human serum albumin (HSA) were loaded with bacteriochlorine a. MRI, atomic emission spectroscopy (AES) and fluorescent imaging were used to study MNP and drug accumulation rates and dynamics in CT26 tumors. Tumor growth curves were evaluated in animals that received PDT at different time points upon MNP systemic injection. Results: Peak MNP accumulation in tumors was detected by MRI 60 min post injection (pi) and the data were verified by AES and fluorescent imaging. Up to 17% of injected dose/g of tissue was delivered to malignant tissues 24 h after injection. Consistent with MRI predicted drug accumulation peak PDT performed 60 min after intravenous injection was more efficient in inhibiting tumor growth than treatment scheduled 30 min and 240 min pi. Conclusions: PS loading on HAS-coated MNPs is a perspective approach to increase drug delivery to tumor site. Tracking for MNP accumulation by MRI can be used to predict drug concentration peak in tumors and to adjust PDT time scheduling for improved antitumor response. Full article
(This article belongs to the Special Issue Nanotheranostics and Cancer: Where Are We Now?)
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Open AccessArticle Enhanced Solubility, Permeability and Anticancer Activity of Vorinostat Using Tailored Mesoporous Silica Nanoparticles
Pharmaceutics 2018, 10(4), 283; https://doi.org/10.3390/pharmaceutics10040283
Received: 16 November 2018 / Revised: 7 December 2018 / Accepted: 10 December 2018 / Published: 17 December 2018
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Abstract
Suberoylanilide hydroxamic acid (SAHA) or vorinostat (VOR) is a potent inhibitor of class I histone deacetylases (HDACs) that is approved for the treatment of cutaneous T-cell lymphoma. However, it has the intrinsic limitations of low water solubility and low permeability which reduces its
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Suberoylanilide hydroxamic acid (SAHA) or vorinostat (VOR) is a potent inhibitor of class I histone deacetylases (HDACs) that is approved for the treatment of cutaneous T-cell lymphoma. However, it has the intrinsic limitations of low water solubility and low permeability which reduces its clinical potential especially when given orally. Packaging of drugs within ordered mesoporous silica nanoparticles (MSNs) is an emerging strategy for increasing drug solubility and permeability of BCS (Biopharmaceutical Classification System) class II and IV drugs. In this study, we encapsulated vorinostat within MSNs modified with different functional groups, and assessed its solubility, permeability and anti-cancer efficacy in vitro. Compared to free drug, the solubility of vorinostat was enhanced 2.6-fold upon encapsulation in pristine MSNs (MCM-41-VOR). Solubility was further enhanced when MSNs were modified with silanes having amino (3.9 fold) or phosphonate (4.3 fold) terminal functional groups. Moreover, permeability of vorinostat into Caco-2 human colon cancer cells was significantly enhanced for MSN-based formulations, particularly MSNs modified with amino functional group (MCM-41-NH2-VOR) where it was enhanced ~4 fold. Compared to free drug, vorinostat encapsulated within amino-modified MSNs robustly induced histone hyperacetylation and expression of established histone deacetylase inhibitor (HDACi)-target genes, and induced extensive apoptosis in HCT116 colon cancer cells. Similar effects were observed on apoptosis induction in HH cutaneous T-cell lymphoma cells. Thus, encapsulation of the BCS class IV molecule vorinostat within MSNs represents an effective strategy for improving its solubility, permeability and anti-tumour activity. Full article
(This article belongs to the Special Issue Porous Inorganic Drug Delivery Systems)
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Open AccessReview A Systematic Review and Critical Analysis of the Role of Graphene-Based Nanomaterials in Cancer Theranostics
Pharmaceutics 2018, 10(4), 282; https://doi.org/10.3390/pharmaceutics10040282
Received: 19 November 2018 / Revised: 8 December 2018 / Accepted: 13 December 2018 / Published: 16 December 2018
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Abstract
Many graphene-based materials (GBNs) applied to therapy and diagnostics (theranostics) in cancer have been developed. Most of them are hybrid combinations of graphene with other components (e.g., drugs or other bioactives, polymers, and nanoparticles) aiming toward a synergic theranostic effect. However, the role
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Many graphene-based materials (GBNs) applied to therapy and diagnostics (theranostics) in cancer have been developed. Most of them are hybrid combinations of graphene with other components (e.g., drugs or other bioactives, polymers, and nanoparticles) aiming toward a synergic theranostic effect. However, the role of graphene in each of these hybrids is sometimes not clear enough and the synergic graphene effect is not proven. The objective of this review is to elaborate on the role of GBNs in the studies evaluated and to compare the nanoformulations in terms of some of their characteristics, such as therapeutic outcomes and toxicity, which are essential features for their potential use as bionanosystems. A systematic review was carried out using the following databases: PubMed, Scopus, and ISI Web of Science (2013–2018). Additional studies were identified manually by consulting the references list of relevant reviews. Only English papers presenting at least one strategy for cancer therapy and one strategy for cancer diagnostics, and that clearly show the role of graphene in theranostics, were included. Data extraction and quality assessment was made by reviewer pairings. Fifty-five studies met the inclusion criteria, but they were too heterogeneous to combine in statistical meta-analysis. Critical analysis and discussion of the selected papers are presented. Full article
(This article belongs to the Special Issue Nanotheranostics and Cancer: Where Are We Now?)
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Open AccessArticle Brain Distribution and Metabolism of Flupirtine, a Nonopioid Analgesic Drug with Antiseizure Effects, in Neonatal Rats
Pharmaceutics 2018, 10(4), 281; https://doi.org/10.3390/pharmaceutics10040281
Received: 11 October 2018 / Revised: 13 December 2018 / Accepted: 14 December 2018 / Published: 16 December 2018
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Abstract
Flupirtine, a nonopioid analgesic drug, is effective in treating neonatal seizures. However, its brain delivery and pharmacokinetics are unknown in neonatal mammals. The purpose of this study was to determine the pharmacokinetics of flupirtine and the formation of its active metabolite D-13223 in
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Flupirtine, a nonopioid analgesic drug, is effective in treating neonatal seizures. However, its brain delivery and pharmacokinetics are unknown in neonatal mammals. The purpose of this study was to determine the pharmacokinetics of flupirtine and the formation of its active metabolite D-13223 in various tissues such as brain in neonate animals. On postnatal day 7, rat pups received 25 mg/kg of flupirtine intraperitoneally. Liver; heart; kidney; lung; spleen; retina; serum; and brain regions hippocampus, cortex, and the remaining brain (devoid of cerebellum) were harvested up to 24-h postdosing. An LC-MS/MS assay was developed to quantify flupirtine and D-13223. Flupirtine was delivered to all tissues assessed, with the highest area under the concentration vs. time curve (AUC0–24h) in liver (488 µg·h/g tissue) and the lowest in spleen (82 µg·h/g tissue). Flupirtine reached the brain, including the hippocampus and cortex, within 1 h of dosing and persisted at 24 h. Flupirtine AUC in various brain regions was approximately 195 µg·h/g tissue. The half-life of flupirtine in various tissues ranged from 3.1 to 5.2 h. D-13223 was formed in vivo and detected in all tissues assessed, with the concentrations being the highest in the liver. Incubation of isolated neonatal rat liver, heart, kidney, lung, spleen, whole eye, serum, or whole brain with flupirtine for 3 h at 37 °C formed D-13223 in all tissues, except serum. D-13223 formation was the highest in isolated liver tissue. Tissue partition coefficients based on isolated tissue uptake correlated well with in vivo tissue:serum drug exposure ratios. Thus, flupirtine reaches the target brain tissues from the systemic route in neonatal rats, and brain tissue forms the active metabolite D-13223. Full article
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Open AccessArticle Potentially Inappropriate Prescribing of Oral Solid Medications in Elderly Dysphagic Patients
Pharmaceutics 2018, 10(4), 280; https://doi.org/10.3390/pharmaceutics10040280
Received: 10 November 2018 / Accepted: 10 December 2018 / Published: 16 December 2018
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Abstract
Pharmaceutical formulations suitable for dysphagic patients are not always commercially available, motivating caregivers to crush tablets or open capsules to facilitate swallowing. Since this action may modify the characteristics of the medicine, it should be considered potentially inappropriate. This paper is the first
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Pharmaceutical formulations suitable for dysphagic patients are not always commercially available, motivating caregivers to crush tablets or open capsules to facilitate swallowing. Since this action may modify the characteristics of the medicine, it should be considered potentially inappropriate. This paper is the first to focus on how hospitalization affected the rate of potentially inappropriate prescriptions (PIPs) and the incidence of dosage form-related PIPs in elderly patients with dysphagia. Data was collected by reviewing patient medical records in the Italian National Research Center on Aging of Ancona. The therapy at admission and discharge was analysed in terms of: inappropriate drug associations, inappropriate drugs for dysphagic patients, inappropriate dosage forms and inappropriate dosage form modifications. Forty-one dysphagic patients with an average age of 88.3 years were included in the study and 451 prescriptions were analysed. PIPs were widespread at admission, and hospitalization did not improve the situation in a statistically significant manner. The most common PIPs identified (>80%) were related to dosage form selection and modification. This study highlights a clear need for continuing medical education about prescription appropriateness and modification of solid dosage forms in patients with dysphagia. Full article
(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)
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Open AccessFeature PaperReview Mesoporous Silica Materials as Drug Delivery: “The Nightmare” of Bacterial Infection
Pharmaceutics 2018, 10(4), 279; https://doi.org/10.3390/pharmaceutics10040279
Received: 2 October 2018 / Revised: 7 December 2018 / Accepted: 7 December 2018 / Published: 15 December 2018
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Abstract
Mesoporous silica materials (MSM) have a great surface area and a high pore volume, meaning that they consequently have a large loading capacity, and have been demonstrated to be unique candidates for the treatment of different pathologies, including bacterial infection. In this text,
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Mesoporous silica materials (MSM) have a great surface area and a high pore volume, meaning that they consequently have a large loading capacity, and have been demonstrated to be unique candidates for the treatment of different pathologies, including bacterial infection. In this text, we review the multiple ways of action in which MSM can be used to fight bacterial infection, including early detection, drug release, targeting bacteria or biofilm, antifouling surfaces, and adjuvant capacity. This review focus mainly on those that act as a drug delivery system, and therefore that have an essential characteristic, which is their great loading capacity. Since MSM have advantages in all stages of combatting bacterial infection; its prevention, detection and finally in its treatment, we can venture to talk about them as the “nightmare of bacteria”. Full article
(This article belongs to the Special Issue Porous Inorganic Drug Delivery Systems)
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Open AccessReview In Vitro Immune Organs-on-Chip for Drug Development: A Review
Pharmaceutics 2018, 10(4), 278; https://doi.org/10.3390/pharmaceutics10040278
Received: 13 October 2018 / Revised: 12 November 2018 / Accepted: 21 November 2018 / Published: 15 December 2018
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Abstract
The current drug development practice lacks reliable and sensitive techniques to evaluate the immunotoxicity of drug candidates, i.e., their effect on the human immune system. This, in part, has resulted in a high attrition rate for novel drugs candidates. Organ-on-chip devices have emerged
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The current drug development practice lacks reliable and sensitive techniques to evaluate the immunotoxicity of drug candidates, i.e., their effect on the human immune system. This, in part, has resulted in a high attrition rate for novel drugs candidates. Organ-on-chip devices have emerged as key tools that permit the study of human physiology in controlled in vivo simulating environments. Furthermore, there has been a growing interest in developing the so called “body-on-chip” devices to better predict the systemic effects of drug candidates. This review describes existing biomimetic immune organs-on-chip, highlights their physiological relevance to drug development and discovery and emphasizes the need for developing comprehensive immune system-on-chip models. Such immune models can enhance the performance of novel drug candidates during clinical trials and contribute to reducing the high attrition rate as well as the high cost associated with drug development. Full article
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Open AccessReview Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles
Pharmaceutics 2018, 10(4), 277; https://doi.org/10.3390/pharmaceutics10040277
Received: 10 November 2018 / Revised: 29 November 2018 / Accepted: 13 December 2018 / Published: 14 December 2018
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Abstract
Preclinical and clinical studies suggest that many food molecules could interact with drug transporters and metabolizing enzymes through different mechanisms, which are predictive of what would be observed clinically. Given the recent incorporation of dietary modifications or supplements in traditional medicine, an increase
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Preclinical and clinical studies suggest that many food molecules could interact with drug transporters and metabolizing enzymes through different mechanisms, which are predictive of what would be observed clinically. Given the recent incorporation of dietary modifications or supplements in traditional medicine, an increase in potential food-drug interactions has also appeared. The objective of this article is to review data regarding the influence of food on drug efficacy. Data from Google Scholar, PubMed, and Scopus databases was reviewed for publications on pharmaceutical, pharmacokinetic, and pharmacodynamic mechanisms. The following online resources were used to integrate functional and bioinformatic results: FooDB, Phenol-Explorer, Dr. Duke's Phytochemical and Ethnobotanical Databases, DrugBank, UniProt, and IUPHAR/BPS Guide to Pharmacology. A wide range of food compounds were shown to interact with proteins involved in drug pharmacokinetic/pharmacodynamic profiles, starting from drug oral bioavailability to enteric/hepatic transport and metabolism, blood transport, and systemic transport/metabolism. Knowledge of any food components that may interfere with drug efficacy is essential, and would provide a link for obtaining a holistic view for cancer, cardiovascular, musculoskeletal, or neurological therapies. However, preclinical interaction may be irrelevant to clinical interaction, and health professionals should be aware of the limitations if they intend to optimize the therapeutic effects of drugs. Full article
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Open AccessArticle Polyurethanes as New Excipients in Nail Therapeutics
Pharmaceutics 2018, 10(4), 276; https://doi.org/10.3390/pharmaceutics10040276
Received: 25 November 2018 / Revised: 9 December 2018 / Accepted: 11 December 2018 / Published: 13 December 2018
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Abstract
Onychomycosis affects about 15% of the population. This disease causes physical and psychosocial discomfort to infected patients. Topical treatment (creams, solutions, gels, colloidal carriers, and nail lacquers) is usually the most commonly required due to the high toxicity of oral drugs. Currently, the
[...] Read more.
Onychomycosis affects about 15% of the population. This disease causes physical and psychosocial discomfort to infected patients. Topical treatment (creams, solutions, gels, colloidal carriers, and nail lacquers) is usually the most commonly required due to the high toxicity of oral drugs. Currently, the most common topical formulations (creams and lotions) present a low drug delivery to the nail infection. Nail lacquers appear to increase drug delivery and simultaneously improve the effectiveness of treatment with increased patient compliance. These formulations leave a polymer film on the nail plate after solvent evaporation. The duration of the film residence in the nail constitutes an important property of nail lacquer formulation. In this study, a polyurethane polymer was used to delivery antifungals drugs, such as terbinafine hydrochloride (TH) and ciclopirox olamine (CPX) and the influence of its concentration on the properties of nail lacquer formulations was assessed. The nail lacquer containing the lowest polymer concentration (10%) was the most effective regarding the in vitro release, permeation, and antifungal activity. It has also been demonstrated that the application of PU-based nail lacquer improves the nail plate, making it smooth and uniform and reduces the porosity contributing to the greater effectiveness of these vehicles. To conclude, the use of polyurethane in nail formulations is promising for nail therapeutics. Full article
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Open AccessArticle Optimization of Quality Attributes and Atomic Force Microscopy Imaging of Reconstituted Nanodroplets in Baicalin Loaded Self-Nanoemulsifying Formulations
Pharmaceutics 2018, 10(4), 275; https://doi.org/10.3390/pharmaceutics10040275
Received: 6 November 2018 / Revised: 7 December 2018 / Accepted: 10 December 2018 / Published: 13 December 2018
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Abstract
The objective of the study was to develop baicalin loaded liquid self-nanoemulsifying drug delivery systems (BSNEDDS) and to characterize them by physicochemical methods in order to optimize the composition and quality attributes. Atomic force microscopy (AFM) was utilized to evaluate the morphological characteristics
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The objective of the study was to develop baicalin loaded liquid self-nanoemulsifying drug delivery systems (BSNEDDS) and to characterize them by physicochemical methods in order to optimize the composition and quality attributes. Atomic force microscopy (AFM) was utilized to evaluate the morphological characteristics and size distribution of reconstituted nanoemulsion droplets with a new sample preparation method for the elucidation of individual nanodroplets without any signs of coalescence. Response surface methodology and desirability approach was used to select the optimized composition related to droplet size, zeta-potential, polydispersity index (PDI), and turbidity characteristics. Droplet size distribution measured by dynamic light scattering method was highly desirable with 52.87 ± 0.5322 nm, which was confirmed by AFM imaging. The optimized formula contains Peceol® (14.29%, w/w), Kolliphor® EL (57.14%, w/w), and Transcutol® P (28.57%, w/w). Long-term stability analysis did not show any significant change in droplet size or PDI over the investigated period. More than 40.5-times solubility improvement was achieved with the optimized BSNEDDS correlated to solubility of baicalin in distilled water. In vitro dissolution studies at pH 1.2 and pH 6.8 were performed and revealed that the optimized BSNEDDS formula showed pH independent drug dissolution, and 100% of incorporated baicalin dissolved within five minutes in rapidly dispersing nanodroplets. Full article
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Open AccessArticle SPC Liposomes as Possible Delivery Systems for Improving Bioavailability of the Natural Sesquiterpene β-Caryophyllene: Lamellarity and Drug-Loading as Key Features for a Rational Drug Delivery Design
Pharmaceutics 2018, 10(4), 274; https://doi.org/10.3390/pharmaceutics10040274
Received: 27 November 2018 / Revised: 7 December 2018 / Accepted: 11 December 2018 / Published: 13 December 2018
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Abstract
The natural sesquiterpene β-caryophyllene (CRY) has been highlighted to possess interesting pharmacological potentials, particularly due to its chemopreventive and analgesic properties. However, the poor solubility of this sesquiterpene in aqueous fluids can hinder its uptake into cells, resulting in inconstant responses of biological
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The natural sesquiterpene β-caryophyllene (CRY) has been highlighted to possess interesting pharmacological potentials, particularly due to its chemopreventive and analgesic properties. However, the poor solubility of this sesquiterpene in aqueous fluids can hinder its uptake into cells, resulting in inconstant responses of biological systems, thus limiting its application. Therefore, identifying a suitable pharmaceutical form for increasing CRY bioavailability represents an important requirement for exploiting its pharmacological potential. In the present study, the ability of soybean phosphatidylcholine (SPC) liposomes to improve bioavailability and absorption of CRY in cancer cells has been evaluated. Liposomal formulations of CRY, differing for lamellarity (i.e., unilamellar and multilamellar vesicles or ULV and MLV) and for the drug loading (i.e., 1:0.1, 1:0.3 and 1:0.5 mol/mol between SPC and CRY) were designed with the aim of maximizing CRY amount in the liposome bilayer, while avoiding its leakage during storage. The low-loaded formulations significantly potentiated the antiproliferative activity of CRY in both HepG2 and MDA-MB-468 cells, reaching a maximum IC50 lowering (from two to five folds) with 1:0.3 and 1:0.1 SPC/CRY MLV. Conversely, increasing liposome drug-loading reduced the ability for CRY release, likely due to a possible interaction between SPC and CRY that affects the membrane properties, as confirmed by physical measures. Full article
(This article belongs to the Special Issue Smart Nanovesicles for Drug Targeting and Delivery)
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Open AccessArticle Effect of Penetration Enhancers on Drug Nail Permeability from Cyclodextrin/Poloxamer-Soluble Polypseudorotaxane-Based Nail Lacquers
Pharmaceutics 2018, 10(4), 273; https://doi.org/10.3390/pharmaceutics10040273
Received: 18 November 2018 / Revised: 6 December 2018 / Accepted: 11 December 2018 / Published: 13 December 2018
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Abstract
Nail delivery has interest for local treatment of nail diseases. Nevertheless, the low permeability of drugs in the nail plaque precludes the efficacy of local treatments. The use of penetration enhancers can increase drug permeability and improve the efficacy of the treatment of
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Nail delivery has interest for local treatment of nail diseases. Nevertheless, the low permeability of drugs in the nail plaque precludes the efficacy of local treatments. The use of penetration enhancers can increase drug permeability and improve the efficacy of the treatment of nail pathologies. In this work, different chemical substances have been evaluated as potential penetration enhancers. With this aim, the effect of different substances such as sodium lauryl sulfate (SLS), polyethylene glycol 300 (PEG 300), carbocysteine, N-acetylcysteine, lactic acid, potassium phosphate, Labrasol® and Labrafil® in the microstructure, nail surface and drug permeability has been evaluated. The models obtained by mercury intrusion porosimetry and PoreXpert™ software show a more porous structure in nails treated with different enhancers. Permeation studies with bovine hooves and nails revealed that all the hydroalcoholic lacquers developed, and particularly those prepared with SLS, provide better nail penetration of the drugs ciclopirox olamine and clobetasol propionate. Results have shown that the increase of the drug penetration in the nail is caused by the formation of a porous random microstructure and by the decrease of the contact angle between lacquers and the surface or the nail plaque. The presence of SLS produces an improvement in the spreading of the solution on the nail surface and promotes the penetration of the solution into the nail pores. The hydroalcoholic lacquer, elaborated with cyclodextrin/poloxamer soluble polypseudorotaxane and sodium lauryl sulfate as an enhancer, allowed the rate of diffusion and penetration of the active ingredient within the nail to be significantly higher than obtained with the reference lacquers when using either ciclopirox olamine or clobetasol propionate as the active ingredient. Full article
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Open AccessReview Drug-Loaded Biomimetic Ceramics for Tissue Engineering
Pharmaceutics 2018, 10(4), 272; https://doi.org/10.3390/pharmaceutics10040272
Received: 22 November 2018 / Revised: 9 December 2018 / Accepted: 11 December 2018 / Published: 13 December 2018
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Abstract
The mimesis of biological systems has been demonstrated to be an adequate approach to obtain tissue engineering scaffolds able to promote cell attachment, proliferation, and differentiation abilities similar to those of autologous tissues. Bioceramics are commonly used for this purpose due to their
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The mimesis of biological systems has been demonstrated to be an adequate approach to obtain tissue engineering scaffolds able to promote cell attachment, proliferation, and differentiation abilities similar to those of autologous tissues. Bioceramics are commonly used for this purpose due to their similarities to the mineral component of hard tissues as bone. Furthermore, biomimetic scaffolds are frequently loaded with diverse therapeutic molecules to enhance their biological performance, leading to final products with advanced functionalities. In this review, we aim to describe the already developed bioceramic-based biomimetic systems for drug loading and local controlled release. We will discuss the mechanisms used for the inclusion of therapeutic molecules on the designed systems, paying special attention to the identification of critical parameters that modulate drug loading and release kinetics on these scaffolds. Full article
(This article belongs to the Special Issue Porous Inorganic Drug Delivery Systems)
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Open AccessReview Cyclodextrin-Based Metal-Organic Frameworks (CD-MOFs) in Pharmaceutics and Biomedicine
Pharmaceutics 2018, 10(4), 271; https://doi.org/10.3390/pharmaceutics10040271
Received: 9 November 2018 / Revised: 3 December 2018 / Accepted: 7 December 2018 / Published: 12 December 2018
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Abstract
Metal-organic frameworks (MOFs) show promising application in biomedicine and pharmaceutics owing to their extraordinarily high surface area, tunable pore size, and adjustable internal surface properties. However, MOFs are prepared from non-renewable or toxic materials, which limit their real-world applications. Cyclodextrins (CDs) are a
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Metal-organic frameworks (MOFs) show promising application in biomedicine and pharmaceutics owing to their extraordinarily high surface area, tunable pore size, and adjustable internal surface properties. However, MOFs are prepared from non-renewable or toxic materials, which limit their real-world applications. Cyclodextrins (CDs) are a typical natural and biodegradable cyclic oligosaccharide and are primarily used to enhance the aqueous solubility, safety, and bioavailability of drugs by virtue of its low toxicity and highly flexible structure, offering a peculiar ability to form CD/drug inclusions. A sophisticated strategy where CD is deployed as a ligand to form an assembly of cyclodextrin-based MOFs (CD-MOFs) may overcome real-world application drawbacks of MOFs. CD-MOFs incorporate the porous features of MOFs and the encapsulation capability of CD for drug molecules, leading to outstanding properties when compared with traditional hybrid materials. This review focuses on the inclusion technology and drug delivery properties associated with CD-MOFs. In addition, synthetic strategies and currently developed uses of CD-MOFs are highlighted as well. Also, perspectives and future challenges in this rapidly developing research area are discussed. Full article
(This article belongs to the Special Issue Micro and Nano Encapsulation Techniques)
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Open AccessArticle Synergistic Action of Sodium Selenite with some Antidepressants and Diazepam in Mice
Pharmaceutics 2018, 10(4), 270; https://doi.org/10.3390/pharmaceutics10040270
Received: 14 November 2018 / Revised: 2 December 2018 / Accepted: 10 December 2018 / Published: 12 December 2018
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Abstract
Background: The antidepressant and anxiolytic effects of selenium (Se) have been proven in many studies. This work was aimed at confirming these activities of its inorganic form—sodium selenite—and examining the possible synergy of action with antidepressants and diazepam. Methods: The antidepressant- and anxiolytic-like
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Background: The antidepressant and anxiolytic effects of selenium (Se) have been proven in many studies. This work was aimed at confirming these activities of its inorganic form—sodium selenite—and examining the possible synergy of action with antidepressants and diazepam. Methods: The antidepressant- and anxiolytic-like activity of Se was assessed using forced swim tests (FSTs) and elevated plus-maze test (EPMs). Spontaneous locomotor activity was measured using photoresistor actimeters. The experiments were conducted on male Albino Swiss mice. Results: Sodium selenite (0.5 mg/kg) reduced the immobility time in the FSTs and extended time spent in the open arms of EPMs without affecting locomotor activity The combined administration of Se at an ineffective dose (0.25 mg/kg) together with imipramine (15 mg/kg), fluoxetine (5 mg/kg), tianeptine (10 mg/kg), but not with reboxetine (2.5 mg/kg), resulted in a reduction of immobility time in FSTs, and with a threshold dose of diazepam (0.25 mg/kg) led to the prolongation of time spent in the open arms of the EPM. Moreover, the antidepressant-like effect of Se (0.5 mg/kg) was significantly reduced by pretreatment with p-chlorophenylalanine (100 mg/kg). Conclusions: The results may indicate the participation of serotonergic transmission to antidepressant action of Se and GABA-ergic transmission to its anxiolytic effects. Full article
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Open AccessReview Blood-Brain Delivery Methods Using Nanotechnology
Pharmaceutics 2018, 10(4), 269; https://doi.org/10.3390/pharmaceutics10040269
Received: 15 November 2018 / Revised: 29 November 2018 / Accepted: 7 December 2018 / Published: 11 December 2018
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Abstract
Pathologies of the brain, of which brain cancer, Alzheimer’s disease, Parkinson’s disease, stroke, and multiple sclerosis, are some of the most prevalent, and that presently are poorly treated due to the difficulties associated with drug development, administration, and targeting to the brain. The
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Pathologies of the brain, of which brain cancer, Alzheimer’s disease, Parkinson’s disease, stroke, and multiple sclerosis, are some of the most prevalent, and that presently are poorly treated due to the difficulties associated with drug development, administration, and targeting to the brain. The existence of the blood-brain barrier, a selective permeability system which acts as a local gateway against circulating foreign substances, represents the key challenge for the delivery of therapeutic agents to the brain. However, the development of nanotechnology-based approaches for brain delivery, such as nanoparticles, liposomes, dendrimers, micelles, and carbon nanotubes, might be the solution for improved brain therapies. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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Open AccessReview Overview of DNA Self-Assembling: Progresses in Biomedical Applications
Pharmaceutics 2018, 10(4), 268; https://doi.org/10.3390/pharmaceutics10040268
Received: 22 November 2018 / Revised: 5 December 2018 / Accepted: 8 December 2018 / Published: 11 December 2018
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Abstract
Molecular self-assembling is ubiquitous in nature providing structural and functional machinery for the cells. In recent decades, material science has been inspired by the nature’s assembly principles to create artificially higher-order structures customized with therapeutic and targeting molecules, organic and inorganic fluorescent probes
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Molecular self-assembling is ubiquitous in nature providing structural and functional machinery for the cells. In recent decades, material science has been inspired by the nature’s assembly principles to create artificially higher-order structures customized with therapeutic and targeting molecules, organic and inorganic fluorescent probes that have opened new perspectives for biomedical applications. Among these novel man-made materials, DNA nanostructures hold great promise for the modular assembly of biocompatible molecules at the nanoscale of multiple shapes and sizes, designed via molecular programming languages. Herein, we summarize the recent advances made in the designing of DNA nanostructures with special emphasis on their application in biomedical research as imaging and diagnostic platforms, drug, gene, and protein vehicles, as well as theranostic agents that are meant to operate in-cell and in-vivo. Full article
(This article belongs to the Special Issue Nanotheranostics and Cancer: Where Are We Now?)
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Open AccessReview The Microfluidic Technique and the Manufacturing of Polysaccharide Nanoparticles
Pharmaceutics 2018, 10(4), 267; https://doi.org/10.3390/pharmaceutics10040267
Received: 15 October 2018 / Revised: 16 November 2018 / Accepted: 27 November 2018 / Published: 9 December 2018
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The microfluidic technique has emerged as a promising tool to accelerate the clinical translation of nanoparticles, and its application affects several aspects, such as the production of nanoparticles and the in vitro characterization in the microenvironment, mimicking in vivo conditions. This review covers
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The microfluidic technique has emerged as a promising tool to accelerate the clinical translation of nanoparticles, and its application affects several aspects, such as the production of nanoparticles and the in vitro characterization in the microenvironment, mimicking in vivo conditions. This review covers the general aspects of the microfluidic technique and its application in several fields, such as the synthesis, recovering, and samples analysis of nanoparticles, and in vitro characterization and their in vivo application. Among these, advantages in the production of polymeric nanoparticles in a well-controlled, reproducible, and high-throughput manner have been highlighted, and detailed descriptions of microfluidic devices broadly used for the synthesis of polysaccharide nanoparticles have been provided. These nanoparticulate systems have drawn attention as drug delivery vehicles over many years; nevertheless, their synthesis using the microfluidic technique is still largely unexplored. This review deals with the use of the microfluidic technique for the synthesis of polysaccharide nanoparticles; evaluating features of the most studied polysaccharide drug carriers, such as chitosan, hyaluronic acid, and alginate polymers. The critical assessment of the most recent research published in literature allows us to assume that microfluidics will play an important role in the discovery and clinical translation of nanoplatforms. Full article
(This article belongs to the Special Issue Micro and Nano Encapsulation Techniques)
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Open AccessArticle Investigation of Different Iontophoretic Currents Profiles for Short-Term Applications in Cosmetics
Pharmaceutics 2018, 10(4), 266; https://doi.org/10.3390/pharmaceutics10040266
Received: 31 October 2018 / Revised: 27 November 2018 / Accepted: 1 December 2018 / Published: 7 December 2018
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This study aimed at investigating the effect of electrical current profile upon the iontophoretic transport of (i) ascorbic acid (AA) and (ii) ellagic acid (EA), into porcine skin in vitro, and the impact of the physicochemical properties of both actives on their mechanism
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This study aimed at investigating the effect of electrical current profile upon the iontophoretic transport of (i) ascorbic acid (AA) and (ii) ellagic acid (EA), into porcine skin in vitro, and the impact of the physicochemical properties of both actives on their mechanism of transport when formulated in cosmetic compositions. The experiments were performed using a proprietary iontophoretic device containing a roller to apply the formulation. Three current profiles were tested: (i) galvanic direct current (DC), (ii) square unipolar pulse current (SPC), and (iii) galvanic direct current (DC) + pulse current (PC). The skin samples were collected at different sampling points, extracted and analyzed by HPLC. Results suggested that the DC + PC mode for only 5 min was able to significantly increase the delivery of AA from o/w cosmetic compositions. The use of this current profile might improve the skin penetration of AA due to electromigration and passive diffusion, the latter being facilitated by the physical enhancement method. The SPC mode significantly improved the passage of EA in its neutral form from cosmetic o/w formulations by electroosmosis. Tailoring specific electrical current modes considering the ionization state of active ingredients would allow the design of short and personalized cosmetic treatments that significantly improve the penetration efficiency of the active ingredients and possibly reduce the doses applied. Full article
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Open AccessArticle Influence of Chemical Enhancers and Iontophoresis on the In Vitro Transdermal Permeation of Propranolol: Evaluation by Dermatopharmacokinetics
Pharmaceutics 2018, 10(4), 265; https://doi.org/10.3390/pharmaceutics10040265
Received: 17 October 2018 / Revised: 18 November 2018 / Accepted: 5 December 2018 / Published: 7 December 2018
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The aims of this study were to assess, in vitro, the possibility of administering propranolol transdermally and to evaluate the usefulness of the dermatopharmacokinetic (DPK) method in assessing the transport of drugs through stratum corneum, using propranolol as a model compound. Four chemical
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The aims of this study were to assess, in vitro, the possibility of administering propranolol transdermally and to evaluate the usefulness of the dermatopharmacokinetic (DPK) method in assessing the transport of drugs through stratum corneum, using propranolol as a model compound. Four chemical enhancers (decenoic and oleic acid, laurocapram, and R-(+)-limonene) and iontophoresis at two current densities, 0.25 and 0.5 mA/cm2 were tested. R-(+)-limonene, and iontophoresis at 0.5 mA/cm2 were proven to be the most efficient in increasing propranolol transdermal flux, both doubled the original propranolol transdermal flux. Iontophoresis was demonstrated to be superior than the chemical enhancer because it allowed faster delivery of the drug. The DPK method was sufficiently sensitive to detect subtle vehicle-induced effects on the skin permeation of propranolol. The shorter duration of these experiments and their ability to provide mechanistic information about partition between vehicle and skin and diffusivity through skin place them as practical and potentially insightful approach to quantify and, ultimately, optimize topical bioavailability. Full article
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Open AccessArticle Formulation of Bioerodible Ketamine Microparticles as an Analgesic Adjuvant Treatment Produced by Supercritical Fluid Polymer Encapsulation
Pharmaceutics 2018, 10(4), 264; https://doi.org/10.3390/pharmaceutics10040264
Received: 7 November 2018 / Revised: 28 November 2018 / Accepted: 4 December 2018 / Published: 6 December 2018
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Pain is inadequately relieved by escalating doses of a strong opioid analgesic such as morphine in up to 25% of patients with cancer-related severe pain complicated by a neuropathic (nerve damage) component. Hence, there is an unmet medical need for research on novel
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Pain is inadequately relieved by escalating doses of a strong opioid analgesic such as morphine in up to 25% of patients with cancer-related severe pain complicated by a neuropathic (nerve damage) component. Hence, there is an unmet medical need for research on novel painkiller strategies. In the present work, we used supercritical fluid polymer encapsulation to develop sustained-release poly(lactic-co-glycolic acid) (PLGA) biodegradable microparticles containing the analgesic adjuvant drug ketamine, for injection by the intrathecal route. Using this approach with a range of PLGA co-polymers, drug loading was in the range 10–60%, with encapsulation efficiency (EE) of 60–100%. Particles were mainly in the size range 20–45 µm and were produced in the absence of organic solvents and surfactants/emulsifiers. Investigation of the ketamine release profiles from these PLGA-based microparticles in vitro showed that release took place over varying periods in the range 0.5–4.0 weeks. Of the polymers assessed, the ester end-capped PLGA5050DLG-1.5E gave the best-controlled release profile with drug loading at 10%. Full article
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Open AccessReview A Comprehensive Map of FDA-Approved Pharmaceutical Products
Pharmaceutics 2018, 10(4), 263; https://doi.org/10.3390/pharmaceutics10040263
Received: 6 November 2018 / Revised: 28 November 2018 / Accepted: 30 November 2018 / Published: 6 December 2018
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With the increasing research and development (R&D) difficulty of new molecular entities (NMEs), novel drug delivery systems (DDSs) are attracting widespread attention. This review investigated the current distribution of Food and Drug Administration (FDA)-approved pharmaceutical products and evaluated the technical barrier for the
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With the increasing research and development (R&D) difficulty of new molecular entities (NMEs), novel drug delivery systems (DDSs) are attracting widespread attention. This review investigated the current distribution of Food and Drug Administration (FDA)-approved pharmaceutical products and evaluated the technical barrier for the entry of generic drugs and highlighted the success and failure of advanced drug delivery systems. According to the ratio of generic to new drugs and the four-quadrant classification scheme for evaluating the commercialization potential of DDSs, the results showed that the traditional dosage forms (e.g., conventional tablets, capsules and injections) with a lower technology barrier were easier to reproduce, while advanced drug delivery systems (e.g., inhalations and nanomedicines) with highly technical barriers had less competition and greater market potential. Our study provides a comprehensive insight into FDA-approved products and deep analysis of the technical barriers for advanced drug delivery systems. In the future, the R&D of new molecular entities may combine advanced delivery technologies to make drug candidates into more therapeutically effective formulations. Full article
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Open AccessCommunication Biodistribution of a Radiolabeled Antibody in Mice as an Approach to Evaluating Antibody Pharmacokinetics
Pharmaceutics 2018, 10(4), 262; https://doi.org/10.3390/pharmaceutics10040262
Received: 29 October 2018 / Revised: 21 November 2018 / Accepted: 1 December 2018 / Published: 5 December 2018
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Abstract
(1) Background: Monoclonal antibodies are used in the treatment of multiple conditions including cancer, autoimmune disorders, and infectious diseases. One of the initial steps in the selection of an antibody candidate for further pre-clinical development is determining its pharmacokinetics in small animal models.
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(1) Background: Monoclonal antibodies are used in the treatment of multiple conditions including cancer, autoimmune disorders, and infectious diseases. One of the initial steps in the selection of an antibody candidate for further pre-clinical development is determining its pharmacokinetics in small animal models. The use of mass spectrometry and other techniques to determine the fate of these antibodies is laborious and expensive. Here we describe a straightforward and highly reproducible methodology for utilizing radiolabeled antibodies for pharmacokinetics studies. (2) Methods: Commercially available bifunctional linker CHXA” and 111Indium radionuclide were used. A melanin-specific chimeric antibody A1 and an isotype matching irrelevant control A2 were conjugated with the CHXA”, and then radiolabeled with 111In. The biodistribution was performed at 4 and 24 h time points in melanoma tumor-bearing and healthy C57BL/6 female mice. (3) The biodistribution of the melanin-binding antibody showed the significant uptake in the tumor, which increased with time, and very low uptake in healthy melanin-containing tissues such as the retina of the eye and melanized skin. This biodistribution pattern in healthy tissues was very close to that of the isotype matching control antibody. (4) Conclusions: The biodistribution experiment allows us to assess the pharmacokinetics of both antibodies side by side and to make a conclusion regarding the suitability of specific antibodies for further development. Full article
(This article belongs to the Special Issue Drug Delivery Technology Development in Canada)
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Open AccessArticle Xylan-Based Hydrogels as a Potential Carrier for Drug Delivery: Effect of Pore-Forming Agents
Pharmaceutics 2018, 10(4), 261; https://doi.org/10.3390/pharmaceutics10040261
Received: 30 September 2018 / Revised: 16 November 2018 / Accepted: 29 November 2018 / Published: 5 December 2018
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Pore-forming agents have a significant influence on the pore structure of hydrogels. In this study, a porogenic technique was employed to investigate the preparation of macroporous hydrogels which were synthesized by radical copolymerization of carboxymethyl xylan with acrylamide and N-isopropylacrylamide under the
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Pore-forming agents have a significant influence on the pore structure of hydrogels. In this study, a porogenic technique was employed to investigate the preparation of macroporous hydrogels which were synthesized by radical copolymerization of carboxymethyl xylan with acrylamide and N-isopropylacrylamide under the function of a cross-linking agent. Six kinds of pore-forming agents were used: polyvinylpyrrolidone K30, polyethylene glycol 2000, carbamide, NaCl, CaCO3, and NaHCO3. The application of these hydrogels is also discussed. The results show that pore-forming agents had an important impact on the pore structure of the hydrogels and consequently affected properties of the hydrogels such as swelling ratio and mechanical strength, while little effect was noted on the thermal property of the hydrogels. 5-Fluorouracil was used as a model drug to study the drug release of the as-prepared hydrogels, and it was found that the drug release was substantially improved after using the NaHCO3 pore-forming agent: a cumulative release rate of up to 71.05% was achieved. Full article
(This article belongs to the Special Issue Micro and Nano Encapsulation Techniques)
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Open AccessArticle Analysis of Vipadenant and Its In Vitro and In Vivo Metabolites via Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry
Pharmaceutics 2018, 10(4), 260; https://doi.org/10.3390/pharmaceutics10040260
Received: 7 October 2018 / Revised: 26 November 2018 / Accepted: 26 November 2018 / Published: 3 December 2018
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A simple and sensitive liquid chromatography–quadrupole-time-of-flight–mass spectrometric (LC-QTOF-MS) assay has been developed for the evaluation of drug metabolism and pharmacokinetics (PK) properties of vipadenant in rat, a selective A2a receptor antagonist as one of the novel immune checkpoint inhibitors. A simple protein precipitation
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A simple and sensitive liquid chromatography–quadrupole-time-of-flight–mass spectrometric (LC-QTOF-MS) assay has been developed for the evaluation of drug metabolism and pharmacokinetics (PK) properties of vipadenant in rat, a selective A2a receptor antagonist as one of the novel immune checkpoint inhibitors. A simple protein precipitation method using acetonitrile was used for the sample preparation and the pre-treated samples were separated by a reverse-phase C18 column. The calibration curve was evaluated in the range of 3.02 ~ 2200 ng/mL and the quadratic regression (weighted 1/concentration) was used for the best fit of the curve with a correlation coefficient ≥0.997. The in vivo PK studies in rats showed that vipadenant bioavailability was 30.4 ± 8.9% with a low to moderate drug clearance. In addition, in vitro/in vivo metabolite profiles in rat were also explored. Five different metabolites were observed in our experimental conditions and the major metabolites were different between in vitro and in vivo conditions. As far as we know, there has been no report on the development of quantitative methods for its PK samples nor the identification of its metabolites since vipadenant was developed. Therefore, this paper would be very useful to better understand the pharmacokinetic and drug metabolism properties of vipadenant in rat as well as other species. Full article
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Open AccessArticle Modeling of Disintegration and Dissolution Behavior of Mefenamic Acid Formulation Using Numeric Solution of Noyes-Whitney Equation with Cellular Automata on Microtomographic and Algorithmically Generated Surfaces
Pharmaceutics 2018, 10(4), 259; https://doi.org/10.3390/pharmaceutics10040259
Received: 21 October 2018 / Revised: 17 November 2018 / Accepted: 23 November 2018 / Published: 3 December 2018
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Abstract
Manufacturing parameters may have a strong impact on the dissolution and disintegration of solid dosage forms. In line with process analytical technology (PAT) and quality by design approaches, computer-based technologies can be used to design, control, and improve the quality of pharmaceutical compacts
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Manufacturing parameters may have a strong impact on the dissolution and disintegration of solid dosage forms. In line with process analytical technology (PAT) and quality by design approaches, computer-based technologies can be used to design, control, and improve the quality of pharmaceutical compacts and their performance. In view of shortcomings of computationally intensive finite-element or discrete-element methods, we propose a modeling and simulation approach based on numerical solutions of the Noyes-Whitney equation in combination with a cellular automata-supported disintegration model. The results from in vitro release studies of mefenamic acid formulations were compared to calculated release patterns. In silico simulations with our disintegration model showed a high similarity of release profile as compared to the experimental evaluation. Furthermore, algorithmically created virtual tablet structures were in good agreement with microtomography experiments. We conclude that the proposed computational model is a valuable tool to predict the influence of material attributes and process parameters on drug release from tablets. Full article
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