A-B block copolymer micelles comprised of thermoresponsive hydrophilic PNIPAAm (poly(Nisopropylacrylamide)) coronae and hydrophobic PNP (poly(N-acryloyl-2-pyrrolidone)), PMNP (poly(Nacryloyl-5-methoxy-2-pyrrolidone)), or PBNP (poly(N-acryloyl-5-butoxy-2-pyrrolidone)) cores were examined to identify how systematic adjustments to core-segment structure affect micellar physicochemical properties, drug loading efficiency (DLE), and thermoresponsive drug release among these novel systems. Critical micelle concentrations (CMCs) were found to decrease by two orders of magnitude in the order of PNIPAAm-PNP, PNIPAAm-PMNP, and PNIPAAm-PBNP indicating that minor modifications to the pyrrolidone scaffold significantly affect its hydrophobic character. Moreover, the structural modifications were also found to influence micelle size and intermicellar aggregation that occurs above the lower critical solution temperature (LCST). In line with the CMC data, DLE values of doxorubicin-loaded (i.e., DOX-loaded) micelles increase in the order of PNIPAAm-PNP, PNIPAAm-PMNP, and PNIPAAm-PBNP, a trend attributed to enhanced cohesive forces (i.e. London dispersion forces) between DOX and core as the latter becomes more hydrophobic. When heated above the LCST, DOX release decreases in the order of PNIPAAm-PNP, PNIPAAm-PMNP, and PNIPAAm-PBNP suggesting that release processes are impeded by the cohesive forces responsible for efficient encapsulation. Finally, cytotoxicity assays performed above the LCST reveal that DOX-loaded micelles are as cytotoxic as the free drug in formulations where DOX concentrations are equivalent.
To date, effective treatment, prophylaxis, and control of tuberculosis (TB) infection is mainly dependent on the use of drugs. However, patient noncompliance with prescribed anti-TB treatment schemes remains a major problem confronting successful pharmacotherapeutic outcomes. Thus, the development of alternative delivery systems that can improve adherence for the existing anti-TB bioactives has been intensified in recent times. The aim of this investigation was to engineer an optimal, thermodynamically stable oral film (OF) formulation containing a key anti-TB agent, pyrazinamide (PYZ), employing molecular modeling and experimental tools. Four PYZ-loaded film variants (OF 1, OF 2, OF 3, OF 4) were constructed in silico and then prepared in vitro using the Accelrys Materials Studio software and solvent casting method, respectively. Screening and selection of the optimal OF was based on the computation of the total interaction energy (ET), kinetic energy (EK), solubility parameter (S), and cohesive energy density (CED) as well as determining mass, thickness, dissolution and disintegration times, dissolution pH, drug loading capacity, and surface morphology in vitro. OF 2 was selected as the optimal formulation as it displayed the lowest ET (-8006.28 kcal/mol), dissolution time (9.96 min), disintegration time (56.49 s), and weight (39.33 mg); moderate EK (1052.98 kcal/mol); highest S (44.55 (J/cm(3))(0.5)) and CED (1.99 × 10(9) J/m(3)), slim dimension (166 μm), good and unvarying drug loading capacity (98.04%), acceptable dissolution pH (6.70), and well-layered surface topography. The drug release behavior of the optimal OF 2 was best elucidated with the zero order (R(2) = 0.97) and Korsmeyer-Peppas (R(2) = 0.99) models. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) analyses showed that OF 2 was made of physically mixed multiple component polymeric and nonpolymeric compounds. OF 2 was semicrystalline in nature and displayed a dual phased ex vivo mucosal permeation pattern. In silico and in vitro physicomechanical quantities revealed OF 2's flexibility, robustness, and compressibility. OF 2 was most stable under controlled environmental humidity, pressure, and temperature conditions in silico and in vitro. OF 2 was potentially non-cytotoxic and biocompatible. Succinctly, this work demonstrated the applicability of a combination of atomistic molecular mechanics and dynamics calculations as well as experimental analyses to the fabrication, screening, optimization, and characterization of drug formulations. Lastly, the fabricated OF 2 formulation can function as a potential alternative for the effective loading and delivery of PYZ.
We discuss the results of an investigation into the structure/property correlations of γ-substituted poly-(N-acryloyl-2-pyrrolidone)s, a recently reported class of pyrrolidone-based polymers prepared from pyroglutamic acid, a bio-derived resource. Monomers bearing alkoxy and thiolate substituents were polymerized by reversible addition-fragmentation chain-transfer (RAFT) polymerization with polymer molecular weights and dispersities (Đ M ) estimated by gel-permeation chromatography (GPC). Single-crystal X-ray diffraction studies reveal a large degree of steric congestion about the monomer acryl-imide functionality, a topological feature that has residual effects on polymer physicochemical properties when variations to γ-substituent structure are applied. Indeed, glass transition temperature T g is significantly influenced by both substituent structure (e.g., saturated linear aliphatic vs. cyclic aliphatic vs. aromatic) and chemical class with the more thermally stable thiolated polymers possessing lower T g values than their alkoxy congeners of comparable molecular weight. Regarding solubility, all polymers dissolve in common organic solvents including chloroform, dichloromethane, and tetrahydrofuran while only those bearing methoxyethoxy ( poly(MeOEthONP)) and tetrahydrofurfuryloxy ( poly(FurONP)) substituents are soluble in water, a medium where they also exhibit thermoresponsive behavior. Despite the structural similarities among these polymers, a remarkable difference of ca. 32°C is observed between their cloud point (CP) temperatures ( poly(MeOEthONP), CP = 47°C, poly(FurONP), CP = 15°C) measured during a phase transition that is sensitive to polymer concentration (0.1-1.0 g L −1 ) and chemical environment (e.g. deionized water vs. phosphate buffered saline (PBS)). Given that both the methoxyethyl thiolate-substituted ( poly(MeOEthSNP) and substituent-free ( poly(NP)) polymers are insoluble in aqueous media, we conclude that the observed thermoresponsivity arises from both the topology of the hydrophilic ether-based moiety and identity of the atom (i.e. O vs. S) that tethers the substituent to the lactam scaffold. Finally, cytotoxicity assays were performed on poly(MeOEthONP) as its lower critical solution temperature (LCST) is close to that of the human body, an attribute that is desirable for hydrophilic materials used in thermoresponsive drug-delivery platforms. The results of this investigation show that over a concentration range of ca. 0.1-100 μg mL −1 , poly(MeOEthONP) formulations are primarily noncytotoxic to both MCF-7 breast cancer cells and human dermal fibroblasts. † Electronic supplementary information (ESI) available: Characterization data including 1 H and 13 C NMR spectra, DSC and TGA thermograms. The X-ray crystallographic file in CIF format. CCDC 1062579. For ESI and crystallographic data in CIF or other electronic format see
This article provides a review of the critical in vitro assays utilized in transdermal drug development. In vitro assays such as percutaneous absorption testing and dissolution (drug release) testing are powerful tools for screening potential transdermal compounds and drug quality control, respectively. Several 2D single-cell cultures and 3D human skin equivalents are available for screening compounds with low irritation and sensitization potential. The role of each assay and its limitations and challenges will be further discussed below.
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