AbstractIn this study, we report the systematic approach for characterization of two major degradant impurities, which are not listed in any compendia and were formed during the stability studies of Dihydroergotamine mesylate injection (DHE). An ion-pair UPLC chromatographic method was developed to quantify the related substances present in the DHE injection drug product. The same was used to monitor the impurity profiling during its stability. The two unknown impurities were observed at RRT about 0.08 (Impurity-1) and RRT about 0.80 (Impurity-5) and found to be significantly increasing on stability. Forced degradation studies revealed the nature of the impurity and conditions required for enriching them. A Mass compatible HPLC method was developed to quantify only these two impurities using 25% ammonia and formic acid in water. Their mass numbers were identified using LC MS/MS with triple quadruple mass spectrometer coupled with a HPLC. These two impurities were then isolated from enriched products using preparative HPLC. These impurities were then characterized using Mass and NMR analysis along with Q-TOF elemental analysis.

A novel and green strategy for the construction of biologically relevant substituted indolyl-4H-chromenes scaffolds is reported using L-proline as a catalyst and water as a promoter solvent. The catalytic system offers wider applicability, crossing over a variety of substrates, besides affording exclusively the desired product in shorter reaction times and high yields. L-proline-Water was found to be an efficient and cheaper catalytic system for regioselective synthesis of indolyl-4H-chromenes. The reaction between 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (1) with active methylene compounds (2a–b) and substituted indoles(3a–f) in the presence of L-proline afforded quinolone substituted indolyl-4H-chromenes (4a–l) in excellent yields. Furthermore, the reactions involve easy workup giving high yields without the need of column chromatography, making it one of the most ideal conditions for green chemistry.

Coexisting hypertension, type 2 diabetes mellitus (T2DM), and dyslipidemia (triple disease) can lead to greater risk of cardiovascular morbidity and mortality. The present study sought to comprehend the prevalence, demographic traits, clinical traits, and treatment patterns in Indian patients with these coexisting conditions. An electronic medical record (EMR)-based, retrospective, multicenter, cross-sectional study was conducted, and data were collected for patients who were diagnosed with coexistent hypertension, T2DM, and dyslipidemia. Baseline patient variables evaluated were the percentage of patients with triple comorbidity, demographic characteristics, diagnostic laboratory parameters, and treatment pattern details. Data from 4793 centers (clinics) were included, with a total of 6,722,173 patients. Of these, 427,835 (6.36%) patients were found to have coexistent hypertension, T2DM, and dyslipidemia. Most of the patients belonged to the 40-64year age group (62.10%) and were males (57.00%), while 27.40% patients had a body mass index (BMI) within normal limits, 43.30% patients were pre-obese, and 20.90% patients were class 1 obese. Further, 3402 patients (0.80%) had a recorded history of smoking. Mean glycated hemoglobin (HbA1c) for the patients included in the study was 8.35±1.96g%. Mean systolic blood pressure (SBP) was 138.81±19.59mmHg, while mean diastolic blood pressure (DBP) was 82.17±10.35mmHg; 27.60% cases had SBP <130mmHg, while 28.37% cases had DBP <80mmHg. The mean low-density lipoprotein (LDL), total cholesterol, and high-density lipoprotein (HDL) inmg/dl were 98.38±40.39, 174.75±46.73, and 44.5±10.05, respectively. Of the enrolled cases, 55.64% had serum LDL below 100mg/dl, 72.03% cases had serum cholesterol below 200mg/dl, and 44.15% males and 71.77% females had serum HDL below the normal prescribed range. The most common monotherapy used for managing hypertension was angiotensin receptor blockers (ARB) (24.80%), followed by beta-blockers (24.30%). The most common combinations administered for management of hypertension were antihypertensives with diuretics (14.30%), followed by ARB plus calcium channel blockers (CCB) (13.30%). For dyslipidemia, the majority of patients (56.60%) received lipid-lowering medication in combination with drugs for other comorbidities. The most common antidiabetic agents prescribed were biguanides (74.60%). Coexistence of triple disease is not uncommon in the Indian population, with middle-aged patients diagnosed as pre-obese and obese being affected more commonly and receiving treatment for the same. The present study highlights that, though there are medications against the three chronic conditions, the rate of uncontrolled cases of hypertension, T2DM, and dyslipidemia remains high. Coexistence of triple disease increases the risk of cardiovascular and renal complications, which need to be closely monitored and effectively treated.

Objective: To analyze and report the maternal, fetal, and neonatal complications in Antenatal hypothyroid women and to give the frequency of the co-existence of Anemia with Hypothyroidism in pregnancy. Methods: A Prospective and an observational study was conducted on 200 Antenatal hypothyroid women admitted to the Obstetrics ward. In the period of 6 mo (August 2022-January 2023), the study was carried out through the examination of medical records of Antenatal women with Hypothyroidism. Results: Of 200 Antenatal hypothyroid women enrolled in the study, Denovo Hypothyroidism was seen in 56% of women. Maternal complications reported include–(Lower Segment Cesarean Section) LSCS seen in 54.5%, Preeclampsia in 19%, mild anemia in 28%, (Post-Partum Hemorrhage) PPH in 7.5%,(Premature Rupture Of Membranes) PROM in 11.5%, Oligohydramnios in 24.5% of women. Fetal complications found were in fetal distress in 21%, in 32.5 %, Respiratory distress in 17.5%, and Low birth weight in 16% of Neonates. Conclusion: Our study concludes that the number of pregnant women affected by Hypothyroidism has increased to a larger extent. Hence, the suspected risk factors of Hypothyroidism have to be addressed and monitored closely to decrease the rate of feto-maternal and neonatal complications in pregnancy, vital for the overall well-being of hypothyroid mothers and their babies.

Over the past few decades, physiologically based biopharmaceutics modeling (PBBM) has demonstrated its utility in both new drug and generic product development. Applications of PBBM for fed bioequivalence study waivers is an upcoming area. Recently Innovation & Quality (IQ) consortium demonstrated utility of PBBM to avoid repeat food effect studies for new drugs. In the similar lines, the current manuscript aims to discuss role of PBBM in generic fed bioequivalence study waivers. Generic industry practices related to PBBM model development to predict fed bioequivalence was portrayed with special emphasis on fed bio-predictive media. Media that can simulate fed bioequivalence study outcome were discussed from practical perspective. In-depth analysis, collating the data from 36 products was performed to understand predictability of PBBM for fed bioequivalence. Cases where PBBM was successful to predict fed bioequivalence was correlated with BCS class, formulation category and type of food effect. Further, two case studies were presented wherein fed bioequivalence study waiver obtained with PBBM approach. Lastly, future direction in terms of fed bioequivalence study waivers, regulatory perspectives and best practices for PBBM were portrayed. Overall, this article paves a way to utilize PBBM for generic fed bioequivalence study waivers.

Background: A low-dose formulation (DFD-29) of minocycline hydrochloride (HCl) is under evaluation for the treatment of moderate-to-severe papulopustular rosacea. The objective of this phase 1 study is to compare the bioavailability of DFD-29 to that of the currently available Solodyn® (minocycline HCl extended release) 105-mg formulation. Methods: This single-center, randomized, open-label, laboratory-blinded, 3-way, 6-sequence crossover study compared the pharmacokinetics of a single dose of DFD-29 40 mg after an overnight fast, DFD-29 40 mg after a high-fat meal, and minocycline HCl extended release 105-mg tablet (minocycline HCl ER 105 mg) after an overnight fast in healthy adult volunteers. Blood samples were collected for PK assessments prior to and up to 72 hours after each drug dose, with a washout period of 7 calendar days between doses. Safety was evaluated by monitoring adverse events (AEs), vital signs, and laboratory tests. Results: A total of 24 subjects were randomized and 23 subjects completed the study. Mean plasma minocycline Cmax levels were 243.9 ng/mL for DFD-29 (fasting), 225.0 ng/mL for DFD-29 (fed), and 497.3 ng/mL for minocycline HCl ER 105 mg (fasting). The geometric least squares (LS) mean ratios for Cmax, AUC0-T, and AUC0-∞ of DFD-29 to minocycline HCl ER 105 mg when administered after fasting were 47.97%, 36.55%, and 38.35%, respectively. When comparing fasting vs fed administration of DFD-29, geometric LS mean ratios for Cmax, AUC0-T, and AUC0-∞ were 97.48%, 116.84%, and 115.26% respectively. Tmax was 1.5 h for DFD-29 (fasting), 4.5 h for DFD-29 (fed), and 4.0 h for minocycline HCl ER 105 mg (fasting). Treatment-emergent AEs (TEAEs) were reported in 17.4%, 13.0%, and 21.7% after administration of DFD-29 (fasting), DFD-29 (fed), and minocycline HCl ER 105 mg, respectively. Most TEAEs were mild in severity (21/22; 95.5%). Conclusion: Bioavailability was significantly lower after a single dose of DFD-29 40 mg vs minocycline HCl ER 105 mg following a single dose under fasting and fed conditions. Food intake had no impact on Cmax but may delay absorption and may slightly increase exposure. Overall, single oral doses of DFD-29 40 mg and minocycline HCl ER 105 mg were generally safe and well tolerated. This study and abstract are funded by Journey Medical Corporation.

Consumption of probiotics, which are beneficial live microorganisms, has received a lot of attention because of their potential to improve health and wellness. Robust quality control measures are necessary to ensure the safety of probiotics and maximize their health effects. This review delves into the topic of quality management in probiotics, highlighting the significance of sticking to strict guidelines from manufacture to storage to distribution. Probiotic quality standards, Good Manufacturing Practices (GMP) implementation, quality control and testing techniques, and documentation and traceability systems are all discussed in detail. The importance of taking precautions to avoid microbial contamination, meeting all applicable regulations, and clearly marking and packaging probiotic products is also emphasized. In addition, it reviews the clinical evidence supporting the possible health advantages of probiotics and investigates the processes through which probiotics enhance health. The review continues by stressing the significance of educating and informing consumers about probiotics and their proper use in order to maximize health benefits. Probiotics' potential health benefits can be maximized and consumer faith in these helpful microbes can be bolstered by adopting thorough quality management measures to ensure their safety, efficacy, and consistency.

Neovascular age-related macular degeneration (nAMD) is a leading cause of vision loss in older adults. nAMD is treated with biologics targeting vascular endothelial growth factor; however, many patients do not respond to the current therapy. Here, a small molecule drug, griseofulvin (GRF), is used due to its inhibitory effect on ferrochelatase, an enzyme important for choroidal neovascularization (CNV).For local and sustained delivery to the eyes, GRF is encapsulated in microparticles based on poly(lactide-co-glycolide) (PLGA), a biodegradable polymer with a track record in long-acting formulations. The GRF-loaded PLGA microparticles (GRF MPs) are designed for intravitreal application, considering constraints in size, drug loading content, and drug release kinetics. Magnesium hydroxide is co-encapsulated to enable sustained GRF release over >30 days in phosphate-buffered saline with Tween 80. Incubated in cell culture medium over 30 days, the GRF MPs and the released drug show antiangiogenic effects in retinal endothelial cells. A single intravitreal injection of MPs containing 0.18µg GRF releases the drug over 6 weeks in vivo to inhibit the progression of laser-induced CNV in mice with no abnormality in the fundus and retina. Intravitreally administered GRF MPs prove effective in preventing CNV, providing proof-of-concept toward a novel, cost-effective nAMD therapy.

Physiologically based biopharmaceutics modelling (PBBM) was recognised as potential approach for biopharmaceutics applications. However, PBBM to justify safety is an unexplored area. In this manuscript, we elucidated PBBM application for safety justification. Product DRL is a generic extended release tablet containing an anti-epileptic narrow therapeutic index (NTI) drug. During dossier review, regulatory agency requested to evaluate the impact of faster dissolution profiles observed during stability on safety aspects. In order to justify, PBBMbased strategy was adapted. Model was validated and population simulations were performed for reference and test formulations and the predictions matched with clinical outcome. The model was found to be sensitive to dissolution changes and hence applied for the prediction of stability batches exhibiting faster dissolution profiles, virtually generated profiles at lower and upper specifications. The maximum predicted plasma levels were well below the reported safety levels, thereby demonstrating safety of the product. Overall, a novel application of PBBM to justify safety was demonstrated. Similar justifications using PBBM and linking with safety can be adopted where safety can be impacted due to aggravated dissolution profiles. Such justifications have potential to avoid clinical safety studies and helps in faster approval of drug product.