Berberine HCl and diacerein loaded dual delivery transferosomes: Formulation and optimization using Box-Behnken design

Introduction: Berberine is a poorly water-soluble alkaloid compound showing significant anti-inflammatory characteristics. It reduces the levels of pro-inflammatory and inflammatory cytokines, including tumour necrosis factor (TNF-????, IFN-????) and interleukin (IL-23, IL-12, and IL-23). Diacerein significantly reduces the splenomegaly associated with psoriasis. It downregulates the production of TNF-α and IL-12. Method: This study reported the development of transferosomes containing berberine HCl and diacerein using a film hydration method followed by optimization using a Box-Behnken design. Sodium deoxycholate was used as an edge activator. The impact of independent variables (amount of phosphatidylcholine, amount of edge activator, and sonication cycles) on dependent variables (particle size and entrapment efficiency) was examined. The optimized formulation was characterized for polydispersity index, vesicle size, entrapment efficiency, ζ potential, spectral analysis like Fourier transform infrared, thermal analysis, X-ray diffraction, deformability, transmission electron microscopy, antioxidant assay, in-vitro release, and ex-vivo skin permeation studies. Results: The optimized formulation had a particle size of 110.90±2.8 nm with high entrapment efficiency (89.50±1.5 of berberine HCl and 91.23±1.8 of diacerein). Deformability, polydispersity index, ζ potential, and antioxidant activity of the optimized formulation were 2.44, 0.296, -13.3, and 38.36 %, respectively. Optimized transferosomes exhibited 82.093±0.81 % and 85.02±3.81 % release of berberine HCl and diacerein after 24 h of dissolution study. The transdermal flux of optimized formulation was 0.0224 µg cm-2 h-1 (2.24 cm h-1 permeation coefficient) and 0.0462 µg cm-2 h-1 (4.62 cm h-1 permeation coefficient), respectively, for berberine HCl and diacerein. Raman analysis of treated pig skin confirmed that the transferosomes can permeate the skin. No change in the skin condition or irritation was observed in BALB/c mice. Formulation stored at 4 and 25±2 °C / 60±5 % relative humidity was stable for 3 months. Conclusions: Thus, the results demonstrated successful optimization of the transferosomes for the efficient topical delivery of berberine HCl and diacerein in the effective management of psoriasis

Association of ADAM33 gene polymorphisms with adult-onset asthma and its severity in an Indian adult population

ADAM33, a member of the ADAM(a disintegrin and metalloprotease) gene family, is an asthma susceptibility gene originally identified by positional cloning. In the present study, we investigated the possible association of five single-nucleotide polymorphisms (SNPs) in the ADAM33 (rs511898, rs528557, rs44707, rs597980 and rs2787094) with adult-onset asthma in an Indian population. The study included 175 patients with mild intermittent (n=44), mild persistent (n=108) or moderate persistent (n=23) subgroups of asthma, and 253 nonasthmatic control individuals. SNPs were genotyped with the help of restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) method, and data were analysed using chi-square test and logistic regression model. Bonferroni’s correction for multiple comparisons was applied for each hypothesis. Genotypes and allele frequencies of SNPs rs511898 and rs528557 were significantly associated with adult-onset asthma(P=0.010-<0.001). A significant association of the homozygous mutant genotype and mutant alleles of SNPs rs2787094, rs44707 and rs597980 with the asthma was also observed (P=0.020-<0.001). A positive association between asthma and haplotypes AGCCT, GGCCT, AGACT, GCAGT, GGACT, ACCCC and AGACC were also found (P=0.036-<0.001,OR=2.07–8.49). Haplotypes AGCGT, GCAGC, ACAGC, ACAGT, GGAGC and GGCGT appear to protect against asthma (P=0.013-<0.0001, OR=0.34–0.10). Our data suggest that ADAM33 gene polymorphisms serve as genetic risk factors for asthma in Indian adult population

PHYTOSOME: MOST SIGNIFICANT TOOL FOR HERBAL DRUG DELIVERY TO ENHANCE THE THERAPEUTIC BENEFITS OF PHYTOCONSTITUENTS

Traditional medicinal system relies on the knowledge and clinical expertization of physicians to regulate the indigenous medicinal system for the sake of well being to humans. Considering the bioavailability issues of phytoconstituents, in this review, we have focused on the various aspects of phytosomes in drug delivery. Phytosome technology is used to enhance the absorption of poorly absorbed lipid soluble active constituents from the herb extracts. So, the article covers a brief introduction of phytosomes, their method of development along with its formulation and evaluation parameters such FTIR, NMR etc. Different types of dosages forms are described in the review, merits and demerits are also discussed along with diagrammatic representation of phytosome development technique. So, the article is the direction for future research to increase the absorption of phytoconstituents. Keywords: Bioavailability, FTIR, lipid, NMR, niosomes, phytoconstituent

A bioinformatic approach to establish P38α MAPK inhibitory mechanism of selected natural products in psoriasis

165-171In the present study, molecular docking studies of some selected natural products were carried out to identify the potential inhibitors and subsequently to suggest their mechanism of action in relation to P38α mitogen-activated protein kinases (P38α MAPK) enzyme. Psoriasis is an inflammatory disorder characterized by skin hyper-proliferation, differentiation in keratin expression, and increased production of pro-inflammatory cytokines. Increased expression of phosphorylated P38α MAPK in the cytoplasm and nucleus is observed in psoriatic lesions. Twelve natural antipsoriatic agents were included in the study and their molecular docking studies were carried out using AutoDock 4.2 simulator using a Lamarckian genetic algorithm. The crystal structure of P38α MAPK was retrieved from the protein data bank and three-dimensional chemical structures of natural ligands were prepared using ChemSketch 2015. Results indicated that all the natural ligands were fitted into the active site. Hypericin and Catechin (−9.00 and −8.05 kcal/mol, respectively) have shown good binding efficacy among other ligands. However, only Epicatechin interacted with residues in the enzyme required for enzyme inhibition. The study concludes that the Epicatechin effectively inhibited the enzyme and proved itself to be a type-I1/2 inhibitor of the enzyme among other natural ligands and responsible for the treatment of psoriasis preclinically through this mechanism of action

Curcumin-loaded nanoemulsion for acute lung injury treatment via nebulization: Formulation, optimization and in vivo studies

Introduction: Curcumin, a polyphenolic bioactive molecule, exhibits potent anti-inflammatory and antioxidant properties by reducing cytokine levels such as IL-6, TNF-α, and TGF-β. It regulates IL-17A and modulates key signaling pathways, including PI3K/AKT/mTOR, NF-κB and JAK/STAT. However, its clinical application is hindered by rapid metabolism, poor solubility, and chemical instability. Method: Using the Box-Behnken design, this study developed and optimized a curcumin-loaded turmeric oil-based nanoemulsion system. The effects of turmeric oil, Tween 80 and sonication cycles on particle size (PS), polydispersity index (PDI), and encapsulation efficiency were analyzed. The optimized nanoemulsion was characterized by zeta potential, PDI, PS, morphology, loading efficiency, EE, and antioxidant activity (DPPH assay). In vitro cytotoxicity was evaluated using A549 cells, while in vivo efficacy was assessed in BALB/c mice through histological analysis, bronchoalveolar lavage fluid analysis, and TNF-α and IL-1β estimation via enzyme-linked immunosorbent assay. Results: The optimized nanoemulsion had high entrapment efficiency (92.45±2.4 %), a PS of 130.6 nm, a PDI of 0.151, and a zeta potential of -1.7±0.6 mV. Nanoparticle tracking analysis confirmed a mean PS of 138.3±1.6 nm with a concentration of 3.78×10¹² particles/mL. Transmission electron microscopy imaging confirmed spherical morphology. The IC50 value was 25.65 µg/mL. The nanoemulsion remained stable for three months at 4±1 and 25±2 °C/ 60±5 % relative humidity. The optimized formulation significantly reduced BALF total cell count, alveolar wall thickening, and TNF-α and IL-1β levels (p < 0.001). Conclusion: Overall, the optimized formulation significantly lowered levels of pro-inflammatory cytokines in the acute lung injury /acute respiratory distress syndrome mouse model

Dual crosslinked pectin–alginate network as sustained release hydrophilic matrix for repaglinide

Repaglinide, an oral antidiabetic agent, has a rapid onset of action and short half–life of approximately 1 h. Developing a controlled and prolonged release delivery system is required to maintain its therapeutic plasma concentration and to eliminate its adverse effects particularly hypoglycemia. The present study aimed to develop controlled release repaglinide loaded beads using sodium alginate and pectin with dual cross–linking for effective control of drug release. The prepared beads were characterized for size, percentage drug entrapment efficiency, in vitro drug release and the morphological examination using scanning electron microscope. For the comparative study, the release profile of a marketed conventional tablet of repaglinide (Prandin® tablets 2 mg, Novo Nordisk) was determined by the same procedure as followed for beads. The particle size of beads was in the range of 698 ± 2.34 to 769 ± 1.43 μm. The drug entrapment efficiency varied between 55.24 ± 4.61 to 82.29 ± 3.42%. The FTIR results suggest that there was no interaction between repaglinide and excipients. The XRD and DSC results suggest partial molecular dispersion and amorphization of the drug throughout the system. These results suggest that repaglinide did not dissolve completely in the polymer composition and seems not to be involved in the cross–linking reaction. The percent drug release was decreased with higher polymer concentrations. In conclusion, the developed beads could enhance drug entrapment efficiency, prolong the drug release and enhance bioavailability for better control of diabetes

Optimizing gefitinib nanoliposomes by Box-Behnken design and coating with chitosan: A sequential approach for enhanced drug delivery

This study aimed to improve the stability and prolonged gefitinib release from the nanoliposomes. Nanoliposomes were prepared by reverse-phase evaporation and optimized using Box-Behnken design to investigate the influence of sonication time (X1), tween 80 / soya phosphatidylcholine ratio (X2), and cholesterol / soya phosphatidylcholine ratio (X3) on nanoliposomes. Optimized nanoliposomes were quasi-spherical shaped, with a mean dimension of 93.2 nm and an encapsulation efficiency of 87.56±0.17 %. Surface decoration of the optimized batch was done using different concentrations of chitosan. The optimal chitosan concentration required to adorn the surface of nanoliposomes was 0.01 %. In comparison to unadorned nanoliposomes (82.16±0.65 %), adorned nanoliposomes (78.04±0.35 %) released the drug consistently over 24 h via Fickian diffusion. The IC50 values for surface-adorned nanoliposomes in A549 and H1299 cells were 6.53±0.75 and 4.73±0.46 µM, respectively. Cytotoxicity of the surface-decorated nanoliposomes may be due to their higher zeta potential and prolonged drug release. At 4°C, adorned and unadorned nanoliposomes are most stable. In conclusion, the developed nanoliposomes may offer a new path for melanoma clinics

Dual crosslinked pectin–alginate network as sustained release hydrophilic matrix for repaglinide

Repaglinide, an oral antidiabetic agent, has a rapid onset of action and short half–life of approximately 1 h. Developing a controlled and prolonged release delivery system is required to maintain its therapeutic plasma concentration and to eliminate its adverse effects particularly hypoglycemia. The present study aimed to develop controlled release repaglinide loaded beads using sodium alginate and pectin with dual cross–linking for effective control of drug release. The prepared beads were characterized for size, percentage drug entrapment efficiency, in vitro drug release and the morphological examination using scanning electron microscope. For the comparative study, the release profile of a marketed conventional tablet of repaglinide (Prandin® tablets 2 mg, Novo Nordisk) was determined by the same procedure as followed for beads. The particle size of beads was in the range of 698 ± 2.34 to 769 ± 1.43 μm. The drug entrapment efficiency varied between 55.24 ± 4.61 to 82.29 ± 3.42%. The FTIR results suggest that there was no interaction between repaglinide and excipients. The XRD and DSC results suggest partial molecular dispersion and amorphization of the drug throughout the system. These results suggest that repaglinide did not dissolve completely in the polymer composition and seems not to be involved in the cross–linking reaction. The percent drug release was decreased with higher polymer concentrations. In conclusion, the developed beads could enhance drug entrapment efficiency, prolong the drug release and enhance bioavailability for better control of diabetes

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk outcome pairs, and new data on risk exposure levels and risk outcome associations. Methods: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings: In 2017,34.1 million (95% uncertainty interval [UI] 33.3-35.0) deaths and 121 billion (144-1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6-62.4) of deaths and 48.3% (46.3-50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39-11.5) deaths and 218 million (198-237) DALYs, followed by smoking (7.10 million [6.83-7.37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6.53 million [5.23-8.23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4.72 million [2.99-6.70] deaths and 148 million [98.6-202] DALYs), and short gestation for birthweight (1.43 million [1.36-1.51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3-6.5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning