Enhancement of solubility of Metaclopramide using solid dispersion technique with different carriers (HPβCD, PVP K-30)

Modern drug discovery has led to the development of drug molecules that exhibit high lipophilicity and poor water solubility, which leads to problematic bioavailability. Approaches have thus been made to enhance dissolution of poorly water soluble drugs through modifications and creation of specific formulations. Metaclopramide is an antiemetic and gastroprokinetic agent, commonly used to treat nausea and vomiting. It is absorbed well after oral administration but a significant first pass effect in some human patients may reduce systemic bioavailability to 30%.The Metaclopramide base is thus modified from Metaclopramide hydrochloride to enhance solubility .This has been achieved by the formulating in solid dispersion since Metaclopramide is poorly water soluble. Though it is absorbed well after oral administration, a significant first pass effect in some patients reduces systemic bioavailability, which can cause adverse side effects. This solid dispersion has then been used through transdermal drug delivery. Enhancement of solubility of poorly water soluble drug by solid dispersion may be attributed to particles modified characters such as particle size reduction, improved wettability, higher porosity, decreased lattice energy, amorphous state. The main objective thus includes modification of drug Metaclopramide  hydrochloride to Metaclopramide base, preparation of solid dispersion of modified Metaclopramide  base drug which has poor water solubility, experimental analysis of Metaclopramide base drug and solid dispersion products with carriers. Keywords: solubility, Metaclopramide, solid dispersion, carriers, HPβCD, PVP K-3

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Connecting C-19 Norditerpenoids to C-20 Diterpenes: Total Syntheses of 6-Hydroxy-5,6-dehydrosugiol, 6-Hydroxysugiol, and Taiwaniaquinone H, and Formal Synthesis of Dichroanone

Oxidation of the B-ring of abietane derivatives by Sharpless dihydroxylation gave the natural products 6-hydroxy-5,6-dehydrosugiol and 6-hydroxysugiol. Moreover, further oxidation gave a hydroxy dione derivative that provides a synthetic entry into the C-19 taiwaniaquinoid family of natural products. This route is based on biosynthetic considerations and involves a benzilic acid rearrangement followed by decarboxylation. On the basis of this approach, a total synthesis of (-)-taiwaniaquinone H and a formal synthesis of (-)-dichroanone have been achieved

Syntheses of Taiwaniaquinone F and Taiwaniaquinol A via an Unusual Remote C-H Functionalization

A protecting-group-free route to (-)-taiwaniaquinone F based on a ring contraction and subsequent aromatic oxidation of a sugiol derivative is reported. In addition, the first synthesis of (+)-taiwaniaquinol A is reported via short time exposure of (-)-taiwaniaquinone F to sunlight triggering a remote C-H functionalization. The hypothesis that the biogenesis of some methylenedioxy bridged natural products could proceed via similar nonenzymatic mechanisms is presented

Syntheses of Taiwaniaquinone F and Taiwaniaquinol A via an Unusual Remote C–H Functionalization

A protecting-group-free route to (−)-taiwaniaquinone F based on a ring contraction and subsequent aromatic oxidation of a sugiol derivative is reported. In addition, the first synthesis of (+)-taiwaniaquinol A is reported via short time exposure of (−)-taiwaniaquinone F to sunlight triggering a remote C–H functionalization. The hypothesis that the biogenesis of some methylenedioxy bridged natural products could proceed via similar nonenzymatic mechanisms is presented

Metal-Free Sequential C(sp²)–H/OH and C(sp³)–H Aminations of Nitrosoarenes and <i>N</i>‑Heterocycles to Ring-Fused Imidazoles

Hydrogen bond assisted <i>ortho</i>-selective C­(sp²)–H amination of nitrosoarenes and subsequent α-C­(sp³)-H functionalization of aliphatic amines is achieved under metal-free conditions. The annulation of nitrosoarenes and 2-hydroxy-C-nitroso compounds with <i>N</i>-heterocycles provides a facile excess to a wide range of biologically relevant ring-fused benzimidazoles and structurally novel polycyclic imidazoles, respectively. Nucleophilic aromatic hydrogen substitution (S_NArH) was found to be preferred over classical S_NAr reaction during the C­(sp²)–H amination of halogenated nitrosoarenes