Chitosan, a Natural Polymer, is an Excellent Sustained-Release Carrier for Amide Local Anesthetics.

Local anesthetics, particularly amide types, play a crucial role in perioperative anesthesia to alleviate pain and manage chronic, long-term pain, with their brief effect period remaining a universal challenge that needs resolution. There is a high anticipation for creating materials that maintain prolonged effectiveness of local anesthetics through a straightforward administration technique. Chitosan is the most typical natural amino polymer, which is highly reactive and easy to modify. It has been widely and deeply used in the field of medicine. At present, it is mainly used in tissue regeneration and repair, hemostasis and wound healing, antibacterial and anti-infection, disease diagnosis and treatment detection, and drug delivery. In the field of anesthesia, chitosan is regarded as a potential perfect carrier for the sustained release of amide local anesthetics. This document aims to analyze the current application of chitosan as a prolonged-release substance in amide-type local anesthetics, encapsulate the associated research advancements, and subsequently investigate the practicality and prospects of its medical uses.

Development and Evaluation of a Cost-Effective, Carbon-Based, Extended-Release Febuxostat Tablet.

This study outlines the development of a cost-effective, extended-release febuxostat (FEB) tablet using activated charcoal as an adsorbent to enhance drug release. FEB, a BCS Class II drug, presents formulation challenges due to low solubility and high lipophilicity. We evaluated eight formulations with varying FEB-to-charcoal ratios using FTIR and DSC for physical interactions and followed USP standards for overall assessment. The optimal 1:0.25 FEB-to-charcoal ratio demonstrated a consistent 12 h zero-order release pattern. In vivo studies indicated a significantly extended plasma profile compared to immediate-release tablets. The optimal tablets demonstrated acceptable hardness and disintegration times. This innovative approach enhances patient compliance, improves bioavailability, and reduces production costs, offering a promising solution for controlled FEB delivery.

Effect of patients in-use and accelerated stability conditions on quality attributes and pharmacokinetic profile of four FDA approved extended-release anti-epileptic-drug products.

Divalproex (DVS) is a popular drug widely used in various neurological and psychiatric disorders. Commercially, it is a multisource-drug available in different generic equivalents. Incidents of (class II)-recalls have been repeated over the last years due to failure to consistently meet dissolution specifications. Class II recalls are known to be associated with temporary or medically reversible adverse health consequences. This study aimed to evaluate the dissolution profiles, among other quality attributes, of select FDA-approved extended-release DVS products before and after exposure to conditions usually seen as short-lived and insignificant on product stability, such as pharmacy dispensing and patients' in-use conditions to assess their possible role in the failures observed. Products were stored for 6 weeks in pharmacy vials at 30 °C/75 % RH to simulate patient in-use conditions, for 12 weeks in unsealed HPDE bottles at 25 °C/65 % RH to simulate the pharmacy storage conditions, and for 3 days in open containers at 40 °C/75 % RH for accelerated stability studies. Physicochemical changes were detected by near infrared imaging, Fourier transformed infrared, X-ray powder diffraction and differential scanning calorimetry. All samples were analyzed for in vitro dissolution. Two products were further selected for in vivo study on Beagle dogs before and after storage. The physicochemical characterization tests revealed changes in tablets' composition and drug crystallinity over time. An improved discriminatory dissolution test was developed and used in this study. The in vitro release testing revealed that short-lived environmental changes at 30 or 25 °C could fail some unit doses and significantly lower the drug release (average reduction among all products was 12.97 ±â€¯11.3 % and 27.48 ±â€¯10.26 %, respectively). Some extended-release products showed a significant increase in the amount of drug dissolved in the first 6 h (early burst) owing to changes in tablet surface morphology and enhanced drug dissolution. In vivo studies showed a decrease in the AUC0-t by overall average of 21.1 % using the non-transformed data, a decrease that mirrored the dissolution results. The study shows that significant changes can occur during routine drug dispensing and patients' use that might variably impact the stability and quality of commercial bioequivalent unit doses. It is possible that these changes may also contribute to the adverse effects reported on DVS or upon drug switches that were previously attributed to the intersubject variability. The study findings are encouraging to further investigate the effect of such minor excursions on the drug effectiveness during products' shelf lives especially for narrow therapeutic index drugs.

Use of Nuclear Factor of Activated T Cell-Regulated Gene Expression for Monitoring Immunosuppression with Extended-Release Tacrolimus after Liver Transplantation-A Proof of Concept.

BACKGROUND: There is a narrow therapeutic window for immunosuppression using calcineurin inhibitors. Drug trough levels do not reflect immunosuppression and should be replaced by pharmacodynamic monitoring. This prospective cohort study was designed to evaluate the effect of an extended-release formulation of tacrolimus (LCP Tac) on the nuclear factor of activated T cell-regulated gene expression (NFAT-RGE). METHODS: The expression of interleukin-2, interferon-γ, granulocyte-macrophage colony-stimulating factor, and three reference genes was measured. Samples from 23 patients at defined time points in the first year after liver transplantation were analyzed using a droplet digital polymerase chain reaction. RESULTS: All samples were within the targeted trough levels of LCP Tac, and their LCP Tac peak levels and residual NFAT-RGE showed a strong inverse correlation (r = -0.8). Most importantly, there was an individual immunosuppressive response to the LCP Tac. The mean individual trough effect of LCP Tac on the three target genes when all time points were pooled was 33% (26-56%) in patients without infection and 81% (53-95%) in those with infection (p < 0.011). The mean individual peak effect was 48% (44-64%) in patients without infection and 91% (90-94%) in those with infection (p < 0.001). CONCLUSIONS: Thus, tailored immunosuppression based on residual NFAT-RGE could prevent infections associated with over-immunosuppression early after liver transplantation.

Development of the novel formulations of perospirone for the treatment of schizophrenia.

Schizophrenia is a severe mental illness. Its clinical features include positive symptoms (hallucinations, delusions, thought disorders), negative symptoms (avolition, anhedonia, poverty of thought, social withdrawal), and cognitive dysfunction. A large number of antipsychotic drugs with traditional dosage forms are available to mitigate the symptoms of schizophrenia but the duration of action is commonly short, often requiring frequent administration. The perospirone hydrochloride hydrate (PER), as a second-generation antipsychotic drug, shows therapeutic effects on both positive and negative symptoms of schizophrenia, with less impact on cognitive function. However, it suffers from a short half-life, fluctuating blood concentration, instability in the circulating leading to peak-trough fluctuations, and poor patient compliance due to the required frequent administration. Based on the hydrophilic matrix, we developed novel formulations of PER, including the extended-release and the controlled-release tablets of PER. The resulting formulations delayed the drug release and prolonged the persistence of PER, leading to an extended half-life and reduced fluctuations in blood concentration with stable therapeutic levels and an improved absorption with higher bioavailability, thus reducing dosing frequency. These oral extended-release and controlled-release tablets promise to alleviate patients' medication discomfort and provide long-term sustained drug release. They would provide a platform with broad prospects for the clinical treatment of schizophrenia.

Provider costs of treating opioid dependence with extended-release buprenorphine in Australia.

INTRODUCTION: The costs of providing medication-assisted treatment for opioid dependence can determine its scale of provision. To provide estimates of the costs of extended-release buprenorphine (BUP-XR), we performed a bottom-up costing analysis of provider operational treatment costs. METHODS: Data were collected in a single-arm open label trial of BUP-XR injections conducted in specialist public drug treatment services and primary care private practices in three Australian states (the CoLAB study). The unit costs of resources used for each activity were combined with quantities used at each participating facility to arrive at the average annual cost per client. RESULTS: One hundred participants across the six health facility sites received monthly subcutaneous BUP-XR injections administered by a health-care practitioner. The average cost of providing 1 year of treatment per participant was $6656 ($6026-$8326). Screening cost (initial assessment and medical history) was $282 while monthly follow-up appointments cost $531 per client. The main cost driver was the monthly treatment costs accounting for 79% of the average annual client cost, with medication costs comprising 95% of this cost. DISCUSSION AND CONCLUSION: With medication costs making up the largest proportion of treatment costs, treatment using BUP-XR has the potential to free up other health system resources, for example, staff time. The costs reported in this study can be used in an economic evaluation to estimate the net benefit or cost-effectiveness of BUP-XR especially when compared to other opioid agonist treatments.

Efficacy of once-nightly sodium oxybate (FT218) on daytime symptoms in individuals with narcolepsy with or without concomitant alerting agent use: A post hoc analysis from the phase 3 REST-ON trial.

OBJECTIVE/BACKGROUND: Extended-release, once-nightly sodium oxybate (ON-SXB) significantly improved narcolepsy symptoms in participants in the phase 3, randomized, double-blind, placebo-controlled REST-ON trial. This post hoc analysis of REST-ON data evaluated ON-SXB efficacy in participants with or without concomitant alerting agent use. PATIENTS/METHODS: Participants with narcolepsy aged >16 years were randomized 1:1 to ON-SXB (week 1: 4.5 g, weeks 2-3: 6 g, weeks 4-8: 7.5 g, weeks 9-13: 9 g) or placebo. Primary endpoints in this post hoc analysis included change from baseline in mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression-Improvement (CGI-I) rating, and number of weekly cataplexy episodes. The secondary endpoints were change from baseline in the Epworth Sleepiness Scale (ESS) score and in objective and subjective disrupted nighttime sleep parameters. Post hoc analyses assessed participants with and without alerting agent use across 6-, 7.5-, and 9-g doses. RESULTS: In the modified intent-to-treat population, 119 (63 %) were (ON-SXB, n = 66; placebo, n = 53) and 71 (37 %) were not (ON-SXB, n = 31; placebo, n = 40) taking alerting agents. Regardless of alerting agent use, treatment with ON-SXB resulted in significant improvements vs placebo (all doses, P < 0.05) for MWT, CGI-I, and number of weekly cataplexy episodes. Significant improvements in ESS (all doses, P < 0.05) with ON-SXB vs placebo were observed in the alerting agent use cohort. Directional improvements in ESS were reported with all doses in the no alerting agent use group. CONCLUSIONS: Regardless of concomitant alerting agent use, ON-SXB improved daytime and nighttime narcolepsy symptoms vs placebo.

Clinical Pharmacology of Pemafibrate Extended-release Formulation in Patients with Hypertriglyceridemia-A Phase 2, Multicenter, Active-controlled, Randomized, Single-blind, Crossover study.

AIMS: Efficacy, safety, and pharmacokinetics of the selective PPARα modulator pemafibrate as once-daily extended-release (XR) tablets were compared with those of twice-daily immediate-release (IR) tablets in patients with hypertriglyceridemia. METHODS: A multicenter, randomized, single-blind, active-controlled crossover, phase 2 clinical pharmacology study was performed in patients with hypertriglyceridemia. Patients were randomly assigned to IR 0.2 mg/day, XR 0.4 mg/day, or XR 0.8 mg/day before/after meals (fasted/fed) and treated for a total of eight weeks. The primary endpoint was percentage change in fasting serum triglycerides (TG). RESULTS: Of 63 randomized patients, 60 received the study drug. Patients were 78.3% male, mean age (±SD) 57.5±9.8 years, BMI 25.5±3.7 kg/m2, and fasting TG 221.3±68.1 mg/dL. Fasting serum TG decreased significantly from baseline in all groups (LS mean [95% CI];-43.6 [-47.7, -39.5] % for IR 0.2 mg/day, -41.1 [-45.1, -37.0] % for XR 0.4mg/day, -39.7 [-43.8, -35.6] % for XR 0.8 mg/day), indicating that XR 0.4 and XR 0.8 mg/day were not inferior to IR 0.2 mg/day. TG-lowering effects tended to be stronger for fed than fasted administration. MRTss, tmax, and t1/2 were longer for XR than for IR. Adverse events showed no major inter-group differences: 12.5% (5/40 patients) for IR 0.2, 17.5% (7/40) for XR 0.4, and 20.0% (8/40) for XR 0.8 mg/day. CONCLUSIONS: In patients with hypertriglyceridemia, XR substantially lowered TG at all doses, with maximum effectiveness at 0.4 mg/day, the dose approved in Japan, to a level comparable to IR 0.2 mg/day. There were no safety concerns up to 0.8 mg/day.

Perceptions of extended-release buprenorphine among people who received medication for opioid use disorder in jail: a qualitative study.

BACKGROUND: Incarceration provides an opportunity for health interventions, including opioid use disorder (OUD) treatment and prevention of opioid-related overdoses post-release. All FDA-approved forms of medication for OUD (MOUD) treatment were mandated in several Massachusetts jails in 2019, with some jails offering extended-release buprenorphine (XR-Bup). Little is known about patient perspectives on and experiences with XR-Bup in carceral settings. METHODS: We conducted semi-structured interviews in 2022 with community-dwelling people who received MOUD during a recent incarceration in a Massachusetts jail. We asked participants about their experiences with and perspectives on XR-Bup while in jail. Qualitative data were double-coded deductively and reviewed inductively to identify emergent themes, which were structured using the Theoretical Framework of Acceptability (TFA). RESULTS: Participants (n = 38) had a mean age of 41.5 years, were 86% male, 84% White, 24% Hispanic, and 95% continued to receive MOUD at the time of their interview, including 11% receiving XR-Bup. Participants who viewed XR-Bup favorably appreciated avoiding the taste of sublingual buprenorphine; avoiding procedural difficulties and indignities associated with daily dosing in carceral settings (e.g., mouth checks, stigmatizing treatment from correctional staff); avoiding daily reminders of their addiction; experiencing less withdrawal; having extra time for other activities, such as work; and reduction of diversion of MOUD within the jail setting. Participants who viewed XR-Bup less favorably preferred to maintain their daily dosing routine; liked daily time out of their housing unit; wanted to know what was "going into my body everyday"; and feared needles and adverse events. Participants also reported that jail clinicians used XR-Bup for patients who were previously caught diverting sublingual buprenorphine, suggesting limited patient participation in decision-making around XR-Bup initiation in some jails. CONCLUSION: People who received MOUD in Massachusetts jails had both favorable and unfavorable views and experiences with XR-Bup. Understanding these preferences can inform protocols in jails that are considering implementation of XR-Bup treatment.

Successful administration of extended-release buprenorphine in the emergency department.

INTRODUCTION: The ongoing opioid epidemic in the United States has resulted in a substantial increase in overdose deaths and related morbidity and mortality. Given that emergency departments (ED) frequently serve as the initial point of contact for individuals experiencing opioid overdose or seeking treatment for opioid use disorder (OUD), ED clinicians have a pivotal role to play in providing prompt and effective treatment for OUD. While ED clinicians routinely administer sublingual and other transmucosal formulations of buprenorphine, extended-release buprenorphine (BUP-XR) remains underutilized in the ED. CASE REPORT: We present a case involving the successful administration of BUP-XR in the ED to a patient experiencing spontaneous opioid withdrawal. The patient tolerated test dosing of sublingual buprenorphine (BUP-SL) and subsequently received BUP-XR in the ED. Following this intervention, the patient was referred to the hospital-affiliated substance use disorder outpatient clinic, where he has since demonstrated successful follow-up and retention in treatment. CONCLUSION: Our report adds to the existing limited literature on the administration of BUP-XR in the ED and highlights the need for more comprehensive clinician teaching and guidance, as well as the establishment of in-hospital protocols for BUP-XR. Despite these challenges, our case indicates that initiating BUP-XR could be a viable and effective option for ED patients with OUD.

A new long-acting analgesic formulation for postoperative pain management.

Local anesthetics (LA), as part of multimodal analgesia, have garnered significant interest for their role in delaying the initiation of opioid therapy, reducing postoperative opioid usage, and mitigating both hospitalization duration and related expenses. Despite numerous endeavors to extend the duration of local anesthetic effects, achieving truly satisfactory long-acting analgesia remains elusive. Drawing upon prior investigations, vesicular phospholipid gels (VPGs) emerge as promising candidates for extended-release modalities in small-molecule drug delivery systems. Therefore, we tried to use the amphiphilicity of phospholipids to co-encapsulate levobupivacaine hydrochloride and meloxicam, two drugs with different hydrophilicity, to obtain a long-term synergistic analgesic effect. Initially, the physicochemical attributes of the formulation were characterized, followed by an examination of its in vitro release kinetics, substantiating the viability of extending the release duration of the dual drugs. Sequentially, in vivo investigations encompassing pharmacokinetic profiling and assessment of analgesic efficacy were undertaken, revealing a prolonged release duration of up to 120 h and attainment of optimal postoperative analgesia. Subsequently, inquiries into the mechanism underlying synergistic analgesic effects and safety evaluations pertinent to the delivery strategy were pursued. In summation, we successfully developed a promising formulation to achieve long-acting analgesia.

LCP-Tacrolimus Extended-Release (Envarsus XR) Use in Adolescent and Young Adult Solid Organ Transplant Recipients.

INTRODUCTION: Limited published experience describes once daily, extended-release tacrolimus (LCP-Tac) use in pediatric solid organ transplantation (SOT), particularly nonrenal SOT. LCP-Tac can simplify immunosuppression (IS) regimens, minimize immediate release-tacrolimus (IR-Tac)-associated adverse effects, and promote adherence. This study describes the successful use of LCP-Tac in adolescent and young adult (AYA) SOT populations. METHODS: A single-center, retrospective chart review of AYA SOT recipients (age < 25 years) converted from IR-Tac to LCP-Tac. Graft survival, biopsy-proven acute rejection (BPAR), infection rates, estimated glomerular filtration rate (eGFR), and pill burden were assessed at five time points postconversion (1, 3, 6, 12, and 24 months). Intrapatient variability of tacrolimus, as assessed by coefficient of variability (CV%), was also analyzed. RESULTS: Twenty-nine AYA SOT recipients (19 heart, 6 kidney, and 4 liver) were converted to LCP-Tac, with a median age of 17.4 years at conversion. Conversion, mainly due to perceived or identified medication nonadherence, occurred at a median of 5.4 years posttransplant. No graft loss occurred within 24 months of conversion, and BPAR incidence rate was consistent with previous reports for these populations. Only one patient experienced CMV infection. Renal function remained stable postconversion. CONCLUSION: Successful conversion from IR-Tac to LCP-Tac was demonstrated in AYA heart, kidney, and liver transplant recipients. These AYA SOT recipients experienced reduced pill burden and improved tacrolimus trough concentration variability. However, the impact on medication adherence warrants further investigation. Future research should explore the targeted use of LCP-Tac to enhance IS tolerability and medication adherence in young SOT populations.

Sustained Reduction of Elevated Intact Parathyroid Hormone Concentrations with Extended-Release Calcifediol Slows Chronic Kidney Disease Progression in Secondary Hyperparathyroidism Patients.

INTRODUCTION: Chronic kidney disease (CKD) drives onerous human and healthcare costs, underscoring an urgent need to avert disease progression. Secondary hyperparathyroidism (SHPT) develops as CKD advances, and persistently elevated parathyroid hormone (PTH) may be nephrotoxic and associated with earlier dialysis onset. This study examines, for the first time, the hypothesis that sustained reduction of elevated intact PTH (iPTH) with extended-release calcifediol (ERC) reduces the nephrotoxic impact of SHPT and forestalls renal decline. METHODS: Changes in estimated glomerular filtration rate (eGFR) were analyzed post hoc in 126 adults with SHPT, stage 3-4 CKD, and low serum 25-hydroxyvitamin D (25D) treated for 1 year with ERC in pivotal trials. ERC was administered at 30 µg/day increasing, as needed, to 60 µg/day to achieve ≥30% reductions in iPTH. Calcium, phosphorus, 25D, 1,25-dihydroxyvitamin D (1,25D), iPTH, eGFR, fibroblast growth factor-23 (FGF23), bone turnover markers (BTMs), and urine albumin-to-creatinine ratio (uACR) were measured at baseline and regular intervals. Participants were categorized by achievement (or not) of sustained ≥30% iPTH reductions over the last 2 quarters of treatment to evaluate differences in eGFR decline. RESULTS: For all participants, 25D increased 58.5 ± 2.3 (SE) ng/mL (p < 0.001) by the end of treatment (EOT), 1,25D increased 10.1 ± 1.8 pg/mL (p < 0.001), iPTH decreased from 143.8 ± 5.8 pg/mL to 108.8 ± 7.2 (p < 0.001), BTMs improved (p < 0.01), and eGFR declined 2.2 ± 0.5 mL/min/1.73 m2 (p < 0.001). The rate of eGFR decline was >5-fold higher (p = 0.014) in participants who did not achieve sustained iPTH reductions of ≥30% (3.2 ± 0.7; 12.7 ± 2.2%) than in those who did (0.6 ± 0.8; 2.9 ± 2.4%). It was highest in the 30 participants who did not exhibit an iPTH lowering response in both of the last 2 quarters of treatment (5.4 ± 0.9; 20.9 ± 3.4%). Duration of iPTH reduction had no impact on safety parameters. Degree of iPTH reduction at EOT was also associated with slower CKD progression. CONCLUSION: Sustained reduction of elevated iPTH with ERC treatment was associated with slower rates of eGFR decline in patients with SHPT and stage 3-4 CKD without raising safety concerns. A prospective trial is warranted to confirm this finding.

Comparative effectiveness of extended-release naltrexone and sublingual buprenorphine for treatment of opioid use disorder among Medicaid patients.

BACKGROUND AND AIMS: Extended-release naltrexone (XR-NTX) and sublingual buprenorphine (SL-BUP) are both approved for opioid use disorder (OUD) treatment in any medical setting. We aimed to compare the real-world effectiveness of XR-NTX and SL-BUP. DESIGN AND SETTING: This was an observational active comparator, new user cohort study of Medicaid claims records for patients in New Jersey and California, USA, 2016-19. PARTICIPANTS/CASES: The participants were adult Medicaid patients aged 18-64 years who initiated XR-NTX or SL-BUP for maintenance treatment of OUD and did not use medications for OUD in the 90 days before initiation. Our cohort included 1755 XR-NTX and 9886 SL-BUP patients. MEASUREMENTS: We examined two outcomes up to 180 days after medication initiation: (1) composite of medication discontinuation and death and (2) composite of overdose and death. FINDINGS: In adjusted analyses, treatment with XR-NTX was more likely to result in discontinuation or death by the end of follow-up than treatment with SL-BUP: cumulative risk 75.9% [95% confidence interval (CI) = 73.9%, 77.9%] versus 62.2% (95% CI = 61.2%, 63.2%), respectively (risk difference = 13.7 percentage points, 95% CI = 11.4, 16.0). There was minimal difference in the cumulative risk of overdose or death by the end of follow-up: XR-NTX 3.9% (95% CI = 3.0%, 4.8%) versus SL-BUP 3.3% (95% CI = 2.9%, 3.7%); risk difference = 0.5 percentage points, 95% CI = -0.4, 1.5. Results were consistent across sensitivity analyses. CONCLUSIONS: Medicaid patients in California and New Jersey, USA, receiving treatment for opioid use disorder stayed in treatment longer on sublingual buprenorphine than on extended-release naltrexone, but the risk of overdose was similar. Most patients in this study discontinued medication within 6 months, regardless of which medication was initiated.

Prescribing of extended release buprenorphine injection for Medicaid beneficiaries, 2018-2022.

BACKGROUND AND AIMS: Extended release buprenorphine injection (INJ-BUP) has been available in the United States since 2018. INJ-BUP has the potential to positively impact opioid use disorder (OUD) treatment outcomes by providing additional treatment options . As one of the largest payers of OUD treatment in the US, Medicaid coverage is important for access and uptake of INJ-BUP. Uptake of INJ-BUP among Medicaid beneficiaries has not been described since 2019 and variation in uptake by state has not previously been explored. We aimed to measure prescribing of INJ-BUP for Medicaid beneficiaries since 2018, nationwide and by state. METHODS: We analyzed State Drug Utilization Data from 2017 to 2022 and calculated the number of prescription fills for INJ-BUP and oral buprenorphine paid by Medicaid. To compare across states, we calculated the number of prescription fills per 100 Medicaid beneficiaries treated for OUD using data from Transformed Medicaid Statistical Information System Substance Use Disorder (T-MSIS SUD) Data Books. Data sources are publicly available. RESULTS: The number of prescription fills for INJ-BUP paid by Medicaid increased from 4322 (0.1% of all buprenorphine prescription fills) in 2018 to 186 861 (2.0%) in 2022. Each year the increase in fills exceeded the prior year change, indicating accelerating uptake. There was notable variability across states. CONCLUSIONS: The number of extended release buprenorphine injection prescriptions among US Medicaid beneficiaries treated for opioid use disorder increased from over 4000 prescriptions in 2018 to over 185 000 in 2022 but uptake is much less than observed in other countries over shorter time periods.

Gastroretentive Delivery Approach to Address pH-Dependent Degradation of (+)- and (-)-Phenserine.

(-)-Phenserine ("phenserine") and (+)-phenserine (posiphen; buntanetap) are longer-acting enantiomeric analogs of physostigmine with demonstrated promise in the treatment of Alzheimer's and Parkinson's diseases. Both enantiomers have short plasma half-lives, and their pharmacokinetics might be improved through the use of either once or twice-daily administration of an extended-release dosage form. Phenserine was observed to form a colored degradation product in near-neutral and alkaline pH environments, and at pH 7, the half-life of posiphen was determined to be ~ 9 h (40 °C). To limit luminal degradation which would reduce bioavailability, a gastroretentive tablet composed of a polyethylene oxide-xanthan gum matrix was developed. When placed in simulated gastric fluid (pH 1.2), approximately 70% of the phenserine was released over a 12 h period, and no degradants were detected in the release medium. In comparison, a traditional hydrophilic-matrix, extended-release tablet showed measurable amounts of phenserine degradation in a pH 7.2 medium over an 8 h release interval. These results confirm that a gastroretentive tablet can reduce the luminal degradation of phenserine or posiphen by limiting exposure to neutral pH conditions while providing sustained release of the drug over at least 12 h. Additional advantages of the gastroretentive tablet include reduced gastric and intestinal concentrations of the drug resulting from the slower release from the gastroretentive tablet which may also limit the occurrence of the dose-limiting GI side effects previously observed with immediate-release phenserine capsules.

The use of extended-release tacrolimus twice a day might be beneficial for selected kidney transplant recipients: a case report.

The calcineurin inhibitor tacrolimus, which is available as an immediate- or extended-release formulation, is the standard-of-care immunosuppression after kidney transplantation with low rejection rates, especially in the first year after transplantation. However, its highly variable metabolism rate, narrow therapeutic window, and nephrotoxic side effects require close drug monitoring and individual dosing. Here, we describe first the application of extended-release tacrolimus (ER-Tac) twice daily with beneficial effects in a kidney transplant recipient under extensive therapeutic drug monitoring. A 47-year-old female kidney transplant recipient, who was identified as a fast metabolizer for tacrolimus, presented with declining allograft function and low tacrolimus through levels over time and 8 years after a second kidney transplantation despite the administration of high doses of ER-Tac once daily. Therefore, the area under the concentration-time curve (AUC) showed exceedingly high blood levels of ER-Tac. The latest biopsy of the kidney transplant showed arteriolar hyalinosis with pole vessel stenosis as a sign of chronic transplant vasculopathy and transplant glomerulopathy as a sign of chronic humoral rejection. After the exclusion of other options for immunosuppressive therapy due to the patient's high immunological risk, the patient was switched from ER-Tac once daily to ER-Tac twice daily. After switching to ER-Tac twice daily, the AUC for oral tacrolimus decreased and the transplant function improved despite higher tacrolimus trough levels and a lower total dose administered. This case highlights the importance of careful therapeutic drug monitoring with the performance of an AUC in the follow-up management of kidney transplant recipients.

Extended Release of Bupivacaine from Temperature-Responsive PNDJ Hydrogels Improves Postoperative Weight-Bearing in Rabbits Following Knee Surgery.

Effective treatment of postoperative pain lasting for multiple days without opioids is an important clinical need. We previously reported analgesia lasting up to 96 h in a porcine soft tissue model of postoperative pain using SBG004, an extended-release formulation of bupivacaine based on the temperature-responsive polymer poly(N-isopropylacrylamide-co-dimethylbutyrolactone acrylamide-co-Jeffamine M-1000 acrylamide) [PNDJ]. Orthopaedic surgical sites such as the knee can involve complex sensory innervation which presents a distinct challenge to local anesthetic delivery. The purpose of this work was to evaluate the pharmacokinetics and efficacy of SBG004 in an orthopaedic surgical model in comparison to currently available local anesthetics. Pharmacokinetics following periarticular (PA) or intraarticular (IA) injection of SBG004 were compared against liposomal bupivacaine (Lip-Bupi) PA in New Zealand White rabbits (all doses 14.5 mg/kg). Analgesic efficacy of SBG004 (IA, PA, or IA + PA), three active comparators, and saline was evaluated following knee surgery in New Zealand White rabbits. Analgesia was assessed via weight-bearing on the operated limb during spontaneous large steps in video recordings. Systemic bupivacaine exposure lasted at least 7 days for SBG004 PA, 4 days for SBG004 IA, and 2 days for Lip-Bupi PA. In the analgesia study, weight-bearing in all active groups except SBG004 IA was more frequent versus saline through 8 h postoperatively (p < 0.05). Only SBG004 IA + PA resulted in a higher proportion of weight-bearing rabbits at 24 h versus saline (6/7 versus 2/10, p = 0.015). Analysis of pooled data from 24-72 h showed significantly greater frequency of weight-bearing in rabbits receiving SBG004 IA + PA (71%) versus saline (37%), ropivacaine cocktail (41%), and Lip-Bupi PA (36%). The results indicate that the release profile from SBG004 PA or IA coincides reasonably with the time course of postoperative pain, and SBG004 may produce longer duration of analgesia than local anesthetics currently used in knee surgery, including during the period of 24-72 h recognized as a target for extended-release local anesthetics.

20-Week intramuscular toxicity study of rotigotine behenate extended-release microspheres for injection via intramuscular injection in cynomolgus monkeys.

Continuous dopaminergic stimulation (CDS) has become an important strategy for the development of drugs to treat Parkinson's disease (PD). Rotigotine behenate extended-release microspheres (RBEM) for injection represents a new treatment regime for CDS and is being applied for clinical trial. Our study in cynomolgus monkeys was a 20-week repeat dose toxicity investigation with RBEM at dosages of 90, 180, 360, with a 12-week recovery period. The results observed some irritations in the application site and surrounding tissues in Placebo microspheres and each dose of RBEM, was accompanied with increased white blood count and fibrinogen. RBEM-treated monkeys were additionally noted with a pharmacological action-related decrease in prolactin. These findings showed certain reversibility after the 12-week recovery phase. No clear sex difference was noted in the plasma exposure to rotigotine. The exposure generally increased in a dose-proportional manner. In summary, major toxicological effects are associated with the dopamine agonist-related properties of rotigotine, and the removal of foreign bodies caused by p oly (lactide-co-glycolide) (PLGA)and sodium carboxymethyl cellulose (SCMC), and the no-observed-adverse-effect-level (NOAEL) was 360 mg/kg.