Rania Hamed

Nanoemulsion-based gel formulation of diclofenac diethylamine: design, optimization, rheological behavior and in vitro diffusion studies

Abstract Chronic oral administration of the non-steroidal anti-inflammatory drug, diclofenac diethylamine (DDEA), is often associated with gastrointestinal ulcers and bleeding. As an alternative to oral administration, a nanoemulsion-based gel (NE gel) formulation of DDEA was developed for topical administration. An optimized formulation for the o/w nanoemulsion of oil, surfactant and cosurfactant was selected based on nanoemulsion mean droplet size, clarity, stability, and flowability, and incorporated into the gelling agent Carbopol® 971P. Rheological studies of the DDEA NE gel were conducted and compared to those of conventional DDEA gel and emulgel. The three gels exhibited an elastic behavior, where G′ dominated G″ at all frequencies, indicating the formation of strong gels. NE gel exhibited higher G′ values than conventional gel and emulgel, which indicated the formation of a stronger gel network. Strat-M® membrane, a synthetic membrane with diffusion characteristics that are well correlated to human skin, was used for the in vitro diffusion studies. The release of DDEA from conventional gel, emulgel and NE gel showed a controlled release pattern over 12 h, which was consistent with the rheological properties of the gels. DDEA release kinetics from the three gels followed super case II transport as fitted by Korsmeyer–Peppas model.

Synergistic Interplay of Medicinal Chemistry and Formulation Strategies in Nanotechnology – From Drug Discovery to Nanocarrier Design and Development

Over the last few decades, nanotechnology has given rise to promising new therapies and diagnostic tools for a wide range of diseases, especially cancer. The unique properties of nanocarriers such as liposomes, polymeric nanoparticles, micelles, and bioconjugates have mainly been exploited to enhance drug solubility, dissolution, and bioavailability. The most important advantage offered by nanotechnology is the ability to specifically target organs, tissues, and individual cells, which ultimately reduces the systemic side effects and improves the therapeutic index of drug molecules. The contribution of medicinal chemistry to nanotechnology is evident in the abundance of new active molecules that are being discovered but are faced with tremendous delivery challenges by conventional formulation strategies. Additionally, medicinal chemistry plays a crucial role in all the steps involved in the preparation of nanocarriers, where structure-activity relationships of the drug molecule as well as the nanocarrier are harnessed to enhance the design, efficacy, and safety of nanoformulations. The aim of this review is to provide an overview of the contributions of medicinal chemistry to nanotechnology, from supplying drug candidates and inspiring high-throughput nanocarrier design strategies, to structure-activity relationship elucidation and construction of computational models for better understanding of nanocarrier physicochemical properties and biological behavior. These two fields are undoubtedly interconnected and we will continue to see the fruits of that communion for years to come.

Interactions of mussel-inspired polymeric nanoparticles with gastric mucin: Implications for gastro-retentive drug delivery

Mussel-inspired polydopamine (pD) coatings have several unique characteristics such as durability, versatility, and robustness. In this study, we have designed pD-coated nanoparticles (NPs) of methoxy polyethylene glycol-b-poly(ε-caprolactone) (mPEG-PCL@pD) as prospective nanoscale mucoadhesive platforms for gastro-retentive drug delivery. Successful pD coating on the NPs was confirmed by Transmission Electron Microscopy and X-ray Photoelectron Spectroscopy. Mucoadhesion of pD-coated NPs was investigated in vitro using commercially available mucin under stomach lumen-mimetic conditions. Mucin-NP interactions were monitored by dynamic light scattering, which showed a significant change in particle size distribution of pD-coated NPs at mucin/NP ratios of 1:1, 1:2, and 1:4w/w. Turbidity measurements indicated the formation of large mucin-NP aggregates causing a significant increase in turbidity at mucin/NP ratios of 2:1 and 4:1w/w. pD-coated NPs exhibited a significantly higher mucin adsorption ability compared to uncoated NPs at mucin/NP ratios of 1:4, 1:2, and 1:1w/w. Zeta potential measurements demonstrated that mucin-pD-coated NP interactions were not electrostatic in nature. An ex vivo wash-off test conducted using excised sheep stomach revealed that 78% of pD-coated NPs remained attached to the mucosa after 8h of incubation, compared to only 33% of uncoated NPs. In vitro release of rifampicin, used as a model drug, showed a similar controlled release profile from both pD-coated and uncoated NPs. Our results serve to expand the versatility of mussel-inspired coatings to the design of mucoadhesive nanoscale vehicles for oral drug delivery.

The effect of pH, buffer capacity and ionic strength on quetiapine fumarate release from matrix tablets prepared using two different polymeric blends

Abstract The objective of this study was to investigate the effect of the different physiological parameters of the gastrointestinal (GI) fluid (pH, buffer capacity, and ionic strength) on the in vitro release of the weakly basic BCS class II drug quetiapine fumarate (QF) from two once-a-day matrix tablet formulations (F1 and F2) developed as potential generic equivalents to Seroquel® XR. F1 tablets were prepared using blends of high and low viscosity grades of hydroxypropyl methylcellulose (HPMC K4M and K100LV, respectively), while F2 tablets were prepared from HPMC K4M and PEGylated glyceryl behenate (Compritol® HD5 ATO). The two formulations attained release profiles of QF over 24 h similar to that of Seroquel® XR using the dissolution medium published by the Food and Drug Administration (FDA). A series of solubility and in vitro dissolution studies was then carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH, buffer capacity and ionic strength range of the GIT. Solubility studies revealed that QF exhibits a typical weak base pH-dependent solubility profile and that the solubility of QF increases with increasing the buffer capacity and ionic strength of the media. The release profiles of QF from F1, F2 and Seroquel® XR tablets were found to be influenced by the pH, buffer capacity and ionic strength of the dissolution media to varying degrees. Results highlight the importance of studying the physiological variables along the GIT in designing controlled release formulations for more predictive in vitro–in vivo correlations.

Correlation between the viscoelastic properties of the gel layer of swollen HPMC matrix tablets and their in vitro drug release

Abstract Drug release from hydroxypropyl methylcellulose (HPMC) hydrophilic matrix tablets is controlled by drug diffusion through the gel layer of the matrix-forming polymer upon hydration, matrix erosion or combination of diffusion and erosion mechanisms. In this study, the relationship between viscoelastic properties of the gel layer of swollen intact matrix tablets and drug release was investigated. Two sets of quetiapine fumarate (QF) matrix tablets were prepared using the high viscosity grade HPMC K4M at low (70 mg/tablet) and high (170 mg/tablet) polymer concentrations. Viscoelastic studies using a controlled stress rheometer were performed on swollen matrices following hydration in the dissolution medium for predetermined time intervals. The gel layer of swollen tablets exhibited predominantly elastic behavior. Results from the in vitro release study showed that drug release was strongly influenced by the viscoelastic properties of the gel layer of K4M tablets, which was further corroborated by results from water uptake studies conducted on intact tablets. The results provide evidence that the viscoelastic properties of the gel layer can be exploited to guide the selection of an appropriate matrix-forming polymer, to better understand the rate of drug release from matrix tablets in vitro and to develop hydrophilic controlled-release formulations.

Influence of HPMC K100LV and Compritol® HD5 ATO on Drug Release and Rheological Behavior of HPMC K4M Matrix Tablets

PurposeThe objectives of this study were to develop once-a-day oral controlled-release tablets of quetiapine fumarate (QF) and to determine the effect of polymer type, viscosity grade, polymer ratio, and polymer rheological properties on the rate of QF release from hydroxypropyl methylcellulose (HPMC) matrix tablets.MethodsTablets were prepared from low-viscosity-grade HPMC K100LV (K100LV), high-viscosity-grade HPMC K4M (K4M), Compritol® HD5 ATO (PEGylated glyceryl behenate (PGB)), and binary combinations of these polymers. In vitro drug release from all tablets was evaluated over 24 h.Results In vitro drug release studies revealed that formulations containing K100LV/K4M and PGB/K4M at a ratio of 170:70 resulted in similar release profiles which extended for 24 h (f2 > 50). QF release kinetics followed either diffusion, anomalous transport, case II transport, or super case II transport, as fitted by the Korsmeyer-Peppas model. Tablet swelling and erosion studies were consistent with dissolution profiles. A linear relationship between % swelling and % QF released was observed in tablets containing K4M alone or in combination with K100LV or PGB, indicating the direct role of polymer swelling in controlling the mechanism of drug release. The viscoelastic properties of single and binary polymeric gels made with the three polymers (K100LV, K4M, and PGB) corroborated the in vitro release studies of QF tablets.ConclusionsOur results provide evidence that blending polymers with different viscosities and hydrophilicities can result in unique matrices with tunable release profiles.

Physiological Parameters of the Gastrointestinal Fluid Impact the Dissolution Behavior of the BCS Class IIa Drug Valsartan

Abstract The objective of this study was to investigate the effect of the physiological parameters (pH, buffer capacity, and ionic strength) of the gastrointestinal (GI) fluid on the dissolution behavior of the class II weakly acidic (BCS class IIa) drug valsartan. A series of in vitro dissolution studies was carried out on Diovan® immediate release tablets using media that cover the physiological range of pH (1.2–7.8), buffer capacity (0–0.047 M/ΔpH), and ionic strength (0–0.4 mol/L) of the GI fluid during fasted and fed states using the conventional USP II apparatus. Valsartan exhibited pH- and buffer capacity-dependent dissolution behavior, where valsartan release was slow and incomplete in media simulating gastric fluid with low pH, and fast and complete in media simulating intestinal fluid with high pH. In addition, the rate of valsartan release increased with increasing the buffer capacity of the dissolution medium. In water and NaCl solutions, valsartan release was incomplete and the dissolution profiles were similar regardless of the ionic strength of the medium, indicating an ionic strength-independent dissolution behavior. These results highlight the significant effect of the physiological parameters of the GI fluid on the dissolution behavior of BCS class IIa drugs.

Development of Hydrogels, Oleogels and Bigels as Local Drug Delivery Systems for Periodontitis

Abstract Periodontal disease is a chronic inflammation of gum and tissues that surround and support the teeth. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used in the treatment of periodontitis to ease swelling and inflammation. One approach of treating periodontitis is loading the NSAIDs in local drug delivery systems. Therefore, the objective of this study was to investigate the local delivery of the NSAIDs model drug ibuprofen to treat periodontitis using different types of gel formulations (hydrogel, oleogel, and bigel). Gel formulations were characterized in terms of their rheological properties (flow behavior, viscoelastic, and bioadhesive properties) using a controlled-stress rheometer. The in vitro drug release of ibuprofen from gel formulations was investigated using Franz diffusion cells. Gels exhibited more solid-like (elastic) behavior. The viscosity and viscoelastic properties were in the order of oleogel > bigel > hydrogel, respectively. In bioadhesion study, mucin dispersion/plain ibuprofen-hydrogel mixture showed a frequency-dependent interaction of ΔG’ = −31 and ΔG’ = + 53 Pa at 1 and 10 rad/s, respectively. A strong positive interaction (ΔG’ = + 6000 and +130,667 Pa at 1 and 10 rad/s, respectively) was found in mucin dispersion/plain ibuprofen–oleogel mixture. The extent of the negative interaction increased in mucin dispersion/plain ibuprofen-bigel mixture (ΔG’ = −59,000 and −79,375 Pa at 1 and 10 rad/s, respectively). After 6 h, ibuprofen release from hydrogel, oleogel, and bigel was 59.5 ± 2.2, 80.6 ± 3.9, and 94.6 ± 3.2%, respectively. Results showed that the rheological and bioadhesive properties and in vitro drug release were influenced by the type of gel formulations.