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Pharmaceutics
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Innovative Drug Formulations Require Tailored Characterization Approaches
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Innovative Drug Formulations Require Tailored Characterization Approaches

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 11056

Special Issue Editors

Prof. Dr. Snezana Savic

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Guest Editor
Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
Interests: nanoplatforms for brain and skin delivery; innovative biocompatible excipients; poorly water-soluble drugs; physicochemical/in vitro/in silico characterization methods; in vivo pharmacokinetics in rats
Special Issues, Collections and Topics in MDPI journals
Dr. Ivana Pantelić

E-Mail Website
Guest Editor
Department of Pharmaceutical Technology and Cosmetology, University of Belgrade-Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
Interests: (trans)dermal delivery systems; film-forming polymers; polysaccharide excipients; in vitro/in vivo characterization; tape stripping
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The pressing need to develop successful treatment strategies has prompted research of both symptomatic and disease-modifying treatments. The advent of new molecular and cellular targets has opened the possibility to re-evaluate certain acknowledged active pharmaceutical ingredients, along with new leads/drug candidates and/or repurposed ones.

Although the usual bottlenecks still challenge treatment success (blood–brain barrier, skin barrier, protein corona, cellular uptake, etc.), new drug formulations, often relying on micro- and nanostructured delivery systems or uniquely ordered materials/excipients, are being designed. Such novel drug formulations require tailored characterization approaches, encompassing diverse in silico, in chemico, in vitro and in vivo methods.

Dr. Snezana Savic
Dr. Ivana Pantelić
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • nanosystems
  • microsystems
  • novel materials/excipients
  • various routes of drug administration
  • innovative characterization methods

Published Papers (6 papers)

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Research

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13 pages, 1327 KiB  
Article
The Effect of Intracellular Tacrolimus Exposure on Calcineurin Inhibition in Immediate- and Extended-Release Tacrolimus Formulations
by Pere Fontova, Lisanne N. van Merendonk, Anna Vidal-Alabró, Raül Rigo-Bonnin, Gema Cerezo, Stefaan van Oevelen, Oriol Bestard, Edoardo Melilli, Nuria Montero, Ana Coloma, Anna Manonelles, Joan Torras, Josep M. Cruzado, Josep M. Grinyó, Helena Colom and Nuria Lloberas
Pharmaceutics 2023, 15(5), 1481; https://doi.org/10.3390/pharmaceutics15051481 - 12 May 2023
Cited by 1 | Viewed by 1470
Abstract
Despite intensive monitoring of whole blood tacrolimus concentrations, acute rejection after kidney transplantation occurs during tacrolimus therapy. Intracellular tacrolimus concentrations could better reflect exposure at the site of action and its pharmacodynamics (PD). Intracellular pharmacokinetic (PK) profile following different tacrolimus formulations (immediate-release (TAC-IR) [...] Read more.
Despite intensive monitoring of whole blood tacrolimus concentrations, acute rejection after kidney transplantation occurs during tacrolimus therapy. Intracellular tacrolimus concentrations could better reflect exposure at the site of action and its pharmacodynamics (PD). Intracellular pharmacokinetic (PK) profile following different tacrolimus formulations (immediate-release (TAC-IR) and extended-release (TAC-LCP)) remains unclear. Therefore, the aim was to study intracellular tacrolimus PK of TAC-IR and TAC-LCP and its correlation with whole blood (WhB) PK and PD. A post-hoc analysis of a prospective, open-label, crossover investigator-driven clinical trial (NCT02961608) was performed. Intracellular and WhB tacrolimus 24 h time-concentration curves were measured in 23 stable kidney transplant recipients. PD analysis was evaluated measuring calcineurin activity (CNA) and simultaneous intracellular PK/PD modelling analysis was conducted. Higher dose-adjusted pre-dose intracellular concentrations (C0 and C24) and total exposure (AUC0–24) values were found for TAC-LCP than TAC-IR. Lower intracellular peak concentration (Cmax) was found after TAC-LCP. Correlations between C0, C24 and AUC0–24 were observed within both formulations. Intracellular kinetics seems to be limited by WhB disposition, in turn, limited by tacrolimus release/absorption processes from both formulations. The faster intracellular elimination after TAC-IR was translated into a more rapid recovery of CNA. An Emax model relating % inhibition and intracellular concentrations, including both formulations, showed an IC50, a concentration to achieve 50% CNA inhibition, of 43.9 pg/million cells. Full article
(This article belongs to the Special Issue Innovative Drug Formulations Require Tailored Characterization Approaches)
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11 pages, 1939 KiB  
Article
Confocal Raman Spectroscopy for Assessing Bioequivalence of Topical Formulations
by Fotis Iliopoulos, Chun Fung Tang, Ziyue Li, Annisa Rahma and Majella E. Lane
Pharmaceutics 2023, 15(4), 1075; https://doi.org/10.3390/pharmaceutics15041075 - 27 Mar 2023
Cited by 5 | Viewed by 1761
Abstract
The evaluation of bioequivalence (BE) for topical dermatological drug products is challenging, and there has been significant interest from regulatory authorities in developing new BE methodologies in recent years. Currently, BE is demonstrated by comparative clinical endpoint studies; these are costly and time-consuming [...] Read more.
The evaluation of bioequivalence (BE) for topical dermatological drug products is challenging, and there has been significant interest from regulatory authorities in developing new BE methodologies in recent years. Currently, BE is demonstrated by comparative clinical endpoint studies; these are costly and time-consuming and often lack sensitivity and reproducibility. Previously, we reported excellent correlations between in vivo Confocal Raman Spectroscopy in human subjects and in vitro skin permeation testing (IVPT) with the human epidermis for skin delivery of ibuprofen and a number of excipients. The aim of the present proof-of-concept study was to evaluate CRS as a method to assess BE of topical products. Two commercially available formulations, Nurofen Max Strength 10% Gel and Ibuleve Speed Relief Max Strength 10% Gel, were selected for evaluation. Delivery of ibuprofen (IBU) to the skin was determined in vitro and in vivo by IVPT and CRS, respectively. The formulations examined were found to deliver comparable amounts of IBU across the skin over 24 h in vitro (p > 0.05). Additionally, the formulations resulted in similar skin uptake values measured with CRS in vivo, either at 1 h or 2 h after application (p > 0.05). This is the first study to report the capability of CRS for the demonstration of BE of dermal products. Future studies will focus on the standardisation of the CRS methodology for a robust and reproducible pharmacokinetic (PK)-based evaluation of topical BE. Full article
(This article belongs to the Special Issue Innovative Drug Formulations Require Tailored Characterization Approaches)
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14 pages, 3174 KiB  
Article
pH-Dependent Behavior of Novel 5-FU Delivery System in Environmental Conditions Comparable to the Gastro-Intestinal Tract
by Geza Lazar, Fran Nekvapil, Branko Glamuzina, Tudor Tamaș, Lucian Barbu-Tudoran, Maria Suciu and Simona Cinta Pinzaru
Pharmaceutics 2023, 15(3), 1011; https://doi.org/10.3390/pharmaceutics15031011 - 21 Mar 2023
Cited by 2 | Viewed by 1437
Abstract
A biogenic carrier for 5-fluorouracil (5-FU) loading and subsequent tableting as a new drug formulation for slow release has been proposed using the biomineral from blue crab carapace. Due to its highly ordered 3D porous nanoarchitecture, the biogenic carbonate carrier could achieve increased [...] Read more.
A biogenic carrier for 5-fluorouracil (5-FU) loading and subsequent tableting as a new drug formulation for slow release has been proposed using the biomineral from blue crab carapace. Due to its highly ordered 3D porous nanoarchitecture, the biogenic carbonate carrier could achieve increased effectiveness in colorectal cancer cure provided that the formulation would successfully pass through the gastric acid conditions. Following the recently proven viability of the concept by demonstrating the slow release of the drug from the carrier using the highly sensitive SERS technique, here we investigated the 5-FU release from the composite tablet drug in pH conditions replicating the gastric environment. The released drug from the tablet was studied in solutions with three relevant pH values, pH 2, pH 3, and pH 4. The 5-FU SERS spectral signature for each pH value was used to build calibration curves for quantitative SERS analysis. The results suggested a similarly slow-releasing pattern in acid pH environments to that in neutral conditions. Although biogenic calcite dissolution was expected in acid conditions, the X-ray diffraction and Raman spectroscopy showed preservation of calcite mineral along with the monohydrocalcite during acid solution exposure for two hours. The total released amount in a time course of seven hours, however, was lower in acidic pH solutions, with a maximum fraction of ~40% of the total amount of loaded drug, for pH 2, as opposed to ~80% for neutral values. Nonetheless, these results clearly prove that the novel composite drug retains its slow-releasing character in environmental conditions compatible with the gastrointestinal pH and that it is a viable and biocompatible alternative for oral delivery of anticancer drug to reach the lower gastro-intestinal tract. Full article
(This article belongs to the Special Issue Innovative Drug Formulations Require Tailored Characterization Approaches)
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16 pages, 4140 KiB  
Article
Comparative Analysis of Physical and Chemical Properties of Differently Obtained Zn—Methionine Chelate with Proved Antibiofilm Properties (Part II)
by Alla V. Marukhlenko, Vladimir N. Tumasov, Leonid A. Butusov, Georgy A. Shandryuk and Mariya A. Morozova
Pharmaceutics 2023, 15(2), 590; https://doi.org/10.3390/pharmaceutics15020590 - 09 Feb 2023
Viewed by 1558
Abstract
The previously demonstrated activity of aqueous solutions of methionine and zinc salts against biofilms of uropathogenic bacteria prompted us to investigate the structure and properties of zinc methionine complex obtained from such solutions. The paper presents the analysis results of zinc coordination complexes [...] Read more.
The previously demonstrated activity of aqueous solutions of methionine and zinc salts against biofilms of uropathogenic bacteria prompted us to investigate the structure and properties of zinc methionine complex obtained from such solutions. The paper presents the analysis results of zinc coordination complexes with methionine obtained by synthesis (0.034 mol of L-methionine, 0.034 mol of NaOH, 40 mL of H2O, 0.017 mol ZnSO4, 60 °C) and simple crystallization from water solution (25 mL of a solution containing 134 mmol/L L-methionine, 67 mmol/L ZnSO4, pH = 5.74, I = 0.37 mmol/L, crystallization at room temperature during more than two weeks). IR spectral analysis and X-ray diffraction showed the structural similarity of the substances to each other, in agreement with the data described in the literature. DSC confirmed the formation of a thermally stable (in the range from −30 °C to 180 °C) chelate compound in both cases and indicated the possible retention of the polymorphic two-dimensional structure inherent in L-methionine with the temperature of phase transition 320 K. The crystallized complex had better solubility in water (100 to 1000 mL per 1.0 g) contra the synthesized analog, which was practically insoluble (more than 10 000 mL per 1.0 g). The results of the solubility assessment, supplemented by the results of the dispersion analysis of solutions by the dynamic light scattering method indicated the formation of zinc-containing nanoparticles (80 nm) in a saturated water solution of a crystallized substance, suggesting the crystallized substance may have higher bioavailability. We predicted a possibility of the equivalent existence of optically active cis and trans isomers in methionine-zinc solutions by the close values of formation enthalpy (−655 kJ/mol and −657 kJ/mol for cis and trans forms, respectively) and also illustrated by the polarimetry measurement results (∆α = 0.4°, pH = 5.74, C(Met) = 134 mmol/L; the concentration of metal ion gradually increased from 0 to 134 mmol/L). The obtained results allowed us to conclude that the compound isolated from the solution is a zinc-methionine chelate with the presence of sulfate groups and underline the role of the synthesis route for the biopharmaceutical characteristics of the resulting substance. We provided some quality indicators that it may be possible to include in the pharmacopeia monographs. Full article
(This article belongs to the Special Issue Innovative Drug Formulations Require Tailored Characterization Approaches)
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Review

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19 pages, 1953 KiB  
Review
The Science of Selecting Excipients for Dermal Self-Emulsifying Drug Delivery Systems
by Daniélle van Staden, Richard K. Haynes and Joe M. Viljoen
Pharmaceutics 2023, 15(4), 1293; https://doi.org/10.3390/pharmaceutics15041293 - 20 Apr 2023
Cited by 1 | Viewed by 1849
Abstract
Self-emulsification is considered a formulation technique that has proven capacity to improve oral drug delivery of poorly soluble drugs by advancing both solubility and bioavailability. The capacity of these formulations to produce emulsions after moderate agitation and dilution by means of water phase [...] Read more.
Self-emulsification is considered a formulation technique that has proven capacity to improve oral drug delivery of poorly soluble drugs by advancing both solubility and bioavailability. The capacity of these formulations to produce emulsions after moderate agitation and dilution by means of water phase addition provides a simplified method to improve delivery of lipophilic drugs, where prolonged drug dissolution in the aqueous environment of the gastro-intestinal (GI) tract is known as the rate-limiting step rendering decreased drug absorption. Additionally, spontaneous emulsification has been reported as an innovative topical drug delivery system that enables successful crossing of mucus membranes as well as skin. The ease of formulation generated by the spontaneous emulsification technique itself is intriguing due to the simplified production procedure and unlimited upscaling possibilities. However, spontaneous emulsification depends solely on selecting excipients that complement each other in order to create a vehicle aimed at optimizing drug delivery. If excipients are not compatible or unable to spontaneously transpire into emulsions once exposed to mild agitation, no self-emulsification will be achieved. Therefore, the generalized view of excipients as inert bystanders facilitating delivery of an active compound cannot be accepted when selecting excipients needed to produce self-emulsifying drug delivery systems (SEDDSs). Hence, this review describes the excipients needed to generate dermal SEDDSs as well as self-double-emulsifying drug delivery systems (SDEDDSs); how to consider combinations that complement the incorporated drug(s); and an overview of using natural excipients as thickening agents and skin penetration enhancers. Full article
(This article belongs to the Special Issue Innovative Drug Formulations Require Tailored Characterization Approaches)
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34 pages, 2772 KiB  
Review
Parenteral Lipid-Based Nanoparticles for CNS Disorders: Integrating Various Facets of Preclinical Evaluation towards More Effective Clinical Translation
by Tanja Ilić, Jelena B. Đoković, Ines Nikolić, Jelena R. Mitrović, Ivana Pantelić, Snežana D. Savić and Miroslav M. Savić
Pharmaceutics 2023, 15(2), 443; https://doi.org/10.3390/pharmaceutics15020443 - 29 Jan 2023
Cited by 5 | Viewed by 1985
Abstract
Contemporary trends in combinatorial chemistry and the design of pharmaceuticals targeting brain disorders have favored the development of drug candidates with increased lipophilicity and poorer water solubility, with the expected improvement in delivery across the blood–brain barrier (BBB). The growing availability of innovative [...] Read more.
Contemporary trends in combinatorial chemistry and the design of pharmaceuticals targeting brain disorders have favored the development of drug candidates with increased lipophilicity and poorer water solubility, with the expected improvement in delivery across the blood–brain barrier (BBB). The growing availability of innovative excipients/ligands allowing improved brain targeting and controlled drug release makes the lipid nanocarriers a reasonable choice to overcome the factors impeding drug delivery through the BBB. However, a wide variety of methods, study designs and experimental conditions utilized in the literature hinder their systematic comparison, and thus slows the advances in brain-targeting by lipid-based nanoparticles. This review provides an overview of the methods most commonly utilized during the preclinical testing of liposomes, nanoemulsions, solid lipid nanoparticles and nanostructured lipid carriers intended for the treatment of various CNS disorders via the parenteral route. In order to fully elucidate the structure, stability, safety profiles, biodistribution, metabolism, pharmacokinetics and immunological effects of such lipid-based nanoparticles, a transdisciplinary approach to preclinical characterization is mandatory, covering a comprehensive set of physical, chemical, in vitro and in vivo biological testing. Full article
(This article belongs to the Special Issue Innovative Drug Formulations Require Tailored Characterization Approaches)
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