Emerging Phytochemical Formulations for Management of Rheumatoid Arthritis: A Review.

Rheumatoid arthritis (RA) is a T-cell-mediated chronic inflammatory disorder affecting 0.5-1% of the global population. The disease with unknown etiology causes slow destruction of joints, advancing to significant deterioration of an individual's quality of life. The present treatment strategy comprises the use of disease-modifying anti-rheumatic drugs (DMARDs) coupled with or without nonsteroidal anti-inflammatory drugs or glucocorticoids. Additionally, involves co-therapy of injectable biological DMARDs in case of persistent or recurrent arthritis. The availability of biological DMARDs and the implementation of the treat-to-target approach have significantly improved the outcomes for patients suffering from RA. Nevertheless, RA requires continuous attention due to inadequate response of patients, development of tolerance and severe side effects associated with long-term use of available treatment regimens. An estimated 60-90% of patients use alternative methods of treatment, such as herbal therapies, for the management of RA symptoms. Over the past few decades, researchers have exploring natural phytochemicals to alleviate RA and associated symptoms. Enormous plant-origin phytochemicals such as alkaloids, flavonoids, steroids, terpenoids and polyphenols have shown anti-inflammatory and immunomodulatory activity against RA. However, phytochemicals have certain limitations, such as high molecular weight, poor water solubility, poor permeability, poor stability and extensive first-pass metabolism, limiting absorption and bioavailability. The use of nanotechnology has aided to extensively improve the pharmacokinetic profile and stability of encapsulated drugs. The current review provides detailed information on the therapeutic potential of phytochemicals. Furthermore, the review focuses on developed phytochemical formulations for RA, with emphasis on clinical trials, regulatory aspects, present challenges, and future prospects.

An Insight on Novel Approaches & Perspectives for Gastro-Retentive Drug Delivery Systems.

The conventional oral drug delivery systems face a lot of difficulties in the gastrointestinal tract, such as inappropriate drug release and reduction in the efficacy of the doses, which makes this system less susceptible to the delivery of drug formulation. For the enhancement of therapeutic efficacy and bioavailability of the drug, many efforts have been made. The drug candidates which are not stable at alkaline pH and soluble in acidic medium were selected to increase their therapeutic effectiveness through gastro retentive drug delivery systems (GRDDS). This article discusses various factors which alter the gastro retention time (GRT) of the gastro retentive drug delivery system in the stomach and intestine (duodenum). It emphasizes on the novel approaches made for the delivery and release of drugs with the use of magnetic systems, floating (low-density) systems, super porous hydrogels, raft systems, mucoadhesive systems, high-density systems and expandable systems. Along with the applications, the key aspects of in vivo, in vitro & clinical studies in different approaches to GRDDS have been addressed. In addition, future perspectives have been summarized to reduce gastric transit time in fasting and fed conditions.

Colorectal cancer management: strategies in drug delivery.

INTRODUCTION: Colorectal cancer (CRC) is the third most common cancer leading to death worldwide following breast and lung cancer with the incidence rate of 10%. The treatment comprises surgery, radiation, and ablation therapy depending upon the stage of cancer. AREAS COVERED: The review focuses on various drug delivery strategies explored to circumvent the major constraints associated with the conventional drug delivery systems-poor bioavailability, intra- and inter individual variability, exposure of normal cells to antineoplastic agents, and presence of efflux pump. All these attributes impact the effective delivery of chemotherapeutic agents at the tumor site. The various target specific drug delivery systems developed for colorectal cancer include pH-dependent, microbiologically triggered, time-dependent, magnetically driven, pressure-dependent, prodrug/polysaccharide-based, osmotic and ligand-mediated systems. This review enumerates novel target specific approaches developed and investigated for potential utility in CRC therapeutics. EXPERT OPINION: The limitations of conventional delivery systems can be overcome by the development of colon-specific targeted drug delivery systems that overcome the obstacles of nonspecific biodistribution, drug resistance, and unwanted adverse effects of conventional drug delivery systems. In addition, nanotechnology approaches help to increase drug solubility, bioavailability, reduce side effects, and provide superior drug response in CRC.

Insights of Lipid Vesicular and Particulate Carrier Mediated Approach for Acne Management.

Acne vulgaris is a universal multifactorial human skin condition of the pilosebaceous units. Although acne majorly prevails in teenagers, it is neither restricted to age group nor gender. Multifarious causative factors like Propionibacterium acnes, dysregulated sebum secretion, and androgens play an integral role in the manifestation of acne. Though abundant new chemical entities are convenient for acne therapy, none can treat this condition without compromising patient compliance. Furthermore, accessible treatment prevents the ailment and alleviates signs and symptoms with no absolute cure. So presently, despite the variety of topical formulations, the current market demands an ideal remedy to fulfill the unmet need for acne management. Extensive research has proved the upper hand of novel carrier systems over conventional formulations by substantially improving efficacy and eliminating unpleasant side effects. Lipid-based vesicular and particulate systems are promising prospects due to their closeness to the intrinsic structure of the skin, which offer delivery of the actives in a more desirable approach. This review underlines the practicability and superiority of liposomes, niosomes, transfersomes, ethosomes, cubosomes, solid lipid nanoparticles, and nanostructured lipid carriers over conventional therapies for acne. The review also highlights acne product market survey and available conventional as well as novel formulations portraying their scope in the market. In a nutshell, lipid-based vesicular and particulate systems prevail as a propitious modality for treating acne vulgaris as they conduce better penetrability, localized action, and reduce adverse effects. These systems have the ability to open a window of opportunities for effective acne alleviation.

Global gene expression profiling under nitrogen stress identifies key genes involved in nitrogen stress adaptation in maize (Zea mays L.).

Maize is a heavy consumer of fertilizer nitrogen (N) which not only results in the high cost of cultivation but may also lead to environmental pollution. Therefore, there is a need to develop N-use efficient genotypes, a prerequisite for which is a greater understanding of N-deficiency stress adaptation. In this study, comparative transcriptome analysis was performed using leaf and root tissues from contrasting inbred lines, viz., DMI 56 (tolerant to N stress) and DMI 81 (susceptible to N stress) to delineate the differentially expressed genes (DEGs) under low-N stress. The contrasting lines were grown hydroponically in modified Hoagland solution having either sufficient- or deficient-N, followed by high-throughput RNA-sequencing. A total of 8 sequencing libraries were prepared and 88-97% of the sequenced raw reads were mapped to the reference B73 maize genome. Genes with a p value ≤ 0.05 and fold change of ≥ 2.0 or ≤ - 2 were considered as DEGs in various combinations performed between susceptible and tolerant genotypes. DEGs were further classified into different functional categories and pathways according to their putative functions. Gene Ontology based annotation of these DEGs identified three different functional categories: biological processes, molecular function, and cellular component. The KEGG and Mapman based analysis revealed that most of the DEGs fall into various metabolic pathways, biosynthesis of secondary metabolites, signal transduction, amino acid metabolism, N-assimilation and metabolism, and starch metabolism. Some of the key genes involved in N uptake (high-affinity nitrate transporter 2.2 and 2.5), N assimilation and metabolism (glutamine synthetase, asparagine synthetase), redox homeostasis (SOD, POX), and transcription factors (MYB36, AP2-EREBP) were found to be highly expressed in the tolerant genotype compared to susceptible one. The candidate genes identified in the present study might be playing a pivotal role in low-N stress adaptation in maize and hence could be useful in augmenting further research on N metabolism and development of N-deficiency tolerant maize cultivars.

Emerging topical drug delivery approaches for the treatment of Atopic dermatitis.

BACKGROUND: Atopic dermatitis is a chronic, relapsing skin inflammation disease that generally affects 20% of children and 1-3% of adults. It is characterized by pruritus, inflammatory skin lesions, and skin barrier defect. The pillar treatment is topical therapies that have shown great adherence and incredible results in alleviating symptoms of atopic dermatitis. Topical corticosteroids and calcineurin inhibitors have shown improvement in the symptoms of atopic dermatitis but have certain side effects. There is need to develop new therapies or novel drug delivery approaches which can overcome drawbacks of the conventional formulation and increase the therapeutic efficacy. AIM: The scope of this review is to describe the new topical therapies including phosphodiesterase inhibitors, Janus kinase inhibitors, and nano-formulations such as nanoemulsion, polymeric and lipid nanoparticles, vesicular system, and micelles. METHODS: The article reviews and discusses the published literature of the topical drug delivery approaches for treatment of Atopic dermatitis. RESULTS: The reported literature highlighted the benefits of novel topical formulations exhibiting targeted drug delivery, better penetration, enhanced therapeutic efficacy, and overcome systemic side effects. CONCLUSION: Literature indicated that the new therapies and novel drug delivery approaches found to be the therapeutically more effective in increasing the efficacy of drugs and reducing the side effects in comparison with the conventional treatments for Atopic dermatitis. This has provided a way to modify and develop more such formulations for dermal delivery.

Controlled Release Gel Encompassing Curcumin Microspheres and Diclofenac Diethylamine for Feat Against Arthritis Inflammation.

BACKGROUND: Diclofenac and curcumin is anticipated to have synergistic action. Hence, topical route of administration can be used in minimizing the issues with oral administration of both drugs. OBJECTIVE: This research aims at formulation of controlled release dosage form containing curcumin microspheres and diclofenac diethylamine and then incorporating it into gel formulation for treatment of inflammation associated with rheumatoid arthritis. METHODS: Curcumin microspheres were prepared, optimized and assayed. Gel containing microspheres was formulated and evaluated for physicochemical parameters like spreadability and viscosity. In vitro and ex vivo diffusion studies were carried out followed by evaluation of efficacy. Efficacy of the developed formulation was evaluated for anti-inflammatory activity. RESULTS: Particle size, Zeta potential, pH, spreadability and viscosity of optimized Batch F1 was found to be in range 0.5 µm - 5 µm,-27.9 mV, 6.2, 105 g cm/s and 7500 cps respectively. In vitro diffusion of developed gel of diclofenac diethylamine and curcumin was found to be 92.16 ± 0.0040 % in 3 h and 92.54 ± 0.0036 % in 12 h as compared to 79.57 ± 0.004 % diffusion in 2 h for marketed gel, thus showing controlled delivery of curcumin. CONCLUSION: Decreased inflammation in formulation treated group by 72.53% and 50.75% in marketed treated group was seen. Thus the formulation developed showed prolonged activity as well as better anti-inflammatory activity.

Formulation and in-vivo Evaluation of Novel Topical Gel of Lopinavir for Targeting HIV.

BACKGROUND: Lopinavir is a specific reversible inhibitor of the enzyme HIV protease with mean oral bioavailability of less than 20 % due to extensive hepatic metabolism by cytochrome P450 3A4. The reported half-life of Lopinavir is 5-6 hours and the maximum recommended daily dose is 400 mg/day. All the marketed tablet and capsule formulations of lopinavir are generally combined with Ritonavir, a potent inhibitor of cytochrome P450 3A4, to minimize presystemic metabolism of lopinavir. Hence, to overcome limitations associated with oral administration of lopinavir and to promote single drug administration, utilization of vesicular nanocarriers through topical route could prove to be effective, as the approach combines the inherent advantages of topical route and the drug-carrying potential of vesicular nanocarriers across the tough and otherwise impervious skin barrier layer, i.e., stratum corneum. OBJECTIVE: The objective was to develop solid lipid nanoparticles (SLN) of lopinavir and formulate a topical gel for improved systemic bioavailability of lopinavir. METHOD: SLNs were prepared using high-pressure homogenization technique and optimized. The nanoparticles were characterized by SEM to confirm their spherical shape. Differential Scanning Calorimetry (DSC) analysis was carried out to ensure the entrapment of drug inside the SLNs. A comparative evaluation was done between SLN based gel and plain gel of drug by performing exvivo skin permeation studies using Franz diffusion cell. To explore the potential of topical route, invivo bioavailability study was conducted in male Wistar rats. RESULTS: The optimized formulation composed of Compritol 888ATO (0.5 %) as a lipid, Poloxamer 407 (0.25 %) as a surfactant and Labrasol (0.25 %) as a co-surfactant gave the maximum entrapment of 69.78 % with mean particle size of 48.86nm. The plain gel of the drug gave a release of 98.406 ± 0.007 % at the end of 4hours whereas SLN based gel gave a more sustained release of 71.197 ±0.006 % at the end of 12hours ex-vivo. As observed from the results of in-vivo studies, highest Cmax was found with SLN based gel (20.3127 ± 0.6056) µg/ml as compared to plain gel (8.0655 ± 1.6369) µg/ml and oral suspension (4.2550 ± 16.380) µg/ml of the drug. Also, the AUC was higher in the case of SLN based gel indicating good bioavailability as compared to oral suspension and plain gel of drug. CONCLUSION: Lopinavir SLN based gel was found to have modified drug release pattern providing sustained release as compared to plain drug gel. This indicates that Lopinavir when given topically has a good potential to target the HIV as compared to when given orally.

Secondary Structure and Glycosylation of Mucus Glycoproteins by Raman Spectroscopies.

The major structural components of protective mucus hydrogels on mucosal surfaces are the secreted polymeric gel-forming mucins. The very high molecular weight and extensive O-glycosylation of gel-forming mucins, which are key to their viscoelastic properties, create problems when studying mucins using conventional biochemical/structural techniques. Thus, key structural information, such as the secondary structure of the various mucin subdomains, and glycosylation patterns along individual molecules, remains to be elucidated. Here, we utilized Raman spectroscopy, Raman optical activity (ROA), circular dichroism (CD), and tip-enhanced Raman spectroscopy (TERS) to study the structure of the secreted polymeric gel-forming mucin MUC5B. ROA indicated that the protein backbone of MUC5B is dominated by unordered conformation, which was found to originate from the heavily glycosylated central mucin domain by isolation of MUC5B O-glycan-rich regions. In sharp contrast, recombinant proteins of the N-terminal region of MUC5B (D1-D2-D'-D3 domains, NT5B), C-terminal region of MUC5B (D4-B-C-CK domains, CT5B) and the Cys-domain (within the central mucin domain of MUC5B) were found to be dominated by the ß-sheet. Using these findings, we employed TERS, which combines the chemical specificity of Raman spectroscopy with the spatial resolution of atomic force microscopy to study the secondary structure along 90 nm of an individual MUC5B molecule. Interestingly, the molecule was found to contain a large amount of α-helix/unordered structures and many signatures of glycosylation, pointing to a highly O-glycosylated region on the mucin.

High precision attachment of silver nanoparticles on AFM tips by dielectrophoresis.

AFM tips are modified with silver nanoparticles using an AC electrical field. The used technique works with sub-micron precision and also does not require chemical modification of the tip. Based on the electrical parameters applied in the process, particle density and particle position on the apex of the tip can be adjusted. The feasibility of the method is proven by subsequent tip-enhanced Raman spectroscopy (TERS) measurements using the fabricated tips as a measurement probe. Since this modification process itself does not require any lithographic processing, the technique can be easily adapted to modify AFM tips with a variety of nanostructures with pre-defined properties, while being parallelizable for a potential commercial application.

Exploring the Nanoscale: Fifteen Years of Tip-Enhanced Raman Spectroscopy.

Spectroscopic methods with high spatial resolution are essential to understand the physical and chemical properties of nanoscale materials including biological and chemical materials. Tip-enhanced Raman spectroscopy (TERS) is a combination of surface-enhanced Raman spectroscopy (SERS) and scanning probe microscopy (SPM), which can provide high-resolution topographic and spectral information simultaneously below the diffraction limit of light. Even examples of sub-nanometer resolution have been demonstrated. This review intends to give an introduction to TERS, focusing on its basic principle and the experimental setup, the strengths followed by recent applications, developments, and perspectives in this field.

Spatial resolution in Raman spectroscopy.

This article is intended to set the scope of the meeting, in particular, the high spatial resolution section.

Dielectrophoretic positioning of single nanoparticles on atomic force microscope tips for tip-enhanced Raman spectroscopy.

Tip-enhanced Raman spectroscopy, a combination of Raman spectroscopy and scanning probe microscopy, is a powerful technique to detect the vibrational fingerprint of molecules at the nanometer scale. A metal nanoparticle at the apex of an atomic force microscope tip leads to a large enhancement of the electromagnetic field when illuminated with an appropriate wavelength, resulting in an increased Raman signal. A controlled positioning of individual nanoparticles at the tip would improve the reproducibility of the probes and is quite demanding due to usually serial and labor-intensive approaches. In contrast to commonly used submicron manipulation techniques, dielectrophoresis allows a parallel and scalable production, and provides a novel approach toward reproducible and at the same time affordable tip-enhanced Raman spectroscopy tips. We demonstrate the successful positioning of an individual plasmonic nanoparticle on a commercial atomic force microscope tip by dielectrophoresis followed by experimental proof of the Raman signal enhancing capabilities of such tips.