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Novel chitosan copolymers (CS-g-SBMA) grafted with [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA) in various molar ratio 1.5:1, 5:1, 11.5:1 and 20:1, were synthesized in the present study. SBMA was selected as zwitterion molecule showing promising antibacterial properties. Grafted chitosan derivatives were fully characterized for their successful synthesis by NMR and FT-IR, for their crystallinity by XRD showing reduced crystallinity compared to CS alone. Furthermore, swelling studies were conducted with the grafted derivatives showing extensive swelling capacity (maximum degree of swelling up to 1800%) and water absorption was studied with differential scanning calorimetry and equilibrium water adsorption/desorption isotherms were analyzed. Caspofungin, a novel antifungal drug, was used to prepare a double-acting system, with both antibacterial and antifungal properties, proper for topical use. Drug loaded hydrogels were prepared with 10, 20 and 30 wt% drug content and the loaded hydrogels were fully characterized while antimicrobial studies showed enhanced properties. Caspofungin in vitro release showed an initial burst effect followed by a diffusion process while data analysis verified the initial burst release followed by a quasi Fickian diffusion-driven sustained release. Enhance antimicrobial properties was also observed in caspofungin-loaded hydrogels showing the successful fulfill of our scope; an amphiphilic system having great potential for the development of patches with inherent antimicrobial properties and prolonged antifungal properties.

In this study, an antimicrobial mumio-based hydrogel dressing was developed for wound healing application. The mechanism of gel formation was achieved via a double crosslink network formation between gelatin (GT) and polyvinyl alcohol (PVA) using polyethylene glycol diglycidyl ether (PEGDE) and borax as crosslinking agents. To enhance the mechanical integrity of the hydrogel matrix, bacterial cellulose (BC) was integrated into the GT-PVA hydrogel to produce a composite gel dressing. The obtained hydrogel was characterized by FTIR, SEM, TGA, and XRD. Gel fraction, in vitro swelling and degradation as well as compressive modulus properties of the gel dressing were investigated as a function of change in PVA and BC ratios. By increasing the ratios of PVA and BC, the composite dressing showed lower swelling but higher mechanical strength. Comparing to other formulations, the gel with 4 %w/v PVA and 1 %w/v BC demonstrated to be most suitable in terms of stability and mechanical properties. In vitro cell cytotoxicity by MTT assay on human alveolar basal epithelial (A549) cell lines validated the gels as non-toxic. In addition, the mumio-based gel was compared to other formulations containing different bioactive agents of beeswax and cinnamon oil, which were tested for microbial growth inhibition effects against different bacteria (S. aureus and K. pneumoniae) and fungi (C. albicans and A. niger) strains. Results suggested that the gel dressing containing combinations of mumio, beeswax and cinnamon oil possess promising future in the inhibition of microbial infection supporting its application as a suitable dressing for wound healing.

Natural oils that are rich in biologically active polyunsaturated fatty acids have many health benefits but have insufficient bioavailability and may oxidize in the gastrointestinal tract. For these reasons and to improve the handling as well, the possibility of incorporating a natural oil, extracted from Serenoa Repens fruits (SR-oil), in alginate-based beads was investigated. SR-oil has been used from centuries in both traditional and modern medicine for various nutraceutical or therapeutic purposes such as, in both sexes, as a general tonic, for genitourinary problems, to increase sexual vigor, as a diuretic or to treat in male lower urinary tract symptoms and benign prostatic hyperplasia. In this study, alginate-based beads prepared by vibration technology, also known as prilling technique, were explored as SR-oil delivery systems. Twenty-seven different formulations (F1-F27) were produced starting from stable emulsions for the period of the production. The formulations having spheroid shape (sfericity factor0.07), high formulation yield (90%) and high encapsulation efficiency (EE%80) were selected for further characterizations. Gas chromatographic analysis revealed a high loading of lauric acid as principal component of SR-oil allowing to calculate the content of total fatty acids (50%) into the beads. Swelling behavior and release features were also studied at different pH values. The swelling of the beads and their SR-oil release were negligible for the first 2 h in simulated gastric fluid (pH 1.2), and appreciable in simulated intestinal fluid (pH 6.8). The release data were fitted by various equations to define the release kinetic mechanism. In addition, the selected formulation (F16) was stable to the oxidation not only during the formulation process, but also after 3 months of storage at room temperature. In summary, these polynucleate alginate beads, produced by prilling technique, are promising systems for improving the intestinal specific delivery and bioavailability of health-promoting bioactive SR-oil.

Rice starch is known to have an excellent film-forming behaviour in the packaging industry but inadequate attention was given to this biopolymer to be developed into thin films for drug delivery. Accordingly, rice starch thin films containing a model drug, paracetamol and plasticisers (glycerol or sorbitol) were developed using film casting technique. This study focuses on investigating the impact of plasticiser and drug loading on drug release pattern of rice starch films which has not been explored to date. The obtained rice films were characterised for their physicochemical properties including swelling and dissolution study. The highest drug dissolution rate was achieved in the rice films with a low drug loading due to drug amorphicity in nature. When drug loading increases, the swelling behaviour of rice films plays a dominant role in releasing drug in the crystalline form. The role of plasticiser was indicated by the plasticiser-starch interaction where a strong interaction allows drug solubilisation more readily in the dissolution medium. It is envisaged that rice films could be tailored to achieve desired drug release pattern with different plasticiser.

The dynamic properties of water and polymer molecules in xanthan hydrogels at different polymer mass fractions were investigated through the combination of conventional and fast-field cycling NMR relaxation to obtain the information about dynamics in different time scales. The results showed that water dynamics were faster in diluted than in concentrated hydrogels. However, the type of polymer-chain dynamics did not change for xanthan fractions from 0.1 to 0.5, although they slowed at higher xanthan fractions as the system approached transition to the glass state. The addition of the nonionic small drug molecules pentoxifylline did not change the dynamics in the hydrogels, but they were affected by the medium pH. The water and polymer-chain dynamics were faster in the hydrogels for the neutral than the acid medium. These differences resulted in slower swelling and thinner and more rigid hydrogel layer of the matrix tablet in the acid medium that was less susceptible to erosion. Consequently, pentoxifylline release from xanthan tablets in acid medium is dominated by drug diffusion. At neutral pH, the molecular mobility is greater, which resulted in rapid and extensive swelling of the hydrogel, leading to erosion-dominated drug release.

Non-healing wounds are among the serious complications of type-2-diabetes around the globe, associated with high incidence of bacterial infection, chronic nerve and blood vessel damage, and eventually repeated amputation of limbs and organs. Silver nanoparticles offer strong wound healing potential due to their well-known antibacterial activities. The present study reports the development of silver nanoparticle impregnated chitosan-poly ethylene glycol (PEG) hydrogel to accelerate wound healing in diabetic patients. The aim of the study was to formulate a sustained and slow release of silver nanoparticle using chitosan-PEG-Silver Nitrate based hydrogel for the treatment of chronic diabetic wounds. The silver nanoparticle containing chitosan-PEG pre-polymer solution was synthesized by reducing silver nitrate with PEG and chitosan solution, thereby, transforming the silver ions into silver nanoparticles. The resulted pre-polymer solution was then crosslinked using glutaraldehyde to form the desired hydrogel. The developed silver nanoparticle impregnated chitosan hydrogel was characterized using ultra-violet (UV) visible spectrophotometry, Fourier Transform-infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM) followed by the determination of porosity, and swelling properties. The release of AgNPs from hydrogel was determined by UV-vis spectroscopy followed by antimicrobial and antioxidant assays. The wound healing efficacy of the synthesized hydrogel was evaluated in diabetic rabbits. The results demonstrated a higher porosity, higher degree of swelling and higher water vapor transition rate (WVTR) for silver nanoparticle impregnated hydrogel compared to bare chitosan-PEG hydrogel as well as improved antimicrobial and antioxidant properties in-vitro and enhanced wound healing capability in-vivo in diabetic rabbits. The hydrogel showed a slow and sustained release of AgNPs over a period of at least seven days manifesting the slow biodegradation of developed hydrogels. The improved antimicrobial, antioxidant and wound healing results indicate that the silver nanoparticle impregnated chitosan-PEG hydrogel can be a promising material for wound healing dressing for chronic diabetic wounds. This article was made possible by the NPRP9-144-3-021 grant funded by Qatar national Research Fund (a part of Qatar Foundation ). The statements made here are totally responsibility of authors. The authors also thankfully acknowledge Mirpur University of Science and Technology ( MUST ), Mirpur, AJK, Pakistan for providing their facilities needed for completion of current study. Scopus

Commercially available cilostazol (CIL) tablet releases drug immediately and is given twice a day as an antiplatelet and vasodilatory agent. However, clinical usefulness of immediate release (IR) preparation is limited due to its extremely poor water solubility and the difficulty in sustaining the blood concentration, resulting in unwanted side effects such as headaches, pyknocardia and heavy-headed symptoms. To achieve once a day dosage form with enhanced solubility and controlled release, double controlled release CIL matrix tablets (DCRT) were designed by modulating a sol–gel process of binary polymeric blends of a pH-independent hydroxylpropylmethylcellulose (HPMC) and a pH-dependent polymer (carbomer) assisted with anionic surfactant (sodium lauryl sulfate, SLS). The release profiles of the DCRT were varied according to the ratio of the two polymers. This DCRT enhanced dissolution rate of CIL in a controlled manner due to the sol–gel and erosion process of HPMC, and SLS-driven modulation of charged carbomer via neutralization and micellar interaction. The near-infrared (NIR) chemical imaging and gravimetric behaviors of DCRT clearly showed dynamic modulation of CIL during the swelling and hydration process. Furthermore, the plasma concentration of CIL in DCRT was highly improved and sustained in beagle dogs in a controlled manner.

The possibility to compress ordinary paper into tablets was systematically investigated in this study. Results proved that tablets can be made from paper, independent of the type of paper used. The tablets appear shiny and with a smooth surface. The pharmaceutical quality was acceptable, i.e. all tablets fulfilled the requirements for tablets according to the European Pharmacopeia. Drug-loaded tablets were produced by compression of drug-loaded paper. Drug loading did not alter the pharmaceutical quality. However, the uncoated tablets possessed an extremely fast disintegration, i.e. intense swelling upon contact with water, which might hamper the swallowing after oral administration. To avoid swelling tablets were successfully coated with a polymer film, leading to a prevention of swelling but immediate disintegration in simulated gastric fluid. In fact, tablets made from paper are a novel and promising strategy for improved oral drug delivery. They can be easily produced without any further excipients and possess pharmaceutical quality according to the European Pharmacopeia.

Different types of in-situ forming implants based on poly(lactic-co-glycolic acid) (PLGA) and N-methyl-pyrrolidone (NMP) were prepared for controlled ocular delivery of dexamethasone. The impact of the volume of the release medium, initial drug content, polymer molecular weight and PLGA concentration on the resulting drug release kinetics were studied and explained based on a thorough physico-chemical characterization of the systems. This included for instance the monitoring of dynamic changes in the implants' wet and dry mass, morphology, PLGA polymer molecular weight, pH of the surrounding bulk fluid and water/NMP contents upon exposure to phosphate buffer pH 7.4. Importantly, the systems can be expected to be rather robust with respect to variations in the vitreous humor volumes encountered in vivo. Interestingly, limited drug solubility effects within the implants as well as in the surrounding aqueous medium play an important role for the control of drug release at a drug loading of only 7.5%. Furthermore, the polymer molecular weight and PLGA concentration in the liquid formulations are decisive for how the polymer precipitates during solvent exchange and for the swelling behavior of the systems. These features determine the resulting inner system structure and the conditions for mass transport. Consequently, they affect the degradation and drug release of the in-situ formed implants.

Water uptake and swelling of tablets are processes occurring during active pharmaceutical ingredient (API) release. Thereby, disintegration is promoted and the enhanced exposure of API surface area to the release medium facilitates API dissolution. An experimental set-up for the simultaneous and time-resolved determination of water uptake and swelling of tablets has been developed. Water uptake was determined with a balance and swelling was determined with a camera. To validate the gravimetrical analysis, real-time water uptake measurements with inert test specimens were performed. The standard deviation of these measurements was considered to depict precision. A complementary gravimetrical analysis was employed to determine accuracy. For both, precision and accuracy, a maximum deviation of 6% was found. An algorithm for the symmetry-based 3D volume reconstruction was applied to obtain volumes of the tablets from 2D images. X-ray micro computed tomography was used to validate the accuracy and the determined volumes were in good accordance within 6% deviation. A case study with binary formulations of a filler and disintegrants confirmed reproducibility and demonstrated the ability of the method to discriminate formulation characteristics, such as disintegrant type, composition and porosity for water uptake and swelling with the necessary temporal resolution.

Herein, a polyoxometalate (POM)-based blend hydrogel system was in situ constructed by incorporating cetyltrimethylammoniumbromide (CTAB)-encapsulated POM cationic micelles to bare hydrogel matrixes followed by copolymerization of multivalent crosslinking groups. It was demonstrated that the fabricated blend hydrogel possessed tunable physicochemical properties, good swelling behavior (maximum swelling rate of 229% in buffer solution of pH 8.0), excellent local action and sustained release of POM component (release ratio achieved nearly 100% at the time of 120 min). Antibacterial activity study revealed that the introduction of POM greatly improved the bioavailability of itself, namely, leading to a more effective enhancement of therapeutic effects (survival ratio of both strains less than 5%). Besides, bactericidal rates (ca. 51%) were achieved even after six runs repeated, thereby verifying the biological application potential of this material. Finally, the practical application potentials were investigated and future prospects in relevant research areas were forecasted.

Current in vitro drug-release testing of the sustained-release parenterals represents the in vivo situation insufficiently. In this work, a thin agarose hydrogel layer surrounding the tested dosage form was proposed to mimic the tissue. The method was applied on implantable formulations of different geometries (films, microspheres, and cylindrical implants); prepared from various polymers (several Resomer® grades or ethyl cellulose) and loaded with different model drugs: flurbiprofen, lidocaine or risperidone. The hydrogel layer did not possess any retarding effect on the released drug and acted as a physical restriction to swelling and/or plastic deformation of the tested dosage forms. This led to a different surface area available for drug-release compared with testing in release medium alone and correspondingly to significantly different release profiles of the majority of the formulations obtained between the two methods (e.g. t50% = 18 days in pure release medium vs. t50% = 26 days in gel-setup for risperidone loaded Resomer® 503 H films or t50% = 7 days vs. t50% = 19 days for risperidone loaded Resomer® 503 H microspheres). The limited space for swelling and the rigidity of the agarose gel might mimic the tight encapsulation of the dosage form in the tissue better than the conventional liquid medium.

The aim of this study was to better understand the underlying drug release mechanisms in poly(lactic-co-glycolic acid) (PLGA) microparticles in which the drug is dispersed in the form of tiny particles (“monolithic dispersions”). Differently sized diprophylline-loaded microparticles were prepared using a solid-in-oil-in-water solvent extraction/evaporation technique. The microparticles were characterized before and after exposure to phosphate buffer pH 7.4 at 4, 20 and 37 °C. In vitro drug release was measured from ensembles and single microparticles. GPC, DSC, SEM, gravimetric analysis, drug solubility measurements and optical microscopy were used to elucidate the importance of polymer swelling & degradation, drug dissolution and diffusion. The diprophylline was initially homogeneously distributed throughout the microparticles in the form of tiny crystals. The burst release (1st phase) was strongly temperature-dependent and likely attributable to the dissolution of drug crystals with direct surface access (potentially via tiny pores). The about constant release rate during the 2nd phase also strongly depended on the temperature. It can probably be explained by the dissolution of drug crystals in surface near regions undergoing local swelling. During the observation period, the 3rd (again rapid) drug release phase was only observed at 37 °C, and seems to be caused by substantial PLGA swelling throughout the entire microparticles. This phase starts as soon as a critical polymer molecular weight of about 25 kDa is reached: Significant amounts of water penetrate into the systems, dissolving the remaining diprophylline crystals and substantially increasing the mobility of the dissolved drug molecules. Thus, this study provides additional experimental evidence (obtained at lower temperatures) confirming the hypothesized root causes for drug release from PLGA microparticles containing dispersed drug particles.

Polydimethylsiloxane (PDMS)-based levonorgestrel intrauterine systems (LNG-IUSs) such as Mirena® are long-acting drug-device combination products designed to release LNG for contraceptive purposes up to 6 years. LNG-IUSs consist of a hollow cylindrical drug-PDMS reservoir mounted with a polyethylene frame and covered by an outer PDMS membrane. PDMS is the release-controlling excipient present in both the matrix and the outer membrane. The degree of PDMS crosslinking is a key parameter in LNG-IUS manufacturing, dictating the elasticity and mechanical strength (which are critical parameters in molding and demolding of the cylindrical reservoirs). In addition, elasticity and mechanical strength are also important to prevent deformation during insertion into the uterine cavity. The objectives of this study were to investigate the impact of PDMS crosslinking on the physicochemical properties of LNG-IUSs and to develop appropriate testing methods for characterization of their mechanical strength. Formulations with different degrees of crosslinking were prepared by varying the ratio of the PDMS elastomer base and the crosslinking agent. A novel solvent swelling and extraction method was developed to determine the degree of PDMS crosslinking. The extent of crosslinking was also characterized via FTIR, Raman, 1H NMR, DSC, TGA and dynamic mechanical analysis. As expected, formulations with higher degrees of crosslinking showed lower crystallinity. Interestingly, the less crystalline formulations showed higher Tg values and storage moduli compared to the high crystalline formulations, implying that crosslinking is the predominant parameter governing the physicochemical and mechanical properties in LNG-IUSs. Correlations were established between PDMS crosslinking and the physicochemical properties of LNG-IUSs which will be useful for quality control purposes during formulation screening and development. A better understanding of the physicochemical characteristics of these complex products will facilitate drug product development.

This work was intended to prepare biodegradable and edible films from polysaccharide extracted from Hammada scoparia leaves (named PSP) and reinforced by poly (vinyl alcohol) (PVA). Four films with different ratios of PSP/PVA: P1 (70:30), P2 (50:50), FP3 (30:70) and pure PVA (100 % PVA) were prepared and characterized in terms of structural (FT-IR), physical (Thickness, solubility and swelling index), optical and thermal properties (TGA). The antioxidant activities of different films were determined in vitro and evaluated in vivo through the examination of wound healing capability. Data revealed that the film P1 displayed the highest antioxidant activity in vitro and accelerated significantly the wound healing, after sixteen days of treatment, attested by higher wound appearance scores and a higher content of collagen (765.924 ± 4.44 mg/g of tissue) confirmed by histological examination, when compared with control, CYTOL CENTELLA® and pure PVA-treated groups. Overall, these results demonstrated that PSP/PVA based films exhibited a higher wound healing potential confirmed with the high antioxidant activities in vitro.

The objective of this work was to evaluate the potential use of a new polymer (PAMgA) in the development sustained release matrix tablets for the treatment of bowel inflammatory diseases. For this purpose, budesonide, a highly lipophilic compound, was used as model drug. Tablets with two reticulation grades of PAMgA (PAMgA 5 and 40) and with 9 mg of budesonide were developed and characterized. All the studies were carried out using biorelevant media (FaSSGF and FaSSIF). Swelling and erosion of PAMgA tablets was influenced by the reticulation grade of the polymer and the biorelevant media assayed, being water uptake higher for PAMgA 40 tablets in intestinal fluid, whereas PAMgA 5 showed more intense erosion in this biorelevant medium. Budesonide was released slowly from PAMgA tablets, both in gastric and intestinal environment, following Super case II transport kinetics (relaxation-controlled delivery), with a lag time of around 1–2 h. When the dissolution medium was changed sequentially throughout the trial, 75% of the budesonide dose was released in a sustained manner between 4 and 20 h of testing from PAMgA tablets, showing a more controlled budesonide release than Entocort® and Budenofalk® (commercially available sustained release formulations of budesonide). In conclusion, PAMgA polymer allows controlling the release of highly lipophilic drugs as budesonide, being an useful excipient for the development of sustained release matrix tablets.

In this study, halloysite nanotubes (HNTs) were subjected to surface functionalization using sodium alginate and incorporated into poly(caprolactone) (PCL) to fabricate nanocomposites for potential wound healing applications. The nanocomposite films were fabricated through the solution casting technique and characterized using various instrumental methods. The films exhibited enhanced thermal and mechanical properties. FE-SEM and AFM analyses confirmed the uniform dispersion of the HNTs and increased roughness of the films, respectively. The swelling properties, in-vitro enzymatic degradation, and anti-inflammatory activity of the films were also analyzed. The MTT assay performed using NIH3T3 cell lines revealed enhanced cell proliferation (126 ± 1.38) of 5 wt% film. Besides, the cell adhesion tests of the films revealed their cytocompatibility. The scratch assay tests conducted for observing the effectiveness of the films for wound closure showed that the 5 wt% film offered a higher rate of fibroblast cell migration (32.24 ± 0.49) than the pristine PCL film. The HRBCMS assay demonstrated the hemocompatibility of these films. The biological test results indicated the delayed enzymatic degradability and haemocompatiblity of nanocomposites with enhanced cell adhesion, cell proliferation, and cell migration capabilities with respect to fibroblast cells. In summary, the synthesized nanocomposite films can be effectively used in wound healing applications after further clinical trials.

Hydrophilic matrices are of utmost interest for oral prolonged release of drugs. However, they show decreasing release rate over time, mainly due to lengthening of the diffusional pathway across the gel formed upon glass-rubber transition of the polymer. Therefore, achievement of zero-order release kinetics, which could reflect in constant drug plasma levels, is still an open issue. With the aim of improving the release performance of hydroxypropyl methylcellulose (HPMC) systems, the use of cellulolytic enzymes was proposed to aid erosion of the swollen matrix, thereby counteracting the release rate decrease particularly toward the end of the process. The effectiveness of this strategy was evaluated by studying the mass loss and drug tracer release from tableted matrices consisting of high-viscosity HPMC (Methocel® K4M), Acetaminophen and increasing amounts (0.5–10% on HPMC) of a cellulolytic product (Sternzym® C13030). A faster erosion and progressive shift to linearity of the overall release profiles were observed as a function of the enzyme concentration. Release was markedly linear from matrices containing 5 and 10% Sternzym® C13030. In partially coated matrices with these cellulase concentrations, such results were in agreement with data of erosion and swelling front movement, which exhibited early and long-lasting synchronization.

Cyclodextrin-based nanosponges have been found to be promising drug delivery systems. This paper investigates an application that still needs to be studied in depth, that is, the oral delivery of peptides and proteins, choosing insulin as a case study. The nanosponge was synthesized by crosslinking β-cyclodextrins with pyromellitic dianhydride, adopting a top-down approach for its subsequent formulation. A physicochemical characterization, in-vitro and in-vivo tests were carried out on the formulation developed. It was nanometric (around 250 nm) with high negative zeta potential, mucoadhesion and swelling properties, good loading capability (about 14%) and encapsulation efficiency (above 90%). The in-vitro release of insulin was negligible at a gastric pH (below 2%) while sustained at an intestinal pH, thus showing a pH-sensitive behaviour of the nanosponge. The Caco-2 cell permeability assay proved that the intestinal permeation of insulin was enhanced when loaded inside the nanosponge. The in-vivo studies confirmed the presence of insulin in rat plasma and a marked hypoglycemic effect in diabetic mice after duodenal and oral administrations, respectively. These preliminary results are encouraging with a view to continuing to study this β-cyclodextrin nanosponge technology for the oral administration of insulin and extending this approach to other proteins of pharmaceutical interest.

In this study, polyacrylic acid-co-maleic acid (PAMA) and polyvinyl alcohol (PVA) (1:4) were used to fabricate dissolving microneedles (DMNs) and hydrogel forming microneedles (HMNs) which incorporated α-arbutin. Αlpha-arbutin is commonly used as a skin lightening agent. However, it has poor penetration ability due to its hydrophilic properties. The purpose of this study was to compare the permeation of α-arbutin into the skin using DMNs and HMNs. Both types of microneedles (MNs) were sharp, strong with elegant appearance and approximately 100% penetrated the neonatal porcine skin. All needles of α-arbutin loaded DMNs were completely dissolved within 45 min, whereas maximum swelling of HMNs was observed at 4 h. In vitro permeation studies showed that α-arbutin loaded DMNs and HMNs provided significantly about 4.5 and 2.8 times, respectively, greater α-arbutin permeability than gel and commercial cream (P 0.05). In vivo study also showed high intradermal delivery of α-arbutin levels using DMNs (5.33 µg/mL) and HMNs (1.47 µg/mL) when compared to that of commercial cream 0.15 µg/mL. Moreover, the micro-holes caused by applying MNs can reseal within 1 h. MNs were also stable at 25 °C for 3 months. The results suggested that DMNs and HMNs developed have a promising platform for transdermal delivery.

Treatment of diabetic, chronic, and full-thickness wounds is a challenge as these injuries usually lead to infections that cause delayed and inappropriate healing. Therefore, fabrication of skin scaffolds with prolonged antibacterial properties are of great interest. Due to this demand, bilayered nanofibrous scaffolds were fabricated based on polycaprolactone and gelatin. The top layer of these scaffolds contained amoxicillin as a model drug and the bottom layer was loaded with zinc oxide nanoparticles to accelerate wound healing. Several characterization techniques including FTIR, SEM, swelling, tensile test, in vitro degradation, drug release, antibacterial activity, and MTT assay were used to assess physical, mechanical, and biological properties of produced nanofibers. SEM results demonstrated that bilayered scaffolds have smooth bead-free microstructures while in vitro release test showed that samples have a sustained release for amoxicillin up to 144 h (tested time). Disk diffusion assessment confirmed the potency of scaffolds for hindering bacterial growth while results of cytotoxicity evaluation revealed that scaffolds could effectively accelerate cell proliferation. Finally, in vivo tests on full-thickness rat models revealed that fabricated nanofibers accelerate wound contraction, increase collagen deposition and angiogenesis, and prevent scar formation. Altogether, results showed that fabricated scaffolds are promising candidates for treatment of full-thickness wounds.

The aim of this research was the development and characterization of three gel dosage forms of Halobetasol propionate loaded lipid nanoparticles (HB-NLC) for the treatment of inflammatory skin diseases. A Pluronic gel (Pl-HB-NLC), a Carbopol gel (Cb-HB-NLC) and a Cremigel (Cg-HB-NLC), were characterized for stability, swelling, degradation, porosity and rheology. The biopharmaceutical behavior of in vitro release and ex vivo permeation, along with microbiological stability were also evaluated. Tolerance and therapeutic efficacy were determined in vivo. The gels proved to have eudermic pH and to be effective to improve HB-NLC stability for more than 6 months. In vitro drug release profiles were adjusted to a first order (Pl-HB-NLC, Cg-HB-NLC) and hyperbola (Cb-HB-NLC) kinetic models, revealing sustained drug release. Ex vivo biopharmaceutical behavior showed slow drug penetration through skin, delaying the drug entrance into systemic circulation. The formulations were effective in reducing inflammation with a lower drug dose in comparison with existing treatments, obtaining the fastest effect when using Pl-HB-NLC. After application of the formulations in volunteers, no irritation, redness or edema reactions were detected, plus, an enhancement of the biomechanical properties of the skin was evidenciated. Therefore, the results indicate that these formulations are a suitable alternative to current treatments.

The use of water-insoluble carriers for amorphous solid dispersions (ASDs) has attracted more recent interest as the kinetic solubility profiles (KSP) from these systems can achieve a more sustained level of supersaturation when compared with ASDs based on water-soluble polymers. However, the effect of swelling capacity of water-insoluble carriers on the resulting KSP of ASDs has not been fully explored in terms of their achievable degree and extent of drug supersaturation. Thus, the objective of this study is to compare kinetic solubility profiles of ASDs based on commercially available water-insoluble carriers in order to bridge this knowledge gap and provide fundamental information important to the design of ASDs based on water-insoluble carriers. This was achieved by comparing the KSP from non-sink dissolution studies of ASDs of two model poorly-water soluble drugs, indomethacin (IND) and posaconazole (PCZ) based on commercially available water-insoluble carriers with different equilibrium water swelling such as fully hydrolyzed (physically crosslinked) poly (vinyl alcohol) (PVA), Eudragit RS PO, as well as chemically crosslinked PHEMA hydrogels . Our results show that the higher the swelling capacity of the water-insoluble carrier, the faster the rate of supersaturation generation, and the shorter the sustained supersaturation due to drug precipitation. The interplay of particle size, total dose and the swelling capacity was also shown to be an essential aspect when tailoring the supersaturation generation from water-insoluble polymer-based ASDs. The importance of the swelling feature was confirmed using firstly different polymer carriers (PVA, Eudragit RS PO, and PHEMA) and then polymer samples of identical composition and drug loading but with different swelling capacities (e.g., PVA, physically crosslinked to different degrees). Furthermore, a large drug partitioning value between the polymer carrier and dissolution medium was found to limit the extent of drug release or supersaturation buildup from these ASDs. Finally, the existence of electrostatic polymer-drug interactions realized from our molecular dynamic simulations supports the observed impact of the large partitioning of the model drug IND between the polymer ED RS PO and the dissolution medium, thereby leading to a lower degree of supersaturation generation (or slower drug release) from this ASD.

Loading of gatifloxacin in contact lenses affects critical lens properties (optical and swelling) owing to drug precipitation in the contact lens matrix. The presence of Pluronic® F-68 in the packaging solution creates in-situ micelles in the contact lens to dissolve gatifloxacin precipitates and provide sustained drug release. The micelles further improved the drug uptake from the drug-packaging solution to create an equilibrium of drug between the lens matrix and the packaging solution. In this study, we optimized gatifloxacin-pluronic-loaded contact lenses to achieve the desired optical transmittance, swelling, and gatifloxacin loading capacity as well as sustained drug delivery. Optimization of gatifloxacin-pluronic-loaded contact lens was carried out using a 32 factorial design by tailoring the concentration of Pluronic® F-68 in the packaging solution (X1) and the amount of gatifloxacin in the monomer solution (X2) to achieve the desired lens properties. The optimized batch (X1 = 0.3%w/v and X2 = 0.3%w/v) showed an optical transmittance of 92.84%, swelling of 92.36% and gatifloxacin loading capacity of 92.56 μg. The in vitro flux data of the optimized batch (GT-Pl-CL) showed sustained release up to 72 h, whereas soaked contact lenses (SM-CL) and direct gatifloxacin-loaded contact lenses (DL-CL) showed a sustained release up to 48 h. The in vivo gatifloxacin release data for rabbit tear fluid showed sustained release with a high gatifloxacin level for the GT-Pl-CL lens in comparison to the SM-CL and the eye drop solution. This study demonstrates the application of the 32 full factorial design to optimize gatifloxacin-pluronic-loaded contact lenses to achieve the desired optical transmittance, swelling, and drug loading capacity.

Due to their ability to swell/deswell under alternating pH conditions, pH-sensitive hydrogels present themselves as a potential candidate for controlled drug delivery. In this paper, a coupled electro-chemo-mechanical transient large deformation homogeneous and inhomogeneous swelling theory is developed for pH-sensitive hydrogels. The hydrogel is treated as a single-phase compressible isotropic hyperelastic material. The Nernst-Planck equation is used for the flux of the ionic species inside the hydrogel through its boundaries. The main reason which causes the hydrogel to swell is the osmotic pressure. The osmotic pressure is treated as external stress to the hydrogel. As soon as the concentration of the ions inside the hydrogel is known one may compute the osmotic pressure. Finally, the mechanical equilibrium equations give the deformation of the hydrogel. After presenting the swelling theory, the theory is implemented into the finite element method, and the experimental data is used in order to validate the theory. The simulation matches closely the experimental data which shows the accuracy of the proposed theory. The free swelling and constrained swelling of the pH-sensitive hydrogel are also simulated to show the capabilities of the proposed formulation and well as its numerical counterpart.

Superdisintegrants are a key excipient used in immediate release formulations to promote fast tablet disintegration, therefore understanding the impact of superdisintegrant variability on product performance is important. The current study examined the impact of superdisintegrant critical material attributes (viscosity for sodium starch glycolate (SSG), particle size distribution (PSD) for croscarmellose sodium (CCS)) on their performance (swelling) and on drug dissolution using surface dissolution UV imaging. Acidic and basic pharmacopoeia (compendial) media were used to assess the role of varying pH on superdisintegrant performance and its effect on drug dissolution. A highly soluble (paracetamol) and a poorly soluble (carbamazepine) drug were used as model compounds and drug compacts and drug-excipient compacts were prepared for the dissolution experiments. The presence of a swelled SSG or CCS layer on the compact surface, due to the fast excipient hydration capacity, upon contact with dissolution medium was visualized. The swelling behaviour of superdisintegrants depended on excipient critical material attributes and the pH of the medium. Drug dissolution was faster in presence compared to superdisintegrant absence due to improved compact wetting or compact disintegration. The improvement in drug dissolution was less pronounced with increasing SSG viscosity or CCS particle size. Drug dissolution was slightly more complete in basic compared to acidic conditions in presence of the studied superdisintegrants for the highly soluble drug attributed to the increased excipient hydration capacity and the fast drug release through the swelled excipient structure. The opposite was observed for the poorly soluble drug as potentially the improvement in drug dissolution was compromised by drug release from the highly swelled structure. The use of multivariate data analysis revealed the influential role of excipient and drug properties on the impact of excipient variability on drug dissolution.

This study presents an innovative multifunctional system in fabricating new functional wound dressing (FWD) products that could be used for skin regeneration, especially in cases of infected chronic wounds and ulcers. The innovation is based on the extraction, characterization, and application of collagen (CO)/chitosan-glucan complex hollow fibers (CSGC)/aloe vera (AV) as a novel FWS. For the first time, specific hollow fibers were extracted with controlled inner (500–900 nm)/outer (2–3 µm) diameters from mycelium of Schizophyllum commune. Further on, research and evaluation of morphology, hydrolytic stability, and swelling characteristics of CO/CSGC@AV were carried out. The obtained FWS showed high hydrolytic stability with enhanced swelling characteristics compared to native collagen. The hemostatic effect of FWS increased significantly in the presence of CSGC, compared to native CO and displayed excellent biocompatibility which was tested by using normal human dermal fibroblast (NHDF). The FWS showed high antibacterial activity against different types of bacteria (positive/negative grams). From in vivo measurements, the novel FWS increased the percentage of wound closure after one week of treatment. All these results imply that the new CO/CSGC@AV-FWD has the potential for clinical skin regeneration and applying for controlled drug release.

The purpose of this study was to develop a novel gastroretentive drug delivery system with immediate buoyancy and high wet strength. The proposed bilayer tablet was composed of a drug layer and a highly porous and swellable gastroretentive (GR) layer. The highly porous GR layer was prepared by sublimating the volatile materials after compaction with swellable polymers. This pore-forming process decreased the density of the GR layer and enabled the tablet to float immediately on the dissolution media. The GR layer formulation was optimized by comparing the swelling, erosion, and mechanical properties of candidate swellable polymers. The release rates were conveniently controlled by changing the polymer content in the drug layer, while the swelling and floating properties were provided by the GR layer. The application of percolation theory revealed that the polymer content above the estimated threshold was required for a reliable drug release profile. In vivo study in fed beagle dogs confirmed the enhanced gastric retention time of the tablets compared to that of conventional single layer tablets. Taken together, our data suggest that the proposed system can be a promising platform technology with superior GR properties and a convenient formulation process.

Statistical moments were evaluated as suitable parameters for describing swelling and erosion processes (along with drug release) in hydrophilic controlled release matrix tablets. The effect of four independent formulation variables, corresponding to the quantity of four polymeric matrix excipients (namely polyethylene glycol, povidone, and two grades of hydroxyl-propylmethyl cellulose) on statistical moments describing swelling (mean swelling time, MST), erosion (mean erosion time, MET) and drug-release (mean dissolution time, MDT) was evaluated with the aid of multi-linear regression (MLR) and artificial neural networks (ANNs) based on a central composite experimental design. Results were compared to conventional model fitting, where the rate of water uptake during swelling (a), the maximum % water uptake (Smax), the time at which Smax is achieved (tmax), the constant of apparent matrix-tablet erosion rate (ke) and the release exponent (n) from Korsmeyer-Peppas drug-release equation were used as model parameters. Fitting to an external validation test set revealed superior prediction efficacy for statistical moments compared to conventional model fitting, while the combination of statistical moments with ANNs presented the most efficient approach (R2 and RMSEp values of 0.922, 0.833, 0.987 and 0.443, 0.691, 0.173 for MST, MET, and MDT, respectively).

Nanostructured lipid carriers (NLCs) can enhance the safe transdermal delivery system of drugs. Moreover, dissolving microneedles (MNs) can enhance the permeability and controlled drug release. In this study, NLCs were formulated as a suitable vehicle for aconitine (ACO) delivery to effectively inhibit the inflammation of fibroblast-like synoviocytes isolated from a rat model of adjuvant-induced arthritis (AA-FLS). To improve drug delivery, the ACO-loaded NLCs (ACO-NLCs) were embedded in polyvinylpyrrolidone-based dissolving MNs fabricated by an ultraviolet cross-linking method. The nanoparticles maintained good physical stability in the dissolving MNs. The insertion capabilities of the ACO-NLCs-MNs were determined by observing histological sections of the skin after insertion, and scanning electron microscopy was used to observe the changes in the MNs over time. In vivo microdialysis showed that the NLCs-MNs enhanced the transdermal delivery of ACO through disrupting the barrier function of the stratum corneum (SC) and releasing the drug continuously. The ACO-NLCs-MNs showed a significant inhibitory effect on the paw swelling and inflammation in AA model rats. Moreover, this dual approach involving NLCs-loaded dissolving MNs formed a drug reservoir and effectively improved the ACO-induced arrhythmia. These results indicate that NLCs-containing MNs could be promising systems for the effective transdermal delivery and controlled local administration of ACO.

Cpl-1, an endolysin derived from Cp-1 phage has been found to be effective in a number of in-vitro and in-vivo pneumococcal infection models. However its lower bioavailability under in-vivo conditions limits its applicability as therapeutic agent. In this study, Cpl-1 loaded chitosan nanoparticles were set up in order to develop a novel therapeutic delivery system to counter antibiotic resistant S. pneumoniae infections. Interactions of chitosan and Cpl-1 were studied by in-silico docking analysis. Chitosan nanoparticles and Cpl-1 loaded chitosan nanoparticles were prepared by using ionic gelation method and the process was optimized by varying chitosan:TPP ratio, pH, stirring time, stirring rate and Cpl-1 concentration. Chitosan nanoparticles and Cpl-1 loaded chitosan nanoparticles were characterized to ascertain successful formation of nanoparticles and entrapment of Cpl-1 into nanoparticles. Chitosan nanoparticles and Cpl-1 loaded nanoparticles were also evaluated for nanoparticle yield, entrapment efficiency, in-vitro release, stability, structural integrity of Cpl-1, in-vitro bioassay, swelling studies, in-vitro biodegradation and heamolysis studies. Mucoadhesion behavior of chitosan nanoparticles and Cpl-1 loaded nanoparticles was explored using mucous glycoprotein assay and ex-vivo mucoadhesion assay, both preparations exhibited their mucoadhesive nature. Cellular cytotoxicity and immune stimulation studies revealed biocompatible nature of nanoparticles. The results of this study confirm that chitosan nanoparticles are a promising biocompatible candidate for Cpl-1 delivery with a significant potential to increase bioavailability of enzyme that in turn can increase its in-vivo half life to treat S. pneumoniae infections.

This study aims at identifying the more suitable polysaccharide in a composite film based on Eudragit RS for 5-ASA delivery to the colon. Different polysaccharides (pectin, chitosan, guar, inulin, and dextran) were examined. The mechanical properties, swelling index, loss of film mass and permeability of films to 5-ASA were recorded at simulating gastric (SGF), intestinal (SIF) and colonic fluids (SCF). Films containing inulin or dextran were more flexible and showed better mechanical properties. Films containing chitosan, pectin or guar exhibited extensive swelling in SGF and SIF. Loss of film mass and drug permeation was more pronounced in SCF than SIF for all samples indicating their sensitivity to colonic bacteria. However, films containing inulin or dextran showed minimum swelling index in SGF and SIF and the highest ratio of permeability in SCF to SIF. Accordingly, inulin and dextran are suggested as appropriate polysaccharides in a film based on Eudragit RS for colon delivery of 5-ASA.

Exfoliated nanocomposites of chitosan-magnesium aluminum silicate (CS-MAS) particles are characterized by good compressibility but poor flowability. Thus, the aims of this study were to investigate agglomerates of CS-MAS nanocomposites prepared using the agglomerating agents water, ethanol, or polyvinylpyrrolidone (PVP) for flowability enhancement and to evaluate the agglomerates obtained as direct compression fillers for tablets. The results showed that the addition of agglomerating agents did not affect crystallinity, but slightly influenced thermal behavior of the CS-MAS nanocomposites. The agglomerates prepared using water were larger than those prepared using 95% ethanol because high swelling of the layer of chitosonium acetate occurred, allowing formation of solid bridges and capillary force between particles, leading to higher flowability and particle strength. Incorporation of PVP resulted in larger agglomerates with good flowability and high strength due to the binder hardening mechanism. The tablets prepared from agglomerates using water showed lower hardness, shorter disintegration times and faster drug release than those using 95% ethanol. In contrast, greater hardness and more prolonged drug release were obtained from the tablets prepared from agglomerates using PVP. Additionally, the agglomerates of CS-MAS nanocomposites showed good carrying capacity and provided desirable characteristics of direct compression tablets.

In the absence of an effective vaccine, vaginal microbicides are essential for preventing the sexual transmission of HIV to women. Antiretroviral vaginal films have emerged as promising choices, especially those offering mucoadhesivity and controlled drug release. Tenofovir-loaded bilayer films based on Eudragit® L100 (EL100) and a biopolymer – gum arabic, karaya gum, pectin or tragacanth gum – were developed in a single-stage process. Cytotoxicity studies in three human cell lines indicated no toxicity of the excipients at the concentrations tested. Raman spectroscopy and SEM confirmed the formation of the two layers and their anchoring. Texture analysis showed no major differences between the batches. The swelling of the film is conditioned by its biopolymer nature and by the amount of EL100, which acts as structuring agent thus enhancing swelling. Tragacanth gum-based batches showed high mucoadhesion regardless the amount of EL100. The controlled release of Tenofovir in simulated vaginal fluid was faster in the presence of simulated seminal fluid due to the dissolution of EL100. Films containing 400 mg of EL100 and tragacanth gum are promising candidates for future studies, as they could sexually safeguard women from HIV for at least one week and ensure greater protection during intercourse.

18β-glycyrrhetinic acid (Gly), a natural compound obtained from licorice, is known both for the anti-inflammatory and antioxidant activities and for this reason useful for wound treatment. Due to its poor solubility, Gly is not suitable for formulations used in conventional topical products such as gels, foams and creams. Polymeric bioadhesive microparticles (MP), loaded with Gly, were developed to be introduced in the wound bed and swell, once in contact with the exudate, to form a hydrogel in situ able to close the wound. The MP were prepared by spray drying method from the polymeric solution of polysaccharide sodium carboxymethyl cellulose (CMC) and copolymer Soluplus® (SL). Soluplus® introduction in MP composition, using a 3:1 ratio (CMC/SL wt./wt.), allowed to stabilize Gly in non-crystalline form, favoring the improvement of water solubility, and to obtain a spherical with rugged surface MP morphology. Ex vivo studies showed these MP maintain high swelling capability and are able to form in situ a hydrogel for wound repair. The controlled release of Gly from the hydrogel stimulates keratinocyte growth, potentially supporting the physiological healing processes.

In the current study, electrostatically-driven pH responsive, supramolecular hydrogels of the trilacunary Wells-Dawson-type 15-tungsto-2-phosphate polyanion (P2W15) and chitosan hydrochloride (ChCl) were prepared, using methacrylic acid as pH responsive agent using benzoyl peroxide (BPO) as initiator. The prepared hydrogels were characterized by FT-IR, SEM, XRD and thermal analyses (TGA-DSC). The swelling and pH based P2W15 release profile of the hydrogels showed maximum swellability and release at pH 7.4. Different mathematical models were applied, showing that P2W15 release followed supercase transport-II mechanism and zero-order kinetics. The cytotoxicity results showed that free and embedded P2W15 exhibited dose-dependent cytotoxicity against cancer cell lines (MCF-7; HeLa) with minimal effects on normal cells (Vero). The developed hydrogels were administered to the rabbits for determining the pharmacokinetic behavior of the polyanion. Moreover, the developed hydrogel system as well as polyanion concentration used were also checked for its oral tolerability and safety evaluation in rabbits. The histopathological studies, serum chemistry (except blood glucose level) and hematological investigations exhibited that administered hydrogel suspension at maximal tolerable dose (4000mg/kg body weight) and polyanion concentration used (20mg) were safe from in-vivo point of view. The developed hydrogels exhibited desirable qualities of a drug delivery system that can be used for the delivery of the embedded polyanion.

There is a clinical need for a novel, more efficient therapy for full thickness wound healing. In the current study, curcumin encapsulated PEG-PLA [poly(lactide)-block-poly(ethylene glycol)] nanomicelles were incorporated into dextran hydrogel for a full thickness dermal wound healing application. To assess the application of the hydrogel as a therapeutic wound dressing, its morphology, swelling pattern, kinetics of degradation, and capacity to control curcumin release were evaluated. It was found that the prepared hybrid hydrogel had acceptable biocompatibility, incorporation capacity of curcumin nanomicelles, and mechanical properties. An in vitro release experiment also demonstrated the sustained release of curcumin from dextran hydrogel, which was first controlled by the diffusion of curcumin from hydrogel and continued through hydrogel matrix erosion at the terminal phase. An in vivo wound healing experiment was carried out using dressing hydrogels on full thickness wounds in BALB/c mice. An histological study demonstrated that the application of curcumin nanomicelles incorporated hydrogel could significantly augment the re-epithelialization of epidermis and collagen deposition in the wound area. Expression of CD31 and vimentin in wound tissue was investigated using immunohistochemistry tests on the eighth day post wounding. The results obtained demonstrated that curcumin nanomicelles incorporated hydrogel could significantly accelerate angiogenesis, fibroblast accumulation, and the process of wound healing. Together, the data indicate that the prepared hybrid curcumin PEG-PLA nanomicelles incorporated dextran hydrogel is a promising candidate for full thickness wound treatment that increases re-epithelialization, collagen deposition, angiogenesis, and tissue granulation.