Current anticancer drug research includes tumor-targeted administration as a critical component because it is the best strategy to boost efficacy and decrease toxicity. Low drug concentration in cancer cells, nonspecific distribution, rapid clearance, multiple drug resistance, severe side effects, and other factors contribute to the disappointing results of traditional chemotherapy. As an innovative technique of treatments for hepatocellular carcinoma (HCC) in recent years, nanocarrier-mediated targeted drug delivery systems can overcome the aforesaid limitations via enhanced permeability and retention effect (EPR) and active targeting. Epidermal growth factor receptor (EGFR) inhibitor Gefitinib (Gefi) has dramatic effects on hepatocellular carcinoma. Herein, we developed and assessed an αvβ3 integrin receptor targeted c(RGDfK) surface modified liposomes for better targeting selectivity and therapeutic efficacy of Gefi on HCC cells. The conventional and modified Gefi loaded liposomes, i.e., denoted as Gefi-L and Gefi-c(RGDfK)-L, respectively, were prepared through the ethanol injection method and optimized via Box Behnken design (BBD). The FTIR and 1H NMR spectroscopy verified that the c(RGDfK) pentapeptides had formed an amide bond with the liposome surface. In addition, the particle size, Polydispersity index, zeta potential, encapsulation efficiency, and in-vitro Gefi release of the Gefi-L and Gefi-c(RGDfK)-L were measured and analyzed. As indicated by the MTT assay on HepG2 cells, Gefi-c(RGDfK)-L displayed considerably higher cytotoxicity than Gefi-L or Gefi alone. Throughout the incubation period, HepG2 cells took up significantly more Gefi-c(RGDfK)-L than Gefi-L. According to the in vivo biodistribution analysis, Gefi-c(RGDfK)-L accumulated more strongly at the tumor site than Gefi-L and free Gefi. Furthermore, HCC-bearing rats treated with Gefi-c(RGDfK)-L showed a substantial drop in liver marker enzymes (alanine transaminase, alkaline phosphatase, aspartate transaminase, and total bilirubin levels) compared to the disease control group. Gefi-c(RGDfK)-L suppresses tumour growth more effectively than Gefi-L and free Gefi, according to an in vivo analysis of their anticancer activities. Thus, c(RGDfK)-surface modified liposomes, i.e., Gefi-c(RGDfK)-L may serve as an efficient carrier for the targeted delivery of anticancer drugs.
Inhaled/oral insulin have been investigated as an alternative to injectable insulin, but are met with unsatisfactory outcomes. Transdermal administration bears several advantages unmet by inhalation/oral delivery, but macromolecular drugs permeation is poor. This study explored microwave to elicit transdermal insulin permeation, and compared against conventional permeation enhancers (fatty acids) in vitro/in vivo. The transdermal insulin permeation was promoted by microwave (2450 MHz/1 mW) > oleic acid (monounsaturated) ~ linoleic acid (double unsaturated bonds). The linolenic acid (triple unsaturated bonds) or combination of microwave/fatty acid reduced skin insulin permeation. Transdermal insulin permeation enhancement was attributed to epidermal lipid bilayer fluidization (CH) and corneocyte shrinkage due to keratin condensation (OH/NH, CO), which had aqueous pore enlarged to facilitate insulin transport. Its reduction by linolenic acid, a molecularly larger and rigid fatty acid with higher surface tension, was due to reduced fatty acid permeation into epidermis and minimal skin microstructural changes. The oleic acid, despite favoured skin microstructural changes, did not provide a remarkably high insulin permeation due to it embedded in skin as hydrophobic shield to insulin transport. Microwave penetrates skin volumetrically with no chemical residue retention. It alone promoted insulin absorption and sustained blood glucose level reduction in vivo.
Raloxifene HCl belongs to a class of selective estrogen receptor modulators (SERMs) which is used for the management of breast cancer. The major problem reported with raloxifene is its poor bioavailability which is only up to 2%. The main objective of the present work was to formulate raloxifene loaded ethosomal preparation for transdermal application and compare it with an oral formulation of the drug. Five ethosomal formulations with different concentrations of ethanol and a conventional liposomes formulation were prepared by rotary evaporation method. The prepared systems were characterised by high resolution transmission electron microscopy (HRTEM), force emission electron microscopy (FESEM), atomic force microscopy (AFM), X-ray diffraction (XRD) and 31P NMR study. All these advanced characterization study established that the ethosome formulation was well defined by its size, shape and its bilayer formation. Transdermal flux of the optimized ethosome formulation was 22.14 ± 0.83 µg/ml/cm2 which was 21 times higher when compared to the conventional liposomes. Confocal microscopy study revealed an enhanced permeation of coumarin-6 dye loaded ethosomes to much deeper layers of skin when compared with conventional liposomes. The gel was found to be pseudoplastic with elastic behaviour. In-vivo studies on rats showed a higher bioavailability of RXL (157% times) for ethosomal formulation when compared with the oral formulation. In conclusion, RXL loaded ethosomal formulation via transdermal route showed superior drug delivery properties as compared to oral formulation.
The application of time-domain NMR (TD-NMR) analysis to quantify water content in pharmaceutical ingredients is demonstrated. The initial phase of the study employed a range of disintegrants with defined amounts of added water (0-30% of the total weight) as samples; the disintegrants included croscarmellose sodium, corn starch, low-substituted hydroxypropyl cellulose, and crospovidone. After acquisition of the T2 relaxation curves of the samples by TD-NMR measurements, these curves were analyzed by partial least squares (PLS) regression. According to the analysis, accurate and reliable PLS models were created that enabled accurate assessment of water content in the samples. A powder blend consisting of acetaminophen (paracetamol) and tablet excipients was also examined. Both a physical mixture of the powder blend and a wet granule prepared with a high-speed granulator were tested as samples in this study. Precise determination of water content in the powder blend was achieved by using the TD-NMR method. The accuracy of water content determination was equivalent to or better than that of the conventional loss on drying method. TD-NMR analysis samples were measured nondestructively and rapidly with low cost; thus, it could be a powerful quantitative method for determining water content in pharmaceuticals.
Zinc (Zn) is a co-factor for a vast number of enzymes, and functions as a regulator for immune mechanism and protein synthesis. However, excessive Zn release induced in pathological situations such as stroke or transient global ischemia is toxic. Previously, we demonstrated that the interaction of Zn and copper (Cu) is involved in the pathogenesis of Alzheimer's disease and vascular dementia. Furthermore, oxidative stress has been shown to play a significant role in the pathogenesis of various metal ions induced neuronal death. Thioredoxin-Albumin fusion (HSA-Trx) is a derivative of thioredoxin (Trx), an antioxidative protein, with improved plasma retention and stability of Trx. In this study, we examined the effect of HSA-Trx on Cu2+/Zn2+-induced neurotoxicity. Firstly, HSA-Trx was found to clearly suppress Cu2+/Zn2+-induced neuronal cell death in mouse hypothalamic neuronal cells (GT1-7 cells). Moreover, HSA-Trx markedly suppressed Cu2+/Zn2+-induced ROS production and the expression of oxidative stress related genes, such as heme oxygenase-1. In contrast, HSA-Trx did not affect the intracellular levels of both Cu2+ and Zn2+ after Cu2+/Zn2+ treatment. Finally, HSA-Trx was found to significantly suppress endoplasmic reticulum (ER) stress response induced by Cu2+/Zn2+ treatment in a dose dependent manner. These results suggest that HSA-Trx counteracted Cu2+/Zn2+-induced neurotoxicity by suppressing the production of ROS via interfering the related gene expressions, in addition to the highly possible radical scavenging activity of the fusion protein. Based on these findings, HSA-Trx has great potential as a promising therapeutic agent for the treatment of refractory neurological diseases.
For effective topical and transdermal drug delivery, it is necessary for most actives to penetrate and permeate through the stratum corneum (SC). Extensive investigation of the thermal behaviour of mammalian SC has been performed to understand the barrier function of the skin. However, little attention has been paid to the related experimental variables in thermal analysis of the SC using differential scanning calorimetry that may influence the results obtained from such studies. In this review, we provide a comprehensive overview of the thermal transitions of the SC of both porcine and human skin. More importantly, the selection and impact of the experimental and instrumental parameters used in thermal analysis of the SC are critically evaluated. New opportunities for the use of thermal analysis of mammalian SC in advancing skin research, particularly for elucidation of the actions of excipients employed in topical and transdermal formulations on the skin are also highlighted.
The human small intestine, with its enormous absorptive surface area, is invariably the principal site of drug absorption. Hence, the residence time of a dosage form in this part of the gut can have a great influence on the absorption of the contained drug. Various methods have been employed to monitor the gastrointestinal transit of pharmaceutical dosage forms, but the use of gamma-scintigraphy has superceded all the other methods. However, careful consideration of the time interval for image acquisition and proper analysis of the scintigraphic data are important for obtaining reliable results. Most studies reported the mean small intestinal transit time of various dosage forms to be about 3-4h, being closely similar to that of food and water. The value does not appear to be influenced by their physical state nor the presence of food, but the timing of food intake following administration of the dosage forms can influence the small intestinal transit time. While the mean small intestinal transit time is quite consistent among dosage forms and studies, individual values can vary widely. There are differing opinions regarding the effect of density and size of dosage forms on their small intestinal transit properties. Some common excipients employed in pharmaceutical formulations can affect the small intestinal transit and drug absorption. There is currently a lack of studies regarding the effects of excipients, as well as the timing of food intake on the small intestinal transit of dosage forms and drug absorption.
Cellulose is a natural homopolymer, composed of β-1,4- anhydro-d-glucopyranose units. Unlike plant cellulose, bacterial cellulose (BC), obtained from species belonging to the genera of Acetobacter, Rhizobium, Agrobacterium, and Sarcina through various cultivation methods and techniques, is produced in its pure form. BC is produced in the form of gel-like, never dry sheet with tremendous mechanical properties. Containing up to 99% of water, BC hydrogel is considered biocompatible thus finding robust applications in the health industry. Moreover, BC three-dimensional structure closely resembles the extracellular matrix (ECM) of living tissue. In this review, we focus on the porous BC morphology particularly suited to host oxygen and nutrients thus providing conducive environment for cell growth and proliferation. The remarkable BC porous morphology makes this biological material a promising templet for the generation of 3D tissue culture and possibly for tissue-engineered scaffolds.
Crystallinity plays a vital role in the pharmaceutical industry. It affects drug manufacturing, development processes, and the stability of pharmaceutical dosage forms. An objective of this study was to measure and analyze the carbamazepine (CBZ) crystallinity before and after formulation. Moreover, it intended to determine the extent to which the crystallinity of CBZ would affect the drug loading, the particle size, and the release of CBZ from the microparticles. The CBZ microparticles were prepared by encapsulating CBZ in ethyl cellulose (EC) polymer using a solvent evaporation method. EC was used here as a release modifier polymer and polyvinyl alcohol (PVA) as an aqueous phase stabilizer. Factorial design was used to prepare the CBZ microparticle formulations, including polymer concentration, solvent (dichloromethane, ethyl acetate), PVA concentrations factor, the homogenization time, and homogenization speed. The crystallinity of CBZ was calculated utilizing differential scanning calorimetry (DSC) thermal analysis. The crystallinity was calculated from the enthalpy of CBZ. Enthalpy was analyzed from the area under the curve peak of CBZ standard and CBZ-loaded microparticles. DSC and ATR-FTIR assessed the possible interaction between CBZ and excipients in the microparticle. The prepared CBZ microparticles showed various changes in the crystallinity rate of CBZ. The changes in the rate of CBZ crystallinity had different effects on the particle size, the drug loading, and the release of CBZ from the polymer. Statistically, all studied factors significantly affected the crystallinity of CBZ after formulation to microparticles.
Nanoprecipitation is a simple and increasingly trending method for nanoparticles preparation. The self-assembly feature of poly (ethylene glycol)-poly (lactide-co-glycolic acid) (PEG-PLGA) amphiphilic copolymer into a nanoparticle and its versatile structure makes nanoprecipitation one of the best methods for its preparation. The aim of this study is to review currently available literature for standard preparation of PEG-PLGA nanoparticles using nanoprecipitation technique in order to draw conclusive evidenceto draw conclusive evidence that can guide researchers during formulation development. To achieve this, three databases (Web of Science, Scopus and PubMed) were searched using relevant keywords and the extracted articles were reviewed based on defined inclusion and exclusion criteria. Data extraction and narrative analysis of the obtained literature was performed when appropriate, along with our laboratory observations to support those claims wherever necessary. As a result of this analysis, reports that matched our criteria conformed to the general facts about nanoprecipitation techniques such as simplicity in procedure, low surfactants requirement, narrow size distribution, and low resulting concentrations. However, these reports showed interesting advantages for using PEG-PLGA as they are frequently reported to be freeze-dried and active pharmaceutical ingredients (APIs) with low hydrophobicity were reported to successfully be encapsulated in the particles.
Intranasal delivery has shown to circumvent blood-brain-barrier (BBB) and deliver the drugs into the CNS at a higher rate and extent than other conventional routes. The mechanism of drug transport from nose-to-brain is not fully understood yet, but several neuronal pathways are considered to be involved. Intranasal nanoemulsion for brain targeting is investigated extensively. Higher brain distribution of drug after administering intranasal nanoemulsion was established by many researchers. Issues with nasomucosal clearance are solved by formulating modified nanoemulsion; for instance, mucoadhesive nanoemulsion or in situ nanoemulgel. However, no intranasal nanoemulsion for brain targeted drug delivery has been able to cross the way from 'benches to bed-side' of patients. Possibilities of toxicity by repeated administration, irregular nasal absorption during the diseased condition, use of a high amount of surfactants are few of the persisting challenges that need to overcome in coming days. Understanding the ways how current developments has solved some challenges is necessary. At the same time, the future direction of the research on intranasal nanoemulsion should be figured out based on existing challenges. This review is focused on the current developments of intranasal nanoemulsion with special emphasis on the existing challenges that would help to set future research direction.
The biological barriers in the body have been fabricated by nature to protect the body from foreign molecules. The successful delivery of drugs is limited and being challenged by these biological barriers including the gastrointestinal tract, brain, skin, lungs, nose, mouth mucosa, and immune system. In this review article, we envisage to understand the functionalities of these barriers and revealing various drug-loaded biodegradable polymeric nanoparticles to overcome these barriers and deliver the entrapped drugs to cancer targeted site. Apart from it, tissue-specific multifunctional ligands, linkers and transporters when employed imparts an effective active delivery strategy by receptor-mediated transcytosis. Together, these strategies enable to deliver various drugs across the biological membranes for the treatment of solid tumors and malignant cancer.
Oral administration of drugs is preferred over other routes for several reasons: it is non-invasive, easy to administer, and easy to store. However, drug formulation for oral administration is often hindered by the drug's poor solubility, which limits its bioavailability and reduces its commercial value. As a solution, amorphous solid dispersion (ASD) was introduced as a drug formulation method that improves drug solubility by changing the molecular structure of the drugs from crystalline to amorphous. The hot melt extrusion (HME) method is emerging in the pharmaceutical industry as an alternative to manufacture ASD. However, despite solving solubility issues, ASD also exposes the drug to a high risk of crystallisation, either during processing or storage. Formulating a successful oral administration drug using ASD requires optimisation of the formulation, polymers, and HME manufacturing processes applied. This review presents some important considerations in ASD formulation, including strategies to improve the stability of the final product using HME to allow more new drugs to be formulated using this method.
This study investigated critical physicochemical attributes of low (LV), medium (MV) and high molecular weight (HV) sodium carboxymethylcellulose (SCMC) scaffolds in partial thickness wound healing. SCMC scaffolds were prepared by solvent-evaporation technique. Their in vitro erosion, moisture affinity, morphology, tensile strength, polymer molecular weight and carboxymethyl substitution, and in vivo wound healing profiles were determined. Inferring from rat wound size, re-epithelialization and histological profiles, wound healing progressed with HV scaffold>LV-MV scaffold>control with no scaffold. The transepidermal water loss (TEWL) from wound of rats treated by control>HV scaffold>LV-MV scaffold. HV scaffold had the highest tensile strength of all matrices and was resistant to erosion in simulated wound fluid. In spite of constituting small nanopores, it afforded a substantial TEWL than MV and LV scaffolds from wound across an intact matrix through its low moisture affinity characteristics. The HV scaffold can protect moisture loss without its excessive accumulation at wound bed which hindered re-epithelialization process. Regulation of transepidermal water movement and wound healing by scaffolds was governed by SCMC molecular weight instead of its carboxymethyl substitution degree or matrix pore size distribution, with large molecular weight HV preferred over lower molecular weight samples.
A polyglycolised glyceride carrier, Gelucire 50/13, was incorporated with paracetamol as a model drug, filled into hard gelatin capsules and stored at three different temperatures for various lengths of time. The resultant solidified matrix within the capsule was subjected to thermal analysis using differential scanning calorimetry (DSC) to ascertain its supramolecular structure. Polymorphic transformations towards more stable gelucire forms were observed upon aging the matrices, with samples stored at a temperature near the melting range of the lower temperature gelucire melting fraction showing the most profound changes. The increase in the rate of drug release from aged samples could be correlated to the alterations to the supramolecular structure of the gelucire. Accelerated drug release from aged samples could also be seen from in vivo studies using healthy human volunteers, although the extent of absorption was not affected. Therefore, even though the sustainability of release may be compromised by aging the gelucire matrices, the bioavailability of the incorporated drug is unlikely to be affected.
In this study, hydroxytyrosol (HT; a potent antioxidant) was co-administered with hydrocortisone (HC) to mitigate the systemic adverse effects of the latter and to provide additional anti-inflammatory and antioxidant benefits in the treatment of atopic dermatitis (AD). The co-loaded nanoparticles (NPs) prepared had shown different particle sizes, zeta potentials, loading efficiencies, and morphology, when the pH of the chitosan solution was increased from 3.0 to 7.0. Ex vivo permeation data showed that the co-loaded NPs formulation significantly reduced the corresponding flux (17.04μg/cm(2)/h) and permeation coefficient (3.4×10(-3)cm/h) of HC across full-thickness NC/Nga mouse skin. In addition, the NPs formulation showed higher epidermal (1560±31μg/g of skin) and dermal (880±28μg/g of skin) accumulation of HC than did a commercial HC formulation. Moreover, an in vivo study using an NC/Nga mouse model revealed that compared to the other treatment groups, the group treated with the NPs formulation efficiently controlled transepidermal water loss (13±2g/m(2)/h), intensity of erythema (207±12), and dermatitis index (mild). In conclusion, NPs co-loaded with HC/HT is proposed as a promising system for the percutaneous co-delivery of anti-inflammatory and antioxidative agents in the treatment of AD.
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 unprecedented outbreak of severe acute respiratory syndrome-2 (SARS-CoV-2) worldwide has rendered it one of the most notorious pandemics ever documented in human history. As of November 2022, nearly 626 million cases of infection and over 6.6 million deaths have been reported globally. The scientific community has made significant progress in therapeutics and prevention for the management of coronavirus disease (COVID-19), including the development of vaccines and antiviral agents such as monoclonal antibodies and antiviral drugs. Although many advancements and a plethora of positive results have been obtained and global restrictions are being uplifted, obstacles in efficiently delivering these therapies, such as their rapid clearance, suboptimal biodistribution, and toxicity to organs, have yet to be addressed. To address these drawbacks, researchers have attempted applying nanotechnology-based formulations. Here, we summarized the recent data about COVID-19, its emergence, pathophysiology and life cycle, diagnosis, and currently-available medications. Subsequently, we discussed the progress in lipid nanocarriers, such as liposomes in infection detection and control. This review provides critical insights into the design of the latest liposomal-based formulations for tackling the barriers to detecting, preventing, and treating SARS-CoV-2.
Major goal of dental treatment is to eradicate the existing diseases of the oral cavity and implement preventive measures to control the spread of the diseases. Various interventions are being used to cure the dental diseases. Due to the nanostructures, high surface volume and biocompatibility, Gold nanoparticles (GNPs) have been experimented in the treatment of gum diseases, dental caries, tissue engineering, dental implantology and diagnosis of cancers. GNPs possess antifungal and antibacterial activity, hence are incorporated in various biomaterials to potentiate the effect. They also enhance the mechanical properties of materials leading to improved outcomes. They are available in different sizes and concentrations to exhibits its beneficial outcomes. These properties of GNPs make these materials as choice of fillers in biomaterials. This review aims to discuss the effect of incorporation of GNPs in several biomaterials used for dental and medical applications.
Photothermal therapy (PTT) is a minimally invasive procedure for treating cancer. The two significant prerequisites of PTT are the photothermal therapeutic agent (PTA) and near-infrared radiation (NIR). The PTA absorbs NIR, causing hyperthermia in the malignant cells. This increased temperature at the tumor microenvironment finally results in tumor cell damage. Nanoparticles play a crucial role in PTT, aiding in the passive and active targeting of the PTA to the tumor microenvironment. Through enhanced permeation and retention effect and surface-engineering, specific targeting could be achieved. This novel delivery tool provides the advantages of changing the shape, size, and surface attributes of the carriers containing PTAs, which might facilitate tumor regression significantly. Further, inclusion of surface engineering of nanoparticles is facilitated through ligating ligands specific to overexpressed receptors on the cancer cell surface. Thus, transforming nanoparticles grants the ability to combine different treatment strategies with PTT to enhance cancer treatment. This review emphasizes properties of PTAs, conjugated biomolecules of PTAs, and the combinatorial techniques for a better therapeutic effect of PTT using the nanoparticle platform.