Safety and Efficacy of IPX203 in Parkinson's Disease: The RISE-PD Open-Label Extension Study.

BACKGROUND: IPX203 is a novel oral extended-release formulation of carbidopa/levodopa (CD/LD) developed to address the short half-life of immediate-release CD/LD. In the phase 3 RISE-PD trial, IPX203 significantly improved "Good On" time in patients with Parkinson's disease compared with immediate-release CD/LD. OBJECTIVES: To evaluate the safety and efficacy of IPX203 in an open-label extension of the pivotal phase 3 study. METHODS: This 9-month extension enrolled patients who completed the randomized, double-blind trial. Key efficacy endpoints included Movement Disorder Society-Unified Parkinson's Disease Rating Scale and Patient and Clinical Global Impression scores. Adverse events (AEs) were recorded. RESULTS: Improvements in efficacy were maintained and dosing frequency and total daily dose remained stable through the trial. A total of 52.7% of patients experienced ≥1 treatment-emergent AE, mostly mild or moderate and occurred within the first 90 days of treatment. CONCLUSIONS: In this phase 3 open-label extension, IPX203 exhibited a favorable safety and tolerability profile and sustained efficacy of comparable magnitude to the end of the double-blind study. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Population pharmacokinetics of rotigotine extended-release microspheres for intramuscular injection in patients with early-stage Parkinson's disease.

AIMS: Rotigotine extended-release microspheres is a weekly intramuscular injection formulation to treat Parkinson's disease. This study aimed to develop a population pharmacokinetics (PK) model for rotigotine extended-release microspheres to investigate its PK ethnic differences. METHODS: Data for the study were obtained from three studies in China, Japan and the US. The population PK model was developed using the Phoenix NLME 8.3.5 software. Two parallel absorption models were created to include both zero- and first-order absorptions. The elimination phase was evaluated for one- and two-compartment linear models. Moreover, covariates including sex, body weight, body mass index, albumin, creatinine clearance and race were input into the model using a stepwise covariate method. RESULTS: We constructed a one-compartment linear model with the first parallel absorption model identified as the best-fitting model. Simulation results in patients with lighter body weight (45 kg) exhibited a 27% increase in Cmax,ss and a 31% increase in AUCtau,ss compared to those with median body weight (65 kg). Patients with heavier body weight (103 kg) showed a 27% decrease in Cmax,ss and a 29% decrease in AUCtau,ss compared to the median body weight group. Asian patients displayed only a 21% increase in Cmax,ss and a 6% increase in AUCtau,ss compared to non-Asian. While we could not fully conclude that race does not affect rotigotine exposure, dosage adjustments based on race were not deemed necessary. CONCLUSIONS: Exposure differences were mainly attributed to body weight, while dose adjustments were not needed for patients of different racial identities.

Early outcomes associated with de novo once-daily extended-release versus twice-daily immediate-release tacrolimus in a predominantly African American kidney transplant population: A single-center observational study.

INTRODUCTION: The purpose of this study was to compare early outcomes of de novo LCPT (once-daily extended-release tacrolimus) to IR TAC (twice-daily immediate-release tacrolimus) in a predominantly African American (AA) adult kidney transplant population. METHODS: This is a single center, retrospective cohort study. Patients were divided into two cohorts: IR TAC (administered between January 1, 2017, and January 31, 2019) and LCPT (administered between February 1, 2019, and May 31, 2020). Primary endpoints were changes in tacrolimus trough levels (ng/mL) and estimated glomerular filtration rate up to 12 months post-transplantation. Clinical endpoints included graft survival, delayed graft function, biopsy-proven rejection, CMV viremia, and BK. A propensity score weighted generalized linear mixed effects model was used for analysis. RESULTS: The rate of change in tacrolimus levels was significantly higher in the LCPT cohort compared to the IR TAC cohort at 14 days post-discharge (.2455 ng/mL per day vs. .1073 ng/mL, respectively; p < .001). Subsequently, the LCPT cohort had a slightly higher rate of decline (-.015 ng/mL per day vs. -.010 ng/mL with IR TAC; p = .0894) up to 12 months post-discharge. Although eGFR was similar between the two cohorts at 12 months post-transplant, the rate of increase was slower in the LCPT cohort (.1371 mL/min per day vs. .1852 mL/min per day, p = .0314). No significant differences were found in graft survival, DGF, BPAR, CMV, or BK infection. CONCLUSION: This study demonstrates that despite higher early trough levels with immediate post-transplant LCPT use, clinical outcomes are comparable to IR TAC at one-year post-transplant. Notably, LCPT use does not increase the incidence of DGF and that this formulation of CNI can be used as first line therapy post-transplant.

Impact of Switching From Immediate- or Prolonged-Release to Once-Daily Extended-Release Tacrolimus (LCPT) on Tremor in Stable Kidney Transplant Recipients: The Observational ELIT Study.

Once-daily extended-release tacrolimus (LCPT) exhibits increased bioavailability versus immediate-release (IR-TAC) and prolonged release (PR-TAC) tacrolimus. Improvements in tremor were previously reported in a limited number of kidney transplant patients who switched to LCPT. We conducted a non-interventional, non-randomized, uncontrolled, longitudinal, prospective, multicenter study to assess the impact of switching to LCPT on tremor and quality of life (QoL) in a larger population of stable kidney transplant patients. The primary endpoint was change in The Essential Tremor Rating Assessment Scale (TETRAS) score; secondary endpoints included 12-item Short Form Survey (SF-12) scores, tacrolimus trough concentrations, neurologic symptoms, and safety assessments. Subgroup analyses were conducted to assess change in TETRAS score and tacrolimus trough concentration/dose (C0/D) ratio by prior tacrolimus formulation and tacrolimus metabolizer status. Among 221 patients, the mean decrease of TETRAS score after switch to LCPT was statistically significant (p < 0.0001 vs. baseline). There was no statistically significant difference in change in TETRAS score after switch to LCPT between patients who had received IR-TAC and those who had received PR-TAC before switch, or between fast and slow metabolizers of tacrolimus. The overall increase of C0/D ratio post-switch to LCPT was statistically significant (p < 0.0001) and from baseline to either M1 or M3 (both p < 0.0001) in the mITT population and in all subgroups. In the fast metabolizers group, the C0/D ratio crossed over the threshold of 1.05 ng/mL/mg after the switch to LCPT. Other neurologic symptoms tended to improve, and the SF-12 mental component summary score improved significantly. No new safety concerns were evident. In this observational study, all patients had a significant improvement of tremor, QoL and C0/D ratio post-switch to LCPT irrespective of the previous tacrolimus formulation administered (IR-TAC or PR-TAC) and irrespective from their metabolism status (fast or slow metabolizers).

Extended-release tacrolimus dosing and outcomes in pediatric and young adult transplant recipients - A single-center experience.

BACKGROUND: Published data on LCP-tacrolimus (LCPT) in the pediatric population are limited. METHODS: This single-center, retrospective, observational study describes LCPT doses needed to reach therapeutic ranges in pediatric and young adult kidney and liver transplant recipients in both de novo usage and conversion from immediate-release tacrolimus (IR-Tac). Adverse outcomes up to 12 months after LCPT initiation were also evaluated. RESULTS: Forty-one transplant recipients (30 kidney, 11 liver) were included. The median initial doses of LCPT were 0.034 mg/kg (IQR 0.019) de novo and 0.09 mg/kg (IQR = 0.076) converted. The median doses at first therapeutic level were 0.086 mg/kg (IQR 0.028) de novo and 0.1 mg/kg (IQR 0.066) converted. The median LCPT:IR-Tac conversion ratio initially was 0.7 and 0.75 at therapeutic levels. The rate of AKI per 100 days of exposure to IR-Tac was 0.546 and 0.439 on LCPT. The percentage of patients with rejection was not different before and after conversion (clinical rejection 8.6% [n = 3] vs 11.4% [n = 4], p = .6; biopsy-proven rejection 2.9% [n = 1] vs 11.4% [n = 4], p = .11). One patient had graft loss unrelated to rejection, and the graft was explanted. CONCLUSION: In this study, pediatric and young adult abdominal transplant recipients had therapeutic tacrolimus levels at LCPT doses below the adult-labeled dose; the conversion ratio from IR-Tac to LCPT at therapeutic level was similar. There were no identified safety concerns in de novo or converted LCPT use in pediatric and young adult patients.

Pharmacokinetics of Envarsus in pediatric kidney transplant recipients - phase 1 pilot conversion study.

INTRODUCTION: Tacrolimus is the standard immunosuppressant for pediatric kidney transplants and is routinely administered twice daily (BD-tac). Envarsus (LCP-tac), an extended-release formulation, is approved for adults but not for pediatric patients. METHODS: We conducted a pilot open-label phase 1 study in stable pediatric kidney transplant recipients (age < 18 at the time of study). Our primary objective was to compare the pharmacokinetics (Pk) of LCP-tac versus BD-tac. We conducted two 24-h Pk studies: pre-conversion (BD-tac) and 4 weeks post-conversion to LCP-tac. Patients were followed for 6 months, with the option to continue LCP-tac. RESULTS: Five patients completed the study, with no returns to BD-tac. Median age was 15 years (range 11-17). LCP-tac exhibited an extended-release profile versus the bimodal profile of BD-tac. Time to maximum concentration was delayed (5 h vs. 1 h), and maximum concentration was lower (9.9 ng/mL vs. 14.4 ng/mL). Tacrolimus area under the curve (24 h) was comparable (141 ± 46.5 ng/mL vs. 164 ± 27.8 ng/mL). No new safety concerns arose. There were no rejection and no difference in eGFR at the study's end (1.5 mL/min/1.73 m2 , range - 1.7 to 2.3 mL/min/1.73 m2 ). Concentration/dose ratio was higher in LCP-tac (1.8 ± 0.64 vs. 0.8 ± 0.39). The final conversion ratio was 0.6 (BD-tac: LCP-tac). CONCLUSION: Our pilot study confirms the extended-release Pk profile and improved absorption of LCP-tac compared to BD-tac. A larger study is needed to further evaluate the population Pk characteristics in children.

Biodegradable Long-Acting Injectables: Platform Technology and Industrial Challenges.

Long-acting injectables have been used to benefit patients with chronic diseases. So far, several biodegradable long-acting platform technologies including drug-loaded polymeric microparticles, implants (preformed and in situ forming), oil-based solutions, and aqueous suspension have been established. In this chapter, we summarize all the marketed technology platforms and discuss their challenges regarding development including but not limited to controlling drug release, particle size, stability, sterilization, scale-up manufacturing, etc. Finally, we discuss important criteria to consider for the successful development of long-acting injectables.

Feasibility and effectiveness of extended-release buprenorphine (XR-BUP) among correctional populations: a systematic review.

Background: Medications for opioid use disorder (MOUD) reduce risks for overdose among correctional populations. Among other barriers, daily dosing requirements hinder treatment continuity post-release. Extended-release buprenorphine (XR-BUP) may therefore be beneficial. However, limited evidence exists.Objectives: To conduct a systematic review examining the feasibility and effectiveness of XR-BUP among correctional populations.Methods: Searches were carried out in Pubmed, Embase, and PsychINFO in October 2023. Ten studies reporting on feasibility or effectiveness of XR-BUP were included, representing n = 819 total individuals (81.6% male). Data were extracted and narratively reported under the following main outcomes: 1) Feasibility; 2) Effectiveness; and 3) Barriers and Facilitators.Results: Studies were heterogeneous. Correctional populations were two times readier to try XR-BUP compared to non-correctional populations. XR-BUP was feasible and safe, with no diversion, overdoses, or deaths; several negative side effects were reported. Compared to other MOUD, XR-BUP significantly reduced drug use, resulted in similar or higher treatment retention rates, fewer re-incarcerations, and was cost-beneficial, with a lower overall monthly/yearly cost. Barriers to XR-BUP, such as side effects and a fear of needles, as well as facilitators, such as a lowered risk of opioid relapse, were also identified.Conclusion: XR-BUP appears to be a feasible and potentially effective alternative treatment option for correctional populations with OUD. XR-BUP may reduce community release-related risks, such as opioid use and overdose risk, as well as barriers to treatment retention. Efforts to expand access to and uptake of XR-BUP among correctional populations are warranted.

Extended-Release Versus Immediate-Release Triamcinolone Acetonide in Patients Who Have Knee Osteoarthritis and Type 2 Diabetes Mellitus.

BACKGROUND: Intra-articular (IA) corticosteroid injections may cause hyperglycemia (glucose level > 180 mg/dL). In a phase 2 study of 33 patients who had osteoarthritis of the knee (OAK) and type 2 diabetes mellitus (T2D), triamcinolone acetonide extended-release (TA-ER) was associated with minimal glycemic control disruption compared with triamcinolone acetonide immediate-release (TA-IR). This post hoc analysis characterizes the clinical relevance of these results. METHODS: Patients who had symptomatic OAK for ≥ 6 months, T2D for ≥ 1 year, and hemoglobin A1c ≥ 6.5 and ≤ 9.0% were randomized to receive an IA injection of either TA-ER or TA-IR. Changes in continuous glucose monitor daily glucose level, percentage of time in or above the target glucose range (> 70 to 180 mg/dL), time to glucose level 250 mg/dL and maximum glucose level > 250 mg/dL, and glycemic variability were evaluated. RESULTS: Across postinjection days 1 to 3, the TA-ER group (n = 18) had a lower median change from baseline in maximum glucose level (92.3 versus 169.1 mg/dL), a reduced percentage of time with a glucose level > 250 mg/dL (12 versus 26%), a smaller proportion of patients who had a maximum glucose level > 250 mg/dL (50 versus 93%), and a greater percentage of time in the target glucose range (62 versus 48%) versus the TA-IR group (n = 15). There was less glycemic variability and lower glucose spikes in the TA-ER versus TA-IR group. Median times to glucose level 250 mg/dL (44 versus 6 hours) and maximum glucose level (34 versus 13 hours) were significantly longer in the TA-ER versus TA-IR group. CONCLUSIONS: Use of TA-ER was associated with a clinically meaningful reduction in hyperglycemia versus TA-IR.

Apixaban and clopidogrel in a fixed-dose combination: Formulation and in vitro evaluation.

Fixed-dose combination (FDC) products represent a novel, safe, and cost-effective formulation. Combined use of anticoagulant and antiplatelet medications is common among comorbid cardiovascular patients. This study aimed to formulate FDC tablets for Apixaban and Clopidogrel, as prophylaxis and treatment of thrombo-embolic events. FDC tablets were developed by combining small tablets of Immediate-Release Clopidogrel 75 mg and Extend-Release Apixaban 5 mg through direct compression and wet granulation. Particularly, Apixaban tablets were developed using design expert software, and various types and concentrations of polymers were entered. For Clopidogrel tablets, various diluents were used to develop the formulation. Then, the dissolution profile for each formula was studied. Finally, the optimized formulations were encapsulated within hard gelatin capsules. Apixaban formulation followed zero-order with super case Ⅱ transport mechanism as the dominant mechanism of drug release. The Apixaban drug release rate was affected by the type and concentration of the polymers in the formulation (P < 0.05). As the HPMC concentration was increased, Apixaban release was retarded. For, Clopidogrel, the formulated tablets with spray-dried lactose filler and sodium stearyl fumarate lubricant were found to be stable with good properties. In conclusion, the optimum formulation yielded Clopidogrel and extended-release Apixaban for 24 h with the desired in vitro drug dissolution.

Generic lamotrigine extended-release tablets are bioequivalent to innovator drug in fully replicated crossover bioequivalence study.

OBJECTIVE: Lamotrigine is a commonly prescribed antiepileptic drug. U.S. Food and Drug Administration (FDA)-funded clinical studies have demonstrated bioequivalence (BE) for generic lamotrigine immediate-release (IR) products in epilepsy patients with generic substitution. To address the potential concerns about the risk of generic-brand substitution of lamotrigine extended-release (ER) products, considering the complexity of controlled release systems and pharmacokinetic variations associated with possible within-subject variability (WSV), this prospective study assessed (1) BE of generic and brand lamotrigine ER products in a fully replicated BE study design in healthy subjects and (2) whether such fully replicated study design and WSV data can better support the approval of generic lamotrigine ER products. METHODS: This open-label, single-dose, two-treatment, four-period, two-sequence, fully replicated crossover BE study compared generic lamotrigine ER tablet to brand Lamictal XR (200 mg) in 30 healthy subjects under fed conditions. Pharmacokinetics (PK) profiles were generated based on intensive blood sampling up to 144 h. RESULTS: The two products showed comparable peak plasma concentration (Cmax ), area under the concentration-time curve (AUC) from time zero to the last measurable time point (AUC0-t ) and AUC extrapolated to infinity (AUC0-inf ), whereas median time to Cmax (Tmax ) values differed, that is, 10 h for generic and 22 h for brand products, respectively. WSVs for PK metrics were small (~8% of Cmax and ~6% of AUC) and similar between these two products. PK simulation predicted equivalent PK measurements of both products at steady state and after brand-to-generic switch, except the first day upon switching. No serious adverse events were reported. SIGNIFICANCE: The generic lamotrigine ER tablet product demonstrates BE to the brand product in a fully replicated BE study design with healthy subjects, supporting the adequacy of the two-way crossover study design to demonstrate BE and generic-brand substitution of lamotrigine ER products.

Approaches to Account for Colon Absorption in Physiologically Based Biopharmaceutics Modeling of Extended-Release Drug Products.

The rate and extent of colon absorption are important determinants of the in vivo performance of extended-release (ER) drug products. The ability to appropriately predict this at different stages of development using mechanistic physiologically based biopharmaceutic modeling (PBBM) is highly desirable. This investigation aimed to evaluate the prediction performance of three different approaches to account for colon absorption in predictions of the in vivo performance of ER drug product variants with different in vitro release profiles. This was done by mechanistic predictions of the absorption and plasma exposure of the ER drug products using GastroPlus and GI-Sim for five drugs with different degrees of colon absorption limitations in humans. Colon absorption was accounted for in the predictions using three different approaches: (1) by an a priori approach using the default colon models, (2) by fitting the colon absorption scaling factors to the observed plasma concentration-time profiles after direct administration to the colon in humans, or (3) from the ER drug product variant with the slowest in vitro release profile. The prediction performance was evaluated based on the percentage prediction error and the average absolute prediction error (AAPE). Two levels of acceptance criteria corresponding to highly accurate (AAPE ≤ 20%) and accurate (AAPE 20-50%) predictions were defined prior to the evaluation. For the a priori approach, the relative bioavailability (Frel), AUC0-t, and Cmax of the ER drug product variants for the low to medium colon absorption limitation risk drugs was accurately predicted with an AAPE range of 11-53 and 8-59% for GastroPlus and GI-Sim, respectively. However, the prediction performance was poor for the high colon absorption limitation risk drugs. Moreover, accounting for the human regional colon absorption data in the models did not improve the prediction performance. In contrast, using the colon absorption scaling factors derived from the slowest ER variant significantly improved the prediction performance regardless of colon absorption limitation, with a majority of the predictions meeting the high accuracy criteria. For the slowest ER approach, the AAPE ranges were 5-24 and 5-32% for GastroPlus and GI-Sim, respectively, excluding the low permeability drug. In conclusion, the a priori PBBM can be used during candidate selection and early product design to predict the in vivo performance of ER drug products for low to medium colon absorption limitation risk drugs with sufficient accuracy. The results also indicate a limited value in performing human regional absorption studies in which the drug is administered to the colon as a bolus to support PBBM development for ER drug products. Instead, by performing an early streamlined relative bioavailability study with the slowest relevant ER in vitro release profile, a highly accurate PBBM suitable for ER predictions for commercial and regulatory applications can be developed, except for permeability-limited drugs.

Drug Extended-Release System Utilizing Micelle Formation of Highly Water-Soluble Drugs and a Counter Polymer.

The objective of this study is to clarify the mechanism of extending release of highly water-soluble drugs via counter polymer (CP) utilization in poly(ethylene oxide) (PEO)/polyethylene glycol (PEG) matrix tablets. Carbomer, poly(acrylic acid), was used as a CP, which has the opposite charges to the drugs. The in vitro release of several highly water-soluble drugs from PEO/PEG tablet with or without CP were tested, the relationship between the sustained release effect by a CP (SRE) and the physicochemical properties of the drugs was investigated. The results demonstrated that the utilization of CP can extend the release of some highly water-soluble drugs by effectively controlling the drug diffusion through matrices. On the other hand, the effectiveness of CP was different depending on the drugs applied. There were not statistical correlations between SRE and physicochemical properties such as solubility, molecular weight, and charge intensity of the drugs, while a micelle forming property of the drugs played an important role in SRE by CP. It was concluded that CP, Carbomer, having negative charges could effectively interact with opposite charges on the surface of stable drug micelles, which could result in a significant decrease in drug diffusion leading to extended drug release. It is considered that the system utilizing CP is a promising approach to achieve extended release of highly water-soluble drugs with a reasonable tablet size, especially in the case of large drug loading.

Outcomes in kidney transplant recipients treated with immediate-release tacrolimus capsules versus extended-release tacrolimus capsules: A cohort study.

INTRODUCTION: Prior randomized trials and observational studies have generally reported similar outcomes in kidney transplant recipients (KTRs) treated with immediate-release tacrolimus (IR-TAC) versus extended-release tacrolimus (ER-TAC). However, many of these previous studies focused on patients with low immunological risks, had small sample sizes and brief follow-up periods, and excluded outcomes associated with graft loss, such as chronic rejection. METHODS: To address these limitations, we conducted a cohort study of 848 KTRs at a single transplantation center who had generally high immunological risks and were treated with either IR-TAC capsules (589 patients, 65.9%) or ER-TAC capsules (289 patients, 34.1%). All patients received their designated maintenance immunosuppressive regimen for at least 3 months post-transplantation. Afterwards, tacrolimus formulation was at the discretion of each patient's transplant nephrologist. For the two treatment groups, we compared the hazards of experiencing a composite outcome of acute or chronic antibody-mediated rejection (AMR), acute or chronic T-cell-mediated rejection, de novo DSA, and/or graft loss over a 3-year period starting at 3 months post-transplantation. RESULTS: In a multivariable Cox proportional hazards regression model, KTRs treated with IR-TAC capsules had an increased hazard of experiencing the composite outcome when compared to patients treated with ER-TAC capsules; however, this result was not significant (adj HR 1.24, 95% CI .92-1.68, p = .163). Similar results were obtained with inverse probability of treatment weighting (IPTW) using a propensity score (adj HR 1.25, 95% CI .93-1.68, p = .146). CONCLUSION: These findings suggest that when compared to IR-TAC capsules, ER-TAC capsules do not reduce the hazard of poor outcomes in KTRs with generally high immunological risks.

The effects of transitioning from immediate release to extended release cysteamine therapy in Norwegian patients with nephropathic cystinosis: a retrospective study.

BACKGROUND: Nephropathic cystinosis is a rare lysosomal storage disorder in which accumulation of cystine and formation of crystals particularly impair kidney function and gradually lead to multi-organ dysfunction. Lifelong therapy with the aminothiol cysteamine can delay the development of kidney failure and the need for transplant. The purpose of our long-term study was to explore the effects of transitioning from immediate release (IR) to extended release (ER) formulation in Norwegian patients in routine clinical care. METHODS: We retrospectively analysed data on efficacy and safety in 10 paediatric and adult patients. Data were obtained from up to 6 years before and 6 years after transitioning from IR- to ER-cysteamine. RESULTS: Mean white blood cell (WBC) cystine levels remained comparable between the different treatment periods (1.19 versus 1.38 nmol hemicystine/mg protein) although most patients under ER-cysteamine underwent dose reductions. For the non-transplanted patients, the mean estimated glomerular filtration rate (eGFR) change/year was more pronounced during ER-treatment (- 3.39 versus - 6.80 ml/min/1.73 m2/year) possibly influenced by individual events, such as tubulointerstitial nephritis and colitis. Growth measured by Z-height score tended to develop positively. Four of seven patients reported improvement of halitosis, one reported unchanged and two reported worsened symptoms. Most adverse drug reactions (ADRs) were of mild severity. One patient developed two serious ADRs and switched back to IR-formulation. CONCLUSIONS: The results from this long-term retrospective study indicate that switching from IR- to ER-cysteamine was feasible and well tolerated under routine clinical practice. ER-cysteamine allowed satisfactory disease control over the long period considered. A higher resolution version of the Graphical abstract is available as Supplementary information.

The switching process from buprenorphine sublingual tablets to the monthly buprenorphine subcutaneous depot injection in opioid dependent patients.

The 2018 European Union (EU) approved weekly and monthly subcutaneous buprenorphine depot injection (BUP-XR), for opioid substitution medication proved to offer some specific treatment benefits. The present study examines the process of switching from buprenorphine sublingual tablets (BUP-SL) to BUP-XR from a patient's point of view. In total, nine patients were surveyed by means of an open-answer questionnaire regarding course and side effects of the medication switch. Six of these patients were surveyed in more detail under BUP-SL, as well as 4 and 16 weeks after the switch to BUP-XR by means of a test battery of questions on socio-demography, withdrawal symptoms, craving, physical well-being, treatment satisfaction and concomitant use of illegal substances. Patients reported significant worse physical well-being and lower treatment satisfaction in 4 weeks compared with 16 weeks after the medication switch to the BUP-XR. Furthermore, they reported significant more frequent co-use of illicit drugs, worse physical well-being, lower treatment satisfaction and more craving experience 4 weeks after the switch compared with the treatment under BUP-SL. Patients 16 weeks under BUP-XR reported significant more illicit co-use and lower treatment satisfaction compared with patients under BUP-SL. Connections between therapy dissatisfaction, physical discomfort, experienced craving and drug co-consumption were discovered. In the first weeks after the medication switch, patients experience potentially distressing symptoms, which, however, seem to diminish over time. Close supervision and comprehensive patient education on possible burdens of the medication switch to the BUP-XR might prevent unfavourable treatment courses and premature therapy dropouts.

Characterization of Channeling Effects Applied to Extended-Release Matrix Tablets Containing Pirfenidone.

Pirfenidone (PRF) is an anti-fibrotic agent that has been approved by the Food and Drug Administration (FDA) for the treatment of mild to moderate idiopathic pulmonary fibrosis. However, the current oral administration dosing regimen of PRF is complex and requires high doses. Patients are instructed to take PRF three times daily, with each dose consisting of up to three capsules or tablets (600 mg/d or 1.8 g/d of PRF) taken with food. To improve the dosing regimen, efforts are being made to develop an extended-release tablet with a zero-order release pattern. In this study, two types of extended-release matrix tablets were compared: non-channeled extended-release matrix tablets (NChMT) and channeled extended-release matrix tablets (ChMT). In vitro release tests, swelling and erosion index, rheology studies, and X-ray microcomputed tomography (XRCT), were conducted. The results indicated that ChMT maintained a zero-order release pattern with a constant release rate, while NChMT exhibited a decreased release rate in the latter half of the dissolution. ChMT exhibited accelerated swelling and erosion compared to other formulations, and this was made possible by the presence of channels within the tablet. These channels allowed for thorough wetting and swelling throughout the entire depth of the tablet. The formation of channels was confirmed through XRCT images. In conclusion, the presence of channels in ChMT tablets increased the rate of swelling and erosion, resulting in a zero-order release pattern. This development offers the potential to improve the dosage of PRF and reduce its associated side effects.

Intestinal Permeability in Patients Early after Kidney Transplantation Treated with Two Different Formulations of Once-Daily Tacrolimus.

Adequate tacrolimus blood exposure is crucial in the early post-renal transplant period and a gut epithelial barrier integrity may play a role. We prospectively investigated several markers of intestinal permeability in recent kidney transplant recipients (KTRs) treated with different tacrolimus extended-release formulations. Within each of the 49 KTR pairs that received grafts from the same donor, an early randomized conversion was performed from twice-daily (Prograf) to once-daily tacrolimus formulation: Advagraf or Envarsus. Plasma zonulin, calprotectin, circulating lipopolysaccharide (LPS), LPS-binding protein (LBP), intestinal fatty acid binding protein (FABP-2), and CD-14 levels were measured. There was no difference in the recipient age, dialysis vintage, BMI, and residual diuresis between Advagraf and Envarsus groups. FABP-2 and LPS levels were significantly associated with tacrolimus trough level, 3-h level, and area under the curve (AUC) in the Envarsus but not in the Advagraf group. AUC was independently increased by LPS and decreased by age, FABP-2 concentration, and the use of Envarsus formulation as compared with Advagraf. Functional changes of gastrointestinal tract in patients treated with Envarsus may influence intestinal tacrolimus absorption to a greater extent than in Advagraf-treated KTRs and may lead to inadequate variability of tacrolimus exposure early after kidney transplantation.

A Bioactive Compound-Loaded Zinc-Aminoclay Encapsulated, Pickering Emulsion System for Treating Acne-Inducing Microbes.

Acne is a common skin condition caused by the growth of certain bacteria. Many plant extracts have been investigated for their potential to combat acne-inducing microbes, and one such plant extract is microwave-assisted Opuntia humifusa extract (MA-OHE). The MA-OHE was loaded onto zinc-aminoclay (ZnAC) and encapsulated in a Pickering emulsion system (MA-OHE/ZnAC PE) to evaluate its therapeutic potential against acne-inducing microbes. Dynamic light scattering and scanning electron microscopy were used to characterize MA-OHE/ZnAC PE with a mean particle diameter of 353.97 nm and a PDI of 0.629. The antimicrobial effect of MA-OHE/ZnAC was evaluated against Staphylococcus aureus (S. aureus) and Cutibacterium acnes (C. acnes), which contribute to acne inflammation. The antibacterial activity of MA-OHE/ZnAC was 0.1 and 0.025 mg/mL to S. aureus and C. acnes, respectively, which were close to naturally derived antibiotics. Additionally, the cytotoxicity of MA-OHE, ZnAC, and MA-OHE/ZnAC was tested, and the results showed that they had no cytotoxic effects on cultured human keratinocytes in a range of 10-100 µg/mL. Thus, MA-OHE/ZnAC is suggested to be a promising antimicrobial agent for treating acne-inducing microbes, while MA-OHE/ZnAC PE is a potentially advantageous dermal delivery system.

Development and In Vitro-In Vivo Correlation Evaluation of IMM-H014 Extended-Release Tablets for the Treatment of Fatty Liver Disease.

This study aimed to develop extended-release tablets containing 25 mg IMM-H014, an original drug formulated by a direct powder pressing method based on pharmaceutical-grade hydrophilic matrix polymers such as hydroxypropyl methylcellulose, to establish an in vitro-in vivo correlation (IVIVC) to predict bioavailability. The tablets' mechanical properties and in vitro and in vivo performance were studied. The formulation was optimized using a single-factor experiment and the reproducibility was confirmed. The in vitro dissolution profiles of the tablet were determined in five dissolution media, in which the drug released from the hydrophilic tablets followed the Ritger-Peppas model kinetics in 0.01 N HCl medium for the first 2 h, and in phosphate-buffered saline medium (pH 7.5) for a further 24 h. Accelerated stability studies (40 °C, 75% relative humidity) proved that the optimal formulation was stable for 6 months. The in vivo pharmacokinetics study in beagle dogs showed that compared to the IMM-H014 immediate release preparation, the maximum plasma concentration of the extended-release (ER) preparation was significantly decreased, while the maximum time to peak and mean residence time were significantly prolonged. The relative bioavailability was 97.9% based on the area under curve, indicating that the optimal formulation has an obvious ER profile, and a good IVIVC was established, which could be used to predict in vivo pharmacokinetics based on the formulation composition.