The purpose of this research was to study processing variables at the laboratory and pilot scales that can affect hydration rates of xanthan gum matrices containing diclofenac sodium and the rate of drug release. Tablets from the laboratory scale and pilot scale proceedings were made by wet granulation. Swelling indices of xanthan gum formulations prepared with different amounts of water were measured in water under a magnifying lens. Granules were thermally treated in an oven at 60 degrees C, 70 degrees C, and 80 degrees C to study the effects of elevated temperatures on drug release from xanthan gum matrices. Granules from the pilot scale formulations were bulkier compared to their laboratory scale counterparts, resulting in more porous, softer tablets. Drug release was linear from xanthan gum matrices prepared at the laboratory scale and pilot scales; however, release was faster from the pilot scales. Thermal treatment of the granules did not affect the swelling index and rate of drug release from tablets in both the pilot and laboratory scale proceedings. On the other hand, the release from both proceedings was affected by the amount of water used for granulation and the speed of the impeller during granulation. The data suggest that processing variables that affect the degree of wetness during granulation, such as increase in impeller speed and increase in amount of water used for granulation, also may affect the swelling index of xanthan gum matrices and therefore the rate of drug release.
This review highlights in vitro drug dissolution/permeation methods available for topical and transdermal nanocarriers that have been designed to modulate the propensity of drug release, drug penetration into skin, and permeation into systemic circulation. Presently, a few of USFDA-approved in vitro dissolution/permeation methods are available for skin product testing with no specific application to nanocarriers. Researchers are largely utilizing the in-house dissolution/permeation testing methods of nanocarriers. These drug release and permeation methods are pending to be standardized. Their biorelevance with reference to in vivo plasma concentration-time profiles requires further exploration to enable translation of in vitro data for in vivo or clinical performance prediction.
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.
Hydrocortisone cream intended for atopic eczema often produces unwanted side effects after long-term use. These side effects are essentially due to repeated percutaneous administration of the medication for skin dermatitis, as atopic eczema is a relapsing disorder. Hence, there is a need to develop a new hydrocortisone formulation that will deliver the drug more effectively and require a reduced dosing frequency; therefore, the side effects could be minimized. In this study, a hydroxypropyl methylcellulose (HPMC) lyogel system based on 80% organic and 20% aqueous solvents containing 1% hydrocortisone was formulated. The hydrocortisone lyogel physicochemical characteristics, rheological properties, stability profile, and in vitro Franz cell drug release properties, as well as the in vivo therapeutic efficacies and dermal irritancy in Balb/c mice were investigated. The HPMC lyogel appeared clear and soft and was easy to rub on the skin. The lyogel also showed a higher drug release profile compared with commercial hydrocortisone cream. Similar to the cream, HPMC lyogels exhibited pseudoplastic behavior. From the mouse model, the hydrocortisone lyogel showed higher inflammatory suppressive effects than the cream. However, it did not reduce the transepidermal water loss as effectively as the control did. The dermal irritancy testing revealed that the hydrocortisone lyogel caused minimal irritation. In conclusion, HPMC lyogel is a promising vehicle to deliver hydrocortisone topically, as it showed a higher drug release in vitro as well as enhanced therapeutic efficacy in resolving eczematous inflammatory reaction compared with commercial cream.
Compaction of controlled-release coated pellets into tablets is challenging because of the fusion of pellets and the rupturing of coated film. The difficulty in compaction intensifies with the use of extremely water-soluble drugs. Therefore, the present study was conducted to prepare and compact pellets containing pseudoephedrine hydrochloride as an extremely water-soluble model drug. The pellets were produced using an extrusion-spheronization technique. The drug-loaded pellets were coated to extend the drug release up to 12-h employing various polymers, and then they were compressed into tablets using microcrystalline cellulose Ceolus KG-801 as a novel tabletting excipient. The in vitro drug release studies of coated pellets and tablets were undertaken using the USP basket method in dissolution test apparatus I. The amount of drug released was analyzed at a wavelength of 215 nm. The combined coatings of hydroxypropyl methylcellulose and Kollicoat SR-30D yielded 12-h extended-release pellets with drug release independent of pH of dissolution medium following zero-order kinetics. The drug release from the tablets prepared using inert Celous KG-801 granules as tabletting excipient was found faster than that of coated pellets. However, a modification in drug release rate occurred with the incorporation of inert Ceolus KG-801 pellets. The drug dissolution profile from tablets containing 40% w/w each of coated pellets and inert granules along with 20% w/w inert pellets was found to be closely similar to that of coated pellets. Furthermore, the friability, tensile strength, and disintegration time of the tablets were within the USP specifications.
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.
Addressing poor solubility and permeability issues associated with synthetic drugs and naturally occurring active compounds is crucial for improving bioavailability. This review explores the potential of phospholipid complex formulation technology to overcome these challenges. Phospholipids, as endogenous molecules, offer a viable solution, with drugs complexed with phospholipids demonstrating a similar absorption mechanism. The non-toxic and biodegradable nature of the phospholipid complex positions it as an ideal candidate for drug delivery. This article provides a comprehensive exploration of the mechanisms underlying phospholipid complexes. Special emphasis is placed on the solvent evaporation method, with meticulous scrutiny of formulation aspects such as the phospholipid ratio to the drug and solvent. Characterization techniques are employed to understand structural and functional attributes. Highlighting the adaptability of the phospholipid complex, the review discusses the loading of various nanoformulations and emulsion systems. These strategies aim to enhance drug delivery and efficacy in various malignancies, including breast, liver, lung, cervical, and pancreatic cancers. The broader application of the drug phospholipid complex is showcased, emphasizing its adaptability in diverse oncological settings. The review not only explores the mechanisms and formulation aspects of phospholipid complexes but also provides an overview of key clinical studies and patents. These insights contribute to the intellectual and translational advancements in drug phospholipid complexes.
Colon cancer is the fourth most common cancer globally with 639,000 deaths reported annually. Typical chemotherapy is provided by injection route to reduce tumor growth and metastasis. Recent research investigates the oral delivery profiles of chemotherapeutic agents. In comparison to injection, oral administration of drugs in the form of a colon-specific delivery system is expected to increase drug bioavailability at target site, reduce drug dose and systemic adverse effects. Pectin is suitable for use as colon-specific drug delivery vehicle as it is selectively digested by colonic microflora to release drug with minimal degradation in upper gastrointestinal tract. The present review examines the physicochemical attributes of formulation needed to retard drug release of pectin matrix prior to its arrival at colon, and evaluate the therapeutic value of pectin matrix in association with colon cancer. The review suggests that multi-particulate calcium pectinate matrix is an ideal carrier to orally deliver drugs for site-specific treatment of colon cancer as (1) crosslinking of pectin by calcium ions in a matrix negates drug release in upper gastrointestinal tract, (2) multi-particulate carrier has a slower transit and a higher contact time for drug action in colon than single-unit dosage form, and (3) both pectin and calcium have an indication to reduce the severity of colon cancer from the implication of diet and molecular biology studies. Pectin matrix demonstrates dual advantages as drug carrier and therapeutic for use in treatment of colon cancer.
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.
The objectives of the present work were to prepare castor oil-based nano-sized emulsion containing cationic droplets stabilized by poloxamer-chitosan emulgator film and to assess the kinetic stability of the prepared cationic emulsion after subjecting it to thermal processing and freeze-thaw cycling. Presence of cryoprotectants (5%, w/w, sucrose +5%, w/w, sorbitol) improved the stability of emulsions to droplet aggregation during freeze-thaw cycling. After storing the emulsion at 4 degrees C, 25 degrees C, and 37 degrees C over a period of up to 6 months, no significant change was noted in mean diameter of the dispersed oil droplets. However, the emulsion stored at the highest temperature did show a progressive decrease in the pH and zeta potential values, whereas the emulsion kept at the lowest temperatures did not. This indicates that at 37 degrees C, free fatty acids were formed from the castor oil, and consequently, the liberated free fatty acids were responsible for the reduction in the emulsion pH and zeta potential values. Thus, the injectable castor oil-based nano-sized emulsion could be useful for incorporating various active pharmaceutical ingredients that are in size from small molecular drugs to large macromolecules such as oligonucleotides.
Orotic acid (OA) nanoparticles were prepared using the freeze-drying method. The antihypertensive activity and antioxidant capacity of OA and orotic acid-loaded gum arabic nanoparticles (OAGANPs) were examined using the angiotensin-converting enzyme (ACE), 1,1-diphenyl-2-picrylhydrazyl (DPPH), nitric oxide (NO), and β-carotene assays, as well as the quantification of total phenolic content (TPC). The DPPH and NO scavenging activities of OAGANPs were significantly higher than those of the OA solution. The β-carotene bleaching assay of OAGANPs showed a dose-dependent trend, while 500 μg/ml was significantly more effective than the other concentrations, which exerted 63.4% of the antioxidant activity. The in vitro antihypertensive assay revealed that the OAGANPs exhibited the most potent ACE inhibition activity, when compared to the OA solution. Hence, results revealed the potential of preparing the OA as a nanoparticle formulation in enhancing the antioxidant and antihypertensive properties compared to the OA solution.
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.
The aim of present research aims to fabricate a system of enteric coating of hydrogel beads with pH-sensitive polymer, which shows solubility at pH > 7, and explore their potential to target the colon for drug delivery. Hydrogel beads were fabricated through the extrusion-dripping technique followed by ion gelation crosslinking. Moreover, freeze-thaw cycle was implemented for crosslinking of polyvinyl alcohol (PVA)/Ca-alginate blend beads. The oil-in-oil solvent evaporation method was adopted for the Eudragit coating of hydrogel beads using different coat: core ratios (4:1 or 8:1). Coated and uncoated hydrogel beads were evaluated by in vitro physicochemical properties, swelling and drug release behaviours, and in vivo pharmacokinetics, swelling, and toxicity evaluation. Diclofenac sodium was loaded as an experimental drug. Drug entrapment efficiency for the PVA/Ca-alginate beads was calculated as 98%, and for Ca-alginate beads, it came out to a maximum of 74%. Drug release study at various pH suggested that, unlike uncoated hydrogel beads, the coated beads delay the release of diclofenac sodium in low pH of the gastric and intestinal environment, thus targeting the colon for the drug release. It was concluded that Eudragit S-100-coated hydrogel beads could serve as a more promising and reliable way to target the colon for drug delivery.Graphical abstract.
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.
Microencapsulation of water-soluble drugs using coacervation-phase separation method is very challenging, as these drugs partitioned into the aqueous polymeric solution, resulting in poor drug entrapment. For evaluating the effect of ovalbumin on the microencapsulation of drugs with different solubility, pseudoephedrine HCl, verapamil HCl, propranolol HCl, paracetamol, and curcuminoid were used. In addition, drug mixtures comprising of paracetamol and pseudoephedrine HCl were also studied. The morphology, encapsulation efficiency, particle size, and in vitro release profile were investigated. The results showed that the solubility of the drug determined the ratio of ovalbumin to be used for successful microencapsulation. The optimum ratios of drug, ovalbumin, and gelatin for water-soluble (pseudoephedrine HCl, verapamil HCl, and propranolol HCl), sparingly water-soluble (paracetamol), and water-insoluble (curcuminoid) drugs were found to be 1:1:2, 2:3:5, and 1:3:4. As for the drug mixture, the optimum ratio of drug, ovalbumin, and gelatin was 2:3:5. Encapsulated particles prepared at the optimum ratios showed high yield, drug loading, entrapment efficiency, and sustained release profiles. The solubility of drug affected the particle size of the encapsulated particle. Highly soluble drugs resulted in smaller particle size. In conclusion, addition of ovalbumin circumvented the partitioning effect, leading to the successful microencapsulation of water-soluble drugs.
The aim of this study was to develop a taste-masked oral disintegrating film (ODF) containing donepezil, with fast disintegration time and suitable mechanical strength, for the treatment of Alzheimer's disease. Hydroxypropyl methylcellulose, corn starch, polyethylene glycol, lactose monohydrate and crosspovidone served as the hydrophilic polymeric bases of the ODF. The uniformity, in vitro disintegration time, drug release and the folding endurance of the ODF were examined. The in vitro results showed that 80% of donepezil hydrochloride was released within 5 minutes with mean disintegration time of 44 seconds. The result of the film flexibility test showed that the number of folding time to crack the film was 40 times, an indication of sufficient mechanical property for patient use. A single-dose, fasting, four-period, eight-treatment, double-blind study involving 16 healthy adult volunteers was performed to evaluate the in situ disintegration time and palatability of ODF. Five parameters, namely taste, aftertaste, mouthfeel, ease of handling and acceptance were evaluated. The mean in situ disintegration time of ODF was 49 seconds. ODF containing 7 mg of sucralose were more superior than saccharin and aspartame in terms of taste, aftertaste, mouthfeel and acceptance. Furthermore, the ODF was stable for at least 6 months when stored at 40°C and 75% relative humidity.
Being a candidate of BCS class II, dolutegravir (DTG), a recently approved antiretroviral drug, possesses solubility issues. The current research was aimed to improve the solubility of the DTG and thereby enhance its efficacy using the solid dispersion technique. In due course, the miscibility study of the drug was performed with different polymers, where Poloxamer 407 (P407) was found suitable to move forward. The solid dispersion of DTG and P407 was formulated using solvent evaporation technique with a 1:1 proportion of drug and polymer, where the solid-state characterization was performed using differential scanning calorimetry, Fourier transform infrared spectroscopy and X-ray diffraction. No physicochemical interaction was found between the DTG and P407 in the fabricated solid dispersion; however, crystalline state of the drug was changed to amorphous as evident from the X-ray diffractogram. A rapid release of DTG was observed from the solid dispersion (>95%), which is highly significant (p<0.05) as compared to pure drug (11.40%), physical mixture (20.07%) and marketed preparation of DTG (35.30%). The drug release from the formulated solid dispersion followed Weibull model kinetics. Finally, the rapid drug release from the solid dispersion formulation revealed increased Cmax (14.56 μg/mL) when compared to the physical mixture (4.12 μg/mL) and pure drug (3.45 μg/mL). This was further reflected by improved bioavailability of DTG (AUC: 105.99±10.07 μg/h/mL) in the experimental Wistar rats when compared to the AUC of animals administered with physical mixture (54.45±6.58 μg/h/mL) and pure drug (49.27±6.16 μg/h/mL). Therefore, it could be concluded that the dissolution profile and simultaneously the bioavailability of DTG could be enhanced by means of the solid dispersion platform using the hydrophilic polymer, P407, which could be projected towards improved efficacy of the drug in HIV/AIDS.
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.
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.