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This article summarizes the critical factors involved in product development of a single dosage form formulated by compacting ethyl cellulose (EC) coated controlled release pellets into a tablet. The greatest challenge associated with this type of complex system is to minimize the effect of compression on the drug release. The effects of compression on the drug release were optimized with combination of the following factors (1) particle size of the core pellets, (2) the selection of the coating polymer's viscosity grade, and (3) emergence of cushioning agents. The optimization of these factors provided superior protection for the controlled release coated pellets; therefore, the desired drug release from the tablet was successfully achieved as designed. However, the drug release rates from the coated pellets before and after the compression were minimized and exhibited only a slight difference. [ABSTRACT FROM AUTHOR]

Development of extended release oral formulations of dexketoprofen trometamol (DT), a rapidly eliminated drug with high solubility, poses a great challenge especially when a portion of the dose is to be absorbed from the colon. In this study, site-specific release-retardant mini-matrix tablets (SSRRMTs) were developed and functionally coated with pH-responsive materials to achieve a site-specific delivery of DT at the duodenojejunal (DSRRMT) and ileocecal (ISRRMT) regions. Stomach-specific coated mini-tablets (SSCMTs) were manufactured for immediate release of about 16% of the daily dose of DT in the stomach. The SSCMT, DSRRMT, and ISRRMT were combined into a solid dosage form (C-SSRRMT tablets or capsules) to achieve the required linear release profile for once daily administration of DT. The SSRRMT and C-SSRRMT formulations were evaluated for the physical properties, in vitro-disintegration and in vitro dissolution and proved to be consistent with the pharmacopeial specifications. The in vitro release profiles of both C-SSRRMT tablets and capsules showed a constant release rate of about 6 mg/h and were similar to that of the theoretical target linear release profile. The pharmacokinetic study using human volunteers showed the bioequivalence of a single oral dose of C-SSRRMT capsules compared to three-successive oral doses of the immediate release market tablets with less ups and downs in the drug levels. The C-SSRRMT capsules formulation, may therefore, constitute an advance in the extended oral delivery of DT without the lack of efficacy and the adverse events frequently encountered in multiple daily dosing of the immediate release tablets. [ABSTRACT FROM AUTHOR]

The University of Florida Center for Pharmacometrics and Systems Pharmacology and the Food and Drug Administration Office of Generic Drugs have collaborated on a research project to develop a mechanism‐ and risk‐based strategy that systematically investigates postmarketing reports of therapeutic inequivalence following the switch between brand and generic drug products. In this study we developed and qualified a physiologically based pharmacokinetic model to systematically investigate the influence of drug‐ and formulation‐related properties on the oral absorption and bioequivalence of modified‐release products using metoprolol as an example. Our findings show that the properties of the release‐controlling polymer are the critical attributes for in vitro dissolution, in vivo absorption, and systemic exposure (ie, pharmacokinetics) and, thus, the bioequivalence of metoprolol extended‐release products rather than the properties of the drug itself. Differences in dissolution rate can result in significant differences in maximum plasma concentration but not in area under the concentration‐time curve. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this investigation was to develop an extended release formulation of diltiazem hydrochloride (DL) for once- and twice-daily administration, based on Eudragit (Eud) RL and RS microspheres using emulsion solvent evaporation. Materials and Methods: Formulations with different drug-polymer concentrations were produced and characterized in terms of yield, encapsulation efficiency (EE), particle size, and surface morphology. The drug release and thermal behavior of the microspheres were also investigated. Selected microspheres were then coated with Eud RS by continuous solvent evaporation, in order to modify the microspheres' properties and burst release. Results: According to the results, the EE was in the range of 56%-93% for uncoated microspheres. The mean particle size of microspheres was different from 470 to above 1000 µm, based on various formulation variables. No difference was observed between the mean size of particles prepared with Eud RL and Eud RS. Microspheres showed sustained release behavior, which was affected by the drug:polymer ratio as well as particle size. Coating the microspheres not only improved the EE values (82%-92%) but also reduced the mean dissolution rate as well as the burst release. Conclusion: Microspheres prepared with DL:Eud RL ratios of 1:3 and 1:4 showed release profiles in accordance with the USP criteria for a DL extended release product for dosing every 12 and 24 h, respectively. [ABSTRACT FROM AUTHOR]

The aim of this work was to develop a mucoadhesive buccal tablet for the buccal delivery of the alendronate via buccal mucosa. Buccal tablets of alendronate are designed to release drug at mucosal site for extended period of time without wash out of drug by saliva. Alendronate sodium is a bisphosphonates which has antiresorptive effect which is implicated in the prophylaxis and treatment of osteoporosis. Sodium alginate, ethyl cellulose and carbopol were selected as mucoadhesive polymers on the basis of their matrix forming properties. The objective of the study is to improve the bioavailability of alendronate buccal tablets. Extensive literature survey was done for the collection of theoretical and technical data. The methodology part includes the explanation of implemented methods in the present study. In present study, an attempt was made to design mucoadhesive buccal tablets containing alendronate, sodium alginate, ethyl cellulose and carbopol using as polymers. The tablets were prepared by direct compression method. The formulations were evaluated for hardness, thickness, friability, weight variation, drug content estimation, surface pH determination, swelling index, in vitro drug release. In vitro bioadhesive strength & in vitro release studies showed that formulation F11 showed optimum bioadhesive & exhibited optimum drug release 97.6% in 7hr. Kinetics results reveals that the F11 formulation follows zero order kinetics as correlation coefficient (r²) values are higher than that of first-order release kinetics. Optimized formula F11 show drug is released by non-Fickian diffusion mechanism. The stability studies of formulation F11 prepared mucoadhesive buccal tablets of alendronate were stable. Overall evaluations of the mucoadhesive of tablets show good mucoadhesive properties. [ABSTRACT FROM AUTHOR]

There is a trend in pharmaceutical research and development to develop depot formulations with dosing once weekly, once monthly, or even less frequently. A novel approach to achieve long acting injectable suspensions is to produce dense inorganic nanoshells with atomic layer deposition (ALD) on active pharmaceutical ingredients. Such particles can be suspended in an aqueous vehicle and administered subcutaneously. The purpose of this work was to study the release of a model drug, indomethacin, coated with aluminium oxide nanoshells. Indomethacin was ball-milled to a median particle size of 6 µm. The nanoshells were produced with a proprietary ALD process that is trademarked as PharmaShell® by Nanexa AB. The drug load was determined with HPLC-UV to 82 wt%. The test materials were administered subcutaneously in rats (1, 10, and 100 mg/kg) from which blood samples were collected during 12 weeks. Plasma was generated and analyzed with regards to indomethacin using UPLC-MS/MS. The release rate was dramatically slower for the nanoshell coated indomethacin compared with uncoated indomethacin. Drug was released in vivo during more than 12 weeks for the 10 and 100 mg/kg doses, and during 10 weeks for the 1 mg/kg dose, while uncoated indomethacin was eliminated with a half-life of 15 h, as calculated from the release data by fitting a one phase decay function. The exposure levels were similar as earlier reported for therapeutic indomethacin doses, but significantly sustained in the present study using coated drug particles in rats. In conclusion, this is the first long-term in vivo evaluation of nanoshell depot formulations. The stable plasma concentrations for more than 12 weeks demonstrate that nanoshells can enable long-term depot injections with high drug load. [ABSTRACT FROM AUTHOR]

Ketoprofen lysine because of a short half-life (1-2 h) multiple dosing regimens are required for oral administration. For this reason, this study is concerned with the preparation of poly lactic-co-glycolic acidbased spray-dried nanoparticles to extend the activity of the ketoprofen lysine. Nanoparticles were produced with a spray dryer (B-90, Büchi, Switzerland) and solid state properties of nanoparticles were analysed using scanning electron microscopy, particle size, polydispersity index, zeta potential, nuclear magnetic resonance spectroscopy, X-ray and differential scanning calorimetry. Drug release from nanoparticles was studied using the dialysis bag method in simulated gastrointestinal environment (pH 7.4). Ketoprofen lysine-loaded particles demonstrated nanostructured and spherical shape while in vitro release studies showed extended release (~8 days) of ketoprofen lysine incorporated and also a fairly good entrapment efficiency (~59-78 %) was detected. Peppas-Sahlin kinetic model was found to fit the best using DDSolver software program. This research may be useful for long-term and optimum use of oral non-steroidal antiinflammatory drug in chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Objectives: To compare gabapentin extended-release, a gastro-retentive formulation, in relieving postamputation pain among gabapentin-experienced and gabapentin-naïve patients. Design: Open-labeled pilot study. Subjects: Sixteen patients with postamputation pain (8 patients in the gabapentin-experienced and 8 patients in the gabapentin-naïve groups). Methods: Patients were started on gabapentin extended-release and were followed up for 8 weeks. Patients reported their pain severity during rest and movement using a numeric rating scale (NRS), interference of pain with daily activities using the modified brief pain inventory (MBPI) questionnaire, and treatment satisfaction using the treatment satisfaction questionnaire for medication (TSQM). Results: Patients from both gabapentin-experienced and gabapentin-naïve groups achieved a significant and sustainable pain relief over the course of therapy. The pain scores at rest decreased in both gabapentin-experienced and gabapentin-naïve groups from 5.88 ± 1.36 and 4.88 ± 2.95 to 1.88 ± 0.99 and 1.38 ± 1.51, respectively. An average percent of pain relief with gabapentin extended-release was noted to be significant (p < 0.01) after 8 weeks of therapy among gabapentin-experienced (81.25 ± 16.42%) and gabapentin-naïve groups (85 ± 17.73%) when compared to baseline for gabapentin-experienced (31.25 ± 29%) and gabapentin-naïve groups (36.25 ± 34.2%), respectively. Gabapentin-experienced and gabapentin-naïve groups had no significant difference in global satisfaction from treatment (79.14 ± 10.47 and 83.3 ± 20.82), convenience of treatment (73.78 ± 19.04 and 90.44 ± 11.66), effectiveness of treatment (72.6 ± 10.1 and 79.73 ± 11.6). The only statistically significant difference among gabapentin-experienced and gabapentin-naïve groups was found in adverse event tolerability (65.78 ± 10.36 and 85.8 ± 10.14, p < 0.01). Conclusion: Once-daily dosing of gabapentin-extended release showed significant improvement in pain severity and functional status, with no difference found between gabapentin-experienced versus gabapentin-naïve patients. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract To avoid severe exacerbations in the load of hepatitis B virus (HBV) as a consequence of discontinuous use of anti-HBV drugs, entecavir (ETV), the first-line anti-HBV drug, was primally formulated as extended-release poly (lactic-co-glycolic acid) microspheres in the present study. Because ETV is slightly soluble in water and in some other organic solvents used for microsphere preparation, methods for solid-microencapsulation were employed to fabricate the ETV microspheres. The optimized microspheres were evaluated for their morphology, particle size, drug loading, in vitro drug release, and in vivo pharmacokinetics in rats. The optimized formulation was found to have a mean particle size of 86 µm and drug loading of 13%. Differential scanning calorimetry and powder X-ray diffraction indicated that ETV existed in crystal, amorphous, and molecular states in the microspheres. In vitro and in vivo release revealed that the dissolution of ETV dominated the release process. The morphology of the microspheres and changes in the morphology during in vitro release were assessed by scanning electron microscopy. The novel ETV-MS described in this study should have great potential for clinical use as an alternative treatment against HBV. [ABSTRACT FROM AUTHOR]

Abstract Apelin, the endogenous ligand for the APJ receptor, has generated interest due to its beneficial effects on the cardiovascular system. Synthesized as a 77 amino acid preproprotein, apelin is post-translationally cleaved to a series of shorter peptides. Though (Pyr)1apelin-13 represents the major circulating form in plasma, it is highly susceptible to proteolytic degradation and has an extremely short half-life, making it challenging to quantify. Literature reports of apelin levels in rodents have historically been determined with commercial ELISA kits which suffer from a lack of selectivity, recognizing a range of active and inactive isoforms of apelin peptide. (Pyr)1apelin-13 has demonstrated beneficial hemodynamic effects in humans, and we wished to evaluate if similar effects could be measured in pre-clinical models. Despite development of a highly selective LC/MS/MS method, in rodent studies where (Pyr)1apelin-13 was administered exogenously the peptide was not detectable until a detailed stabilization protocol was implemented during blood collection. Further, the inherent high clearance of (Pyr)1apelin-13 required an extended release delivery system to enable chronic dosing. The ability to deliver sustained doses and stabilize (Pyr)1apelin-13 in plasma allowed us to demonstrate for the first time the link between systemic concentration of apelin and its pharmacological effects in animal models. Highlights • Several commonly used commercial apelin ELISA kits were shown to cross-react with multiple apelin peptides. • (Pyr)1apelin-13 was least stable in rodent whole blood vs. other species. • Stabilization required a guanidine hydrochloride/inhibitor cocktail at blood draw. • Sustained systemic concentrations were achieved with controlled release. • Rat PD was successfully linked to plasma exposure. [ABSTRACT FROM AUTHOR]

Background: Nimodipine is the only drug approved in the treatment of aneurysmal subarachnoid hemorrhage (aSAH) in many countries. EG-1962, a product developed using the Precisa™ platform, is an extended-release microparticle formulation of nimodipine that can be administered intraventricularly or intracisternally. It was developed to test the hypothesis that delivering higher concentrations of extended-release nimodipine directly to the cerebrospinal fluid would provide superior efficacy compared to systemic administration.Results: A Phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation study determined the maximum tolerated dose and supported the safety and tolerability of EG-1962 in patients with aSAH. EG-1962, 600 mg, was selected for a pivotal, Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy, and safety study comparing it to standard of care oral nimodipine in adults with aSAH. Key inclusion criteria are patients with a ruptured saccular aneurysm repaired by clipping or coiling, World Federation of Neurological Surgeons grade 2-4, and modified Fisher score of > 1. Patients must have an external ventricular drain as part of standard of care. Patients are randomized to receive intraventricular investigational product (EG-1962 or NaCl solution) and an oral placebo or oral nimodipine in the approved dose regimen (active control) within 48 h of aSAH. The primary objective is to determine the efficacy of EG-1962 compared to oral nimodipine.Conclusions: The primary endpoint is the proportion of subjects with favorable outcome (6-8) on the Extended Glasgow Outcome Scale assessed 90 days after aSAH. The secondary endpoint is the proportion of subjects with favorable outcome on the Montreal Cognitive Assessment 90 days after aSAH. Data on safety, rescue therapy, delayed cerebral infarction, and health economics will be collected. Trail registration NCT02790632. [ABSTRACT FROM AUTHOR]

Dissolution of poorly water-soluble active pharmaceutical ingredients (APIs) in polymeric melts plays an important role in the manufacturing of solid dispersions and solid solutions. The understanding of the dissolution is essential for selecting the processing equipment, the operating conditions, and the polymer excipients. The methodology presented in this work for ketoprofen (KTO) and polymer excipients serves as a screening process to select the best API-polymer formulation for hot melt extrusion (HME) to target a specific release profile. KTO dispersion within the polymer was characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), and dissolution tests. Thermal characterization shows that a single phase amorphous solid solution (one glass transition temperature [Tg]) was achieved under the HME processing conditions and screw configuration; and with the combination of polymer excipients, an extended release profile of KTO was accomplished, releasing 100% of KTO in 24 h. [ABSTRACT FROM AUTHOR]

Pharmacokinetic (PK)/pharmacodynamic (PD) correlations were explored in 2 human abuse potential studies of orally and intranasally administered hydrocodone extended‐release (ER) 45 mg in healthy, nondependent opioid users. In a crossover study design, subjects received intact hydrocodone ER, finely milled hydrocodone ER, and hydrocodone powder in solution in the oral study and finely milled hydrocodone ER, hydrocodone powder, and finely milled Zohydro® ER in the intranasal study. Spearman ρ2 and Pearson r2 values were calculated for PD (maximum effect [Emax] for "at the moment" Drug Liking, Overall Drug Liking, and Take Drug Again visual analog scales [VAS]) vs PK (partial area under the concentration‐time curve [AUC], maximum drug concentration [Cmax], time to Cmax [Tmax], and abuse quotient [PK AQ; Cmax/Tmax]) for all treatments. In the oral study, correlations were strongest between Emax of "at the moment" Drug Liking and PK parameters (Cmax [ρ2 = 0.4446], PK AQ [ρ2 = 0.5179], Tmax [ρ2 = 0.5093], and early systemic exposure [ρ2 = 0.4782]). For Overall Drug Liking and Take Drug Again VAS, ρ2 values for correlations with PK parameters ranged from 0.2620 to 0.3637. In the intranasal study, no clear correlations between PK and PD parameters were apparent. [ABSTRACT FROM AUTHOR]

Background: We developed a novel polymer insect repellent conjugate for extended release and decreased skin permeation of the volatile insect repellent p-menthane-3,8-diol (PMD). Methods: PMD was conjugated with acryloyl chloride via an ester bond to form acryloyl–PMD, which was subsequently copolymerised with acrylic acid at varying molar ratios. Copolymer structures were characterised by 1H NMR and FT-IR, analysed by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), molecular weights and reactivity ratios determined, and repellent loading assessed. Results: Using porcine liver esterases, ~45% of the insect repellent was released over five days. Penetration and permeation studies of the copolymer and free repellent using excised, full-thickness porcine ear skin showed no detectable permeation of the copolymer through skin compared to the PMD. Moreover, tape stripping revealed that over 90% of the copolymer remained on the outer surface of the skin, whereas free PMD was within all skin layers. A planarian toxicity fluorescence assay indicated that that the copolymer is unlikely to be a significant irritant when applied topically. Conclusions: this study demonstrates the feasibility of the copolymer approach to develop extended-release insect repellents while reducing skin uptake and transdermal permeation of the small-molecular-weight active ingredient, in order to minimise any adverse effects.

(1) Background: Dissolving microneedles (DMNs), a transdermal drug delivery system, have been developed to treat various diseases in a minimally invasive, painless manner. However, the currently available DMNs are based on burst release systems due to their hydrophilic backbone polymer. Although hydrophobic biodegradable polymers have been employed on DMNs for sustained release, dissolution in an organic solvent is required for fabrication of such DMNs. (2) Method: To overcome the aforementioned limitation, novel separable polycaprolactone (PCL) DMNs (SPCL-DMNs) were developed to implant a PCL-encapsulated drug into the skin. PCL is highly hydrophobic, degrades over a long time, and has a low melting point. Under thermal melting, PCL encapsulated capsaicin and could be fabricated into a DMN without the risk of toxicity from an organic solvent. (3) Results: Optimized SPCL-DMNs, containing PCL (height 498.3 ± 5.8 µm) encapsulating 86.66 ± 1.13 µg capsaicin with a 10% (w/v) polyvinyl alcohol and 20% (w/v) polyvinylpyrrolidone mixture as a base polymer, were generated. Assessment of the drug release profile revealed that this system could sustainably release capsaicin for 15 days from PCL being implanted in porcine skin. (4) Conclusion: The implantable SPCL-DMN developed here has the potential for future development of toxicity-free, sustained release DMNs.

[Display omitted] Extended release formulations play a crucial role in the pharmaceutical industry by maintaining steady plasma levels, reducing side effects, and improving therapeutic efficiency and compliance. One commonly used method to develop extended release formulations is direct compression, which offers several advantages, such as simplicity, time savings, and cost-effectiveness. However, successful direct compression-based extended release formulations require careful assessment and an understanding of the excipients' attributes. The scope of this work is the characterization of the compaction behavior of some matrix-forming agents and diluents for the development of extended release tablets. Fifteen excipients commonly used in extended release formulations were evaluated for physical, compaction and tablet properties. Powder properties (e.g., particle size, flow properties, bulk density) were evaluated and linked to the tablet's mechanical properties in a fully integrated approach, and data were analyzed by constructing a principal component analysis (PCA). Significant variability was observed among the various excipients. The present work successfully demonstrates the applicability of PCA as an effective tool for comparative analysis, pattern and clustering recognition and correlations between excipients and their properties, facilitating the development and manufacturing of direct compressible extended release formulations. [ABSTRACT FROM AUTHOR]

While anthelmintic treatment in young calves at first vaccination has not proven repeatedly effective in improving weight gain, there is evidence that treatment 90 day prior to weaning can enhance weight gain. This is difficult in most California cow/calf operations as after initial vaccination, calves are not again handled until preconditioning just prior to weaning. In an attempt to increase weight gain without the need for anthelmintic retreatment prior to preconditioning, 130 cow/calf pairs were stratified and assigned to three treatments of eprinomectin extended release injection (150 d efficacy), doramectin conventional injection, and an untreated control. Dams and calves received the same treatment. All treatments were commingled on irrigated pasture in Northern California. Sampling included weight (d 0, 75, and 145), fecal parasite (d 0, 14, 75, and 145), cow body condition score (d 0, 75, and 145), and cow pregnancy detection (days bred). Calf weight gain was not impacted by anthelmintic treatment (P = 0.44). However, cow weight gain was impacted by treatment (P < 0.01), with eprinomectin extended release showing higher weight gain than both doramectin conventional and the control (ADG kg 0.29, 0.23, 0.22, respectively). Cow weight gain differences were expressed greater toward the end of the trial than early on. Fecal egg count sampling failed to explain the difference in cow weight gain. Cow body condition score (P = 0.15) and days bred (P = 0.50) were not significantly affected by treatment. Although cow weight gain increased with an extended release anthelmintic treatment, this effect did not seem to be evident in suckling calves on high quality irrigated pastures in Northern California when compared to a conventional injectable and control treatments. Neither anthelmintic treatment appeared beneficial over a control when administered to suckling calves during initial vaccination at approximately 90 days of age. • Extended release and conventional injectable anthelmintics did not increase weight gain in suckling calves when compared to controls. • Nursing dams showed increased weight gain with an extended release anthelmintic when compared to conventional and control treatments. • Cow weight gain in the extended release treatment was greater than the conventional and control treatments 75 to 145 days post treatment. • Future research testing extended release anthelmintic treatments on heifer gain and pregnancy would be valuable. [ABSTRACT FROM AUTHOR]

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 ( F rel ), AUC 0-t , and C max 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.

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.

Study Objectives: Post hoc analyses from the phase 3 REST-ON trial evaluated efficacy of extended-release once-nightly sodium oxybate (ON-SXB; FT218) vs placebo for daytime sleepiness and disrupted nighttime sleep in narcolepsy type 1 (NT1) and 2 (NT2)., Methods: Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5 g, week 1; 6 g, weeks 2-3; 7.5 g, weeks 4-8; and 9 g, weeks 9-13) or placebo. Assessments included mean sleep latency on Maintenance of Wakefulness Test (MWT) and Clinical Global Impression-Improvement (CGI-I) rating (coprimary endpoints) and sleep stage shifts, nocturnal arousals, and patient-reported sleep quality, refreshing nature of sleep, and Epworth Sleepiness Scale (ESS) score (secondary endpoints) separately in NT1 and NT2 subgroups., Results: The modified intent-to-treat population comprised 190 participants (NT1, n = 145; NT2, n = 45). Significant improvements were demonstrated with ON-SXB vs placebo in sleep latency for NT1 (all doses, p < .001) and NT2 (6 and 9 g, p < .05) subgroups. Greater proportions of participants in both subgroups had CGI-I ratings of much/very much improved with ON-SXB vs placebo. Sleep stage shifts and sleep quality significantly improved in both subgroups (all doses vs placebo, p < .001). Significant improvements with all ON-SXB doses vs placebo in refreshing nature of sleep (p < .001), nocturnal arousals (p < .05), and ESS scores (p ≤ .001) were reported for NT1 with directional improvements for NT2., Conclusions: Clinically meaningful improvements of a single ON-SXB bedtime dose were shown for daytime sleepiness and DNS in NT1 and NT2, with less power for the limited NT2 subgroup., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society.)

Abstract The current study was aimed to develop extended release (ER) pellets formulations containing zaltoprofen as a model drug and cross-linked starch-κ-carrageenan (Sκ-C) hydrogel composite as a binder and extended release polymer. The Sκ-C cross-linked hydrogel composites were prepared using a 32 full factorial design approach and characterized by FTIR, DSC, XRD and SEM analysis. The matrix pellets were prepared by extrusion-spheronization technique and characterized production yield, FTIR, DSC, XRD, SEM, optical microscopy, flow characteristics, mucoadhesiveness, in-vitro dissolution and in-vivo pharmacokinetic parameter. The FTIR interpretation of Sκ-C cross-linked hydrogel composite provides the significant result as a formation of hemiacetal group and keton group of glyoxal is abolished; hence it could be satisfied that Sκ-C cross-linked hydrogel composite was formed. The optimized formulation (Sκ-C2) was contained 4:2 ratio of starch and κ-carrageenan of Sκ-C cross-linked hydrogel composite showed in-vitro drug release up to 99.15 ± 2.20% up to 12h, and mucoadhesion of 94.00 ± 2.00 up to 12 h, respectively and in-vivo parameter were showed decrease in C max and increase in t 1/2 significantly and drug release >12 h. Hence it was concluded that optimized formulation (Sκ-C2) showed acceptable release pattern, hence would be the viable alternative to ER type formulations. Highlights • A novel starch-κ-carrageenan cross-linked hydrogel composite was prepared and characterized. • Cross-linked starch-κ-carrageenan hydrogel composites were used as binder and extended release polymer for pellets. • ER pellets were characterized for FTIR, DSC, XRD,SEM, Optical microscopy, mucoadhesion, drug release and pharmacokinetics • 4. Starch-κ-carrageenan cross-linked hydrogel composites could be promising being a novel excipient for the ER pellets. [ABSTRACT FROM AUTHOR]

The current study reports on the manufacturing of extended release dosage forms of metoprolol succinate via hot-melt extrusion (HME) technology. Either Eudragit®S100 and Eudragit®L100 alone or in combination with release modifying agent Polyox™ WSR 303 and Eudragit®L100-55 were processed to obtain complete and faster release. Metoprolol succinate with similar solubility parameters to polymer was dispersed in polymer matrix and was characterized by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and scanning electron microscopy (SEM). Stability of drug after extrusion was confirmed by thermogravimetric analysis and high-performance liquid chromatography. Physical characterization method exhibited that the drug was homogeneously dispersed in non-crystalline state in Eudragit®L100-55-based formulations whereas in semi-crystalline state in Polyox™ WSR 303. The drug release percentage was below 3 and 40% in 0.1 N HCL with Eudragit®L100-55- and Polyox™ WSR 303-containing formulations, respectively, and exhibited pH-dependent dissolution properties. The drug-release mechanism was anomalous with Polyox™ WSR 303 formulations whereas diffusion through pore formation was obtained with Eudragit®L100-55. Both Eudragit®L100-55 and Polyox™ WSR 303 changed the release mechanism and kinetics of drug release from thermally processed dosage forms. The optimized stable formulation is similar to the marketed formulation with F2 value of 72.36. Thus, it can be concluded that HME was exploited as an effective process for the preparation of controlled release matrix system based on pH-dependent polymer matrices Eudragit®S100 and Eudragit®L100. [ABSTRACT FROM AUTHOR]

Purpose: To compare the estimated glomerular filtration rate (eGFR) at 12 months together with other outcomes among adult kidney transplant recipients (KTRs) who received extended release, once daily tacrolimus (ER-Tac) compared to those who received the immediate release, twice daily tacrolimus (IR-Tac) administration.Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement, we systematically reviewed all randomized controlled trials (RCTs) that compared clinical outcomes between ER-Tac versus IR-Tac in KTRs. The systematic searches were conducted on PubMed, EMBASE, Cochrane Register of Controlled Trials, Scopus, Web of Science, and CINAHL without language restriction. The trials registered and reference lists were also searched and reviewed. Data were extracted for eGFR, serum creatinine (Scr), creatinine clearance (CrCl), biopsy-proven acute rejection rate (BPAR), graft survival, and overall patient survival at different times over 24 months after kidney transplant (KT). A meta-analysis was performed to integrate the results from eligible studies.Results: From 1145 articles screened, 11 RCTs were included. The pooled results of included RCTs showed no significant difference of eGFR at 12 months between ER-Tac and IR-Tac groups (four trials, n = 1738; mean difference − 0.77 mL/min/1.73 m2, 95% CI: − 2.41 to 0.87; p = 0.56; I2 = 0%). Comparing between the two tacrolimus formulations, there were no significant differences of eGFR, CrCl, Scr, BPAR, graft survival, and patient survival at different times over 4 years after transplantation.Conclusions: Based upon currently available evidences in KTRs, the impact on kidney allograft function appears to be comparable between ER-Tac and IR-Tac. [ABSTRACT FROM AUTHOR]

Objective: To develop and evaluate Nevirapine (NVP) Extended release tablets for reducing the dosing frequency using Methylcellulose USP Methocel A15-LV and Hypromellose USP Methocel K4M Premium CR used as rate retarding polymers and Magnesium stearate as lubricant. Methods: Tablets were prepared by using roller compaction technique by employing Quality by Design (QbD) and Design of Experimentation (DoE) to study the effect of various process related parameters like Bulk density, Tapped density, Compressibility index, mesh size and in-vitro release data at 20th hour. Results: Obtained results had suggested that concentration of polymer had shown a potential effect over various process parameters and in-vitro drug release studies suggested that formulated tablets had shown a sustained release up to 24h when compared with marketed formulations. Conclusion: From the obtained results it can be concluded that formulation of Nevirapine ER Tablets employing QbD lead to a single dose per day in the management of HIV/AIDS. [ABSTRACT FROM AUTHOR]

Objective To assess the intranasal abuse potential of hydrocodone extended-release (ER) tablets developed with CIMA Abuse-Deterrence Technology compared with hydrocodone powder and hydrocodone bitartrate ER capsules (Zohydro ER, original formulation [HYD-OF]). Design Single-dose, randomized, double-blind, quadruple-dummy, active- and placebo-controlled, crossover study. Setting One US site. Subjects Healthy, adult, nondependent, recreational opioid users. Methods Subjects able to tolerate intranasal hydrocodone and discriminate hydrocodone from placebo were eligible for study enrollment. Eligible participants randomly received intranasal hydrocodone ER, intranasal hydrocodone powder, intranasal HYD-OF, intact oral hydrocodone ER, and placebo. Coprimary pharmacodynamic end points were a maximum effect on “at the moment” Drug Liking visual analog scale and Overall Drug Liking visual analog scale. Pharmacokinetics and safety were assessed. Results Mean maximum effect for “at the moment” Drug Liking was significantly (P  < 0.01) lower for intranasal hydrocodone ER (72.8) compared with hydrocodone powder (80.2) and HYD-OF (83.2). Similar results were observed for Overall Drug Liking maximum effect (68.5 vs 77.1 and 79.8, respectively; P  < 0.01). Secondary end points, including balance of effects and positive, sedative, and other effects, were consistent with these results. Intranasal treatments showed significantly greater effects vs placebo, while intact oral hydrocodone ER was similar to placebo. For each treatment, plasma concentration-time profiles paralleled “at the moment” Drug Liking over time. Incidences of adverse events for intranasal treatments were 52% for hydrocodone ER, 53% for hydrocodone powder, and 61% for HYD-OF. Conclusions The statistically significant differences between hydrocodone ER vs hydrocodone powder and HYD-OF for the primary drug liking end points indicate a lower intranasal abuse potential with hydrocodone ER in healthy, nondependent, recreational opioid users. [ABSTRACT FROM AUTHOR]

Robust in vitro drug release behavior is an important feature of extended release (ER) hydrophilic matrix formulations for accurate prediction of in vivo drug release. In this study, ER hydrophilic matrix tablets of metoprolol tartrate were formulated using a high viscosity grade of hypromellose as a rate-limiting polymer. Expectedly, this formulation showed an undesirable initial burst release followed by controlled drug release. Application of a barrier membrane (BM) coating of ethylcellulose with a pore former (hypromellose) resulted in the elimination of the burst effect. The aim of this study was to investigate the robustness of in vitro metoprolol release from BM-coated hydrophilic matrix tablets by simulating the physicochemical properties of gastrointestinal fluids and mechanical stress in the fasted- and fed state human gastrointestinal (GI) tract. Uncoated and BM-coated matrices were subjected to various dissolution studies simulating the varying pH conditions and additional physicochemical parameters, and the mechanical stress that can be caused by GI motility during both fasted and fed state GI passage. The BM-coated formulation showed robust drug release without an initial burst in all test scenarios. BM-coated matrix formulations thus represent a very promising approach for obtaining a highly controlled and robust drug release from oral ER formulations. [ABSTRACT FROM AUTHOR]

Physically crosslinked hydrogels were developed via solvent casting methods using a temperature-sensitive polymer, poly(N-isopropylacrylamide-co-acrylic acid), and a therapeutic polymer, salicylate-based poly(anhydride-esters), to concurrently release salicylic acid and bovine serum albumin in a sustained manner. The physical interactions between the two polymer systems were confirmed using Fourier transform infrared spectroscopy. The crosslinked polymers were porous, thus able to encapsulate bovine serum albumin (23 wt%) and then released the protein in a sustained fashion over 96 h. Concurrently, the hydrogel releases salicylic acid in a sustained manner up to 120 h. Hydrogel systems were cytocompatible at relevant therapeutic concentrations. These hydrogel systems can be used for simultaneous delivery of salicylic acid and protein to achieve synergic effects. [ABSTRACT FROM AUTHOR]

Abstract: Anagrelide is an established therapy for essential thrombocythemia. Common adverse effects have been linked to peak plasma concentrations of anagrelide and its 3OH metabolite. Our study was performed to investigate the pharmacokinetics (PK) of a novel anagrelide extended‐release (AER) formulation and its active metabolites. Thirty healthy volunteers were randomized to receive either 2 mg AER (under fasting and fed conditions) or 2 mg commercially available reference product (CARP) in an open‐label, 3‐way crossover trial with washout periods of 6 days. Plasma concentrations of anagrelide and its active metabolites were assessed by tandem mass spectrometry. The PK differed significantly between all treatment periods. Bioavailability of AER was 55% of the CARP under fasting conditions and 60% under fed conditions. Cmax, AUCt, and AUC∞ were significantly higher and Tmax and T1/2 were significantly shorter after the CARP compared with AER. Food had a significant impact on the PK of AER, increasing the Cmax and AUCt while reducing the T1/2, plateau, and mean residence time. Both formulations were well tolerated, with a trend toward more frequently occurring adverse events after the CARP. The PK of AER and the CARP differed significantly in all parameters. Food enhanced the bioavailability of AER. [ABSTRACT FROM AUTHOR]

The objective of the present study was to identify critical formulation parameters affecting the drug release from controlled porosity osmotic tablet of milnacipran hydrochloride. Most of the highly water-soluble drugs, if not formulated properly, may readily release the drug at a faster rate and are likely to produce undesirable side effects on oral administration. Controlled porosity osmotic tablets were developed in which the pores are formed by the incorporation of a leachable component in the coating. Once the tablet come in contact with the aqueous environment, the water-soluble component will dissolve and pores are generated. Subsequently, water diffuses into the core through the micro porous membrane, setting up an osmotic gradient and thereby controlling the release of drug. Ethocel was used as a release retarding agent in core tablet. The objective of using Ethocel was to explore the possibility of use of this type of release retardants for the development of the novel formulation of milnacipran HCl. Mannitol was used as osmogent in present study because mannitol is directly compressible and it exhibits good osmogenic property. Cellulose acetate is used as semi permeable membrane as a film former. Sorbitol was selected as pore former, because it is hydrophilic material. It is best suited with cellulose acetate as pore former. The presence of insoluble excipients such as Ethocel is desirable in the core for modulation of drug release. The amount of mannitol played a dominant role in controlling the drug release in the initial phase. Sorbitol created pores in the coat for smooth passage of drug solution. These can be considered as critical formulation parameters while going for optimization study. [ABSTRACT FROM AUTHOR]