Exploring the Ocular Absorption Pathway of Fasudil Hydrochloride towards Developing a Nanoparticulate Formulation with Improved Performance.

Rho-kinase (ROCK) inhibitors represent a new category of anti-glaucoma medications. Among them, Fasudil hydrochloride, a selective ROCK inhibitor, has demonstrated promising outcomes in glaucoma treatment. It works by inhibiting the ROCK pathway, which plays a crucial role in regulating the trabecular meshwork and canal of Schlemm's aqueous humor outflow. This study aims to investigate the ocular absorption pathway of Fasudil hydrochloride and, subsequently, develop a nanoparticle-based delivery system for enhanced corneal absorption. Employing the ionic gelation method and statistical experimental design, the factors influencing chitosan nanoparticle (Cs NP) characteristics and performance were explored. Fasudil in vitro release and ex vivo permeation studies were performed, and Cs NP ocular tolerability and cytotoxicity on human lens epithelial cells were evaluated. Permeation studies on excised bovine eyes revealed significantly higher Fasudil permeation through the sclera compared to the cornea (370.0 µg/cm2 vs. 96.8 µg/cm2, respectively). The nanoparticle size (144.0 ± 15.6 nm to 835.9 ± 23.4 nm) and entrapment efficiency range achieved (17.2% to 41.4%) were predominantly influenced by chitosan quantity. Cs NPs showed a substantial improvement in the permeation of Fasudil via the cornea, along with slower release compared to the Fasudil aqueous solution. The results from the Hen's Egg Test Chorioallantoic Membrane (HET-CAM) and Bovine Corneal Opacity and Permeability (BCOP) tests indicated good conjunctival and corneal biocompatibility of the formulated chitosan nanoparticles, respectively. Lens epithelial cells displayed excellent tolerance to low concentrations of these nanoparticles (>94% cell viability). To the best of our knowledge, this is the first report on the ocular absorption pathway of topically applied Fasudil hydrochloride where the cornea has been identified as a potential barrier that could be overcome using Cs NPs.

Efficient removal of antibiotics from water by highly crosslinked metal-alginate particles: Preparation, isotherms, kinetics, and microbiological assay.

Traces of antibiotics reaching aquatic environment lead to the emergence of antimicrobial resistance (AMR). The efficient removal of antibiotics (ATBs) traces from wastewater is essential to tackle the AMR. In this study, a novel solid-state crosslinking method of alginate (ALG) was developed and applied to specifically remove ATBs from water. A wide range of crosslinkers (Ca2+, Zn2+, Cu2+, Ni2+, Fe3+ and Al3+) was used and the crosslinking nature, density, and distribution were evidenced by FTIR, ICP-MS, and SEM-EDS. Compared with ionotropic gelation, the novel solid-state crosslinking method proved superior in term of ease of production, high crosslinking degree, and ATBs removal capacity. Fe-ALG and Zn-ALG showed high removal capacity of ciprofloxacin (356.5 mg/g and 928.6 mg/g) and doxycycline (90 mg/g and 690 mg/g), however, they were less effective toward amoxicillin (11.5 mg/g and 6 mg/g). Removal isotherms and kinetics followed type I and pseudo-second order suggesting a chemisorption removal mechanism. Fe-ALG was successfully regenerated with no loss in ATB removal capacity. The microbiological assay showed significant reductions of antibacterial activities after ATBs removal from water. Overall, metal-ALG systems obtained by solid-state crosslinking are promising for ATBs removal from wastewater giving the ease of production, high efficiency, regenerability, and scalability potential.

Review: The Chemistry, Toxicity and Antibacterial Activity of Curcumin and Its Analogues.

Antimicrobial resistance is a global challenge that is already exacting a heavy price both in terms of human health and financial cost. Novel ways of approaching this crisis include the investigation of natural products. Curcumin is the major constituent in turmeric, and it is commonly used in the preparation of Asian cuisine. In addition, it possesses a wide range of pharmacological properties. This review provides a detailed account of curcumin and its analogues' antibacterial activity against both gram-positive and gram-negative isolates, including its potential mechanism(s) of action and the safety and toxicity in human and animal models. We also highlight the key challenges in terms of solubility/bioavailability associated with the use of curcumin and include research on how these challenges have been overcome.

Maillard Reaction Crosslinked Alginate-Albumin Scaffolds for Enhanced Fenofibrate Delivery to the Retina: A Promising Strategy to Treat RPE-Related Dysfunction.

There are limited treatments currently available for retinal diseases such as age-related macular degeneration (AMD). Cell-based therapy holds great promise in treating these degenerative diseases. Three-dimensional (3D) polymeric scaffolds have gained attention for tissue restoration by mimicking the native extracellular matrix (ECM). The scaffolds can deliver therapeutic agents to the retina, potentially overcoming current treatment limitations and minimizing secondary complications. In the present study, 3D scaffolds made up of alginate and bovine serum albumin (BSA) containing fenofibrate (FNB) were prepared by freeze-drying technique. The incorporation of BSA enhanced the scaffold porosity due to its foamability, and the Maillard reaction increased crosslinking degree between ALG with BSA resulting in a robust scaffold with thicker pore walls with a compression modulus of 13.08 KPa suitable for retinal regeneration. Compared with ALG and ALG-BSA physical mixture scaffolds, ALG-BSA conjugated scaffolds had higher FNB loading capacity, slower release of FNB in the simulated vitreous humour and less swelling in water and buffers, and better cell viability and distribution when tested with ARPE-19 cells. These results suggest that ALG-BSA MR conjugate scaffolds may be a promising option for implantable scaffolds for drug delivery and retinal disease treatment.

Preparation and Characterisation of Zinc Diethyldithiocarbamate-Cyclodextrin Inclusion Complexes for Potential Lung Cancer Treatment.

Zinc diethyldithiocarbamate (Zn (DDC)2), a disulfiram metabolite (anti-alcoholism drug), has shown a strong anti-cancer activity in vitro. However, its application was limited by its low aqueous solubility and rapid metabolism. In this study, the solubility enhancement of Zn (DDC)2 is investigated by forming inclusion complexes with cyclodextrins. The inclusion complexes were prepared using two different types of beta-cyclodextrins, SBE-CD and HP-CD. Phase solubility diagrams for the resulting solutions were assessed; subsequently, the solutions were freeze-dried for further characterisation studies using DSC, TGA, XRD, and FTIR. The cytotoxic activity of the produced inclusion complexes was evaluated on human lung carcinoma cells using the MTT assay. The solubility of Zn (DDC)2 increased significantly upon adding beta-cyclodextrins, reaching approximately 4 mg/mL for 20% w/w CD solutions. The phase solubility diagram of Zn (DDC)2 was of the Ap-type according to the Higuchi and Connors model. Characterisation studies confirmed the inclusion of the amorphous drug in the CD-Zn (DDC)2 complexes. The cytotoxicity of Zn (DDC)2 was enhanced 10-fold by the inclusion complexes compared to the free drug. Overall, the resulting CD-Zn (DDC)2 inclusion complexes have a potential for treatment against lung cancer.

Pharmaceutical, biomedical and ophthalmic applications of biodegradable polymers (BDPs): literature and patent review.

In the last few decades, the interest in biodegradable materials for biomedical applications has increased significantly. Both natural and synthetic biodegradable polymers (BDPs) have been broadly explored for various biomedical applications. These include sutures and wound dressings, screws for bone fracture, scaffolds in tissue engineering, implants, and other carriers for targeted and sustained release drug delivery. Owing to their unique characteristics, including their surface charge variable copolymer block and composition and film-forming properties, BDPs have been widely used as favourable materials for ophthalmic drug delivery. Mucoadhesive BDPs have been used in ophthalmic formulations to prolong drug retention time and improve bioavailability, allowing ophthalmic controlled release systems to design. Furthermore, BDPs-based implants, microneedles, and injectable nano- and micro-particles enabled ocular posterior segment targeting and, most importantly, circumvented the need for removing the delivery systems after application. This review outlines the major advances of BDPs and highlights the latest progress of employing natural and synthetic BDPs for various biomedical applications, emphasising the treatment and management of ophthalmic conditions.

A Novel Multilayer Natural Coating for Fed-State Gastric Protection.

Several nutraceutical products require gastric protection against the hostile environment in the stomach. Currently marketed synthetic and semi-synthetic coatings suffer from major shortcomings such as poor gastric protection, slow-release response to pH change, and the use of artificial ingredients. The challenge of coating natural products is further exacerbated by the relatively high gastric pH in the fed state. In this work, a novel natural enteric coating is presented as a breakthrough alternative to current solutions. Two coating systems were devised: (i) a triple-layer coating that comprises a wax layer embedded between two alginate-based coatings, and (ii) a double-layer coating, where an overcoat of organic acids (fumaric or citric acid) is applied to an alginate-based coating. The multi-layer architecture did not impact the pH-responsive nature of the coating even when more biologically relevant Krebs bicarbonate buffer of lower buffer capacity was used. Interestingly, the gastric protection barrier of organic acid-based coating remained resistant at elevated gastric pH 2, 3, or 4 for 2 h. This is the first report of using an alginate-based coating to provide gastric protection against fed-state stomach conditions (pH 2-4). Being biodegradable, naturally occurring, and with no limit on daily intake, the reported novel coating provides a superior platform to current coating solutions for pharmaceutical and nutraceutical products.

Solid Dispersions of Gefitinib Prepared by Spray Drying with Improved Mucoadhesive and Drug Dissolution Properties.

Gefitinib is a tyrosine kinase inhibitor that is intended for oral administration yet suffers poor bioavailability along with undesirable side effects. To enhance its solubility and allow colon targeting, gefitinib (ZD) and blends of different ratios of polymers (ternary dispersion) were prepared in organic solution, and solid dispersions were generated employing the spray drying (SD) technique. The methylmethacrylate polymer Eudragit S 100 was incorporated for colon targeting; polyvinylpyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) were utilised to improve the solubility of ZD. SEM, DSC, XRPD, FT-IR, dissolution and cytotoxicity studies were undertaken to characterise and evaluate the developed formulations. SEM images revealed that the rod-shaped crystals of ZD were transformed into collapsed spheres with smaller particle size in the spray-dried particles. DSC, FTIR and XRPD studies showed that ZD loaded in the spray-dried dispersions was amorphous. ZD dissolution and release studies revealed that while a significant (P < 0.05) increase in the ZD dissolution and release was observed from HPMC-based solid dispersion at pH 7.2 (up to 95% in 15 h), practically no drug was released at pH 1.2 and pH 6.5. Furthermore, the HPMC-based solid dispersions displayed enhanced mucoadhesive properties compared with PVP-based ones. Interestingly, cell viability studies using the neutral red assay showed that PVP and HPMC-based solid dispersions had no additional inhibitory effect on Caco-2 cell line compared to the pure drug.

Sunscreens Containing Cyclodextrin Inclusion Complexes for Enhanced Efficiency: A Strategy for Skin Cancer Prevention.

Unprotected exposure of skin to solar ultraviolet radiation (UVR) may damage the DNA of skin cells and can lead to skin cancer. Sunscreens are topical formulations used to protect skin against UVR. The active ingredients of sunscreens are UV filters that absorb, scatter, and/or reflect UVR. Preventing the formation of free radicals and repairing DNA damages, natural antioxidants are also added to sunscreens as a second fold of protection against UVR. Antioxidants can help stabilise these formulations during the manufacturing process and upon application on skin. However, UV filters and antioxidants are both susceptible to degradation upon exposure to sunlight and oxygen. Additionally, due to their poor water solubility, natural antioxidants are challenging to formulate and exhibit limited penetration and bioavailability in the site of action (i.e., deeper skin layers). Cyclodextrins (CDs) are cyclic oligosaccharides that are capable of forming inclusion complexes with poorly soluble drugs, such as antioxidants. In this review, we discuss the use of CDs inclusion complexes to enhance the aqueous solubility of antioxidants and chemical UV filters and provide a protective shield against degradative factors. The role of CDs in providing a controlled drug release profile from sunscreens is also discussed. Finally, incorporating CDs inclusion complexes into sunscreens has the potential to increase their efficiency and hence improve their skin cancer prevention.

Controlling drug release with additive manufacturing-based solutions.

3D printing is an innovative manufacturing technology with great potential to revolutionise solid dosage forms. Novel features of 3D printing technology confer advantage over conventional solid dosage form manufacturing technologies, including rapid prototyping and an unparalleled capability to fabricate complex geometries with spatially separated conformations. Such a novel technology could transform the pharmaceutical industry, enabling the production of highly personalised dosage forms with well-defined release profiles. In this work, we review the current state of the art of using additive manufacturing for predicting and understanding drug release from 3D printed novel structures. Furthermore, we describe a wide spectrum of 3D printing technologies, materials, procedure, and processing parameters used to fabricate fundamentally different matrices with different drug releases. The different methods to manipulate drug release patterns including the surface area-to-mass ratio, infill pattern, geometry, and composition, are critically evaluated. Moreover, the drug release mechanisms and models that could aid exploiting the release profile are also covered. Finally, this review also covers the design opportunities alongside the technical and regulatory challenges that these rapidly evolving technologies present.

Cyclodextrin Diethyldithiocarbamate Copper II Inclusion Complexes: A Promising Chemotherapeutic Delivery System against Chemoresistant Triple Negative Breast Cancer Cell Lines.

Diethyldithiocarbamate Copper II (DDC-Cu) has shown potent anticancer activity against a wide range of cancer cells, but further investigations are hindered by its practical insolubility in water. In this study, inclusion complexes of DDC-Cu with hydroxypropyl beta-cyclodextrin (HP) or sulfobutyl ether beta-cyclodextrin (SBE) were prepared and investigated as an approach to enhance the apparent solubility of DDC-Cu. Formulations were prepared by simple mixing of DDC-Cu with both cyclodextrin (CDs) at room temperature. Phase solubility assessments of the resulting solutions were performed. DDC-Cu CD solutions were freeze-dried for further characterisations by DSC, thermogravimetric analysis (TGA) and FT-IR. Stability and cytotoxicity studies were also performed to investigate the maintenance of DDC-Cu anticancer activity. The phase solubility profile deviated positively from the linearity (Ap type) showing significant solubility enhancement of the DDC-Cu in both CD solutions (approximately 4 mg/mL at 20% w/w CD solutions). The DSC and TGA analysis confirmed the solid solution status of DDC-Cu in CD. The resulting solutions of DDC-Cu were stable for 28 days and conveyed the anticancer activity of DDC-Cu on chemoresistant triple negative breast cancer cell lines, with IC50 values less than 200 nM. Overall, cyclodextrin DDC-Cu complexes offer a great potential for anticancer applications, as evidenced by their very positive effects against chemoresistant triple negative breast cancer cells.

An innovative wax-based enteric coating for pharmaceutical and nutraceutical oral products.

In this work, a novel enteric coating based on natural waxes and alginate was reported. Initially, theophylline tablets were coated with emulsified ceresin wax in heated aqueous alginate solution using a fluidised bed coating technology. A coating level of 10% proved sufficient to prevent tablets from uptaking gastric medium (<5%) and produced a delayed release profile that complies to the pharmacopeial criteria of enteric coating release. Then, a wide range of emulsions based on other natural waxes (white beeswax, yellow beeswax, cetyl palmitate, carnauba wax or rice bran wax) yielded coatings with similar disintegration times and release profiles. Interestingly, the ceresin-based coating showed a superior performance at inhibiting acid uptake and enabling highly pH-responsive drug release in comparison to different commercially available GRAS enteric coating products (Eudraguard® Control, Swanlac® ASL10, and Aquateric™ N100). The coating was stable for 6 months at 30 °C and 65% RH. This innovative approach of applying hot O/W emulsion of natural waxes yielded an aesthetically attractive and stable coating with gastric protection and pH-sensitive release properties. The novel coating can be an efficient and promising alternative to overcome the shortcomings of current GRAS grade enteric coating products.

A novel natural GRAS-grade enteric coating for pharmaceutical and nutraceutical products.

In this study, enteric coatings based exclusively on naturally occurring ingredients were reported. Alginate (Alg) and pectin (Pec) blends with or without naturally occurring glyceride, glycerol monostearate (GMS), were initially used to produce solvent-casted films. Incorporating GMS in the natural polymeric films significantly enhanced the acid-resistance properties in gastric medium. Theophylline tablets coated with Alg-Pec blends without GMS disintegrated shortly after incubation in gastric medium (pH 1.2), leading to a premature and complete release of theophylline. Interestingly, tablets coated with Alg-Pec blends that contain the natural glyceride (GMS) resisted the gastric environment for 2 h with minimal drug release (<5%) and disintegrated rapidly following introduction to the intestinal medium, allowing a fast and complete drug release. Furthermore, the coating system proved to be stable for six months under accelerated conditions. These findings are particularly appealing to nutraceutical industry as they provide the foundation to produce naturally-occurring GRAS based enteric coatings.

Retinal cell regeneration using tissue engineered polymeric scaffolds.

Degenerative retinal diseases, such as age-related macular degeneration (AMD), can lead to permanent sight loss. Although intravitreal anti-vascular endothelial growth factor (VEGF) and steroid injections are effective for the management of early stages of wet and/or neovascular AMD (nAMD), no proven treatments currently exist for dry AMD or for the advanced geographic atrophy of the retina that follows. Tissue engineering (TE) has recently emerged as a promising alternative to repair retinal damaged and restore its functions. Here, we review recent advances in TE, with a particular emphasis on retinal regeneration. We provide an overview of retinal diseases, followed by a comprehensive review of TE techniques, cells, and polymers used in the fabrication of scaffolds for retinal cell regenerations, in particular the retinal pigment epithelium (RPE).

Potential Use of the Maillard Reaction for Pharmaceutical Applications: Gastric and Intestinal Controlled Release Alginate-Albumin Beads.

In this study, bovine serum albumin (BSA) and alginate (ALG) conjugates were synthesized by the Maillard reaction in order to evaluate their potential to develop controlled release drug delivery systems. The progress of the Maillard reaction was evidenced using ultraviolet (UV) absorbance, determination of BSA remaining free amino groups, and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). BSA-ALG conjugates possessed enhanced and tunable viscosity, foamability and foam stability. Foam generated from BSA-ALG conjugate solution was used to prepare floating gastroretentive calcium ALG beads. Unlike traditional ALG beads, BSA-ALG foam beads were able to float and sustain the ciprofloxacin (CIP) release in gastric medium. Interestingly, intestinal beads made of ALG, BSA-ALG physical mixture and BSA-ALG conjugate resulted in different release rates and orders of indomethacin (IND) in simulated intestinal fluids; while beads based on a physical mixture of BSA-ALG resulted in a first order sustained release profile, both systems based on ALG and BSA-ALG conjugate displayed zero order sustained release profiles with IND being released at a slower rate from the conjugate beads.

The use of albumin solid dispersion to enhance the solubility of unionizable drugs.

In this study, solid dispersions of prednisolone (PRD) and bovine serum albumin (BSA) were prepared by spray drying and freeze drying methods using a PRD:BSA solution [20:1 molar ratio (MR)]. PRD-BSA dispersed mixtures were characterized by scanning electron microscopy (SEM), and powder X-ray diffraction (XRD), and differential scanning calorimetry (DSC). PRD-BSA physical and dispersed mixtures showed significantly higher solubility in water than that of unprocessed drug. Enhancement factor of six was obtained in both physical mixture and solid dispersion solubility studies. In-vitro dissolution and release studies under physiological conditions showed an immediate release of PRD from the solid dispersions, with almost 90% of the drug dissolved in the first 10 min. PRD was immediately released from BSA binding complex. This study demonstrates the potential for the use of BSA to enhance the solubility and dissolution rate, hence bioavailability, of the unionizable drugs.

In Vitro Evaluation of Third Generation PAMAM Dendrimer Conjugates.

The present study compares the use of high generation G3 and low generation G0 Polyamidoamine (PAMAM) dendrimers as drug carriers of naproxen (NAP), a poorly water soluble drug. Naproxen was conjugated to G3 in different ratios and to G0 in a 1:1 ratio via a diethylene glycol linker. A lauroyl chain (L), a lipophilic permeability enhancer, was attached to G3 and G0 prodrugs. The G3 and G0 conjugates were more hydrophilic than naproxen as evaluated by the measurement of partitioning between 1-octanol and a phosphate buffer at pH 7.4 and pH 1.2. The unmodified surface PAMAM-NAP conjugates showed significant solubility enhancements of NAP at pH 1.2; however, with the number of NAP conjugated to G3, this was limited to 10 molecules. The lactate dehydrogenase (LDH) assay indicated that the G3 dendrimer conjugates had a concentration dependent toxicity towards Caco-2 cells. Attaching naproxen to the surface of the dendrimer increased the IC50 of the resulting prodrugs towards Caco-2 cells. The lauroyl G3 conjugates showed the highest toxicity amongst the PAMAM dendrimer conjugates investigated and were significantly more toxic than the lauroyl-G0-naproxen conjugates. The permeability of naproxen across monolayers of Caco-2 cells was significantly increased by its conjugation to either G3 or G0 PAMAM dendrimers. Lauroyl-G0 conjugates displayed considerably lower cytotoxicity than G3 conjugates and may be preferable for use as a drug carrier for low soluble drugs such as naproxen.

Efficient approach to enhance drug solubility by particle engineering of bovine serum albumin.

The aim of this study was to investigate the use of bovine serum albumin (BSA) as a solubility enhancer for indometacin (IND) as a model drug. IND-BSA solid dispersions were prepared by both spray drying and freeze drying techniques using IND:BSA solution (20:1 Molar Ratio (MR)) and IND:BSA suspension (100:1 MR). The solid state of IND in solid dispersions was characterised by SEM, DSC and XRD. The aqueous solubility of IND in the presence of increased amounts of BSA was evaluated. Additionally, IND dissolution and release profiles were evaluated. IND in solid dispersions with BSA showed significantly higher solubility in water than that of the physical mixture of both. Enhancement factors of 24,000 and 100,000 were obtained for the solid dispersion formulated in 20:1 MR and 100:1 MR, respectively. Dissolution studies in-vitro indicated a significant increase in the dissolution rate of IND from solid dispersions compared to that of the free drug, with almost 95% of the drug dissolved in the first 5min. Furthermore, an immediate release of IND from BSA solid dispersions was shown. The potential use of albumin as solubility enhancer for poorly soluble drugs, particularly, for immediate release volume-limited dosage forms is reported.

Effect of non-cross-linked calcium on characteristics, swelling behaviour, drug release and mucoadhesiveness of calcium alginate beads.

In this study, ibuprofen-loaded calcium alginate beads (CABs) with varying amounts of non-cross-linked calcium (NCL-Ca) were prepared using different washing methods. The influence of NCL-Ca on beads properties was investigated. Increasing the number or duration of washes led to significant decreases in the amount of NCL-Ca whereas the impact of the volume of washes was not significant. Approximately 70% of the initial amount of Ca(2+) was NCL-Ca which was removable by washing while only 30% was cross-linked (CL-Ca). Ca(2+) release from the CABs was bimodal; NCL-Ca was burst-released followed by a slower release of CL-Ca. Washing methods and the amount of NCL-Ca had significant influences on the encapsulation efficiency, beads weight, beads swelling, drug release profile and the mucoadhesiveness of CABs. This study highlighted the importance of washing methods and the amount of NCL-Ca to establish CABs properties and understand their behaviour in the simulated intestinal fluids (SIFs).

Removal of residual colonic ciprofloxacin in the rat by activated charcoal entrapped within zinc-pectinate beads.

Residual antibiotics reaching the colon have many deleterious effects on the colonic microbiota including the selection of new antibiotic resistances. In order to avoid the selection of ciprofloxacin resistance, intestine or colon-targeted zinc-pectinate beads containing activated charcoal (AC) were designed for the inactivation of residual ciprofloxacin in the gastrointestinal tract of rats. Bead stability after oral administration was adjusted by tuning the concentration of zinc in the gelling bath and the number of washings. Intestine and colon-targeted beads were administered along with 50mg/kg of ciprofloxacin and ciprofloxacin was dosed in the plasma and the feces using HPLC. Ciprofloxacin pharmacokinetics was not affected by the oral co-administration of beads. The co-administration of intestine-targeted beads led to a significant decrease of the residual fecal free ciprofloxacin with a pronounced dose effect. Our study suggests the rat model is not appropriate for the investigation of bacteria responsive colon-targeted beads probably due to the important anatomical and physiological differences between human and rat gastrointestinal tracts. The ability of AC loaded zinc-pectinate beads to selectively decrease the intestinal residual fraction of ciprofloxacin could provide a better protection of the intestinal microbiota and may prevent the emergence of ciprofloxacin resistance in the gastrointestinal tract.