Modified Release Research Articles

Physiologically based in vitro – in vivo correlation of modified release oral formulations with non-linear intestinal absorption: A case study using mirabegron

Establishing an in vitro – in vivo correlation (IVIVC) for oral modified release (MR) formulations would make it possible to substitute an in vitro dissolution test for human bioequivalence (BE) studies when changing the formulation or manufacturing methods. However, the number of IVIVC applications and approvals are reportedly low. One of the main reasons for failure to obtain IVIVCs using conventional methodologies may be the lack of consideration of the dissolution and absorption mechanisms of drugs in the physiological environment. In particular, it is difficult to obtain IVIVC using conventional methodologies for drugs with non-linear absorption processes. Therefore, the aim of the present study was to develop a physiologically based biopharmaceutics model (PBBM) that enables Level A IVIVCs for mirabegron MR formulations with non-linear absorption characteristics.Using human pharmacokinetic (PK) data for immediate-release formulations of mirabegron, the luminal drug concentration-dependent membrane permeation coefficient was calculated through curve fitting. The membrane permeation coefficient data were then applied to the human PK data of the MR formulations to estimate the in vivo dissolution rate by curve fitting. It was assumed that in vivo dissolution could be described using a zero-order rate equation. Furthermore, a Levy plot was generated using the estimated in vivo dissolution rate and the in vitro dissolution rate obtained from the literature. Finally, the dissolution rate of the MR formulations from the Levy plot was applied to the PBBM to predict the oral PK of the mirabegron MR formulations.This PB-IVIVC approach successfully generated linear Levy plots with slopes of almost 1.0 for MR formulations with different dose strengths and dissolution rates. The Cmax values of the MR formulations were accurately predicted using this approach, whereas the prediction errors for AUC exceeded the Level A IVIVC criteria. This can be attributed to the incomplete description of colonic absorption in the current PBBM.

Optimization and evaluation of modified release solid dosage forms using artificial neural network

This study aims to optimize and evaluate drug release kinetics of Modified-Release (MR) solid dosage form of Quetiapine Fumarate MR tablets by using the Artificial Neural Networks (ANNs). In training the neural network, the drug contents of Quetiapine Fumarate MR tablet such as Sodium Citrate, Eudragit® L100 55, Eudragit® L30 D55, Lactose Monohydrate, Dicalcium Phosphate (DCP), and Glyceryl Behenate were used as variable input data and Drug Substance Quetiapine Fumarate, Triethyl Citrate, and Magnesium Stearate were used as constant input data for the formulation of the tablet. The in-vitro dissolution profiles of Quetiapine Fumarate MR tablets at ten different time points were used as a target data. Several layers together build the neural network by connecting the input data with the output data via weights, these weights show importance of input nodes. The training process optimises the weights of the drug product excipients to achieve the desired drug release through the simulation process in MATLAB software. The percentage drug release of predicted formulation matched with the manufactured formulation using the similarity factor (f2), which evaluates network efficiency. The ANNs have enormous potential for rapidly optimizing pharmaceutical formulations with desirable performance characteristics.

Impact of Gliclazide Modified Release or Glimepiride as Add-on Therapy to Metformin on Glycemic and Oxidative Stress Parameters in Type 2 Diabetic Patients

Background: Type 2 diabetes mellitus is a condition characterized by an elevation of oxidative stress, which has been implicated in diabetic progression and its vascular complications. Aim: Assessing the impact of gliclazide modified release (MR) versus glimepiride on oxidative stress markers, glycemic indices, lipid profile, and estimated glomerular filtration rate in uncontrolled type 2 diabetic patients on metformin monotherapy. Methods: This was an observational comparative study conducted in Thi-Qar specialized diabetic, endocrine, and metabolism center. Sixty-six patients were randomized into two groups based on the addition of the sulfonylureas (SUs). Group 1 (33 patients) was on gliclazide MR, whereas Group 2 (33 patients) was on glimepiride. The measured oxidative stress markers were reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and protein carbonyl (PC) evaluated before and after 16 weeks of SUs addition. Results: There were significant drops in SOD (P < 0.001), MDA (P < 0.001), and PC (P = 0.001) and a significant increase in GSH (p = 0.029) levels after gliclazide MR add-on therapy. There were significant drops in SOD (P = 0.026) and MDA (P < 0.001) levels with non-significant changes in both GSH (P = 0.214) and PC (P = 0.538) after glimepiride add-on therapy. There was a significant difference in improvement of PC level (P = 0.048) in the gliclazide group compared to the glimepiride group, with a non-significant numerically higher improvement of GSH, SOD, and MDA in gliclazide MR than glimepiride. At the end of the study, there were no significant differences in glycemic control, lipid profile, or eGFR improvement between the two groups. Conclusion: Glycemic control plays a pivotal role in decreasing oxidative stress. The control of diabetes with the gliclazide-MR-metformin combination reduced oxidative stress more than the glimepiride-metformin combination, indicating its antioxidant property. Keywords: Oxidative Stress, T2DM, Gliclazide MR, Glimepiride, Metformin.

Current Position of Gliclazide and Sulfonylureas in the Contemporary Treatment Paradigm for Type 2 Diabetes: A Scoping Review.

The increasing burden of type 2 diabetes (T2D), in relation to alarming rise in the prevalence; challenges in the diagnosis, prevention, and treatment; as well as the substantial impact of disease on longevity and quality of life, is a major concern in healthcare worldwide. Sulfonylureas (SUs) have been a cornerstone of T2D pharmacotherapy for over 60years as oral antidiabetic drugs (OADs), while the newer generation SUs, such as gliclazide modified release (MR), are known to be associated with low risk of hypoglycemia in addition to the cardiovascular neutrality. This scoping review aimed to specifically address the current position of gliclazide MR among other SUs in the contemporary treatment paradigm for T2D and to provide a practical guidance document to assist clinicians in using gliclazide MR in real-life clinical practice. The main topics addressed in this paper include the role of early and sustained glycemic control and use of SUs in T2D management, the properties of gliclazide MR in relation to its effectiveness and safety, the use of gliclazide therapy in special populations, and the place of SUs as a class and gliclazide MR specifically in the current T2D treatment algorithm.

Postoperative opioids administered to inpatients with major or orthopaedic surgery: A retrospective cohort study using data from hospital electronic prescribing systems.

Opioids administered in hospital during the immediate postoperative period are likely to influence post-surgical outcomes, but inpatient prescribing during the admission is challenging to access. Modified-release(MR) preparations have been especially associated with harm, whilst certain populations such as the elderly or those with renal impairment may be vulnerable to complications. This study aimed to assess postoperative opioid utilisation patterns during hospital stay for people admitted for major/orthopaedic surgery. Patients admitted to a teaching hospital in the North-West of England between 2010-2021 for major/orthopaedic surgery with an admission for ≥1 day were included. We examined opioid administrations in the first seven days post-surgery in hospital, and "first 48 hours" were defined as the initial period. Proportions of MR opioids, initial immediate-release(IR) oxycodone and initial morphine milligram equivalents (MME)/day were calculated and summarised by calendar year. We also assessed the proportion of patients prescribed an opioid at discharge. Among patients admitted for major/orthopaedic surgery, 71.1% of patients administered opioids during their hospitalisation. In total 50,496 patients with 60,167 hospital admissions were evaluated. Between 2010-2017 MR opioids increased from 8.7% to 16.1% and dropped to 11.6% in 2021. Initial use of oxycodone IR among younger patients (≤70 years) rose from 8.3% to 25.5% (2010-2017) and dropped to 17.2% in 2021. The proportion of patients on ≥50MME/day ranged from 13% (2021) to 22.9% (2010). Of the patients administered an opioid in hospital, 26,920 (53.3%) patients were discharged on an opioid. In patients hospitalised with major/orthopaedic surgery, 4 in 6 patients were administered an opioid. We observed a high frequency of administered MR opioids in adult patients and initial oxycodone IR in the ≤70 age group. Patients prescribed with ≥50MME/day ranged between 13-22.9%. This is the first published study evaluating UK inpatient opioid use, which highlights opportunities for improving safer prescribing in line with latest recommendations.

Integrating Clinical Variability into PBPK Models for Virtual Bioequivalence of Single and Multiple Doses of Tofacitinib Modified-Release Dosage Form.

Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a high degree of selectivity within the human genome's set of protein kinases. Currently approved formulations for tofacitinib citrate are immediate-release (IR) tablets, modified-release (MR) tablets, and IR solution. A once daily MR microsphere formulation was developed for use in pediatric patients. Demonstration of bioequivalence (BE) between the 10 mg once daily (q.d.) MR microsphere formulation and 5 mg twice daily (b.i.d.) IR solution is needed to enable the exposure-response analyses-based bridging to support regulatory approval. To assess BE between MR microsphere and IR solution, an innovative approach was utilized with physiologically-based pharmacokinetic (PBPK) virtual BE trials (VBE) in lieu of a clinical BE trial. A PBPK model was developed to characterize the absorption of different formulations of tofacitinib using Simcyp ADAM module. VBE trials were conducted by simulating PK profiles using the verified PBPK model and integrating the clinically observed intrasubject coefficient of variation (ICV) where BE was assessed with a predetermined sample size and prespecified criteria. The VBE trials demonstrated BE between IR solution 5 mg b.i.d. and MR microsphere 10 mg q.d. after a single dose on day 1 and after multiple doses on day 5. This research presents an innovative approach that incorporates clinically observed ICV in PBPK model-based VBE trials, which could reduce unnecessary drug exposure to healthy volunteers and streamline new formulation development strategies.

Frailty in clinical drug trials: Frailty assessments, subgroup analyses and outcomes.

With population ageing, drug trials are increasingly turning their attention to including older, frailer people. This review aimed to provide an overview of how frailty was assessed in published studies related to clinical pharmacological trials, and on the interaction of frailty on the efficacy of the treatments. We searched MEDLINE, EMBASE and Cochrane for clinical drug trials in older people. A total of 4031 abstracts were screened and 17 relevant studies were included in this review. We summarized the findings of these 17 trials into five main clinical areas: cardiovascular (eight studies), cognition (one study), vaccination (two studies), cancer (four studies) and other (two studies). Frailty was assessed retrospectively in most of the studies. Frailty was treated as an ordinal variable (with different levels of frailty) or binary variable (frail/non-frail) using cut-offs in some studies, and as a continuous in some other studies. The effect of frailty on the treatment efficacy was not consistent among the studies. While several trials, such as the Action in Diabetes and Vascular Disease-Preterax and Diamicron Modified Release Controlled Evaluation trials, the Systolic Blood Pressure Intervention Trial and the Aspirin in Reducing Events in the Elderly trial, showed some reduced effects of the treatment in frail patients, most of the trials showed that the benefits of the treatment are not affected by frailty. Some trials even showed that the benefits of the treatment were more significant in frailer patients (the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure and the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure trials). The results of this review suggest that routine measurement of frailty in participants in clinical drug trials would improve our knowledge of the effect of treatment in the frail and identify those who have more or least to gain from treatment.

Exploring Sensitivity and Significance of Tamsulosin as Modified Release in Benign Prostatic Hyperplasia

This abstract outline the use of Tamsulosin, a selective α (1A and 1D)-adrenoreceptor blocker, to treat benign prostatic hyperplasia (BPH). The study's background highlights the most prevalent symptoms and prevalence of BPH in elderly men. The research objective and goal are to better understand the mechanism of action, pharmacokinetics, dose, clinical efficacy, safety, and tolerance of Tamsulosin, particularly in its modified release (MR) version. Considering evidence-based medicines have recently been made available, the treatment approach for current cases of benign prostatic hyperplasia has evolved. Considerations including therapeutic benefits, potential for morbidity, likely long-term effectiveness, and expenses must be made before selecting a therapy to relieve symptoms. When individuals with benign prostatic hyperplasia report with symptoms related to the lower urinary tract, the main treatment option is α1-adrenergic receptor antagonists. The technique includes a review of the literature on Tamsulosin's development, discovery, and approval, as well as its pharmacodynamics and pharmacokinetics. The findings show that Tamsulosin MR is successful in treating BPH, with a preference for the 0.4mg once-daily dose.

Can 3D Printed Tablets Be Bioequivalent and How to Test It: A PBPK Model Based Virtual Bioequivalence Study for Ropinirole Modified Release Tablets.

As the field of personalized dosing develops, the pharmaceutical manufacturing industry needs to offer flexibility in terms of tailoring the drug release and strength to the individual patient's needs. One of the promising tools which have such capacity is 3D printing technology. However, manufacturing small batches of drugs for each patient might lead to huge test burden, including the need to conduct bioequivalence trials of formulations to support the change of equipment or strength. In this paper we demonstrate how to use 3D printing in conjunction with virtual bioequivalence trials based on physiologically based pharmacokinetic (PBPK) modeling. For this purpose, we developed 3D printed ropinirole formulations and tested their bioequivalence with the reference product Polpix. The Simcyp simulator and previously developed ropinirole PBPK model were used for the clinical trial simulations. The Weibull-fitted dissolution profiles of test and reference formulations were used as inputs for the model. The virtual bioequivalence trials were run using parallel design. The study power of 80% was reached using 125 individuals. The study demonstrated how to use PBPK modeling in conjunction with 3D printing to test the virtual bioequivalence of newly developed formulations. This virtual experiment demonstrated the bioequivalence of one of the newly developed formulations with a reference product available on a market.

ETHNIC DIFFERENCES IN RISK FACTORS FOR COGNITIVE DECLINE AND DEMENTIA, IN INDIVIDUALS WITH DIABETES: RESULTS FROM THE ADVANCE TRIAL

Objective: Ethnic differences in risk factors for dementia remain underexplored. This project will estimate ethnic differences on the associations between risk factors, and treatment effects, with cognitive decline (CD) and/or dementia, in individuals with type 2 diabetes (T2D). Design and method: This study uses the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial of 11,140 individuals with T2D from 20 countries. Multivariable adjusted multinomial logistic regression models were used to examine the associations between baseline characteristics and odds of subsequent CD/dementia, by Asian and non-Asian ethnicity. Results: There were 4242 (38%) participants of Asian ethnicity. During 5-years (median) follow-up, 1827 participants (40% Asian) had CD/dementia (1718 with CD only (41% Asian); 21 with dementia only (19% Asian); 88 with CD and dementia (32% Asian)), and 929 (30% Asian) died without CD/dementia. Participants of Asian ethnicity had a higher odds of CD/dementia than non-Asians (odds ratio [OR] [95% confidence interval (CI)], 1.25 [1.09, 1.44]). In both Asians and non-Asians, older age, longer diabetes duration was associated with greater odds of CD/dementia; higher years at education completion and taller stature reduced the odds of CD/dementia. Higher baseline cognitive function was associated with a lower odds of CD/dementia in non-Asians 0.93 [0.90, 0.96], but not in Asians 1.01 [0.97, 1.04]. Stroke/transient ischaemic attack, retinal disease, higher body mass index, waist circumference, and current smoker (vs. never), were associated with a higher odds of CD/dementia in non-Asians but not in Asians. Moderate/vigorous physical activity vs none/mild was associated with a higher odds of CD/dementia in Asians 1.26 [1.10, 1.45] but a lower odds in non-Asians 0.81 [0.68, 0.97]. There was no evidence that intensive glucose control (vs. standard control) or blood pressure lowering (vs. placebo) conferred a lower risk of CD/dementia, overall nor by ethnicity. Conclusions: People of Asian ethnicity had a 25% higher risk of CD/dementia than non-Asians in this study. There were some differential effects of risk factors for CD/dementia by ethnicity. More data from Asian populations are required to verify ethnic differences and the mechanisms that underlie these differences.

Optimal dosing of gliclazide - a model-based approach.

Gliclazide was approved as a treatment for type 2 diabetes in an era before model-based drug development and consequently the recommended doses were not optimized with modern methods. To investigate various dosing regimens of gliclazide, we used publicly available data to characterise the dose-response relationship using pharmacometric models. A literature search identified 21 published gliclazide pharmacokinetic (PK) studies with full profiles. These were digitized and a PK model was developed for immediate- (IR) and modified-release (MR) formulations. Data from a gliclazide dose-ranging study of postprandial glucose were used to characterise the concentration-response relationship, using the integrated glucose-insulin model. Simulations from the full model showed that the maximum effect was 44% of the patients achieving HbA1c<7 % with 11% experiencing glucose<3 mmol/L and the most sensitive patients (i.e., 5% most extreme) experiencing 35 min of hypoglycaemia. Simulations revealed that the recommended IR dose (320 mg) was appropriate with no efficacy gain with increased dose. However, the recommended dose for the MR formulation may be increased to 270 mg, with more patients achieving HbA1c goals (i.e., HbA1c<7%) without a hypoglycaemic risk higher than the resulting risk from the recommended IR dose.

Reconciling sprinkle administration information in approved NDA labeling with sprinkle bioequivalence study recommendations in FDA product-specific guidances for generic drug development

Objectives: Certain patient populations (e.g., children and the elderly) may not be able to swallow solid oral dosage forms. In the absence of availability of a dosage form that is appropriate for these patient groups, liquids and/ or soft foods as described in the Food and Drug Administration (FDA)-approved product labeling can be used as a suitable vehicle(s) for oral administration of the specific drug product. The approved labeling of some new drug application (NDA) products contains information for sprinkle administration on liquids or soft foods. Since abbreviated new drug application (ANDA) products must demonstrate bioequivalence (BE) to the reference listed drug (RLD) products, and since the generic drug labeling is the same as RLD, generic applicants are recommended to conduct in vivo BE sprinkle study using one of the soft foods mentioned in RLD labeling. The current FDA guidance specifically recommends that generic applicants conduct a sprinkle BE study if the labeling of a modified-release (MR) RLD product states that the product can be administered sprinkled on soft foods. For ANDAs, such recommendations for in vivo BE sprinkle studies for MR products are routinely communicated in the respective product-specific guidance (PSG) published by FDA and readily available for prospective ANDA applicants. FDA guidance does not recommend sprinkle BE study for an immediate-release (IR) product since the formulation differences between IR generic and RLD products are not expected to impact administration with food vehicle. Materials and Methods: FDALabel and PSG databases were searched for current NDAs with sprinkle labeling and individual PSGs with recommendations for an in vivo sprinkle BE study, respectively. Results from FDALabel were narrowed to NDAs for oral solid dosage forms with approved labeling for sprinkle administration on food vehicles. Only MR NDAs with sprinkle labeling were included in the final analysis as recommended by FDA for inclusion of in vivo sprinkle BE study recommendations in PSGs for generic products. We searched the FDA external PSG database for availability of respective PSGs containing in vivo sprinkle study recommendations for those MR products with approved NDA labeling for sprinkle administration. Results: Of the 57 NDAs with FDA-approved drug products that are labeled to include sprinkle administration, 45 NDAs were MR (tablet, capsule, and granule) products. Forty-two (93%) of the 45 MR products have PSGs with in vivo sprinkle BE study recommendations. Standardized data extraction sheets created by Microsoft Excel 2019 for data extraction were utilized. Conclusion: FDA has a sprinkle-study PSG for almost all currently approved MR NDAs. The results of our study show that in vivo BE study recommendations in PSGs closely match information in the approved drug labeling. Applicants who plan to develop MR generic products should visit the FDA public web page for the availability of the product-specific BE recommendations for the proposed products.

Nateglinide Modified Release Dosage Form Using Elementary Osmotic Pump and Push Pull Osmotic Pump Methods: Formulation and in-vivo evaluation

Objective: The aim was to develop osmotic tablets of nateglinide by two methods namely elementary osmotic pump (EOP) and push-pull osmotic pump (PPOP) method for controlled drug release.&#x0D; Methods: The tablets were prepared by the wet granulation and were evaluated for various physicochemical parameters, in-vitro dissolution and in-vitro dissolution. The optimised formulation obtained in both methods was further characterised for FTIR, stability studies and pharmacokinetic studies.&#x0D; Results: In EOP method coated tablet F14 showing highest drug release of 98.82%. In PPOP formulation FF14 was optimized with highest drug release of 99.97% and also its granules were having better flow property. Both F14 and FF14 were further characterized for FTIR, which showed no significant interaction and the accelerated studies indicated formulations were stable for 3months. The in-vivo studies in rabbits revealead Cmax of the optimised formulation (FF14) was 469.67±0.034 ng/ml, and the Cmax of the marketed product was 401.27±0.08 ng/ml. The Tmax of the formulation and the pure drug were 6.0±0.07 h and 1.5±0.04 h, respectively. The AUC0-infinity of the FF14 was higher ((2829.83±1.47 ng.h/ml) than the marketed suspension (1310.62±0.82 ng.h/ml). The AUC0-t of the FF14 formulation was significantly higher than that of the marketed product (p&lt;0.05).&#x0D; Conclusion: A better improvement in-vitro dissolution profile and bioavailability of the osmotic tablet of nateglinide was observed using PPOP method.&#x0D;

1283. Safety, Tolerability, and Pharmacokinetics of BRII-778, A Modified-Release Oral Formulation of Rilpivirine in Healthy Adult Subjects

Abstract Background BRII-778 is a modified release (MR) formulation of rilpivirine for once-weekly (QW) oral administration. BRII-778 aims to prolong oral absorption, lower Cmax, relatively, and reduce peak to trough ratio achieved with a MR formulation of rilpivirine, within the known efficacy and safety bounds established by once daily oral administration of rilpivirine. QW BRII-778 dosing may have advantages over once daily rilpirvirine in terms of patient convenience, and treatment adherence. Multiple MR formulations of rilpivirine were evaluated in healthy adult subjects in this Phase 1 study. Methods This was a Phase 1, randomized, double-blinded, placebo-controlled, study of single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, evaluating the safety, tolerability, and PK of BRII-778. Three MR formulations of rilpivirine, BRII-778-A1, -A2, and -A3, were evaluated in this study. Rilpivirine PK profiles after single or multiple doses of the three BRII-778 formulations were characterized under the fed state over the dose range of 150 mg to 750 mg. Food effect was assessed after a single oral dose of BRII-778-A3 750 mg. Exploratory concentration-QTc (C-QTc) analysis was conducted using combined SAD and MAD data. Results BRII-778 as single dose or multiple doses was generally safe and well-tolerated when administered to healthy adult subjects. There were no Grade ≥3 AEs, SAEs or AEs leading to withdrawal in BRII-778 dosing arms. PK profiles of BRII-778 were consistent with slower oral absorption with MR formulation. The increase in exposure was less than dose proportional. Mild accumulation in plasma was observed after 3 QW BRII-778-A3 doses. BRII-778-A3 750 mg under the fed state enhanced bioavailability by improving gastric dissolution and/or subsequent absorption. Exploratory C-QTc analysis confirmed a concentration-dependent effect on the QTc interval with escalating doses of BRII-778, but the interpretations are limited by small sample size. There were no clinically significant EKG changes and no individual subject met QTc stopping criteria. Conclusion SAD and MAD administration of BRII-778 formulations were generally safe and well tolerated. Rilpivirine PK profiles post BRII-778 dosing supports further evaluation of BRII-778 for potential QW regimen. Disclosures David A. Margolis, MD MPH, Brii Biosciences: Stocks/Bonds Ji Ma, PhD, Brii Biosciences: Stocks/Bonds Michael Watkins, PharmD, Brii Biosciences: Stocks/Bonds Yujin Wang, M.Sc., Brii Biosciences: Stocks/Bonds Chetana Trivedi, B.A., Brii Biosciences: Stocks/Bonds Xuelian Wei, PhD, Brii Biosciences: Stocks/Bonds Lijie Zhong, PhD, Brii Biosciences: Stocks/Bonds Kamlesh Patel, PhD, Brii Biosciences: Stocks/Bonds Li Yan, MD PhD, Brii Biosciences: Stocks/Bonds Zhi Hong, PhD, Brii Biosciences: Ownership Interest Jean-Luc Girardet, PhD, Brii Biosciences: Stocks/Bonds Lianhong Xu, PhD, Brii Biosciences: Stocks/Bonds.

Comparison of gliclazide vs linagliptin on hypoglycemia and cardiovascular events in type 2 diabetes mellitus: A systematic review.

Cardiovascular outcome trials have demonstrated cardiovascular safety of glimepiride (a sulfonylureas) against dipeptidyl peptidase-4 inhibitor linagliptin. Gliclazide (another newer sulfonylureas) has shown similar glycemic efficacy and 50% decreased risk of hypoglycemia compared to glimepiride. Considering the absence of cardiovascular outcome trials for gliclazide, we decided to conduct a systematic review of the literature to assess the car-diovascular (CV) safety by assessing the risk for major adverse CV events and hypoglycemia risk of gliclazide vs linagliptin in patients with type 2 diabetes (T2D). This systematic review followed the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to analyze all the clinical studies published from 2008 that compared the two drugs in patients with T2D with no risk of CV disease (CVD). We included only evidence designated high quality by the Oxford Center for Evidence-based Medicine-Levels of Evidence. Eight clinical studies were included in the narrative descriptive analysis (gliclazide: 5 and linagliptin: 3). The CV safety of gliclazide in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial and of linagliptin in the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA) and CARdiovascular Outcome study of LINAgliptin vs glimepiride in patients with T2D (CAROLINA) trials were excluded from the comparative analysis as these trials demonstrated CV and hypoglycemia benefits in patients at high risk of CVD. However, since these are landmark trials, they were discussed in brief to show the CV benefits and low hypoglycemia risk of gliclazide and linagliptin. We did not find any study comparing gliclazide with linagliptin. Hence, direct comparison of their major adverse CV events and hypoglycemia risk could not be carried out. However, the literature meeting the inclusion criteria showed that both drugs were effective in achieving the desired glycemic control and had low major adverse CV events and hypoglycemia risk in adult patients with no history of CVD. Gliclazide can be considered an effective and safe glucose-lowering drug in T2D patients with no established CVD but at high risk of CVD due to their T2D status. Future randomized controlled trials comparing gliclazide with linagliptin or dipeptidyl peptidase-4 inhibitors can confirm these findings.

3D printing hybrid materials using fused deposition modelling for solid oral dosage forms.

3D printing in the pharmaceutical and healthcare settings is expanding rapidly, such as the rapid prototyping of orthotics, dental retainers, drug-loaded implants, and pharmaceutical solid oral dosage forms. Through 3D printing, we have the capability to precisely control dose, release kinetics, and several aesthetic features of dosage forms such as colour, shape, and texture. Additionally, polypills can be created with combinations of medications in one solid dosage form at completely customisable strengths that would be extremely difficult to obtain commercially. As the technology and formulations developed through 3D printing are expanding, the development of new hybrid materials to obtain superior formulations are also gaining momentum. In this review we collate data on the importance of developing hybrid formulations of polymers, drugs and excipients necessary to produce reliable and high-quality 3D printed dosage forms with a special emphasis on fused deposition modelling (FDM). FDM technology is one of the most widely used forms of 3D printing and has demonstrated compatibility with unique polymer-based hybrids to allow for enhanced drug delivery, protection of thermolabile drugs, modifiable release kinetics, and more. The data collated covers different categories of hybrids as well as the methods used to fabricate them, and their respective effects on the properties of 3D printed solid oral dosage forms. Therefore, this review will provide an overview of upcoming and emerging trends in pharmaceutical 3D printing formulation compositions.

Evaluating gliclazide for the treatment of type 2 diabetes mellitus

ABSTRACT Introduction Sulfonylureas have been the standard second-line treatment after failure of metformin monotherapy in patients with type 2 diabetes (T2D) but they are becoming less popular as the newer glucose lowering agents have relatively lower risk of hypoglycemia and some of them have been shown to reduce cardiovascular and renal events. Gliclazide differs from other sulfonylureas in several respects and may provide a suitable option for some patients with T2D. Areas covered In this article we review the pharmacokinetics, pharmacodynamics and clinical efficacy of gliclazide based on the available literature. Expert opinion Gliclazide in the modified release (MR) formulation given once daily provides good 24-hour glycemic efficacy comparable to most other groups of glucose lowering drugs. Hypoglycemic events are less frequent than with some other sulfonylureas and weight gain is not a major problem. Cardiovascular outcome studies have shown no evidence of increased cardiovascular events with gliclazide and the durability of glucose lowering effects is comparable to other drug groups. Lower doses of gliclazide appear to have an incretin enhancing effect and overall it can provide a cost-effective treatment that is useful in many patients.

Assessment of Manufacturing Related Deficiencies for Modified Release Tablet in Abbreviated New Drug Applications.

Generic drugs play an important role in public health. However, the first review cycle approval rate for Abbreviated New Drug Applications (ANDAs) is generally low. To identify if the drug product (DP) manufacturing related deficiencies are the potential root causes of low first review cycle approval of the modified release (MR) tablet ANDAs, we collected and analyzed the review recommendations from each review discipline and the DP manufacturing (process and facility) related deficiencies for original MR tablet ANDAs submitted between FY17 and FY19. We identified 193 original MR tablet ANDAs. The analysis showed that 12% of the applications were approved in first review cycle, while 88% received complete responses (CR). Of the 169 CR applications, 91% were found inadequate for multiple review disciplines. A total of 1345 DP manufacturing process-related deficiencies were issued to 184 ANDAs during the first review cycle. We have identified common deficiencies across ANDAs based on DP manufacturing process categories. The top deficiencies cited reasons include facilities are out of compliance/not ready to commercialize/not ready for inspection; critical process parameter (CPP) ranges are not proposed/proposed CPP ranges are too wide and/or not supported by studied range and no in-process controls (IPCs) are proposed/proposed IPCs acceptance criteria (limits) are too wide and/or not supported by observed data etc. Avoiding the common DP manufacturing deficiencies may reduce the need for issuing DP manufacturing related deficiencies in information requests (IRs), discipline review letters (DRLs), and CRs for MR tablet ANDAs.

Population pharmacokinetic analysis of acetaminophen overdose with immediate release, extended release and modified release formulations

Objectives The introduction of delayed release formulations of acetaminophen (APAP) has created concern about the role of formulation in overdose. We examined the APAP overdose pharmacokinetic (PK) profiles to assess the role of dose, coingestants and formulation: immediate release (IR), extended release (ER), and modified release (MR) on APAP pharmacokinetic measures. Methods We collected by-subject APAP PK data: subject description, timed blood APAP concentrations, dose, and coingestants. We sought both overdose and randomized controlled trials (RCTs) for supratherapeutic doses involving ER or MR formulations. Data analysis and simulation used the non-linear mixed-effects modeling program NONMEM-version 7.4. Results The final dataset comprised 3,033 [APAP] from 356 subjects and 15 sources including 3 RCTs (179 subjects receiving IR, 122 ER, 65 MR). The final population PK (PopPK) model was a linear 2-compartment model with first-order (oral) absorption. Covariate relationships included: APAP absorption rate and bioavailability decreased with increased oral dose (p < 0.00005) for all 3 formulations (MR > ER > IR). Post hoc analyses showed opioid coingestant increased exposure (area under the curve, AUC) by factor of 1.6. Simulations of 100 g vs 10 g doses for IR, ER and MR showed overdose of the ER formulation exhibits slower absorption and lower C max, overall exposure (AUC) is less than 80% of an equivalent dose of IR acetaminophen. The overall exposure for the MR formulation is less than 70% of an equivalent dose of IR. Conclusions Acetaminophen ER and MR formulations have slower absorption and decreased bioavailability leading to a lower C max and later T max than the IR formulation. These results have potential clinical implications because delayed absorption could confound use of the Rumack-Matthew nomogram by underestimating the severity of ingestion early in the course of treatment.

Cumulative Systolic Blood Pressure Load and Cardiovascular Risk in Patients With Diabetes

BackgroundStandard measures of blood pressure (BP) do not account for both the magnitude and duration of exposure to elevated BP over time. ObjectivesThe purpose of this study was to assess the association between cumulative systolic blood pressure (SBP) load and risk of cardiovascular events in patients with type 2 diabetes. MethodsA post hoc analysis of patients with type 2 diabetes followed by the ADVANCE-ON (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation - Observational Study). Cumulative SBP load was defined as the area under curve for SBP values ≥130 mm Hg divided by the area under curve for all measured SBP values over a 24-month exposure period. HRs for the association between cumulative SBP load with major cardiovascular events and death were estimated using Cox models. ResultsOver a median 7.6 years of follow-up, 1,469 major cardiovascular events, 1,615 deaths, and 660 cardiovascular deaths were observed in 9,338 participants. Each 1-SD increase in cumulative SBP load was associated with a 14% increase in major cardiovascular events (HR: 1.14; 95% CI: 1.09-1.20), 13% increase in all-cause mortality (HR: 1.13; 95% CI: 1.13-1.18), and 21% increase in cardiovascular death (HR: 1.21; 95% CI: 1.13-1.29). For the prediction of cardiovascular events and death, cumulative SBP load outperformed mean SBP, time-below-target SBP, and visit-to-visit SBP variability in terms of Akaike information criterion and net reclassification indexes. ConclusionsCumulative SBP load may provide better prediction of major cardiovascular events compared with traditional BP measures among patients with type 2 diabetes. These findings reinforce the importance of both the magnitude and duration of exposure to elevated SBP in assessing cardiovascular risk. (Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation Post Trial Observational Study [ADVANCE-ON]; NCT00949286)