Overcoming Skin Barrier with Transfersomes: Opportunities, Challenges, and Applications.

BACKGROUND: Transdermal drug delivery systems (TDDS) offer several advantages over traditional methods like injections and oral administration, including preventing first-pass metabolism, providing consistent and sustained activity, reducing side effects, enabling the use of short halflife drugs, improving physiological response, and enhancing patient convenience. However, the permeability of skin poses a challenge for TDDS, as it is impermeable to large molecules and hydrophilic drugs but permeable to small molecules and lipophilic medications. To overcome this barrier, researchers have investigated vesicular systems, such as transfersomes, liposomes, niosomes, and ethosomes. Among these vesicular systems, transfersomes are particularly promising for non-invasive drug administration due to their deformability and flexible membrane. They have been extensively studied for delivering anticancer drugs, insulin, corticosteroids, herbal medicines, and NSAIDs through the skin. Transfersomes have demonstrated efficacy in treating skin cancer, improving insulin delivery, enhancing site-specific corticosteroid delivery, and increasing the permeation and therapeutic effects of herbal medicines. They have also been effective in delivering pain relief with minimal side effects using NSAIDs and opioids. Transfersomes have been used for transdermal immunization and targeted drug delivery, offering site-specific release and minimizing adverse effects. Overall, transfersomes are a promising approach for transdermal drug delivery in various therapeutic applications. OBJECTIVES: The aim of the present review is to discuss the various advantages and limitations of transfersomes and their mechanism to penetration across the skin, as well as their application for the delivery of various drugs like anticancer, antidiabetic, NSAIDs, herbal drugs, and transdermal immunization. METHODS: Data we searched from PubMed, Google Scholar, and ScienceDirect. RESULTS: In this review, we have explored the various methods of preparation of transferosomes and their application for the delivery of various drugs like anticancer, antidiabetic, NSAIDs, herbal drugs, and transdermal immunization. CONCLUSION: In comparison to other vesicular systems, transfersomes are more flexible, have greater skin penetration capability, can transport systemic medicines, and are more stable. Transfersomes are capable of delivering both hydrophilic and hydrophobic drugs, making them suitable for transdermal drug delivery. The developed transfersomal gel could be used to improve medicine delivery through the skin.

Gastroretentive Metformin Loaded Nanoparticles for the Effective Management of Type-2 Diabetes Mellitus.

INTRODUCTION: Metformin, an anti-diabetic drug, has low bioavailability and short biological half-life. Thus, bioavailability enhancement and prolonged release of the drug are highly desirable. In this regard, we aimed to developed gastroretentive nanoparticles made of jackfruit seed starch (JFSS) loaded with metformin. METHODS: Developed nanoparticles were optimized for various process variables and were further characterized. Nanoparticles exhibited good results with respect to particle size (244.3 to 612.4 nm), particle size distribution, shape and drug entrapment efficiency (75.8 to 89.2%) with sustained drug release for 24 h and a high buoyancy (89% for F7; formulation made of highest concentration of Jackfruit seed starch prepared at 1000 RPM stirring speed). RESULTS: The hypoglycemic potential of these nanoparticles was tested in nicotinamide streptozocin induced diabetic model, there was a significant reduction in blood glucose level (50% reduction from 4-8 h; p < 0.01) for prolonged period of time (up to 24 h) in comparison to diabetic control and plain metformin solution. CONCLUSION: The outcome of the study suggested that developed formulations are suitable for gastro- retentive delivery of Metformin in a controlled manner appropriate for a single administration per day.

Liposomes: An Emerging Approach for the Treatment of Cancer.

BACKGROUND: Conventional drug delivery agents for a life-threatening disease, i.e., cancer, lack specificity towards cancer cells, producing a greater degree of side effects in the normal cells with a poor therapeutic index. These toxic side effects often limit dose escalation of anti-cancer drugs, leading to incomplete tumor suppression/ cancer eradication, early disease relapse, and ultimately, the development of drug resistance. Accordingly, targeting the tumor vasculatures is essential for the treatment of cancer. OBJECTIVE: To search and describe a safer drug delivery carrier for the treatment of cancer with reduced systemic toxicities. METHOD: Data were collected from Medline, PubMed, Google Scholar, Science Direct using the following keywords: 'liposomes', 'nanocarriers', 'targeted drug delivery', 'ligands', 'liposome for anti-cancerous drugs', 'treatment for cancer' and 'receptor targeting.' RESULTS: Liposomes have provided a safe platform for the targeted delivery of encapsulated anti-cancer drugs for the treatment of cancer, which results in the reduction of the cytotoxic side effects of anti-cancer drugs on normal cells. CONCLUSION: Liposomal targeting is a better emerging approach as an advanced drug delivery carrier with targeting ligands for anti-cancer agents.

Repaglinide and Metformin-Loaded Amberlite Resin-Based Floating Microspheres for the Effective Management of Type 2 Diabetes.

BACKGROUND: Low bioavailability of anti-diabetic drugs results in the partial absorption of the drug as they are mainly absorbed from the stomach and the lower part of the GIT. Drug bioavailability of anti-diabetic drugs can be significantly increased by prolonging gastric retention time through gastro-retentive dosage form such as floating microspheres. OBJECTIVE: The study was aimed to develop and characterize resin based floating microspheres of Repaglinide and Metformin for superior and prolonged maintenance of normoglycaemia in type-2 diabetes mellitus. METHODS: Repaglinide and metformin were complexed with amberlite resin; later resin complexed drug was encapsulated in Ethylcellulose floating microspheres. Floating microspheres were characterized for morphology, particle size, IR spectroscopy, DSC, in vitro release and buoyancy studies. Further, floating microspheres were tested for in vivo blood glucose reduction potential in Streptozocin- induced diabetic mice. RESULTS: Floating microspheres had a spherical shape and slightly rough surface with the entrapment efficiency in a range of 49-78% for metformin and 52-73% for repaglinide. DSC studies revealed that no chemical interaction took place between polymer and drugs. Floating microspheres showed good buoyancy behavior (P<0.05) and prolonged drug release as compared to plain drug (P<0.05). The blood glucose lowering effect of floating microspheres on Streptozocin induced diabetic rats was significantly greater (P<0.05) and prolonged (˃12h) and normoglycaemia was maintained for 6hr. CONCLUSION: Floating microspheres containing drug resin complex were able to prolong drug release in an efficient way for a sustained period of time; as a result, profound therapeutic response was obtained.

In Silico Docking of Anti Cancerous Drugs with ß-Cyclodextrin polymer as a Prominent Approach to Improve the Bioavailability.

BACKGROUND: ß-Cyclodextrin, a cyclic oligosaccharides having 7 macrocyclic rings of glucose subunits usually linked together by α-1,4 glycosidic bond, bears characteristic chemical structure, with an exterior portion as hydrophilic to impart water solubility and interior cavity as hydrophobic, for hosting the hydrophobic molecules. OBJECTIVE: In the present work binding affinities and interactions between various anti-cancerous drugs and ß- cyclodextrin using molecular docking simulations was examined for the bioavailability enhancement of cytotoxic drugs through improved solubility for the treatment of breast cancer. METHODS: Molegro Virtual Docker, an integrated software was used for the prediction and estimation of interaction between ß-cyclodextrin and anti cancerous drugs. RESULTS: Out of tested anti cancerous drug, Olaparib having pyridopyridazione scaffold possess highest MolDock (-130.045) and Re-ranks score (-100.717), ensuring strong binding affinity. However, 5-Fluoro Uracil exhibited the lowest MolDock score (-61.0045), indicating weak or no binding affinity, while few drugs showed no H-bond interaction with the ß-cyclodextrin. CONCLUSION: The binding conformations of anti cancerous drugs obtained from the present study can be selected for the development of improved formulation having superior solubility which will lead to attain better pharmacological profile with negligible toxicity.

Polymeric Nanoparticles of Aromatase Inhibitors: A Comprehensive Review.

Being the second most frequent cancer, breast cancer is emerging worldwide with an alarming rate, specifically in post-menopausal women. Targeted drug delivery has been in the focus for the successful treatment of breast cancer by enhancing the drug delivery efficiency and reducing the systemic toxicity of drugs. Also, it eliminates the drawbacks associated with conventional chemotherapy, including neuropathy, memory loss, cardiotoxicity and low RBCs count. This review elaborates the polymeric nanoparticles based formulation approaches for selective and sustained delivery for effective cure of breast cancer. However, breast cancer, a life-threatening disease, is mostly caused because of estrogen, thus aromatase inhibitors and estrogen synthesis inhibitors could prevent chances of breast cancer. The disease is associated with drug resistance and some side effects, which could be easily eliminated by using novel therapeutic approaches. Aromatase inhibitors, when entrapped in nanoparticles, have shown sustained drug release, advocating themselves to be beneficial for the treatment of breast cancer.

In Silico Molecular Interaction Studies of Chitosan Polymer with Aromatase Inhibitor: Leads to Letrozole Nanoparticles for the Treatment of Breast Cancer.

BACKGROUND: It takes a lot more studies to evaluate the molecular interaction of nanoparticles with the drug, their drug delivery potential and release kinetics. Thus, we have taken in silico and in vitro approaches into account for the evaluation of the drug delivery ability of the chitosan nanoparticles. OBJECTIVE: The present work was aimed to study the interaction of chitosan nanoparticles with appropriate aromatase inhibitors using in silico tools. Further, synthesis and characterization of chitosan nanoparticles having optimal binding energy and affinity between drug and polymer in terms of size, encapsulation efficiency were carried out. METHODS: In the current study, molecular docking was used to map the molecular interactions and estimation of binding energy involved between the nanoparticles and the drug molecules in silico. Letrozole is used as a model cytotoxic agent currently being used clinically; hence Letrozole loaded chitosan nanoparticles were formulated and characterized using photomicroscope, particle size analyzer, scanning electron microscope and fourier transform infra-red spectroscopy. RESULTS: Letrozole had the second-highest binding affinity within the core of chitosan with MolDock (-102.470) and Re-rank (-81.084) scores. Further, it was investigated that formulated nanoparticles were having superior drug loading capacity and high encapsulation efficiency. In vitro drug release study exhibited prolonged release of the drug from chitosan nanoparticles. CONCLUSION: Results obtained from the in silico and in vitro studies suggest that Letrozole loaded nanoparticles are ideal for breast cancer treatment.

Expedition of Eudragit® Polymers in the Development of Novel Drug Delivery Systems.

Eudragit® polymer has been widely used in film-coating for enhancing the quality of products over other materials (e.g., shellac or sugar). Eudragit® polymers are obtained synthetically from the esters of acrylic and methacrylic acid. For the last few years, they have shown immense potential in the formulations of conventional, pH-triggered, and novel drug delivery systems for incorporating a vast range of therapeutics including proteins, vitamins, hormones, vaccines, and genes. Different grades of Eudragit® have been used for designing and delivery of therapeutics at a specific site via the oral route, for instance, in stomach-specific delivery, intestinal delivery, colon-specific delivery, mucosal delivery. Further, these polymers have also shown their great aptitude in topical and ophthalmic delivery. Moreover, available literature evidences the promises of distinct Eudragit® polymers for efficient targeting of incorporated drugs to the site of interest. This review summarizes some potential researches that are being conducted by eminent scientists utilizing the distinct grades of Eudragit® polymers for efficient delivery of therapeutics at various sites of interest.

In vitro and in vivo characterization of pharmaceutical nanocarriers used for drug delivery.

Nanotechnology has emerged strongly in most of the field of sciences at a tiny scale. At this size, atoms and molecules work differently and present a diversity of amazing and appealing applications. Pharmaceutical nanocarriers comprise nanoparticles, nanospheres, nanocapsules, nanoemulsion, nanoliposomes and nanoniosomes. The major objectives in designing nanocarriers are to manage particle size, surface properties as well as drug release in order to fulfil specific objectives. Hence, characterizations of nanocarriers are very critical to control their desired in vitro and in vivo behaviour. Nanocarriers are characterized by their size, morphology and surface charge, using highly advanced microscopic techniques as scanning electron microscopy, transmission electron microscopy and atomic force microscopy. Surface morphology and size are measured by electron microscopy while dynamic light scattering and photon-correlation spectroscopy are used to determine the particle size and size distribution. Colloidal stability is ascertained through zeta potential which is an indirect measure of the surface charge and differential scanning calorimetry is used to characterize particles and drug interaction. Further, binding and internalization of targeted carriers to the specific cells could be determined by cell uptake study. Biodistribution study of targeted nanocarriers is carried out and intracellular uptake and subcellular localization of the nanocarrier could be confirmed using confocal microscopy. This review covers all the aforementioned aspect related to in vitro and in vivo characterization of pharmaceutical nanocarriers.

Effective oral delivery of insulin in animal models using vitamin B12-coated dextran nanoparticles.

The potential utility of vitamin B12 carrier system for the oral delivery of conjugated peptides/proteins and enhancement of nanoparticles (NPs) transport has been demonstrated. The present study aims to optimize the effectiveness of VB12-NPs conjugates using different levels of cross-linking, linked with different VB(12)-coatings and evaluates in animal models to investigate an efficient insulin carrier. Amino alkyl VB12 derivatives suitable for oral delivery were synthesized at 5'hydoxy ribose and e-propionamide sites via carbamate and ester/amide linkages, and were coupled to succinic acid modified dextran NPs of varied cross-linking. VB12 binding was confirmed by XPS analysis, and was quantified by HPLC (4.0 to 5.7% w/w of NPs). These polydisperse NPs conjugates showed higher size, high insulin entrapment and faster insulin release with low levels of cross-linking. These VB12-NPs conjugates (150-300 nm) showed profound (70-75% blood glucose reductions) and prolonged (54 h) anti-diabetic effects with biphasic behaviour in STZ diabetic rats. NPs with the low levels of cross-linking were found to be superior carriers, and were more effective with VB12 derivatives of carbamate linkage. The pharmacological availability relative to SC insulin was found to be 29.4%, which was superior compared to NPs conjugate of ester linked VB12 (1.5 fold) and relatively higher cross-linked particles (1.1 fold). Further, the NPs carrier demonstrated a similar oral insulin efficacy in congenital diabetic mice (60% reduction at 20 h). Significant quantities of plasma insulin were found in both animal models (231 and 197 muIU/ml). At two investigated doses, the carrier system shows dose response. Pre-dosing with a large excess of free VB12 minimized the observed activity, indicating predominance of VB12 mediated uptake. It is concluded that VB12-dextran NPs conjugate is a viable carrier for peroral insulin delivery to treat diabetics.

Muco-adhesive multivesicular liposomes as an effective carrier for transmucosal insulin delivery.

Considering limitations of conventional insulin therapies, the present study characterizes usefulness of novel mucoadhesive multivesicular liposomes as a mucoadhesive sustained release carrier of insulin via nasal and ocular routes, thus attempts to develop non-invasive carrier system for the controlled release of bioactives. Multivesicular liposomes (MVLs) of 26-34 microm were prepared with a high protein loading (58-62%) and were coated with chitosan and carbopol. These mucoadhesive carriers were characterized by zeta potential studies, in vitro mucoadhesion test and insulin protective ability against nasal aminopeptidase. In vitro, mucoadhesive carriers released insulin for a period of 7-9 days compared to 24 h of conventional liposomes. After intranasal administration to STZ induced diabetic rats, the mucoadhesive MVLs (chitosan coated MVLs) effectively reduced plasma glucose level up to 2 days (35% reduction), compared to non-coated MVLs (32% at 12 h) and conventional liposomes (34% at 8 h). Although the differences are statistically insignificant, chitosan coated formulation has shown a better hypoglycemic profile as the effects were prolonged compared to carbopol coated formulation. When compared to ocular route, chitosan formulation after nasal administration has shown better therapeutic profile as the hypoglycemic effects were prolonged until 72 h. The effectiveness of this chitosan coated MVLs was further demonstrated by the significant quantities of ELISA detectable insulin levels after nasal (334.6 microIu/ml) and ocular (186.3 microIu/ml) administration. These results demonstrate that mucoadhesive carrier is a viable option for a sustained release transmucosal insulin carrier, and open an avenue to develop a non-invasive carrier platform for the controlled release of bioactives.

Controlled systemic delivery of indomethacin using membrane-moderated, cream formulation-based transdermal devices.

The present study was carried out to design a viable and practically effective transdermal systems of indomethacin using cream-based drug reservoirs and suitable rate controlling membranes. As vehicles, a more lipophilic base (F(1)) and a cream formulation containing predominant aqueous phase (F(2)) were chosen to study the influence of vehicle nature and role of permeation enhancers that increases thermodynamic activity and to provide diffusible species of drug to skin. Rate controlling membranes of cellulose acetate (CA) and ethyl cellulose (EC) with polyvinyl pyrollidine and hydroxypropyl methyl cellulose were used to design transdermal devices. In vivo, effective plasma concentrations of indomethacin are maintained up to 24 hr whereas oral formulation showed only up to 8 hr. Although the plasma drug levels between both EC films differ insignificantly, PVP film showed a better pharmacokinetic profile. The pharmacodynamic performance of the transdermal devices exhibited good anti-inflammatory activity over 24 hr compared with orally administered indomethacin. In vivo studies indicate the superiority of CA films over the EC films. Further, enhancement may be achieved with other classic enhancers/enhancement strategies with such devices containing aqueous cream vehicle and the optimum membranes.

Dendrimer-mediated transdermal delivery: enhanced bioavailability of indomethacin.

The transdermal delivery of aqueous formulations of indomethacin, a model drug, with different concentrations of three types of dendrimer showed a linear increase in flux with increasing concentration of each of the dendrimers. This result was in contrast to phase solubility studies, where Higuchi's A(N) profile was observed. The steady-state flux of the drug increased significantly and was highest with the G4-NH2 dendrimer at 0.2% w/v concentration, which showed an enhancement factor of 4.5 compared to the pure drug suspension. In vivo, a steady-state flux was achieved in 5 h, and the C(max) values were significantly higher with G4-NH2 and G4-OH dendrimer formulations. The [AUC](0-24h) of G4-NH2 (2.27 times) and G4-OH (1.95 times) formulations were significantly higher than that of the pure drug, but was only marginally higher in the case of G-4.5 dendrimer formulation. The % inhibition of paw volume showed a trend comparable to the pharmacokinetic data and a maximum of 1.6- and 1.5-fold increase was found with G4-NH2 and G4-OH formulations, respectively, compared to the pure drug suspension.