In the present study, we report the properties of a mucoadhesive chitosan-pectinate nanoparticulate formulation able to retain its integrity in the milieu of the upper gastrointestinal tract and subsequently, mucoadhere and release curcumin in colon conditions. Using this system, we aimed to deliver curcumin to the colon for the possible management of colorectal cancer. The delivery system comprised of a chitosan-pectinate composite nanopolymeric with a z-average of 206.0 nm (±6.6 nm) and zeta potential of +32.8 mV (±0.5 mV) and encapsulation efficiency of 64%. The nanoparticles mucoadhesiveness was higher at alkaline pH compared to acidic pH. Furthermore, more than 80% release of curcumin was achieved in pectinase-enriched medium (pH 6.4) as opposed to negligible release in acidic and enzyme-restricted media at pH 6.8. SEM images of the nanoparticles after exposure to the various media indicate a retained matrix in acid media as opposed to a distorted/fragmented matrix in pectinase-enriched medium. The data strongly indicates that the system has the potential to be applied as a colon-targeted mucoadhesive curcumin delivery system for the possible treatment of colon cancer.
This study aims to investigate the use of palm olein as the oil phase for betamethasone 17-valerate (BV) emulsions. The physicochemical properties of the formulations were characterized. In vitro drug release study was performed with the Hanson Vertical Diffusion Cell System; the samples were quantified with HPLC and the results were compared with commercial products. Optimized emulsion formulations were subjected to stability studies for 3 months at temperatures of 4, 25, and 40°C; the betamethasone 17-valerate content was analyzed using HPLC. The formulations produced mean particle size of 2-4 μm, viscosities of 50-250 mPa.s, and zeta potential between -45 and -68 mV. The rheological analyses showed that the emulsions exhibited pseudoplastic and viscoelastic behavior. The in vitro release of BV from palm olein emulsion through cellulose acetate was 4.5 times higher than that of commercial products and more BV molecules deposited in rat skin. Less than 4% of the drug was degraded in the formulations during the 3-month period when they were subjected to the three different temperatures. These findings indicate that palm olein-in-water emulsion can be an alternative vehicle for topical drug delivery system with superior permeability.
Surface-modified nanostructured lipid carriers (NLC) represent a promising mode of drug delivery used to enhance retention of drugs at absorption site. Formulated chitosan-coated amphotericin-B-loaded NLC (ChiAmp NLC) had a size of 394.4 ± 6.4 nm, encapsulation and loading efficiencies of 86.0 ± 3% and 11.0 ± 0.1% respectively. Amphotericin-B release from NLCs was biphasic with no changes in physical properties upon exposure to simulated gastrointestinal conditions. Antifungal properties of Amphotericin-B and ChiAmpB NLC were comparable but ChiAmpB NLC was twice less toxic to red blood cells and ten times safer on HT-29 cell lines. In vitro mucoadhesion data were observed ex vivo, where ChiAmpB NLC resulted in higher retention within the small intestine compared to the uncoated formulation. The data strongly offers the possibility of orally administering a non-toxic, yet effective Amphotericin-B nanoformulation for the treatment of systemic fungal infections.
The aim of this study is to investigate the dissolution properties of poorly soluble drugs from their pure form and their amorphous formulation under physiological relevant conditions for oral administration based on surface dissolution ultraviolet (UV) imaging. Dissolution of two poorly soluble drugs (cefuroxime axetil and itraconazole) and their amorphous formulations (Zinnat® and Sporanox®) was studied with the Sirius Surface Dissolution Imager (SDI). Media simulating the fasted state conditions (compendial and biorelevant) with sequential media/flow rate change were used. The dissolution mechanism of cefuroxime axetil in simulated gastric fluid (SGF), fasted state simulated gastric fluid (FaSSGF) and simulated intestinal fluid (SIF) is predominantly swelling as opposed to the convective flow in fasted state simulated intestinal fluid (FaSSIF-V1), attributed to the effect of mixed micelles. For the itraconazole compact in biorelevant media, a clear upward diffusion of the dissolved itraconazole into the bulk buffer solution is observed. Dissolution of itraconazole from the Sporanox® compact is affected by the polyethylene glycol (PEG) gelling layer and hydroxypropyl methylcellulose (HPMC) matrix, and a steady diffusional dissolution pattern is revealed. A visual representation and a quantitative assessment of dissolution properties of poorly soluble compounds and their amorphous formulation can be obtained with the use of surface dissolution imaging under in vivo relevant conditions.
Asenapine, an atypical antipsychotic agent, has been approved for the acute and maintenance treatment of schizophrenia and manic episodes of bipolar disorder. However, the extensive hepatic metabolism limits its oral bioavailability. Therefore, the objective of the current investigation was to develop sublingual film containing asenapine to enhance the therapeutic efficacy. Sublingual films containing asenapine were fabricated using polyethylene oxide and hydroxypropyl methylcellulose by solvent casting method. Design of experiment was used as a statistical tool to optimize the proportion of the film-forming polymers in order to establish the critical quality attributes of the drug formulation. The process was studied in detail by assessing risk of each step as well as parameters and material attributes to reduce the risk to a minimum. A control strategy was defined to ensure manufacture of films according to the target product profile by evaluation of intermediate quality attributes at the end of each process step. Results of optimized formulations showed rapid disintegration, adequate folding endurance, good percentage elongation, tensile strength, and viscosity. Besides, the results from the in vitro dissolution/ex vivo permeation studies showed rapid dissolution (100% in 6 min) and higher asenapine permeation (~ 80% in 90 min) through the sublingual epithelium. In vivo study indicates greater asenapine absorption (31.18 ± 5.01% of administered dose) within 5 min and was comparable with marketed formulation. In summary, the designing plan to develop asenapine formulation was successfully achieved with desired characteristics of the delivery tool for sublingual administration.
Over the past decade, intranasal (IN) delivery has been gaining attention as an alternative approach to conventional drug delivery routes targeting the brain. Carbamazepine (CBZ) is available as an orally ingestible formulation. The present study aims to develop a thermoreversible in situ gelling system for delivering CBZ via IN route. A cold method of synthesis has been used to tailor and optimize the thermoreversible gel composition, using poloxamer 407 (P407) (15-20% w/v) and iota carrageenan (ɩ-Cg) (0.15-0.25% w/v). The developed in situ gel showed gelation temperatures (28-33°C), pH (4.5-6.5), rheological properties (pseudoplastic, shear thinning), and mucoadhesive strength (1755.78-2495.05 dyne/cm2). The in vitro release study has shown sustained release behavior (24 h) for gel, containing significant retardation of CBZ release. The release kinetics fit to the Korsmeyer-Peppas model, suggesting the non-Fickian diffusion type controlled release behavior. Ex vivo permeation through goat nasal mucosa showed sustained release from the gel containing 18% P407 with the highest cumulative drug permeated (243.94 µg/cm2) and a permeation flux of 10.16 µg/cm2/h. After treatment with CBZ in situ gel, the barrier function of nasal mucosa remained unaffected. Permeation through goat nasal mucosa using in situ gel has demonstrated a harmless nasal delivery, which can provide a new dimension to deliver CBZ directly to the brain bypassing the blood-brain barrier.
Protein biologics are prone to conformational changes during formulation development. Limited methods are available for conformational analysis of proteins in solid state and in the presences of formulation excipients. The aim of this study was to investigate the secondary structures of proteins encased in solid lipid matrices as a novel indicator of their stability upon in vitro release. Model proteins namely catalase and lysozyme were incorporated into lipid namely Precirol® AT05 (glycerol palmitostearate, melting point 58°C) at 30% w/w loading using melting and mixing and wet granulation methods. Attenuated total reflectance (ATR-FTIR) spectroscopy, size-exclusion chromatography (SEC) and biological activity analyses were performed. The information about secondary structure was acquired using second derivative analysis of amide-I band (1600-1700 cm-1). ATR analysis demonstrated interference of lipid spectrum with protein amide-I band which was subsequently subtracted to allow the analysis of the secondary structure. ATR spectra amide-I bands showed shifts peak band positions compared to native protein for matrices prepared using wet granulation. SEC analysis gave evidence of protein aggregation for catalase which was increased using wet granulation. The biological activity of catalase was statistically different from that of control and was affected by the incorporation method and was found to be in alignment with ATR spectral changes and extent of aggregation. In conclusion, ATR spectroscopy could analyze protein secondary structure in lipid matrices provided lipid interference was minimized. The ATR spectral changes and formation of aggregates can indicate the loss in biological activity of protein released from solid lipid matrices.
Coenzyme Q10 (CoQ10) is a vitamin-like oil-soluble molecule that has anti-oxidant and anti-ageing effects. To determine the most optimal CoQ10 delivery vehicle, CoQ10 was solubilised in both water and fish oil, and formulated into hydrogel, oleogel and bigel. Permeability of CoQ10 from each formulation across porcine ear skin was then evaluated. Furthermore, the effects of the omega-3 fatty eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids from fish oil on skin permeation were investigated by means of nuclear magnetic resonance (NMR) and computerised molecular modelling docking experiments. The highest drug permeation was achieved with the bigel formulation that proved to be the most effective vehicle in delivering CoQ10 across the skin membrane due to a combination of its adhesive, viscous and lipophilic properties. Furthermore, the interactions between CoQ10 and fatty acids revealed by NMR and molecular modelling experiments likely accounted for skin permeability of CoQ10. NMR data showed dose-dependent changes in proton chemical shifts in EPA and DHA. Molecular modelling revealed complex formation and large binding energies between fatty acids and CoQ10. This study advances the knowledge about bigels as drug delivery vehicles and highlights the use of NMR and molecular docking studies for the prediction of the influence of drug-excipient relationships at the molecular level.
The dissolution and subsequent oral bioavailability of acyclovir (ACY) is limited by its poor aqueous solubility. An attempt has been made in this work to provide mechanistic insights into the solubility enhancement and dissolution of ACY by using the water-soluble carrier polyethylene glycol 6000 (PEG6000). Solid dispersions with varying ratios of the drug (ACY) and carrier (PEG6000) were prepared and evaluated by phase solubility, in vitro release studies, kinetic analysis, in situ perfusion, and in vitro permeation studies. Solid state characterization was done by powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR) analysis, and surface morphology was assessed by polarizing microscopic image analysis, scanning electron microscopy, atomic force microscopy, and nuclear magnetic resonance analysis. Thermodynamic parameters indicated the solubilization effect of the carrier. The aqueous solubility and dissolution of ACY was found to be higher in all samples. The findings of XRD, DSC, FTIR and NMR analysis confirmed the formation of solid solution, crystallinity reduction, and the absence of interaction between the drug and carrier. SEM and AFM analysis reports ratified the particle size reduction and change in the surface morphology in samples. The permeation coefficient and amount of ACY diffused were higher in samples in comparison to pure ACY. Stability was found to be higher in dispersions. The results suggest that the study findings provided clear mechanical insights into the solubility and dissolution enhancement of ACY in PEG6000, and such findings could lay the platform for resolving the poor aqueous solubility issues in formulation development.
Bacterial biofilm which adheres onto wound surface is shown to be impervious to antibiotics and this in turn delays wound healing. Previous studies showed that antibiofilm agents such as xylitol and ethylenediaminetetraacetic acid (EDTA) prevent bacterial adherence onto surfaces. Formulation of a wound dressing containing antibiofilm agents may be a plausible strategy in breaking the biofilm on wound surfaces and at the same time increase the efficacy of the antibiotic. The purpose of this study was to develop hydrogel formulations containing antibiofilm agents along with antibiotic (gentamicin) for bacterial biofilm-associated wound infection. Sodium carboxymethyl cellulose (NaCMC) hydrogels loaded with antibiofilm agents and antibiotic were prepared. The hydrogels were characterized for their physical properties, rheology, Fourier transform infrared spectroscopy (FTIR), drug content uniformity, differential scanning calorimetry (DSC) and in vitro drug release study. The antibiofilm (Crystal Violet staining and XTT assay) and antibacterial performances of the hydrogels against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli were assessed in vitro. The formulated hydrogels showed adequate release of both antibiofilm agents (xylitol and EDTA). Both antimicrobial and antibiofilm tests showed promising results and demonstrated that the combination of xylitol, EDTA, and gentamicin had an additive effect against both Gram-positive and Gram-negative bacteria. In summary, NaCMC (sodium carboxymethyl cellulose) hydrogels containing the combination of antimicrobial and antibiofilm agents were successfully developed and this can be a new strategy in combating biofilm in wound infection which in turn accelerate wound healing.
The treatment of wounds is a serious problem all over the world and imposes a huge financial burden on each and every nation. For a long time, researchers have explored wound dressing that speeds up wound healing. Traditional wound dressing does not respond effectively to the wound-healing process as expected. Therapeutic active derived from plant extracts and extracted bioactive components have been employed in various regions of the globe since ancient times for the purpose of illness, prevention, and therapy. About 200 years ago, most medical treatments were based on herbal remedies. Especially in the West, the usage of herbal treatments began to wane in the 1960s as a result of the rise of allopathic medicine. In recent years, however, there has been a resurgence of interest in and demand for herbal medicines for a number of reasons, including claims about their efficacy, shifting consumer preferences toward natural medicines, high costs and negative side effects of modern medicines, and advancements in herbal medicines brought about by scientific research and technological innovation. The exploration of medicinal plants and their typical uses could potentially result in advanced pharmaceuticals that exhibit reduced adverse effects. This review aims to present an overview of the utilization of nanocarriers in plant-based therapeutics, including its current status, recent advancements, challenges, and future prospects. The objective is to equip researchers with a comprehensive understanding of the historical background, current state, and potential future developments in this emerging field. In light of this, the advantages of nanocarriers based delivery of natural wound healing treatments have been discussed, with a focus on nanofibers, nanoparticles, nano-emulsion, and nanogels.
Middle East respiratory syndrome (MERS) is a lethal respiratory disease with its first case reported back in 2012 (Jeddah, Saudi Arabia). It is a novel, single-stranded, positive-sense RNA beta coronavirus (MERS-CoV) that was isolated from a patient who died from a severe respiratory illness. Later, it was found that this patient was infected with MERS. MERS is endemic to countries in the Middle East regions, such as Saudi Arabia, Jordan, Qatar, Oman, Kuwait and the United Arab Emirates. It has been reported that the MERS virus originated from bats and dromedary camels, the natural hosts of MERS-CoV. The transmission of the virus to humans has been thought to be either direct or indirect. Few camel-to-human transmissions were reported earlier. However, the mode of transmission of how the virus affects humans remains unanswered. Moreover, outbreaks in either family-based or hospital-based settings were observed with high mortality rates, especially in individuals who did not receive proper management or those with underlying comorbidities, such as diabetes and renal failure. Since then, there have been numerous reports hypothesising complications in fatal cases of MERS. Over the years, various diagnostic methods, treatment strategies and preventive measures have been strategised in containing the MERS infection. Evidence from multiple sources implicated that no treatment options and vaccines have been developed in specific, for the direct management of MERS-CoV infection. Nevertheless, there are supportive measures outlined in response to symptom-related management. Health authorities should stress more on infection and prevention control measures, to ensure that MERS remains as a low-level threat to public health.
Innovative strategies for periodontal regeneration have been the focus of research clusters across the globe for decades. In order to overcome the drawbacks of currently available options, investigators have suggested a novel concept of functionally graded membrane (FGM) templates with different structural and morphological gradients. Chitosan (CH) has been used in the past for similar purpose. However, the composite formulation of composite and tetracycline when cross-linked with glutaraldehyde have received little attention. Therefore, the purpose of the study was to investigate the drug loading and release characteristics of novel freeze gelated chitosan templates at different percentages of glutaraldehyde. These were cross-linked with 0.1 and 1% glutaraldehyde and loaded with doxycycline hyclate. The electron micrographs depicted porous morphology of neat templates. After cross-linking, these templates showed compressed ultrastructures. Computerized tomography analysis showed that the templates had 88 to 92% porosity with average pore diameter decreased from 78 to 44.9 μm with increasing concentration. Fourier transform infrared spectroscopy showed alterations in the glycosidic segment of chitosan fingerprint region which after drug loading showed a dominant doxycycline spectral composite profile. Interestingly, swelling profile was not affected by cross-linking either at 0.1 and 1% glutaraldehyde and template showed a swelling ratio of 80%, which gained equilibrium after 15 min. The drug release pattern also showed a 40 μg/mL of release after 24 h. These doxycycline-loaded templates show their tendency to be used in a functionally graded membrane facing the defect site.
Tuberculosis (TB) is among the top 10 infectious diseases worldwide. It is categorized among the leading killer diseases that are the reason for the death of millions of people globally. Although a standardized treatment regimen is available, non-adherence to treatment has increased multi-drug resistance (MDR) and extensive drug-resistant (XDR) TB development. Another challenge is targeting the death of TB reservoirs in the alveoli via conventional treatment. TB Drug resistance may emerge as a futuristic restraint of TB with the scarcity of effective Anti-tubercular drugs. The paradigm change towards nano-targeted drug delivery systems is mostly due to the absence of effective therapy and increased TB infection recurrent episodes with MDR. The emerging field of nanotechnology gave an admirable opportunity to combat MDR and XDR via accurate diagnosis with effective treatment. The new strategies targeting the lung via the pulmonary route may overcome the new incidence of MDR and enhance patient compliance. Therefore, this review highlights the importance and recent research on pulmonary drug delivery with nanotechnology along with prevalence, the need for the development of nanotechnology, beneficial aspects of nanomedicine, safety concerns of nanocarriers, and clinical studies.
The protective efficacies of current licensed vaccines against COVID-19 have significantly reduced as a result of SARS-CoV-2 variants of concern (VOCs) which carried multiple mutations in the Spike (S) protein. Considering that these vaccines were developed based on the S protein of the original SARS-CoV-2 Wuhan strain, we designed a recombinant plasmid DNA vaccine based on highly conserved and immunogenic B and T cell epitopes against SARS-CoV-2 Wuhan strain and the Omicron VOC. Literature mining and bioinformatics were used to identify 6 immunogenic peptides from conserved regions of the SARS-CoV-2 S and membrane (M) proteins. Nucleotide sequences encoding these peptides representing highly conserved B and T cell epitopes were cloned into a pVAX1 vector to form the pVAX1/S2-6EHGFP recombinant DNA plasmid vaccine. The DNA vaccine was intranasally or intramuscularly administered to BALB/c mice and evaluations of humoral and cellular immune responses were performed. The intramuscular administration of pVAX1/S2-6EHGFP was associated with a significantly higher percentage of CD8+ T cells expressing IFN-γ when compared with the empty vector and PBS controls. Intramuscular or intranasal administrations of pVAX1/S2-6EHGFP resulted in robust IgG antibody responses. Sera from mice intramuscularly immunized with pVAX1/S2-6EHGFP were found to elicit neutralizing antibodies capable of SARS-CoV-2 Omicron variant with the ACE2 cell surface receptor. This study demonstrated that the DNA vaccine construct encoding highly conserved immunogenic B and T cell epitopes was capable of eliciting potent humoral and cellular immune responses in mice.
The current study sought to create graphene oxide-based superstructures for gastrointestinal drug delivery. Graphene oxide has a large surface area that can be used to load anti-cancer drugs via non-covalent methods such as surface adsorption and hydrogen bonding. To enhance the bio-applicability of graphene oxide, nano-hybrids were synthesized by encapsulating the graphene oxide into calcium alginate hydrogel beads through the dripping-extrusion technique. These newly developed bio-nanocomposite hybrid hydrogel beads were evaluated in structural analysis, swelling study, drug release parameters, haemolytic assay, and antibacterial activity. Doxorubicin served as a model drug. The drug entrapment efficiency was determined by UV-spectroscopy analysis and was found to be high at ⁓89% in graphene oxide hybrid hydrogel beads. These fabricated hydrogel beads ensure the drug release from a hybrid polymeric matrix in a more controlled and sustained pattern avoiding the problems associated with a non-hybrid polymeric system. The drug release study of 12 h shows about 83% release at pH 6.8. In vitro drug release kinetics proved that drug release was a Fickian mechanism. The cytotoxic effect of graphene oxide hybrid alginate beads was also determined by evaluating the morphology of bacterial cells and red blood cells after incubation. Additionally, it was determined that the sequential encapsulation of graphene oxide in alginate hydrogel beads hides its uneven edges and lessens the graphene oxide's negative impacts. Also, the antibacterial study and biocompatibility of fabricated hydrogel beads made them potential candidates for gastrointestinal delivery.
Targeting the small intestine employing nanotechnology has proved to be a more effective way for site-specific drug delivery. The drug targeting to the small intestine can be achieved via nanoparticles for its optimum bioavailability within the systemic circulation. The small intestine is a remarkable candidate for localized drug delivery. The intestine has its unique properties. It has a less harsh environment than the stomach, provides comparatively more retention time, and possesses a greater surface area than other parts of the gastrointestinal tract. This review focuses on elaborating the intestinal barriers and approaches to overcome these barriers for internalizing nanoparticles and adopting different cellular trafficking pathways. We have discussed various factors that contribute to nanocarriers' cellular uptake, including their surface chemistry, surface morphology, and functionalization of nanoparticles. Furthermore, the fate of nanoparticles after their uptake at cellular and subcellular levels is also briefly explained. Finally, we have delineated the strategies that are adopted to determine the cytotoxicity of nanoparticles.
Currently, pharmaceutical research is directed wide range for developing new drugs for oral administration to target disease. Acyclovir formulation is having common issues of short half-life and poor permeability, causing messy treatment which results in patient incompliance. The present study formulates a lipid polymeric hybrid nanoparticles for antiviral acyclovir (ACV) agent with Phospholipon® 90G (lecithin), chitosan, and polyethylene glycol (PEG) to improve controlled release of the drugs. The study focused on the encapsulation of the ACV in lipid polymeric particle and their sustained delivery. The formulation developed for the self-assembly of chitosan and lecithin to form a shell encapsulating acyclovir, followed by PEGylation. Optimisation was performed via Box-Behnken Design (BBD), forming nanoparticles with size of 187.7 ± 3.75 nm, 83.81 ± 1.93% drug-entrapped efficiency (EE), and + 37.7 ± 1.16 mV zeta potential. Scanning electron microscopy and transmission electron microscopy images displayed spherical nanoparticles formation. Encapsulation of ACV and complexity with other physical parameters are confirmed through analysis using Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. Nanoparticle produced was capable of achieving 24-h sustained release in vitro on gastric and intestinal environments. Ex vivo study proved the improvement of acyclovir's apparent permeability from 2 × 10-6 to 6.46 × 10-6 cm s-1. Acyclovir new formulation was achieved to be stable up to 60 days for controlled release of the drugs. Graphical abstract.
The main objective of the present study is the physicochemical characterization of naturally available Terminalia catappa gum (Badam gum [BG]) as a novel pharmaceutical excipient and its suitability in the development of gastroretentive floating drug delivery systems (GRFDDS) to retard the drug for 12 h when the dosage form is exposed to gastrointestinal fluids in the gastric environment. As BG was being explored for the first time for its pharmaceutical application, physicochemical, microbiological, rheological, and stability studies were carried out on this gum. In the present investigation, the physicochemical properties, such as micromeritic, rheological, melting point, moisture content, pH, swelling index, water absorption, and volatile acidity, were evaluated. The gum was characterized by scanning electron microscopy, differential scanning calorimetry (DSC), powder X-ray diffraction studies (PXRD), and Fourier transform infrared spectroscopy (FTIR). Gastroretentive floating tablets of BG were prepared with the model drug propranolol HCl by direct compression methods. The prepared tablets were evaluated for all their physicochemical properties, in vitro buoyancy, in vitro drug release, and rate order kinetics. PBG 04 was selected as an optimized formulation based on its 12-h drug release and good buoyancy characteristics. The optimized formulation was characterized with FTIR, DSC, and PXRD studies, and no interaction between the drug and BG was found. Thus, the study confirmed that BG might be used in the gastroretentive drug delivery system as a release-retarding polymer.