In-Vitro and in-Vivo Evaluation of the Developed Curcumin-Cyclosporine-Loaded Nanoemulgel for the Management of Rheumatoid Arthritis.

BACKGROUND: Topical nanogel-based formulations have shown potential in the management of rheumatoid arthritis (RA). The aim of this research work was to explore the synergistic effect of Curcumin (CUR) and Cyclosporine (CYC) in combination via a topical route for the management of RA. METHODS: The CUR+CYC loaded nanoemulsion was developed using the spontaneous emulsification technique and was subsequently incorporated into Carbopol® Ultrez 30-NF gel. The effect of the developed formulation on levels of proinflammatory cytokines (IL-6, TNF-α) and anti-inflammatory cytokine (IL-10) was evaluated using lipopolysaccharide (LPS) induced RAW 264.7 cell culture model. The anti-arthritic activity was evaluated in a Complete Freund's Adjuvant (CFA) induced arthritic rat model. RESULTS: The optimized nanoemulgel (CUR + CYC NE gel) exhibited average globule size of 15.32 nm ±2.7 nm, poly-dispersity index of 0.181 ± 0.034 and zeta potential of -16.3 mV ± 0.9 mV. The cumulative drug release from ex-vivo diffusion studies on porcine ear skin was 99.189% ± 1.419% at the of 24 h and 99.177% ± 1.234% at the end of 18 h for CUR and CYC, respectively. The cell culture studies revealed that the formulation was able to significantly lower (p < .001) the levels of IL-6 and TNF-α, inhibited prostaglandin E2 (PGE2) while significantly elevating (p < .001) the levels of anti-inflammatory cytokine (IL-10). The gel was found to be non-irritating and showed the inhibition of paw edema and substantial reduction of arthritic symptoms in an arthritic rat model as compared to commercial and other conventional alternatives. CONCLUSION: This study highlights the potential of the developed nanoemulgel for the management of RA by enhancing the topical permeation of CUR and CYC.

Unraveling the Role of the Glycogen Synthase Kinase-3ß, Bruton's Tyrosine Kinase, and Sphingosine 1 Phosphate Pathways in Multiple Sclerosis.

Inflammation, demyelination, and neurodegeneration are symptoms of the central nervous system (CNS) condition known as Multiple sclerosis (MS). Due to its crucial function in controlling immune cell activation and inflammation, the glycogen synthase kinase-3ß (GSK3ß), Bruton's tyrosine kinase (BTK), and Sphingosine 1 phosphate (S1P) signaling pathway have become a viable target for the therapy of MS. The GSK-3ß signaling system, which controls several biological target processes, including cell survival, proliferation, and inflammation, depends on the GSK-3ß enzyme. In MS animal models and human studies, GSK-3ß inhibition has been demonstrated to lessen demyelination and inflammation. Clinical research on MS has demonstrated that BTK inhibitors decrease inflammation and disease activity by preventing B cell activation and the subsequent release of cytokines. Clinical investigations for MS have demonstrated that S1P modulators, such as fingolimod, lower disease activity and inflammation by limiting immune cell migration to the central nervous system and preventing cytokine production. The GSK-3ß /BTK/S1P signaling pathway in MS is the subject of this paper's summary and discussion of prospective treatment targets.

Fluocinolone Acetonide Loaded Chitosan Nanofiber Scaffolds for Treatment of Ocular Disorders: In Vitro Characterization, Ex-Vivo Corneal and Ex-Vivo Scleral Evaluation.

PURPOSE: Drugs administered in the ocular region need to overcome ocular barriers without permanently damaging the ocular tissues. Moreover, ocular disorders of the posterior segment are more difficult to treat due to invasive procedures required to reach the posterior segment. Hence, to treat posterior disorders of the eye an attempt was made to develop nanofiber (NF) scaffolds for effective management of chronic posterior uveitis. Nanofibers (NFs) were formulated using the electrospinning technique. METHODS: NF scaffolds were formulated using the electrospinning technique. The effect of different concentrations of chitosan on NF production was studied by considering different ratios of chitosan (CS) and polyvinyl alcohol (PVA). Physicochemical characterization of NFs was performed to evaluate developed NFs. RESULTS: The optimized NF scaffold had a diameter of 129 ± 3 nm. NF scaffolds were found to have a tensile strength of 0.2882 ± 0.078 N/m2, thickness of 0.16 ± 0.05 mm, and drug entrapment of 95 ± 2.0%. The bioadhesive strength of the NF was found to be 257.3 ± 0.04 g/cm2 indicating high bioadhesion of NFs to the ocular tissues. The in-vitro, ex-vivo corneal and ex-vivo scleral drug release after 12 h was found to be 78.4 ± 1.0%, 65.33 ± 0.2% and 78.41 ± 1.0%, respectively. Ex-vivo whole eye model experiment indicated a concentration of about 40 ± 1.75% of drug permeated from corneal layer to the vitreous humor after 12 h. The Hen's egg test-chorioallantoic membrane study (HET-CAM) study and in-vitro cytotoxicity study on Statens Seruminstitut Rabbit Cornea (SIRC) cell lines indicated that the developed drug-loaded NF scaffolds were found to be non-toxic as compared to pure drug, thus suggesting cytocompatibility. CONCLUSION: Results of HET-CAM, sterility and ex-vivo studies indicate that the developed formulation is non-toxic, sterile, and effective for the ocular delivery of fluocinolone acetonide to the posterior segment of eye.

Development and preclinical assessment of nanoemulgel loaded with phytoconstituents for the management of rheumatoid arthritis.

In recent years, natural ingredients have gained importance for therapeutic treatment due to their minimal toxicity. However, the delivery of these phytoconstituents poses a challenge to provide better efficacy. Current research reports the development of nanoemulgel (NEG) loaded with ginger oleoresin (GOR) and lipid guggul extract (LGE) for the management of rheumatoid arthritis (RA). The nanoemulsion (NE) was developed using the spontaneous emulsification technique by the pseudo-ternary method. The optimized nanoemulsion exhibited globule size of 16.08 ± 2.55 nm, PDI of 0.187 ± 0.06, and zeta potential of - 22.4 ± 0.31 mV. The cumulative release from in vitro diffusion studies at pH 7.4 was about 99.72 ± 3.47%, 57.98 ± 2.11%, and 86.42 ± 5.13% of 6-gingerol, E-guggulsterone, and Z-guggulsterone respectively at the end of 24 h. The ex vivo studies on porcine ear skin showed sustained release with 92.8 ± 3.21% for 6-gingerol, 55.61 ± 0.91% for E-guggulsterone, and 84.2 ± 4.22% for Z-guggulsterone released at the end of 24 h. The cell culture studies on RAW 264.7 cells indicated a robust inhibition of LPS-induced IL-6 and TNF-α production indicating its efficacy in the management of RA. The preclinical studies on male Wistar rats suggest that the developed NEG exhibited a comparable decrease in paw edema inflammation as compared to the marketed diclofenac sodium gel. These encouraging results demonstrate the potential of the developed nanoemulgel containing combination of GOR and LGE for the management of RA.

Modification and Functionalization of Polymers for Targeting to Bone Cancer and Bone Regeneration.

Bone is one of the most complex, inaccessible body structures, responsible for calcium storage and haematopoiesis. The second highest cause of death across the world is cancer. Amongst all the types of cancers, bone cancer treatment modalities are limited due to the structural complexity and inaccessibility of bones. The worldwide incidence of bone diseases and bone defects due to cancer, infection, trauma, age-related bone degeneration is increasing. Currently different conventional therapies are available for bone cancer such as chemotherapy, surgery and radiotherapy, but they have several disadvantages associated with them. Nanomedicine is being extensively researched as viable therapeutics to mitigate drug resistance in cancer therapy and promote bone regeneration. Several natural polymers such as chitosan, dextran, alginate, hyaluronic acid, and synthetic polymers like polyglycolic acid, poly(lactic-co-glycolic acid), polycaprolactone are investigated for their application in nanomedicine for bone cancer treatment and bone regeneration. Nanocarriers have shown promising results in preclinical experimental studies. However, they still face a major drawback of inadequate targetability. The paper summarizes the status of research and the progress made so far in modifications and functionalization of natural polymers for improving their site specificity and targeting for effective treatment of bone cancer and enhancing bone regeneration.

Exploring Cytokines as Potential Target in Peptic Ulcer Disease: A Systematic Update.

Peptic ulcer disease (PUD) is a widespread condition that affects millions of people each year, with an incidence rate of 0.1%-1.5%, and has a significant impact on human health. A range of stimuli, such as Helicobacter pylori, non-steroidal anti-inflammatory drugs, hyperacidity, stress, alcohol, smoking, and idiopathic disease states, can produce a sore in the gastrointestinal mucosal layer. For individuals infected with H. pylori, 2%-3% remain asymptomatic throughout their life. Although PUD treatments are available, genetic variations occurring in individuals because of geographical dissimilarity and antibiotic resistance pose limitations. Specifically, inflammatory cytokine gene polymorphisms have received immense attention in recent years because they appear to affect the severity and duration of stomach inflammation, which is induced by H. pylori infection, contributing to the initiation of PUD. In such a context, in-depth knowledge of interleukins may aid in the discovery of new targets and provide precautionary approaches for the treatment of PUD. This review aims to give insights into the importance of several interleukins that cognate with PUD and contribute to ulcer progression or healing by activating or dampening the host immunity. Furthermore, the available targets with clinical evidence have been explored in this review.

Recent advancements in polymeric nanofibers for ophthalmic drug delivery and ophthalmic tissue engineering.

Nanofibers due to their unique properties such as high surface-to-volume ratio, porous structure, mechanical strength, flexibility and their resemblance to the extracellular matrix, have been researched extensively in the field of ocular drug delivery and tissue engineering. Further, different modifications considering the formulation and process parameters have been carried out to alter the drug release profile and its interaction with the surrounding biological environment. Electrospinning is the most commonly used technique for preparing nanofibers with industrial scalability. Advanced techniques such as co-axial electrospinning and combined system such as embedding nanoparticles in nanofiber provide an alternative approach to enhance the performance of the scaffold. Electrospun nanofibers offers a matrix like structure for cell regeneration. Nanofibers have been used for ocular delivery of various drugs like antibiotics, anti-inflammatory and various proteins. In addition, lens-coated medical devices provide new insights into the clinical use of nanofibers. Through fabricating the nanofibers researchers have overcome the issues of low bioavailability and compatibility with ocular tissue. Therefore, nanofibers have great potential in ocular drug delivery and tissue engineering and have the capacity to revolutionize these therapeutic areas in the field of ophthalmology. This review is mainly focused on the recent advances in the preparation of nanofibers and their applications in ocular drug delivery and tissue engineering. The authors have attempted to emphasize the processing challenges and future perspectives along with an overview of the safety and toxicity aspects of nanofibers.

Recent Advancements in Electrospun Nanofibers for Wound Healing: Polymers, Clinical and Regulatory Perspective.

Wound management is an unmet therapeutic challenge and a global healthcare burden. Current treatment strategies provide limited efficiency in wound management, thus undergoing constant evolution in the treatment approaches. As wound healing is a complex physiological process involving precise synchronization of various phases like hemostasis, inflammation and remodelling, which necessitates innovative treatment strategies. Nanotechnology platforms like polymeric nanofibers (NFs) offer a promising solution for wound management. NFs contain a porous mesh-like structure that mimics the natural extracellular matrix and promote the cell adhesion and proliferation in the wound bed, thus displaying a great potential as a wound healing scaffold. Electrospinning is a simple, versatile and scalable technique for producing highly porous and tuneable NFs with a high surface area. Electrospun NFs are presenting extensive application in wound management, especially for burns and diabetic foot ulcers. This review briefly discusses the wound physiology and conventional treatment strategies. It also provides an overview of the electrospinning process and its principle, highlighting the application of electrospun polymeric NFs in wound management. The authors have made an attempt to emphasizes on the clinical challenges and future perspectives along with regulatory aspects of NFs as a wound dressing.

An update on novel therapeutic intervention in Rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder that is slow progressive destruction of the joints and is caused by autoantibodies that target a variety of organs thereby leading to auto-destruction. Patients diagnosed with RA develop deformity of joints and show gradual functional impairment if they do not receive treatment within the desired timeline. The availability of biological treatments and the introduction of treat-to-target regimens have dramatically enhanced the outcome for patients treated with RA conditions. Nevertheless, there is still attention required for RA because patients do not respond adequately to currently available treatment regimens. Over the past few decades, newer therapy methods are evolving to better understand the in-depth literature behind the actual cause of RA. Thus, getting an insight into the importance of RA there is a need for a shift in the existing treatment. This article focuses on a comprehensive review of the therapeutic potential of newer targets such as Janus Kinase-signal transducer and activator of transcription pathway, Granulocyte macrophage-colony stimulating factor, Bruton's Tyrosine Kinase Pathway, Phosphoinositide-3-kinase Pathway, Dendritic cells, Neuropathway, Receptor activator of nuclearfactor-kappa-Β ligand (RANKL) Inhibitors, Mesenchymal Stem Cells and Synovial Anatomy emphasizing on Synovial fibroblasts Myeloid Cells which have been summarized. In addition, novel therapeutic targets such as proteins, small molecular metabolites, and epigenetics are described in this article. Cytokines, chemokines, and other protein targets are among the protein target. Prostaglandins, leukotrienes, platelet-activating factor, cannabinoids, and specific fatty acid amide hydrolase are all examples of small molecular metabolites. DNA, RNA, and Histone Modification are epigenetic targets. Furthermore, the article provides an in-depth understanding of the exact mechanism in underlying pathophysiology in RA and thereby substantiating their evident therapeutic effect with ongoing clinical trials. Nevertheless, these newer targets would help to bring and paradigm shift in the treatment of this ancient autoimmune disorder.

A Review of Anti-Aging Nanoformulations: Recent Developments in Excipients for Nanocosmeceuticals and Regulatory Guidelines.

Skin aging is the progressive biological process generally characterized by the appearance of wrinkles, age spots, sagging of skin, and dryness. Since skin is an essential part of physical appearance, this has led to increased concerns about skincare. Anti-aging products help in improving the quality and health of the skin by nourishing it. However, due to large particle size they are less efficacious. Nanotechnological approaches for topical anti-aging products have a significant effect on the product performance. Lipidic, polymeric, and metallic nanoparticles have shown potential advantages like enhanced stability and efficacy due to their smaller size. The excipients used in these nanoformulations play an important role in improving the efficacy and shelf-life of the product. The optimal selection of excipients plays a major role in the nanoformulation approach for their enhanced efficacy and stability. For the past three decades the ingredients of natural origin for cosmetic formulations have been widely recognized for being safe and less toxic. The objective of this article is to review the nanoformulations used in anti-aging along with the potential excipients used, currently marketed formulations, and patents filed for cosmetic use. Recent updates related to regulatory aspects of the nanocosmetics have also been highlighted.

Cellulosic Polymers for Enhancing Drug Bioavailability in Ocular Drug Delivery Systems.

One of the major impediments to drug development is low aqueous solubility and thus poor bioavailability, which leads to insufficient clinical utility. Around 70-80% of drugs in the discovery pipeline are suffering from poor aqueous solubility and poor bioavailability, which is a major challenge when one has to develop an ocular drug delivery system. The outer lipid layer, pre-corneal, dynamic, and static ocular barriers limit drug availability to the targeted ocular tissues. Biopharmaceutical Classification System (BCS) class II drugs with adequate permeability and limited or no aqueous solubility have been extensively studied for various polymer-based solubility enhancement approaches. The hydrophilic nature of cellulosic polymers and their tunable properties make them the polymers of choice in various solubility-enhancement techniques. This review focuses on various cellulose derivatives, specifically, their role, current status and novel modified cellulosic polymers for enhancing the bioavailability of BCS class II drugs in ocular drug delivery systems.

Recent advancements in cellulose-based biomaterials for management of infected wounds.

INTRODUCTION: Chronic wounds are a substantial burden on the healthcare system. Their treatment requires advanced dressings, which can provide a moist wound environment, prevent bacterial infiltration, and act as a drug carrier. Cellulose is biocompatible, biodegradable, and can be functionalized according to specific requirements, which makes it a highly versatile biomaterial. Antimicrobial cellulose dressings are proving to be highly effective against infected wounds. AREAS COVERED: This review briefly addresses the mechanism of wound healing and its pathophysiology. It also discusses wound infections, biofilm formation, and progressive emergence of drug-resistant bacteria in chronic wounds and the treatment strategies for such types of infected wounds. It also summarizes the general properties, method of production, and types of cellulose wound dressings. It explores recent studies and advancements regarding the use of cellulose and its derivatives in wound management. EXPERT OPINION: Cellulose and its various functionalized derivatives represent a promising choice of wound dressing material. Cellulose-based dressings loaded with antimicrobials are very useful in controlling infection in a chronic wound. Recent studies showing its efficacy against drug-resistant bacteria make it a favorable choice for chronic wound infections. Further research and large-scale clinical trials are required for better clinical evidence of its efficiency.

Metallic nanoparticles as drug delivery system for the treatment of cancer.

INTRODUCTION: The targeted delivery of anticancer agents to tumor is a major challenge because most of the drugs show off-target effect resulting in nonspecific cell death. Multifunctionalized metallic nanoparticles (NPs) are explored as new carrier system in the era of cancer therapeutics. Researchers investigated the potential of metallic NPs to target tumor cells by active and passive mechanisms, thereby reducing off-target effects of anticancer agents. Moreover, photocatalytic activity of upconversion nanoparticles (UCNPs) and the enhanced permeation and retention (EPR) effect have also gained wide potential in cancer treatment. Recent advancement in the field of nanotechnology highlights their potency for cancer therapy. AREAS COVERED: This review summarizes the types of gold and silver metallic NPs with targeting mechanisms and their potentiality in cancer therapy. EXPERT OPINION: Recent advances in the field of nanotechnology for cancer therapy offer high specificity and targeting efficiency. Targeting tumor cells through mechanistic pathways using metallic NPs for the disruption/alteration of molecular profile and survival rate of the tumor cells has led to an effective approach for cancer therapeutics. This alteration in the survival rate of the tumor cells might decrease the proliferation thereby resulting in more efficient management in the treatment of cancer.

Management of epileptic disorders using nanotechnology-based strategies for nose-to-brain drug delivery.

INTRODUCTION: Epilepsy, a major neurological disorder affects about 1% of the Indian population. The discovery of noninvasive strategies for epilepsy presents a challenge for the scientists. Different types of nose-to-brain dosage-forms have been studied for epilepsy management. It aims to give new perspectives for developing new and existing anti-epileptic drugs. Combining nanotechnology with nose-to-brain approach can help in promoting the treatment efficacy by site-specific delivery. Also, it will minimize the side-effects and patient noncompliance observed in conventional administration routes. Peptide delivery can be an interesting approach for the management of epilepsy. Drug-loaded intranasal nanoformulations exhibit diverse prospective potentials in the management of epilepsy. Considering that, nanotherapy using nose-to-brain delivery as a prospective technique for the efficient management of epilepsy is reviewed. AREAS COVERED: The authors have compiled all recently available data pertaining to the nose-to-brain delivery of therapeutics using nanotechnological strategies. The fundamental mechanism of nose-to-brain delivery, claims for intranasal delivery and medical devices for epilepsy are discussed. EXPERT OPINION: Drug-loaded intranasal nanoformulations exhibit different prospective potentials in the management of epilepsy. Considering the foregoing research done in the field of nanotechnology, globally, authors propose nose-to-brain delivery of nanoformulations as a potential technique for the efficient management of epilepsy.

Functionalized and graft copolymers of chitosan and its pharmaceutical applications.

INTRODUCTION: Chitosan is the second most abundant natural polysaccharide. It belongs a family of polycationic polymers comprised of repetitive units of glucosamine and N-acetylglucosamine. Its biodegradability, nontoxicity, non-immunogenicity and biocompatibility along with properties like mucoadhesion, fungistatic and bacteriogenic have made chitosan an appreciated polymer with numerous applications in the pharmaceutical, comestics and food industry. However, the limited solubility of chitosan at alkaline and neutral pH limits its widespread commercial use. This can be circumvented by fabrication of chitosan by graft copolymerization with acyl, alkyl, monomeric and polymeric moieties. Areas covered: Modifications like quarterization, thiolation, acylation and grafting result in copolymers with higher mucoadhesion strength, increased hydrophobic interactions (advantageous in hydrophobic drug entrapment), and increased solubility in alkaline pH, the ability for adsorption of metal ions, protein and peptide delivery and nutrient delivery. Insights on methods of polymerization, including atomic transfer radical polymerization and click chemistry are discussed. Applications of such modified chitosan copolymers in medical and surgical, and drug delivery, including nasal, oral and buccal delivery have also been covered. Expert opinion: Despite a number of successful investigations, commercialization of chitosan copolymers still remains a challenge. Further advancements in polymerization techniques may address the unmet needs of the healthcare industry.

Oral Squamous Cell Carcinoma: Current Treatment Strategies and Nanotechnology-Based Approaches for Prevention and Therapy.

Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer; it involves damage to oral epithelial cells due to accumulation of multiple genetic mutations in the cells. OSCC remains major cause of morbidity and mortality in patients with head and neck cancers. Tobacco, smoking, alcohol consumption alone or with chewing tobacco, and betel quid are potential carcinogens contributing to the high occurrence of OSCC. Current treatment modalities for OSCC like chemoradiotherapy, surgery, EGFR inhibitors and COX-2 inhibitors, and photodynamic therapy have led to the major problems related to non-specific cell death. Nanoengineered systems offer solutions to these problems that not only minimize the major drawbacks of nonspecific cell death but also maximize the efficacy of the cancer therapeutic agents. Various efficacious nanotechnology-based carrier systems are being widely investigated for their potential in OSCC treatment: polymeric nanoparticles, polymeric micelles, nanoemulsions and layered nanoemulsions, nanoliposomes, solid lipid nanoparticles and nanolipid carriers, cyclodextrin complexes, hydrogels, metallic nanoparticles, nanocarbon tubes, and receptor mediated drug delivery systems. We highlight the etiology, line of the treatment and chemopreventive measures related to OSCC. We focus on data available in the research carried out worldwide in past 15 years related to the management of OSCC.