ULTRA HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC DETERMINATION OF GENOTOXIC IMPURITIES IN FEBUXOSTAT DRUG SUBSTANCE AND PRODUCTS

Objective: An efficient ultra-high performance liquid chromatographic (UHPLC or Infinity LC 1290) method has been developed and validated for the quantification of possible carcinogenic or genotoxic impurities in febuxostat drug substances and drug products at 18 µg/ml level.Methods: This method includes the conclusion of four potential genotoxic impurities in febuxostat. The mobile phase is trifluoroacetic acid, acetonitrile, and water with linear gradient elution. The UHPLC column used for the analysis was zorbax RRHD eclipse plus C18 with a length of100 mm, internal diameter of 2.1 mm, and particle size of 1.8 µ.Results: The limit of detection and limit of quantitation of the impurities are <0.1 (0.00001%) and 0.3 µg/ml (0.00003%) with respect to febuxostat test concentration of 1000 µg/ml, respectively. This method has been validated as per ICH guidelines Q2 (R1).Conclusion: A rapid, cost-effective infinity LC method was wonderfully established for quantitative analysis of possible genotoxic impurities of febuxostat drug substance and drug products.Keywords: Febuxostat, Genotoxic impurities, Ultra-high performance liquid chromatograph, Infinity-LC 1290, Validatio

Diagnosis and management of gout: are the British Society for Rheumatology and National Institute for Health and Care Excellence guidelines both needed?

Numerous international guidelines have been developed relating to the diagnosis and/or management of gout, including those published by the ACR [1], EULAR [2, 3] and the American College of Physicians [4]. In the UK, the first British Society for Rheumatology (BSR) gout guideline was published in 2007 and updated in 2017 [5, 6], whereas the National Institute for Health and Care Excellence (NICE) published its guideline for the diagnosis and management of gout in 2022 [7]. Not surprisingly, given that 5 years elapsed between the publication of these two UK guidelines, there are some differences between their recommendations. In this editorial, we compare and contrast the 2017 BSR and 2022 NICE gout guidelines [6, 7] and consider the extent to which the BSR guideline is superseded by the NICE guideline

MODIFIED FORMULATION OF FEBUXOSTAT: IMPROVED EFFICACY AND SAFETY

Objective: Febuxostat, a xanthine oxidoreductase inhibitor, is a drug of choice for hyperuricemia and Gout. But it also suffers from drawbacks in terms of pharmacokinetic profile and toxicity. It is available as immediate release formulation in the market. The objective is to develop a modified release formulation of febuxostat that can serve the dual purpose of increasing the efficacy and decreasing the toxicity, thereby improving safety.Methods: Pharmacokinetic and pharmacodynamic data, including drug concentration profile, efficacy data and toxicity data have been reviewed thoroughly. Based on available data, target pharmacokinetic profile has been identified as about 50 % reduction in Cmax and improvement in plasma drug concentration above required level during 6-24 hour. Desired in-vitro dissolution profile has been selected, and formulation modification has been sought to achieve the desired profile. The formulation has been prepared with a partial dose in the form of immediate release (IR) and remaining dose as an extended release (ER). IR and ER formulations have been developed separately and combined to form Inlay tablets containing ER inner tablet surrounded by IR.Results: Based on dissolution data and Wagner-Nelson calculations, the plasma concentration profile has been predicted for the developed formulation. It reconfirms that developed formulation will achieve the desired objectives. Formulation stability has been established up to 6 months under accelerated conditions.Conclusion: The developed formulation is a potential candidate for filing to a regulatory agency with the advantage of higher efficacy and less toxicity, which will be beneficial to the patient population and has good commercial viability.Â

The Effects Of Eurycoma Longifolia Extract And Eurycomanone On The Steroidogenesis In Mouse Leydig Cells

Eurycoma longifolia Jack (Tongkat Ali) is one of the most popular traditional plants found in the tropical rainforest of Southeast Asia, especially in Malaysia and Indonesia. Although E. longifolia is widely used as traditional medicine, little is understood of the in vitro effect on Leydig cells; the testosterone-producing cells. Therefore, the effect of a standardised E. longifolia extract (F2) and pure compound, eurycomanone (EN) on the productions of testosterone, estrogen and aromatase in mouse Leydig cells were determined in this study, whereby the Formestane (FM) was used as a positive control. The effect of F2, EN and FM on the cell viability was first determined using MTT assay

A narrative review on pharmacological significance of Eurycoma longifolia jack roots

Objective: This review is focused on the pharmacological properties of Eurycoma longifolia which is a popular herb and widely used by local folks in Southeast Asia including Malaysia. Background: The wide application of the herb is mainly contributed by its efficacy in treating many chronic diseases and promoting wellbeing. With the remarkable ethnomedicinal value, the plant, especially its root extracts have been intensively investigated for pharmacological significance in a systematic manner for decades. This includes both in vitro and in vivo studies focusing on the aphrodisiac, anticancer, antimalarial, antiosteoporotic and antidiabetic properties using different assays. Methods: A narrative review of previously reported data on the pharmacological importance of E. longifolia was systematically carried out. This covers data published in literature retrieved from the search engine of Google from 1980s until to date. The findings of the previous studies are gathered, organized and presented with the support of technical evidences and explanation. Conclusions: E. longifolia root extract was mostly reported to exhibit anticancer properties using different human cancerous cell lines, particularly breast cancer cells. Many reports also revealed the properties could be due to the presence of phytochemicals such as quassinoids, canthin-6-one and carboline alkaloids in the plant extracts. Eurycomanone and eurycomanol were likely to be compounds of quassinoids in promoting the other frequently reported activities such as antimalarial and anti-hyperglycaemic potentials. Interestingly, the water extract of the plant was not toxic with the acute oral LD50 up to 6 g/kg body weight of rats. The toxicity was most probably attributed to eurycomanone at high LD50 (5.27 g/kg). Most studies were focused on crude extract which was not properly characterized in term of phytochemical composition. It is important to well characterise plant extract in order to relate to its pharmacological significance. Possibly, optimized or standardized plant extract is used for subsequent experiments to ensure continuity in research activities. Plant species authentication is of utmost importance prior to any experimental works

アジア熱帯モンスーン地域の菌類の多様性とその生態的機能の調査研究

科学研究費助成事業（科学研究費補助金）研究成果報告書：基盤研究(A) 平成14～17年度 課題番号：1425500