Proof of Concept in Assignment of Within-Subject Variability During Virtual Bioequivalence Studies: Propagation of Intra-Subject Variation in Gastrointestinal Physiology Using Physiologically Based Pharmacokinetic Modeling

While the concept of ‘Virtual Bioequivalence’ (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as ‘not plausible’. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations.

Development of a Once-Daily Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772 using DiffCORE Technology

Purpose GSK2982772 is a selective inhibitor of receptor-interacting protein kinase-1 (RIPK1) with a short 2- to 3-h half-life. In a previous modified-release (MR) study, a matrix monolithic formulation (80% GSK2982772 released over 12 h) provided a once-daily (QD) pharmacokinetic (PK) profile in the fasted state; however, it was susceptible to food effects. The current study evaluated the safety and PK of MR formulations using GSK proprietary DiffCORE™ technology. Methods Part A evaluated PK following single-dose (240 mg) fasted and fed (high-fat meal) administration of three DiffCORE MR formulations within pre-defined in vitro extremes of 80% GSK2982772 released over 12 h (MR-12 h) to 80% GSK2982772 released over 18 h (MR-18 h) versus an immediate-release formulation. Part B evaluated MR-16 h (120–960 mg) in different prandial states. Results Pharmacokinetic profiles for all MR formulations and doses tested in the fasted and fed states were consistent with QD dosing. Conclusions The DiffCORE technology overcame the food effect vulnerability observed with the matrix monolithic formulation. The MR-16 h formulation was selected for further clinical development as a QD dosing regimen (NCT03649412 September 26, 2018).

Case Law: A Review of selected Pharmaceutical Patents in the UK Courts during 2020

Patentslie at the interface between technology and law. This article provides a criticalreview of four high profile cases from 2020 in which patents relating topharmaceuticals were litigated in the UK Courts. The selectedcases om this review involved ‘sufficiency’, ‘inventiveness’, ‘plausibility’and ‘equivalency’ issues. The first case is a dispute between Regeneron Pharmaceuticals and Kymab Ltd in relation to Regeneron’spatent for a transgenic mouse platform. The second case relates to Pfizer’s patent for their Prevnar®13pneumococcal vaccineand the alleged infringement of this patent by concerns the validity of apatent belonging to NeurimPharmaceuticals Ltd relating to a slow-release formulation of melatonin fortreating primary insomnia. The final case is a dispute between FibroGen Inc. and AkebiaTherapeutics concerning FibroGen’spatents for hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors (“HIF-PHIs”) for use in treating anaemia. The article aims to focus onthe technology behind the patents and to provide an insight into how science interactswith law in the context of patent enforcement and infringement. 

Prolyl-hydroxylase inhibitor-induced regeneration of alveolar bone and soft tissue in a mouse model of ligature-induced periodontitis

Bone injuries and fractures reliably heal through a process of regeneration with restoration to original structure and function when the gap between adjacent sides of a fracture site is small. However, when there is significant volumetric loss of bone, bone regeneration usually does not occur. In the present studies, we explore a particular case of volumetric bone loss in a mouse model of human periodontal disease (PD) in which alveolar bone surrounding teeth is permanently lost and not replaced. This model employs the placement a ligature around the upper second molar which leads to inflammation and bone breakdown and faithfully replicates the bacterially-induced inflammatory etiology of human PD to induce bone degeneration. After 10 days, the ligature is removed and the mice are treated with a timed-release formulation of a small molecule inhibitor of prolylhydroxylases (PHDi; 1,4-DPCA) previously shown to induce epimorphic regeneration of soft tissue in non-regenerating mice. This PHDi induces high expression of HIF-1α and the regenerative response is completely blocked by siHIF1a. Here, we observe that timed-release 1,4-DPCA rapidly and completely restores bone and soft tissue with normal anatomic fidelity and with increased stem cell markers due to stem cell migration into the site and/or de-differentiation of local tissue, PDL cell proliferation, and increased vascularization. In-vitro studies using gingival tissue show that 1,4-DPCA indeed induces de-differentiation and the expression of stem cell markers but does not exclude the role of migrating stem cells.

OPTIMIZED FAST DISINTEGRATING TABLETS, BOOSTED OSELTAMIVIR PHOSPHATE ORALLY FAST DISINTEGRATING TABLETS

Background Around 33% of the populace (fundamentally pediatric and geriatric) has gulping hardships, bringing about helpless consistence with oral tablet drug treatment which prompts decreased in general treatment viability. For this explanation, tablets that can quickly break down or deteriorate in the oral cavity have drawn in a lot of consideration. Objective research was designed to develop and evaluate boosted orally fast disintegrating tablets (OFDT) for oro-buccal drug delivery of oseltamivir phosphate. Methods In the present study six formulations of mouth dissolving tablet of oseltamivir were prepared by direct compression method using SSG as a super disintegrating agent with lactose, talcum, mannitol, SLS and starch. The prepared tablets were then subjected to various evaluation parameters. Results every one of the outcomes was observed to be inside satisfactory reaches. The formulation F6 manufacturing utilizing SSG 50mg and SLS 10mg showed the higher medication content (98%), while the formulation F2 showed the least medication content (92%). It was seen that with the increment in SSG concentration, the medication content was additionally increased. SEM concentrate on showed request of expanding unpleasantness of tablet surface is F1<F2<F3<F4<F5<F6. The expanding unpleasantness may be answerable for higher % of medication release. Formulation F1 showed the most elevated medication discharge (97.735%), while the formulation F5 showed the least medication discharge (56.24%). Finally, it was inferred that SSG, SLS, D-mannitol, starch, lactose, and talcum powder can be effectively utilized in the formulation of Oseltamivir phosphate mouth dissolving tablets. Conclusion: From the above work it was presumed that the formulation of the Oseltamivir Phosphate was observed to be more achievable than the regular one.

Nefecon (targeted-release formulation-budesonide) for the treatment of IgA nephropathy

Budesonide is a second-generation synthetic, nonhalogenated corticosteroid; it acts locally with minimal systemic absorption. The oral formulation Nefecon® is under clinical development from the treatment of IgA nephropathy. Thanks to its specific formulation, it could inhibit the pathogenetic process of IgA nephropathy at its source while avoiding the toxicity of systemic glucocorticoids. A Phase II clinical trial has shown a statistically significant antiproteinuric effect of budesonide on top of therapy with inhibitors of the renin–angiotensin system, with a good safety profile. More recently, preliminary results of a larger, Phase III clinical trial have confirmed the antiproteinuric efficacy of oral budesonide. These findings were submitted to the US FDA and the EMA to undergo fast revision and approval for clinical use.

Carboxymethyl Cellulose Hydrogel Based Formulations of Zinc Hydroxide Nitrate-Sodium Dodecylsulphate-Bispyribac Nanocomposite: Advancements in Controlled Release Formulation of Herbicide

The usefulness of carboxymethyl cellulose (CMC) as a matrix material in enhancing the controlled release formulations of bispyribac (BP) herbicide from the interlayer gallery of zinc hydroxide nitratesodium dodecylsulphate–bispyribac (ZHN–SDS–BP) nanocomposite was investigated. The CMC coated nanocomposite, ZHN–SDS–BP–CMC was characterised using several instruments for the determination of its physicochemical properties. The release rates of the BP were measured using a UV spectrophotometer, and the aqueous solutions containing PO3−4 , SO2−4 and Cl− were selected as release media in the release studies so as to mimic the real conditions of environmental soil. Significant release time delays, triggered by the gelation forming ability and hygroscopic nature of CMC, were observed in all release media, and the release processes were found to behave in a concentration-dependent manner in all release media. Fitting the release data into several kinetic models demonstrated that release in aqueous solutions of Na3PO4 and Na2SO4 was governed by pseudo second order processes, whereas the release in an aqueous NaCl solution was governed by the parabolic diffusion kinetic model. The potential of CMC in prolonging the release of BP from ZHN–SDS–BP–CMC can potentially help in reducing the pollution resulting from the overuse of pesticides.

Development and Evaluation of Gastro Retentive Floating Drug Delivery System of Ondansetron Hydrochloride

The Aim of the present study was to develop & evaluate Gastro-retentive floating Tablet of Ondansetron hydrochloride. The Objective was to calibrate and validate the UV- spectroscopy analytical method and to prepare and optimize the GR Floating tablets of Ondansetron hydrochloride in terms of dissolution release profile. The FDDS of the drug can minimize the fluctuation of drug plasma levels and result to associated adverse reactions, dosing frequency, and improved patient compliance. Conventionally, Ondansetron hydrochloride is taken up 2-3 times daily in the treatment of nausea and vomiting. Gastro retentive floating tablet of Ondansetron hydrochloride is better suited for treatment of postoperative nausea vomiting. In the present study, nine Gastro retentive Floating tablet formulations (F1, F2.....F9) of Ondansetron hydrochloride were prepared by the method of direct compression and polymers HPMC K15 were used and Guargum and Chitosan, in different quantity to normalise their effect on the’ release profile of drug . Target release profile was >80% release of drug in 12 hours. Tablets were evaluated for various parameters namely: thickness, weight variation’, friability, hardness, assay, in-vitro buoyancy study & drug release. Formulation F8 containing Chitosan (26.66% w/w), Guargum (26.66% w/w) and Sod. Carbonate (25.83% w/w) had the desirable release profile. Keywords: Ondansetron hydrochloride; Gastro retentive floating tablet, Chitosan, Guar gum, Drug release

FORMULATION, DEVELOPMENT AND EVALUATION OF IMMEDIATE RELEASE ROSUVASTATIN CALCIUM TABLET

Rosuvastatin belongs to the statin medication class, which is used to treat excessive cholesterol and prevent heart disease. The Biopharmaceutical Classification System classifies it as class II. The goal of this project is to create 10 mg Rosuvastatin instant release pills using several types of materials. To boost the drug's bioavailability, superdisintegrants were used to speed up the disintegration and dissolution of Rosuvastatin calcium. Cited research work aims to formulate an immediate release tablet of Rosuvastatin for the treatment of hypercholesterolemia, hypolipoproteinemia, and atherosclerosis. The present work used a cost-effective wet granulation process to create an immediate release formulation of Rosuvastatin calcium. All of the batches were manufactured, and the granules were evaluated for pre-compression properties such as loss on drying, bulk density, tapped density, and compressibility index. Disintegration time and assay were determined to be within acceptable parameters, as were weight fluctuation, thickness, hardness, and friability of tablets. The effect of several superdisintegrants on in vitro dissolutions in 6.8 PH phosphate buffer was investigated. The final formulation was chosen based on the dissolving profile; dissolution studies revealed that formulations F2 and F4 released 80 percent of the medication within 15 minutes. Two different formulations of Rosuvastatin Calcium 5.199 and 10.398 mg employing immediate-release tablets were successfully generated using Crospovidone, Meglumine, and Comprecel 112D+®. The tablets showed complete drug release in 60 minutes and fair flow characteristics when compared to the innovators' product.