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Rabab Kamel,1 Nahla A El-Wakil,2 Nermeen A Elkasabgy3 1Pharmaceutical Technology Department, National Research Centre, Cairo, Egypt; 2Cellulose and Paper Department, National Research Centre, Cairo, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, EgyptCorrespondence: Nermeen A ElkasabgyFaculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, EgyptTel +20 1141404144Email nermeen.ahmed.elkasabgy@pharma.cu.edu.eg; nermeenadelahmed@outlook.comPurpose: TEMPO-oxidized nanofibrillated cellulose (TONFC) originating from an agricultural waste (sugar cane) was utilized to prepare injectable in-situ forming hydrogel scaffolds (IHS) for regenerative medicine.Methods: TONFC was prepared and characterized for its morphology and chemical structure using TEM and FT-IR, respectively. The cold method was applied to prepare hydrogels. Various concentrations of poloxamer 407 were added to the prepared TONFC (0.5%w/w). Different sources of calcium, Fujicalin® (DCP) or hydroxyapatite (TCP), were used to formulate the aimed calcium-enriched raloxifene hydrochloride-loaded IHS. Gelation temperature, drug content, injectability and in-vitro drug release were evaluated along with the morphological characters. Cytocompatibility studies and tissue regeneration properties were assessed on Saos-2 cells.Results: TEM photograph of TONFC showed fibrous nanostructure. The selected formulation “Ca-IHS4” composed of TONFC+15% P407+10% TCP showed the most prolonged release pattern for 12 days with the least burst effect (about 25% within 24 h). SEM micro-photographs of the in-situ formed scaffolds showed a highly porous 3D structure. Cytocompatibility studies of formulation “Ca-IHS4” revealed the biocompatibility as well as improved cell adhesion, alkaline phosphatase enzyme activity and calcium ion deposition.Conclusion: The outcomes suggest that Ca-IHS4 presents a simple, safe-line and non-invasive strategy for bone regeneration.Keywords: nanofibrillated cellulose, raloxifene hydrochloride, calcium phosphate, in-situ forming hydrogel scaffolds, bone regeneration

Islam M Adel,1 Mohamed F ElMeligy,1 Mohamed EA Abdelrahim,2 Amr Maged,3,4 AbdelFattah A Abdelkhalek,5 Azza MM Abdelmoteleb,6 Nermeen A Elkasabgy1 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt; 2Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt; 3Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt; 4Pharmaceutical Factory, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt; 5Department of Microbiology of Supplementary General Science, Faculty of Oral & Dental Medicine, Future University in Egypt, Cairo, Egypt; 6Department of Chemistry, Toxicology and Feed Deficiency, Animal Health Research Institute, Agricultural Research Center, Giza, EgyptCorrespondence: Islam M AdelFaculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, 11562, EgyptTel +20 1226445511Email islam.hashim@pharma.cu.edu.egPurpose: The goal was to directly deliver curcumin, a natural polyphenolic anticancer and anti-inflammatory compound, to the lung tissues with minimal systemic exposure through the fabrication of proliposomes, overcoming its poor aqueous solubility and oral bioavailability.Methods: Nano-spray drying was employed to prepare proliposomes using hydroxypropyl beta-cyclodextrin as a carrier. Lecithin and cholesterol were used as lipids, stearylamine and Poloxamer 188 were added as positive charge inducer and a surfactant, respectively. Different characterization parameters were evaluated like percentage yield, entrapment efficiency, drug loading, aerodynamic particle size, in vitro release besides morphological examination. Cytotoxicity studies on cell line A549 lung tumor cells as well as in vivo lung pharmacokinetic studies were also carried.Results: The optimized formulations showed superior aerosolization properties coupled their enhanced ability to reach deep lung tissues with a high % of fine particle fraction. Cytotoxicity studies using MTT assay demonstrated enhanced growth inhibitory effect on lung tumor cells A549 and significant reduction of proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6 and interleukin-10 compared to the pure drug. Results of lung pharmacokinetic tests confirmed the superiority of proliposomal curcumin over curcumin powder in both, the rate and extent of lung tissue absorption, as well as the mean residence time within the lung tissues.Conclusion: The pulmonary delivery of curcumin-loaded proliposomes as dry powder provides a direct approach to lung tissues targeting while avoiding the limitations of the oral route and offering a non-invasive alternative to the parenteral one.Keywords: curcumin, proliposomes, cyclodextrin, dry powder inhalers, human epithelial cell line, pulmonary delivery

The current study aimed to fabricate curcumin-loaded bilosomal hydrogel for topical wound healing purposes, hence alleviating the poor aqueous solubility and low oral bioavailability of curcumin. Bilosomes were fabricated via the thin film hydration technique using cholesterol, Span ® 60, and two different types of bile salts (sodium deoxycholate or sodium cholate). Bilosomes were verified for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%), and in vitro drug release besides their morphological features. The optimum formulation was composed of cholesterol/Span ® 60 (molar ratio 1:10 w / w ) and 5 mg of sodium deoxycholate. This optimum formulation was composed of a PS of 246.25 ± 11.85 nm, PDI of 0.339 ± 0.030, ZP of -36.75 ± 0.14 mv, EE% of 93.32% ± 0.40, and the highest percent of drug released over three days (96.23% ± 0.02). The optimum bilosomal formulation was loaded into alginate dialdehyde/chitosan hydrogel cross-linked with calcium chloride. The loaded hydrogel was tested for its water uptake capacity, in vitro drug release, and in vivo studies on male Albino rats. The results showed that the loaded hydrogel possessed a high-water uptake percent at the four-week time point (729.50% ± 43.13) before it started to disintegrate gradually; in addition, it showed sustained drug release for five days (≈100%). In vivo animal testing and histopathological studies supported the superiority of the curcumin-loaded bilosomal hydrogel in wound healing compared to the curcumin dispersion and plain hydrogel, where there was a complete wound closure attained after the three-week period with a proper healing mechanism. Finally, it was concluded that curcumin-loaded bilosomal hydrogel offered a robust, efficient, and user-friendly dosage form for wound healing.

Statins have been long used in tissue engineering, besides their marketed hypolipidemic benefits. The aim of this research was to sustain the release of rosuvastatin calcium from bi-polymeric hydrogel scaffolds. A bi-polymer blend technique was used to enhance the mechanical properties of the fabricated hydrogels. Briefly, hydrogels were prepared via crosslinking gellan gum as the main polymer together with a secondary polymer in the presence of Ca 2+ . The fabricated hydrogels were assessed in terms of % swelling capacity, hydrolytic degradation and % drug released to determine the most efficient carrier system. The selected hydrogel exhibited a swelling capacity of 131.45±1.49 % following 3 weeks in an aqueous environment with a % weight loss of 15.73±1.86 % after 4 weeks post-equilibrium in aqueous medium. The results ensure a proper window for adequate drug diffusion and nutrient exchange. Sustained release was attained where 94.61±2.77 % of rosuvastatin was released at the 4-week mark. Later, FT-IR and DSC, were carried out and suggested the successful crosslinking and formation of new matrix. SEM images demonstrated the porous surface of the hydrogel while a Young's modulus of 888.558±73.549 kPa indicated the suitability of the hydrogel for soft tissue engineering. In-vivo testing involved implanting the selected hydrogel at precisely surgical cuts in the Achilles tendon of male Wistar Albino rats. Upon visual and microscopic evaluation, enhanced rates of fibrous tissue formation, vascularization and collagen expression were clearly noticed in the treatment group., Competing Interests: Declaration of Competing Interest The authors of this work confirm that there is no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cellulose, the most abundant biopolymer in nature, is derived from various sources. The production of pharmaceutical textiles based on cellulose represents a growing sector. In medicated textiles, textile and pharmaceutical sciences are integrated to develop new healthcare approaches aiming to improve patient compliance. Through the possibility of cellulose functionalization, pharmaceutical textiles can broaden the applications of cellulose in the biomedical field. This narrative review aims to illustrate both the methods of extraction and preparation of cellulose fibers, with a particular focus on nanocellulose, and diverse pharmaceutical applications like tissue restoration and antimicrobial, antiviral, and wound healing applications. Additionally, the merging between fabricated cellulosic textiles with drugs, metal nanoparticles, and plant-derived and synthetic materials are also illustrated. Moreover, new emerging technologies and the use of smart medicated textiles (3D and 4D cellulosic textiles) are not far from those within the review scope. In each section, the review outlines some of the limitations in the use of cellulose textiles, indicating scientific research that provides significant contributions to overcome them. This review also points out the faced challenges and possible solutions in a trial to present an overview on all issues related to the use of cellulose for the production of pharmaceutical textiles.

Bones are subject to different types of damages ranging from simple fatigue to profound defects. In serious cases, the endogenous healing mechanism is not capable of healing the damage or restoring the normal structure and function of the bony tissue. The aim of this research was to achieve a sustained delivery of rosuvastatin and assess its efficacy in healing bone tissue damage. Rosuvastatin was entrapped into silica nanoparticles and the system was loaded into an alginate hydrogel to be implanted in the damaged tissue. Silica nanoparticles were formulated based on a modified Stöber technique and alginate hydrogel was prepared via sprinkling alginate onto silica nanoparticle dispersion followed by addition of CaCl 2 to promote crosslinking and hydrogel rigidification. The selected nanoparticle formulation possessed high % drug content (100.22 ± 0.67%), the smallest particle size (221.00 ± 7.30 nm) and a sustained drug release up to 4 weeks (98.72 ± 0.52%). The fabricated hydrogel exhibited a further delay in drug release (81.52 ± 4.81% after 4 weeks). FT-IR indicated the silica nanoparticle formation and hydrogel crosslinking. SEM visualized the porous and dense surface of hydrogel. In-vivo testing on induced bone defects in New Zealand rabbits revealed the enhanced rate of new bone tissue formation, its homogeneity in color as well as similarity in structure to the original tissue., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Islam M. Adel reports equipment, drugs, or supplies was provided by Ellebedy Fellowship., (© 2023 The Authors.)

Stimuli-responsive transformable biomaterials development can be manipulated practically by fine-tuning the built-in molecular design of their structural segments. Here, we demonstrate a peptide assembly by the bola-type amphiphilic polypeptide, glycolic acid-polysarcosine (PSar) 13 - b -(L-Leu-Aib) 6 - b -PSar 13 -glycolic acid (S 13 L 12 S 13 ), which shows morphological transformations between hydrophilic chain-driven and hydrophobic unit-driven morphologies. The hydrophobic α-helical unit (L-Leu-Aib) 6 precisely controls packing in the hydrophobic layer of the assembly and induces tubule formation. The densified, hydrophilic PSar chain on the assembly surface becomes slightly more hydrophobic as the temperature increases above 70 °C, starting to disturb the helix-helix interaction-driven formation of tubules. As a result, the S 13 L 12 S 13 peptide assembly undergoes a reversible vesicle-nanotube transformation following a time course at room temperature and a heat treatment above 80 °C. Using membrane fluidity analysis with DPH and TMA-DPH and evaluating the environment surrounding the PSar side chain with NMR, we clarify that the vesicle was in a kinetically stable state driven by the dehydrated PSar chain, while the nanotube was in a thermodynamically stable state.

Rasagiline mesylate (RSM) is a hydrophilic drug with poor oral bioavailability (36%) because of hepatic first-pass metabolism. The present study focuses on delivering RSM directly to the brain through its inclusion within transferosomal in situ gel administered through the intranasal (IN) route. Transferosomes were formed by the thin-film hydration method with the aid of Design-Expert ® software by varying the edge activator (EA) type in the absence or presence of cholesterol. By desirability calculations, the optimum formulation was composed of phosphatidylcholine and sodium deoxycholate as an EA (5:1% w / w ) with no cholesterol. The optimum formulation was 198.63 ± 34.98 nm in size and displayed an entrapment efficiency of 95.73 ± 0.09%. Transmission electron microscopy revealed discrete and spherical vesicles. Optimized transferosomes were further incorporated into an in situ gel composed of 0.5% pectin, 15% Pluronic ® F-127, and 5% Pluronic ® F-68 and tested for the in vivo performance. The systemic as well as brain kinetics were assessed in rats by comparing the IN-administered in situ gel to the IV aqueous solution. The optimum in situ gel showed safety and biocompatibility on rats' nasal mucosa with enhanced brain bioavailability (131.17%). Drug targeting efficiency and direct transport percentage indices (304.53% and 67.16%, respectively) supported successful brain targeting offering direct nose-to-brain drug delivery.

Curcumin or turmeric is the active constituent of Curcuma longa L. It has marvelous medicinal applications in many diseases. When the skin integrity is compromised due to either acute or chronic wounds, the body initiates several steps leading to tissue healing and skin barrier function restoration. Curcumin has very strong antibacterial and antifungal activities with powerful wound healing ability owing to its antioxidant activity. Nevertheless, its poor oral bioavailability, low water solubility and rapid metabolism limit its medical use. Tailoring suitable drug delivery systems for carrying curcumin improves its pharmaceutical and pharmacological effects. This review summarizes the most recent reported curcumin-loaded delivery systems for wound healing purposes, chiefly hydrogels, films, wafers, and sponges. In addition, curcumin nanoformulations such as nanohydrogels, nanoparticles and nanofibers are also presented, which offer better solubility, bioavailability, and sustained release to augment curcumin wound healing effects through stimulating the different healing phases by the aid of the small carrier.

The eye is an invulnerable organ with intrinsic anatomical and physiological barriers, hindering the development of a pioneer ocular formulation. The aim of this work was to develop an efficient ocular delivery system that can augment the ocular bioavailability of the antifungal drug, terconazole. Mesoporous silica microparticles, Syloid ® 244 FP were utilized as the carrier system for terconazole. Preliminary studies were carried out using different drug:Syloid ® weight ratios. The optimum weight ratio was mixed with various concentrations (30 and 60%w/w) of poly (lactic-co-glycolic acid) (PLGA), ester or acid-capped and with different monomers-ratio (50:50 and 75:25) using the nano-spray dryer. Results revealed the superiority of drug:Syloid ® weight ratio of 1:2 in terms of yield percentage (Y%), SPAN and drug content percentage (DC%). Furthermore, incorporation of PLGA with lower glycolic acid monomer-ratio significantly increased Y%. In contrast, increasing the glycolic acid monomer-ratio resulted in higher DC% and release efficiency percentage (RE%). Additionally, doubling PLGA concentration significantly reduced Y%, DC%, drug loading percentage (DL%) and RE%. Applying desirability function in terms of increasing DC%, DL% besides RE% and decreasing SPAN, the selected formulation was chosen for DSC, XRD and SEM investigations. Results confirmed the successful loading of amorphized terconazole on PLGA-modified Syloid ® microparticles. Moreover, pharmacokinetic studies for the chosen formulation on male Albino rabbits' eyes revealed a 2, 6.7 and 25.3-fold increase in mean residence time, C max and AUC 0-24 -values, respectively, compared to the drug suspension. PLGA-modified Syloid ® microparticles represent a potential option to augment the bioavailability of ocular drugs.

Microfluidics is used to manipulate fluid flow in micro-channels to fabricate drug delivery vesicles in a uniform tunable size. Thanks to their designs, microfluidic technology provides an alternative and versatile platform over traditional formulation methods of nanoparticles. Understanding the factors that affect the formulation of nanoparticles can guide the proper selection of microfluidic design and the operating parameters aiming at producing nanoparticles with reproducible properties. This review introduces the microfluidic systems' continuous flow (single-phase) and segmented flow (multiphase) and their different mixing parameters and mechanisms. Furthermore, microfluidic approaches for efficient production of nanoparticles as surface modification, anti-fouling, and post-microfluidic treatment are summarized. The review sheds light on the used microfluidic systems and operation parameters applied to prepare and fine-tune nanoparticles like lipid, poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles as well as cross-linked nanoparticles. The approaches for scale-up production using microfluidics for clinical or industrial use are also highlighted. Furthermore, the use of microfluidics in preparing novel micro/nanofluidic drug delivery systems is presented. In conclusion, the characteristic vital features of microfluidics offer the ability to develop precise and efficient drug delivery nanoparticles.

Tissue engineering has emerged as an interesting field nowadays; it focuses on accelerating the auto-healing mechanism of tissues rather than organ transplantation. It involves implanting an In Vitro cultured initiative tissue or a scaffold loaded with tissue regenerating ingredients at the damaged area. Both techniques are based on the use of biodegradable, biocompatible polymers as scaffolding materials which are either derived from natural (e.g. alginates, celluloses, and zein) or synthetic sources (e.g. PLGA, PCL, and PLA). This review discusses in detail the recent applications of different biomaterials in tissue engineering highlighting the targeted tissues besides the in vitro and in vivo key findings. As well, smart biomaterials (e.g. chitosan) are fascinating candidates in the field as they are capable of elucidating a chemical or physical transformation as response to external stimuli (e.g. temperature, pH, magnetic or electric fields). Recent trends in tissue engineering are summarized in this review highlighting the use of stem cells, 3D printing techniques, and the most recent 4D printing approach which relies on the use of smart biomaterials to produce a dynamic scaffold resembling the natural tissue. Furthermore, the application of advanced tissue engineering techniques provides hope for the researchers to recognize COVID-19/host interaction, also, it presents a promising solution to rejuvenate the destroyed lung tissues., (© 2022. The Author(s).)

This research assesses the beneficial effects of loading terconazole, a poorly water-soluble antifungal drug in silica/chitosan nanoparticles (SCNs) for ocular delivery. Nanoparticles were fabricated by the simple mixing of tetraethyl ortho silicate (TEOS) and chitosan HCl as sources of silica and nitrogen, respectively, along with alcoholic drug solution in different concentrations. Freeze-dried nanoparticles were fabricated using cyclodextrins as cryoprotectants. SCNs were assessed for their particle size, PDI, yield, drug loading and in vitro release studies. A 2 3 .3 1 full factorial experimental design was constructed to optimize the prepared SCNs. DSC, XRD, FTIR, in addition to morphological scanning were performed on the optimized nanoparticles followed by an investigation of their pharmacokinetic parameters after topical ocular application in male Albino rabbits. The results reveal that increasing the water content in the preparations causes an increase in the yield and size of nanoparticles. On the other hand, increasing the TEOS content in the preparations, caused a decrease in the yield and size of nanoparticles. The optimized formulation possessed excellent mucoadhesive properties with potential safety concerning the investigated rabbit eye tissues. The higher C max and AUC 0-24 values coupled with a longer t max value compared to the drug suspension in the rabbits' eyes indicated the potential of SCNs as promising ocular carriers for poorly water-soluble drugs, such as terconazole.

Tissue regeneration is an auto-healing mechanism, initiating immediately following tissue damage to restore normal tissue structure and function. This falls in line with survival instinct being the most dominant instinct for any living organism. Nevertheless, the process is slow and not feasible in all tissues, which led to the emergence of tissue engineering (TE). TE aims at replacing damaged tissues with new ones. To do so, either new tissue is being cultured in vitro and then implanted, or stimulants are implanted into the target site to enhance endogenous tissue formation. Whichever approach is used, a matrix is used to support tissue growth, known as 'scaffold'. In this review, an overall look at scaffolds fabrication is discussed, starting with design considerations and different biomaterials used. Following, highlights of conventional and advanced fabrication techniques are attentively presented. The future of scaffolds in TE is ever promising, with the likes of nanotechnology being investigated for scaffold integration. The constant evolvement of organoids and biofluidics with the eventual inclusion of organ-on-a-chip in TE has shown a promising prospect of what the technology might lead to. Perhaps the closest technology to market is 4D scaffolds following the successful implementation of 4D printing in other fields.

In situ forming implants (IFIs) are non-surgical approach using biodegradable polymers to treat bone fractures. The study aimed at preparing dual-drug-loaded IFIs to deliver pitavastatin (osteogenic drug) and tedizolid (antibiotic) using zein as the implant matrix via solvent-induced phase inversion method. At first, several investigations were done on pitavastatin-loaded zein IFIs, where three concentrations of zein were used (10, 20, and 30% w/v ). IFIs were evaluated for their solidification time, rheological properties, injectability, and in vitro release. IFIs containing bioactive glass nanoparticles were prepared by the addition of non-doped bioactive glass nanoparticles (BGT 0 ; 1, 3, 5, and 10% w/v ) or titanium-doped bioactive glass nanoparticles (BGT 5 ; 1% w/v ) to the selected concentration of zein (30% w/v ) and then evaluated. The optimized dual-medicated implant (D-ZIFI 1) containing pitavastatin, tedizolid, sodium hyaluronate (3% w/v ), and BGT 5 (1% w/v ) was prepared and compared to IFI lacking both sodium hyaluronate and BGT 5 (D-ZIFI 2). D-ZIFI 1 and 2 sustained the release profiles of both drugs for 28 days. SEM images proved the interconnected porous structure of D-ZIFI 1 due to sodium hyaluronate. In vivo studies on surgically induced bone defects in Sprague-Dawley rats signified the proper accelerated bone healing ability of D-ZIFI 1 over D-ZIFI 2. Results presented D-ZIFI 1 as a promising, effective, non-surgical approach for bone healing.

This study aimed at delivering intranasal zolmitriptan directly to the brain through preparation of bilosomes incorporated into a mucoadhesive in situ gel with extended nasal mucociliary transit time. Zolmitriptan-loaded bilosomes were constructed through a thin film hydration method applying Box-Behnken design. The independent variables were amount of sodium deoxycholate and the amount and molar ratio of cholesterol/Span ® 40 mixture. Bilosomes were assessed for their entrapment efficiency, particle size and in vitro release. The optimal bilosomes were loaded into mucoadhesive in situ gel consisting of poloxamer 407 and hydroxypropyl methylcellulose. The systemic and brain kinetics of Zolmitriptan were evaluated in rats by comparing intranasal administration of prepared gel to an IV solution. Statistical analysis suggested an optimized bilosomal formulation composition of sodium deoxycholate (5 mg) with an amount and molar ratio of cholesterol/Span ® 40 mixture of 255 mg and 1:7.7, respectively. The mucoadhesive in situ gel containing bilosomal formulation had a sol-gel temperature of 34.03 °C and an extended mucociliary transit time of 22.36 min. The gelling system possessed enhanced brain bioavailability compared to bilosomal dispersion (1176.98 vs. 835.77%, respectively) following intranasal administration. The gel revealed successful brain targeting with improved drug targeting efficiency and direct transport percentage indices. The intranasal delivery of mucoadhesive in situ gel containing zolmitriptan-loaded bilosomes offered direct nose-to-brain drug targeting with enhanced brain bioavailability.

The goal of this research was to evaluate the beneficial effects of topical curcumin loaded freeze-dried wafers in wound healing. Curcumin wafers were fabricated by cross-linking of chitosan with beta glycerophosphate under magnetic stirring. Composite wafers were prepared by the addition of sodium hyaluronate. Wafers were fabricated by freeze-drying technique. The resulted wafers were examined by naked eye and their dimensions were measured using a caliper. % Drug content, in-vitro release and % water uptake tests were conducted to characterize the fabricated wafers. Porosity testing, compressive mechanical behavior, morphological examination using scanning electron microscopy, thermal behavior using differential scanning calorimetry and Fourier transform infrared spectroscopy were all carried out on the optimized cross-linked wafers followed by their microbiological assays and cytotoxicity studies. The results showed that the optimized wafers possessed high water uptake capabilities while entertaining very high porosity levels (86-89%). Microbiological assay revealed the superiority of the selected curcumin wafers versus free curcumin in bacterial growth inhibition against Staphylococcus epidermidis and Staphylococcus aureus (MRSA) bacteria. The anti-inflammatory effects of the selected curcumin wafers were evaluated against pro-inflammatory cytokines. The results suggested that they were significantly better than free curcumin in lowering cytokines levels. To conclude, the obtained findings revealed that curcumin wafers offered a promising solution in the field of wound healing., (Copyright © 2021. Published by Elsevier B.V.)

Mucilage is a soluble dietary fiber used as a food additive to give foods a firmer texture, aside from its many health benefits and pharmacological properties. It is a polysaccharide in nature, composed of large molecules of sugars and uronic acid moieties. The extraction of mucilage is achieved from a wide variety of plant parts, including rhizomes, roots, and seeds, and it has also been reported from microorganisms. In this review, the nutritional and medicinal applications of mucilage are described in the context of the different mucilage types. The current article highlights state-of-the-art valorization practices relating to mucilage and its potential novel usages in the food industry and nutraceuticals, and as a prebiotic, in addition to its nutritional and anti-nutritional values. Analysis of the prebiotic action of mucilage with respect to its structure activity relationship, as well as how it modulates gut bacteria, is presented for the first time and in the context of its known health benefits inside the colon. It is recommended that more investigations are carried out to maximize the health benefits of mucilage and ensure its safety, especially upon long-term usage.

Demand for safe, environmentally friendly and minimally processed food additives with intrinsic technological (stabilizing, texturizing, structuring) and functional potential is already on the rise. There are actually several natural excipients eligible for pharmaceutical formulation. Mucilage, as a class constitutes arabinoxylan and rhamnogalacturonan-based biomolecules used in the pharmaceutical, environmental as well as phytoremediation industries owing to its particular structure and properties. These compounds are widely used in pharmaceutical, food and cosmetics, as well as, in agriculture, paper industries. This review emphasizes mucilage valuable applications in the pharmaceutical and industrial fields. In this context, much focus has recently been given to the valorization of mucilage as an ingredient for food or nutraceutical applications. Furthermore, different optimization and extraction techniques are presented to develop better utilization and/or enhanced yield of mucilage. The highlighted mucilage extraction methods warrant assessing up-scale processes to encourage for its industrial applications. The current article capitalizes on cutting-edge characteristics of mucilage and posing for other possible innovative applications in non-food industries. Here, the first holistic overview of mucilage with regards to its physicochemical properties and potential novel usages is presented., Competing Interests: Declaration of competing interest Authors declare no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cellulose was and still is the most abundant biopolymer generated from all plant fibers including agricultural wastes. Using this waste as a starting material in the production of new products is a field of great interest. The demand for renewable and available resources in combination with advanced technologies is a necessity to develop new generations of advanced nanomaterials. This review aims to present integrated details on the extraction techniques and structure of nanofibrillated cellulose as well as cellulose nanocrystals derived from agricultural wastes besides the different treatment methods used to be suitable for several pharmaceutical applications. Different pharmaceutical applications are described, including controlled, sustained or rapid drug delivery, stabilizing agent, and its use as safe and sustained environment for cell culture allowing its use in tissue engineering field., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In the recent decade, three-dimensional (3D) printers started to grow strongly in the field of drug delivery and personalized medicine, as they can tailor dosage forms according to the needs of each individual. This review gives an overview on the basic principles of layer-by-layer building of pharmaceutical dosage forms using different types of 3D printers. Also, the effect of infill percentage and pattern, raster orientation, layer thickness, thermal processing parameters on the printed formulations is highlighted. Additionally, the complex designs constructed by the 3D printers in order to modify the product shape, density, mucoadhesion and drug release are recapitulated. This review summarizes numerous applications for 3D printing in building drug-loaded structures including tablets, scaffolds, implants, microneedles, capsules, films, hydrogels, mouthguards, tubes, stents, vaginal suppositories and rings as well as in pediatric field. Finally, we suggest further investigational researches to aid in the widespread of 3D printing in the industrial pharmaceutical field. The 3D printing technology is expected to revolutionize drug delivery systems through customization of pharmaceutical formulations., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Respiratory tract is one of the oldest routes for drug delivery. It can be used for local and systemic drug deliveries. Inhalation therapy has several advantages over oral. It delivers the drug efficiently to the lung with minimal systemic exposure, thus avoiding systemic side effects common with oral route. In this review, different types of inhaler devices are illustrated like metered dose inhalers (MDIs), dry powder inhalers (DPIs), nebulizers, and the new soft mist inhalers (SMIs). Since dry powder is more stable than when in liquid form, we will discuss in detail DPIs highlighting different techniques utilized in preparation of dry powders with or without carrier to improve flowability and drug delivery to deep lungs. Types of DPIs are briefly discussed with examples from the market. Several mechanisms for particle deposition are mentioned with factors governing the process. Pharmacokinetic profile of the inhaled particles is detailed starting from the dissolution, followed by the rapid absorption and ending with systemic clearance. New technologies like 3D printing in pulmonary field are also highlighted.

This study intended to design novel nanofibrillated cellulose/cyclodextrin-based 3D scaffolds loaded with raloxifene hydrochloride for bone regeneration. The scaffolds were prepared using two different types of cyclodextrins namely; beta-cyclodextrin and methyl-beta-cyclodextrin. The prepared scaffolds were evaluated by characterizing their porosity, compressive strength, in-vitro drug release, FT-IR and XRD as well as their morphological properties using SEM. Results presented that the prepared scaffolds were highly porous, additionally, the scaffold containing drug/beta-cyclodextrin kneaded complex (SC5) showed the most controlled drug release pattern with the least burst effect and reached almost complete release at 480 h. The in-vitro cytocompatibility and regenerative effect of the chosen scaffold (SC5) was assessed using Saos-2 cell line. Results proved that SC5 was biocompatible. Moreover, it enhanced the cell adhesion, alkaline phosphatase enzyme expression and calcium ion deposition which are essential factors for bone mineralization. The obtained observations presented a novel, safe and propitious approach for bone engineering., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In-situ forming implants receive great attention for repairing serious bone injuries. The aim of the present study was to prepare novel chitosan in-situ forming implants (CIFI) loaded with bioactive glass nanoparticles and/or raloxifene hydrochloride (RLX). Incorporating raloxifene hydrochloride (RLX) as a selective estrogen receptor modulator was essential to make use of its anti-resorptive properties. The prepared formulae were tested for their in-vitro gelation time, drug release, injectability, rheological properties, erosion rate and morphological properties. Results revealed that the formulation composed of 1% (w/v) chitosan with 2% (w/v) NaHCO 3 and 1% (w/v) bioactive glass nanoparticles (CIFI-BG) possessed the most sustained drug release profile which extended over four months with low burst release effect compared to the same formulation lacking bioactive glass nanoparticles (CIFI). Selected formulations were tested for their ability to enhance bone regeneration in induced puncture in rate tibia. Results declared that these formulations were able to enhance bone regeneration after 12 weeks in comparison to the untreated tibial punctures and that containing bioactive glass could be considered as novel approach for treatment of serious bone injuries which require long term treatment and internal mechanical bone support during healing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Osteoarthritis is a major problem in elder people. Etoricoxib-loaded bio-adhesive hybridized nanoparticles were prepared using polylactic acid (PLA) and chitosan hydrochloride (CS-HCl) in presence of Captex®200 as a liquid oil, polyvinyl alcohol (PVA) and Tween®80 as surfactants. The study aimed to present a new intra-articular treatment of osteoarthritis with anti-inflammatory as well as bone rebuilding effects. Hybridized nanoparticles were fabricated applying the emulsion solvent evaporation technique then assessed for particle size, zeta potential, entrapment efficiency and in-vitro drug release. Furthermore, FT-IR and DSC in addition to morphological examination were done. Results revealed that the formulation composed of PLA:Captex®200 in ratio 1:2 (w/w), 1%w/v Tween®80, 0.3% w/v CS-HCl and 3%w/v PVA possessed the smallest particle size and the most sustained drug release, thus was sorted for further analyses. The selected formulation ability to interact with the negatively charged sodium fluroscein was evaluated to predict its binding with the naturally occurring hyaluronic acid in the knee joint where promising results were obtained. Results showed the cytocompatibility of the formulation when tested using MC3T3-E1 normal bone cell line, enhanced ALP activity and increased calcium ion deposition and binding. Results suggested that the presented formulation can be considered as an innovative approach for osteoarthritis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries., (Copyright © 2019. Published by Elsevier B.V.)

Febuxostat suffers from relatively low bioavailability owing to the poor drug solubility and hepatic first-pass effect. This study aimed to prepare highly drug-loaded self-nanoemulsifying self-nanosuspension systems (SNESNS). SNESNS were designed to improve febuxostat's oral bioavailability by enhancing its solubility. Different oil and surfactant/co-surfactant mixtures were used for the preparation of SNESNS. The prepared SNESNS were estimated for their particle size, in vitro drug release and transmission electron microscopy (TEM). Results revealed that the oil mixture of Capryol™ 90:Miglyol ® 812 (1:1 w/w) with surfactant/co-surfactant mixture of Cremophor ® RH 40/Transcutol ® HP loaded with drug in 4-fold greater concentration than its saturated solubility resulted in the formation of SNESNS by dilution under the effect of magnetic stirring. SNESNS were freeze-dried using trehalose as a cryoprotectant. TEM images and the bimodal particle size curve confirmed the formation of the biphasic nanosystems after dilution (nanoemulsion and nanosuspension). Higher C max and AUC 0-48 values compared to those of the market product Feburic ® tablets confirmed the success of the SNESNS as a promising carrier for drugs suffering from poor water solubility like febuxostat.

Designing scaffolds with optimum properties is an essential factor for tissue engineering success. They can be seeded with isolated cells or loaded with drugs to stimulate the body ability to repair or regenerate the injured tissues by acting as centers for new tissue formation. Recently, scaffolds gained a significant interest as principal candidates for tissue engineering due to overcoming the autograft or allograft's associated problems. The advancement of the tissue engineering field relies mainly on the introduction of new biomaterials for scaffolds' fabrication. This review presents and criticizes different scaffolds' fabrication techniques with particular emphasis on the fibrous, injectable in situ forming, foam, 3D freeze-dried, 3D printed, and 4D scaffolds. This article highlights on scaffolds' composition which would be beneficial for developing scaffolds that could potentially help to meet the demand for both drug delivery and tissue regeneration.

Mucoadhesive olaminosomes are novel nanocarriers designed to control agomelatine release and enhance its bioavailability. Olaminosomes were prepared using oleic acid, oleylamine and sorbitan monooleate adopting thin film hydration technique. Chitosan HCl was added to impart the mucoadhesive properties to the olaminosomes. Mucoadhesive olaminosomes were characterized for their particle size, in-vitro drug release and irritation potentiality in rabbit eyes. The reduction in intraocular pressure (IOP) through 8 h in male New Zealand Albino rabbits was measured after administration of the selected formulations. Histopathological changes in rabbits' eye were also evaluated. Results revealed that increasing the amount of the added oleylamine decreased the particle size of the resulted vesicles and increased the drug release rate. Olaminosomes showed enhanced drug absorption, hence more reduction in IOP was observed. Moreover, using chitosan HCl might increase the residence time of the formulation in the eye and hence improved the absorption of the drug. No histopathological changes in rabbits' eye were detected after the application of mucoadhesive olaminosomes concluding their safety on the ocular tissues. In conclusion, mucoadhesive olaminosomes succeeded in enhancing agomelatine bioavailability in rabbits' eyes confirming the development of a novel ocular nanocarrier for insoluble drugs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Roflumilast is a selective inhibitor of phosphodiesterase-4 isoenzyme in lung cells. Having psychiatric adverse reactions when administered orally affects negatively the patients' adherence to the drug. This work aimed to prepare emulsified spray dried alginate microparticles for the pulmonary delivery of roflumilast. Sodium alginate was used as microparticle-forming material, isopropyl myristate as an oil, Tween®80 as surfactant and calcium beta-glycerophosphate as cross-linking agent to enhance the mechanical properties of the particles. The prepared particles were evaluated for their encapsulation efficiency, particle size and in-vitro drug release. From the studied carriers, beta-cyclodextrin (CD) was the best regarding giving formulation with smaller particle size and more sustained drug release. The inhalation profile of CD-based microparticles was investigated using Anderson cascade impactor. The aerosolization profile of CD-based microparticles suggested their efficiency to deliver the drug deep in the lung. The CD-based microparticles possessed more inhibitory effects on the viability of A549 cells and on the pro-inflammatory cytokines (TNF-α, IL-6 and IL-10) compared to the pure drug. Hence, CD-based microparticles could regulate the tumorigenesis besides tumor-associated inflammation. Finally, CD-based microparticles showed more sustained bronchodilatation properties in healthy human volunteers when compared to Ventolin®HFA. CD-based microparticles proved to be a promising carrier for inhaled roflumilast in human., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Quetiapine fumarate (QF), an anti-schizophrenic drug, suffers from rapid elimination and poor bioavailability due to extensive first-pass effect. Intramuscularly (IM) injected lipospheres were designed to enhance the drug's bioavailability and extend its release. A central composite design was applied to optimize the liposphere preparation by a melt dispersion technique using Compritol® 888 ATO or glyceryl tristearate as lipid component and polyvinyl alcohol as surfactant. Lipospheres were evaluated for their particle size, entrapment efficiency, and in vitro release. The optimized QF lipospheres were prepared using a Compritol® 888 ATO fraction of 18.88% in the drug/lipid mixture under a stirring rate of 3979 rpm. The optimized lipospheres were loaded into a thermoresponsive in situ forming gel (TRIFG) and a liquid crystalline in situ forming gel (LCIFG) to prevent in vivo degradation by lipases. The loaded gels were re-evaluated for their in vitro release and injectability. Bioavailability of QF from liposphere suspension and bio-shielding in situ gels loaded with QF lipospheres were assessed in rabbits compared to drug suspension. Results revealed that the AUC 0-72 obtained from the liposphere-loaded TRIFG was ∼3-fold higher than that obtained from the aqueous drug suspension indicating the bio-shielding effect of Poloxamer® 407 gel to inhibit the biodegradation of the lipospheres prolonging the residence of the drug in the muscle for higher absorption. Our results propose that bio-shielding in situ Poloxamer® 407 gels loaded with lipospheres is promising for the development of IM depot injection of drugs having extensive first-pass metabolism and rapid elimination.

Periapical lesions are considered one of the common pathological conditions affecting alveolar bone. The primary focus of this study was to investigate the effectiveness of formulating an injectable in-situ forming scaffold-loaded with risedronate (bone resorption inhibitor) and with lornoxicam (anti-inflammatory drug) for the non-surgical treatment of periapical lesions. The scaffolds were prepared using solvent-induced phase inversion technique. Two insoluble copolymers were investigated namely; PLGA (ester-terminal) and PLGA-A (acid-terminal), additionally, SAIB was added as a high viscosity water-insoluble carrier. The addition of porogenic agents like hydrolyzed collagen was also investigated. The prepared scaffolds were characterized by analyzing their in-vitro release, DSC and rheological properties, besides their morphological properties. The results showed that the scaffolds prepared using 30% (w/v) PLGA or combined PLGA: SAIB (1:1, w/w) with total polymer concentration of 30% (w/v) possessed the most sustained drug release profile. Selected scaffolds were tested for their therapeutic effect to study the effect of porogenic agent, anti-inflammatory drug and risedronate in periapical lesions induced in dogs' teeth. Results declared that the selected scaffolds succeeded in improving the inflammation and enhancing the formation of new bony regions confirming the success of the prepared scaffolds as an innovative approach in the treatment of bone defects., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Lipotomes were designed to enhance lacidipine's oral bioavailability by improving its solubility and enhancing the oral lymphatic uptake. Lipotomes were prepared using cetyl alcohol and Tween(®) 80 using a thin film hydration technique. Cetyl alcohol was chosen for imparting a lipophilic environment that would enforce the lymphatic uptake while Tween(®) 80 would improve drug solubility within the lipotomes. Lipotomes were characterized by analyzing their particle size, solubilization efficiency and in-vitro drug release. Central composite design was applied to statistically optimize the formulations using Design-Expert(®) software. The optimum formula (OLT) was made up of excipients:drug ratio of 36.59:1 w/w and Tween(®) 80:cetyl alcohol ratio of 4:1 w/w. OLT was lyophilized and filled into Eudragit(®) L100 enteric coated capsules. Mannitol (10% w/v) was the ideal cryoprotectant to retain the physicochemical characteristics of the OLT formulation after lyophilization. In conclusion, the selected lyophilized formula (L3) succeeded in enhancing drug's oral bioavailability in human volunteers compared to the commercial product confirming the success of lipotomes as a novel oral nanocarrier for insoluble drugs having extensive first pass metabolism., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Context: Drotaverine hydrochloride (DRT) is used to treat gastrointestinal spasms accompanied with diarrhoea. Hence, the drug suffers from brief residence in the highly moving intestine during diarrhoea which leads to poor bioavailability and frequent dosing., Objective: This study aimed to extend DRT residence in the stomach., Methods: Calcium alginate floating beads were prepared using sodium alginate, isopropylmyristate (oil), and Gelucire® 43/01 (lipid) adopting emulsion gelation technique. The beads were evaluated for their floating ability, DRT entrapment efficiency and in-vitro release. Gelucire® 43/01 /oil-based beads of the selected formula were coated using ethylcellulose and different plasticizers as polyethylene glycol 400 and triethyl citrate to retard the drug release. The coated beads were re-characterized. Finally, the best formulae were investigated for their in-vivo floating ability in dogs besides their delivery to the systemic circulation compared to drug powder in human volunteers., Results: Incorporation of Gelucire® 43/01 to oil-based beads enhanced the in-vitro performance of the beads. Coated beads prepared using drug:sodium alginate ratio of 1:3 (w/w), 20% (w/v) isopropylmyristate, 20% (w/v) Gelucire® 43/01 showed promising in-vitro performance. The beads floated for 12 h in the dogs' stomach and produced three-fold increase of the total amount of DRT absorbed within 24 h compared to that of DRT powder., Conclusions: Gelucire® 43/01 /isopropylmyristate-based calcium alginate floating beads coated with ethylcellulose using either PEG 400 or TEC as plasticizers proved to be a successful dosage form in extending DRT release.

Econazole nitrate (ECO) is a poorly water soluble antifungal drug. Having low aqueous solubility affects negatively its use for ocular treatment. This work aimed to prepare ocular supersaturated self-nanoemulsifying drug delivery systems (S-SNEDDS) of ECO employing hydroxypropyl methylcellulose as a precipitation inhibitor to improve the drug solubility by avoiding its precipitation after administration. Various oils, surfactants and co-surfactants were used to construct SNEDDS. The SNEDDS were evaluated for globule size, polydispersity index and their irritation potential using hen's egg test-chorioallantoic membrane (HET-CAM). The best SNEDDS was loaded with ECO and HPMC to prepare S-SNEDDS. In-vitro precipitation test of the S-SNEDDS was done to study the effect of the precipitation inhibitor. ECO permeation in rabbits' eyes from the selected S-SNEDDS (with and without HPMC) was evaluated. The results showed that SNEDDS-X consisting of 20% Capmul(®) MCM C10 as an oil, 60% Cremophor RH40(®) as a surfactant and 20% Transcutol(®) HP as co-surfactant possessed the lowest PDI value and a non-irritant effect on the CAM. The in-vitro precipitation test showed that the use of HPMC successfully sustained the supersaturated state by avoiding ECO precipitation. Higher Cmax, AUC0-8 and longer tmax confirm the development of a successful ECO-loaded S-SNEDDS., (Copyright © 2013 Elsevier B.V. All rights reserved.)