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Multiple unit particulate system (MUPS) is more recent, challenging, effective and attractive option for the pharmaceutical industries that gives an efficient way to deliver drugs in modified pattern. This study aimed to improve the release profile of venlafaxine hydrochloride by developing modified release MUPS using polyvinyl pyrrolidone K-30, ethyl cellulose 20 cps and Hypromellose E 5LV. Preliminary trials were carried out to select the inert carrier, binder, and viscosity grade of rate controlling polymers. Further, optimization of binder concentration and extended-release coating was carried out. The formulation development of MUPS was divided into two categories as (i) drug layering on inert carrier, i.e., sugar spheres and (ii) extended-release coating. Comparative multimedia dissolution study of venlafaxine hydrochloride extended-release capsules was carried out and compared with the marketed formulation to ascertain the in vitro drug release behavior. XRD study indicated conversion of monohydrate form of venlafaxine hydrochloride and remained unaffected during storage. SEM images confirmed smooth surface of MUPS without any pores. The coated spheres had more dense surface compared to the uncoated pellets. Hypromellose E 5 LV showed better binding properties. Ethyl cellulose (20 cps) showed sustained release profile. The blend containing ER -- I spheres (10% coating) and ER -- II spheres (11% coating) at 60: 40 ratio showed dissolution profile similar to that of the innovator product. The formulated venlafaxine hydrochloride loaded MUPS filled in hard gelatin capsule can open a new avenue for the delivery of therapeutics with improved potential. [ABSTRACT FROM AUTHOR]

Plain Language Summary Ambroxol is used to relieve the symptoms of respiratory conditions in which abnormal mucus secretion is a problem, including the common cold, acute and chronic bronchitis, and chronic obstructive pulmonary disease. Different formulations of ambroxol are available, including tablets and effervescent tablets that release the drug as soon as they are digested, but need to be taken twice a day, or extended release (retard) capsules that release the drug slowly over 24 h and can be taken once a day. This randomized, three-period, six-sequence crossover study in 24 healthy volunteers compared the pharmacokinetics of three formulations of ambroxol: tablets, effervescent tablets, and retard capsules. The amount of drug in the bloodstream over 24 h was similar with all three formulations, but (as expected) the time to reach peak plasma concentration was longer with the retard capsules than both forms of tablet. These results show that people who take ambroxol for respiratory conditions will receive the same amount of ambroxol whether they take retard capsules, standard tablets, or effervescent tablets.

This work aimed to formulate xanthan gum microspheres for the encapsulation of metformin hydrochloride, according to the process of ionotropic gelation. The obtained microparticles, based on various fractions of xanthan gum (0.5–1.25), were subjected to different physico-chemical tests and a drug release study. Microspheres with an average size varying between 110.96 μm and 208.27 μm were obtained. Encapsulation efficiency reached 93.11% at a 1.25% biopolymer concentration. The swelling study showed a swelling rate reaching 29.8% in the gastric medium (pH 1.2) and 360% in the intestinal medium (pH 6.8). The drug release studies showed complete metformin hydrochloride release from the beads, especially those prepared from xanthan gum at the concentration of 1.25%, in intestinal medium at 90.00% after 6 h. However, limited and insignificant drug release was observed within the gastric medium (32.50%). The dissolution profiles showed sustained release kinetics.

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/m 2 , 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. MRT ss , t max , and t 1/2 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.

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: YD is a consultant/advisory board member for Avadel Pharmaceuticals, Bioprojet, Harmony Biosciences, Idorsia, Jazz Pharmaceuticals, Centessa Pharmaceuticals, and Takeda Pharmaceutical Co. TR is a consultant for Avadel Pharmaceuticals, Eisai, Idorsia, Jazz Pharmaceuticals, Merck & Co., Orexo, and Takeda Pharmaceutical Co. RB is a shareholder in WaterMark Medical and Healthy Humming, LLC; serves on the board of directors for WaterMark Medical; is a consultant for Jazz Pharmaceuticals, Takeda Pharmaceutical Co., Avadel Pharmaceuticals, and Oventus; has received industry-funded research from Avadel Pharmaceuticals, BresoTec, Bayer, Idorsia, Suven Life Sciences Ltd., Jazz Pharmaceuticals, Balance, Vanda, Merck & Co., Eisai, Philips, FRESCA Medical, Takeda Pharmaceutical Co., LivaNova, Roche, and Sommetrics; and has served on speakers bureaus for Jazz Pharmaceuticals, Eisai, and Harmony Biosciences. MJT has served as a consultant or on advisory boards for Avadel Pharmaceuticals, Axsome Therapeutics, Balance Therapeutics, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences Ltd., and Takeda Pharmaceutical Co. AMM has served as a consultant, speaker, and/or on advisory boards for Avadel Pharmaceuticals, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Alkermes, and Takeda Pharmaceutical Co; has received grant funding from National Institutes of Health, UCB Pharmaceuticals, Jazz Pharmaceuticals, ResMed Foundation, Coverys Foundation, and Geisinger Health Plan; is the CEO of DAMM Good Sleep, LLC; and has served as an advisor for Neura Health. AR has received grant/research support from Jazz Pharmaceuticals, Suven, Inspire, Nyxoah, LivaNova, and Avadel Pharmaceuticals; is a speaker for Avadel Pharmaceuticals; is a consultant for Jazz Pharmaceuticals, Suven, Inspire, and Avadel Pharmaceuticals; and has served on speakers bureaus for Jazz Pharmaceuticals and Eisai. JG is an employee of Avadel Pharmaceuticals., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Over past 30 years as the expanse and complication involved in marketing new drug entities have increased, with concomitant recognition of the therapeutic advantages of controlled drug delivery, greater attention has been focused on development of extended or controlled release drug delivery systems. In the present research work an attempt has been made to optimize, formulate and characterize extended-release tablet of Cefaclor. The preformulation studies were performed for the drug (e.g., physico-chemical properties, melting point, solubility etc.). The drug had shown the results under standard specifications. UV spectroscopic analytical method was also performed for quantitative determinations by plotting standard curve. Before this the pure drug was also scanned for the λ max value at different concentrations. The pre-compressions parameters and the post compression parameters for the nine formulated tablets were performed. The drug release study of the selected formulations EF3, EF6 and EF9 was performed as those formulations has shown the results within pharmacopoeia limits. The Formulation EF9 was then taken for release kinetic study as it has shown best results among the other three formulations. So, it confirms the drug release by Higuchi diffusion mechanism. From the results, conclusion can be drawn that the formulation consisting 10-12% concentration of hydroxypropyl methyl cellulose K4-M with 1% microcrystalline cellulose and 25% of lactose are considered as ideal for the optimized extended-release tablet formulation for Cefaclor. [ABSTRACT FROM AUTHOR]

Nitrofurantoin is an old antibiotic currently prescribed to treat urinary tract infections. High dosing frequency causes fluctuations in the drug plasma concentration making less desirable prescription. This work was aimed to overcome these shortcomings by developing extended-release formulations. Tablets were prepared using nitrofurantoin and crosslinked poly(acrylic acid) and hydroxypropyl methylcellulose (HPMC) as hydrophilic polymer matrices. Modified tablets containing HPMC exhibited adequate swelling, erosion, and dissolution profiles and showed potential to decrease the frequency of administrations and reduce fluctuations in the drug plasma concentration. This would result in higher therapeutic effect and increases patient compliance by reducing adverse effects. [ABSTRACT FROM AUTHOR]

Cyclodextrin has been recognized as a linker molecule that can link with the various drug substances to produce a nano-porous structure called nanosponges (NS) and increase the dissolution rate of poorly soluble drug substances. This work aimed to load rosuvastatin calcium (RSC) with solubility enhancer's ß-cyclodextrin (ß-CD) or polyvinyl alcohol (PVA). ß-CD based RSC-NS were fabricated by the emulsion solvent diffusion technique; with solubilizer dichloromethane and different ratios of ethyl cellulose as a co-polymer. Characterization of the prepared nanosponges was done by various testing procedures that confirm its nanosize and particle size and drug release. RSC loading in NS was assessed by DSC, FTIR and SEM. Among all the formulations F5 has 78.23 % entrapment efficiency. 2-3 folds of increased solubility were obtained with RSC-NS. F1-F6 formulations released 76.35 % - 98.69 % of the drug at the end of 30 min. In the preparation of extended-release tablets, NS prepared from F5 formulation was used and the best tablet formulation was selected based on various evaluation tests. All the formulations except S3, S8 followed first-order release kinetics. S1 & S2 drug release mechanism is Higuchi while other formulations are Korsemeyer-Peppas, so the release mechanism for most of the formulations is erosion than diffusion. [ABSTRACT FROM AUTHOR]

In this study, a novel approach for compression of matrix pellets into matrix tablets has been studied in an attempt to overcome the issues pertaining to rupture of polymer coat during compression of reservoir type pellets. Extended release matrix pellets were prepared by the extrusion/spheronization technique using commercially available aqueous dispersions of ethyl cellulose, acrylic polymers and sodium alginate at 10 %, 20 % and 30 % w/w levels. Galantamine Hydrobromide was used as the model drug and an in vitro release profile of 12 h was targeted. Tablets containing matrix pellets were prepared by the direct compression process. Acceptance Value, a pharmacopeial test, was applied to study the uniformity of drug distribution. Effect of compression force (2-6 kN), extrusion screen aperture size, diluent blend composition and pellet percentage on drug release and acceptance value were studied. As polymer is uniformly distributed within each pellet, the drug release pattern from uncompressed pellets was comparable to compressed tablets. The pellet segregated from the surface of the tablet was found to be flattened in the direction of applied compression force with minor deformities. In conclusion, matrix pellets can constitute an alternative approach to reservoir-type pellets in obtaining matrix tablets for extended delivery of drugs. [ABSTRACT FROM AUTHOR]

The goal of the present study is to prepare a stable, multiple-unit, extended-release dosage form containing oxycodone pellets coated with aqueous ethylcellulose (EC) dispersion, Surelease E-7-19050. The application of 18% w/w of EC leads to the similar drug release with the hydrophobic, non-swelling, matrix reference product containing 20 mg of oxycodone. Increasing the compression force to 9 kN and including more than 50% w/w of oxycodone pellets into the formulation resulted in faster drug release, indicating the damaging to the EC film coating. The physical appearance of the final formulation, assay of oxycodone, moisture content, and dissolution data over the stability period showed that the multiple-unit pellet system (MUPS) is efficient for the production of highly stable product.

To develop poly(d,l-lactide-co-glycolide) (PLGA) microspheres to achieve controlled and sustained release of brexpiprazole in vivo. Brexpiprazole microspheres were prepared by oil-in-water emulsion-solvent evaporation method and evaluated for morphology, particle size, encapsulation efficiency, drug loading, conformation and compatibility of drug and polymer, in vitro release, and in vivo pharmacokinetics. By establishing the relationship between in vitro and in vivo release, it helps identify the appropriate in vitro release conditions to explore release profiles of brexpiprazole microspheres. Porous PLGA microspheres with near spherical morphology were obtained displaying an average diameter of 20.43 ± 0.06 μm, a drug loading capacity of 27.24 ± 0.33% and an encapsulation efficiency of 81.87 ± 1.07%. Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC) analysis showed that some drugs encapsulated in the microspheres remained in the amorphous state and some were in the crystalline state. Different release setups resulted in different release kinetics. The dialysis release setup displayed a cumulative release of about 65% within 60 days, while the sample-and-separate setup showed a cumulative release of about 77% within 35 days. Per pharmacokinetic studies in rats, a burst phase in the plasma concentration–time curve was observed after intramuscular injection in the first 2 h followed by a clear zero-order release phase. Overall, brexpiprazole achieved in vivo sustained release from PLGA microspheres for up to 40 days. A PLGA microsphere loaded with brexpiprazole was successfully developed and demonstrated potential for extended-release of therapeutics for schizophrenia treatment. [ABSTRACT FROM AUTHOR]

The generic drug product DRL ABC is an Extended Release (ER) Tablet manufactured by Dr. Reddy's Laboratories Limited and have multi point dissolution as part of release specification. A proposal is being made to revise the dissolution specification and the aim of present work was to evaluate if this would still provide bioequivalent product. PBBM was developed for DRL ABC using literature reported pharmacokinetic (PK) data. The intravenous PK data and in vitro metabolic rate constants were utilized for developing PBPK model first, followed by that in conjugation with mechanistic ACATTM model, a PBBM is developed for per-oral immediate release formulations. The validated model was applied to predict clinical bioequivalence (BE) study data for the Reference (Innovator ER Tablet) and Test product. For Reference and Test product, in vivo dissolution profiles were mechanistically deconvoluted from plasma concentration (Cp)-time profiles. Further, mechanistic in vitro-in vivo relationship (IVIVR) applied to in vitro release profiles of two hypothetical Test product batches (one with single point low dissolution profile (SPLP) and other with overall low dissolution profile (LP)) in order to calculate their in vivo releases and population simulation was performed with 40 virtual subjects. Results from the cross-over virtual trials showed BE between the Reference and various Test product batches (SPLP and LP), with maximum Cp (Cmax) and area under the Cp-time curve (AUC0-inf) well within 80-125% range. PBBM in conjugation with IVIVR and virtual BE was successfully applied for justifying changes in dissolution specification of DRL ABC. [ABSTRACT FROM AUTHOR]

Metformin is extensively used antidiabetic drug and has been associated with gastrointestinal side effects. This study was intended to compare the gastrointestinal side effects observed in type 2 diabetes mellitus patients receiving metformin tablets of immediate, sustained and extended release. In this prospective study, 702 patients were assessed from January to June 2018 at a super speciality hospital. Adult patients with type 2 diabetes mellitus who were appropriately fulfilling the inclusion criteria received metformin tablets. Hemoglobin A1c, gastrointestinal side effects were recorded and patient satisfaction was assessed on the basis of numerical rating scale and visual analogue scale. They were categorized into three groups with 234 patients in each category receiving metformin immediate, sustained and extended release tablet respectively. Treatment with metformin extended release was well tolerated. Out of 42 patients (17.95%) receiving metformin immediate release and reporting gastrointestinal side effects, 2 patients (4.76%) were relieved by dose titration of the same drug and its adjustment with the meals. The other 40 patients (95.24%) were switched to metformin sustained release and extended release tablet each for a week. 37 patients (92.50%) who switched to extended release metformin were relieved gastro-intestinal side effects while 3 patients (7.50%) discontinued the metformin therapy due to no improvements even after the switch. This study concludes that the incidence of gastrointestinal side effects of metformin immediate release tablets in patients with type 2 diabetes mellitus can be reduced by switching to metformin sustained release and extended release tablets with no further side effect complications. [ABSTRACT FROM AUTHOR]

Objectives: The present work was designed to formulate extended-release tablets of clarithromycin by means of central composite design. To assess the systematic considerate of input and output variables and to construct design space, the central composited design was used. Methods: The concentrations of tamarind kernel powder (X1), ethyl cellulose (X2) and polyvinyl pyrrolidone (X3) remained as independent variables and responses were drug release in 2 h, 8 h and t50%. Polynomial equations were employed to forecast the quantitative result of nondependent constraints at different levels on responses. The model stood nonlinear and the curvature outcome was significant. Henceforth the study employed central composite design for optimization. Wet granulation method was used to prepare the tablets and were evaluated for pharmacotechnical properties. Results: FTIR and DSC studies signposted that drug and excipients were compatible. Precompression constraints specified respectable flow properties. The in vitro drug release of entire formulations at the end of 12 h was found to be 96.14% - 98.23%. Increase in the concentration of tamarind kernel powder, ethyl cellulose decreased percentage drug release. Contour plots were utilized to assess the relationship between independent variables and dependent variables. Conclusion: The statistical model is scientifically effective as the investigational estimates and foreseen estimates proposed by the model were relatively close to each other. The outcomes confirmed the success of the anticipated design for development of clarithromycin extended-release tablets with optimized properties. [ABSTRACT FROM AUTHOR]

Utilizing peptides as therapeutic agents is considered an attractive approach for the treatment of various diseases due to their high binding and selectivity to novel drug targets. However, the physicochemical properties of peptides make them challenging to administer exogenously, which places a high burden on drug delivery technology selection to successfully achieve the desired response. Various peptide drug delivery systems have been used in clinical and marketed products to overcome the problems associated with exogenous administration of peptide therapeutics. This review details the trends observed pertaining to the delivery of peptides such as changes in the routes of administration, advancements in formulation platforms, patient-centric product design, and various other aspects of peptide delivery.

Objective: Orphenadrine is an anticholinergic, antimuscarinic, centrally acting skeletal muscle relaxant. It presents in the form of citrate and HCl salts which are used in treatment of the symptoms of mild Parkinson's disease and also it is used as adjuvant with other drugs in the therapy. Method: Many trials were made to formulate orphenadrine citrate as tablet using wet granulation or direct compression technique in order to get a satisfactory formula through studying the effect of various factors such as binders, diluents and disintegrants types. The best formula was obtained by using poly vinyl pyrrolidone (PVP) as a binder also the results indicated that starch and mannitol gave acceptable physical properties to the tablets when they were used as diluents. At the same time, the results showed that avicel which was used as a disintegrant gave an acceptable disintegration and dissolution time in comparison with the reference tablet DISIPAL. In addition, the selected formula was used to study the effect of method of incorporation of disintegrant on the physical properties of tablets. Result: It was found that the intragranular incorporation resulted in a shorter disintegration and dissolution times. The stability of orphenadrine citrate prepared tablets was also studied upon storage at 50C, 60C and 70C for four months. Conclusion: The overall results of this study indicate that the drug can be prepared as tablets, which fit the requirements of British Pharmacopoeia since the prepared tablets gave satisfactory results.

To reduce cost and time for product development, an ideal strategy for the development of oral extended release (ER) product is to identify the desired formulation with minimum needs for clinical evaluation. The aim of this work was to demonstrate the feasibility of adopting a "prediction-then-validation" strategy for the development of oral ER formulations. Instead of the traditional approach using multiple ER formulations for IVIVC development, an enteric-coated fast release formulation was successfully utilized for the development of a biopredictive tool to estimate the drug release from enteric coated polymeric ER formulations in the intestine. A TS1 (time scale factor between T vitro and T vivo equals to 1) system was designed and developed, based on which the in vivo pharmacokinetic (PK) performance of ER formulations in dog and in human were well predicted prior to in vivo evaluations. The model further passed a posteriori validation using the criteria for level A IVIVC and, as designed, provided a T scale value of 1 for the IVIVC model. [ABSTRACT FROM AUTHOR]

Background: For patients with Parkinson's disease, clinicians commonly assess duration of benefit for individual doses of levodopa in order to consider medication changes.Objective: To determine the mean duration of ON time per dose and mean duration of ON time without troublesome dyskinesia (WoTD) per dose of CD-LD IR vs. CD-LD ER in the ADVANCE-PD trial.Methods: We performed a post hoc analysis of the ADVANCE-PD trial. Mean ON time per dose and ON time WoTD was calculated at baseline and end-of-study (EOS). Changes were compared between CD-LD IR and CD-LD ER (Rytary®) treatment groups using an ANCOVA model.Results: Mean (SD) baseline ON time per dose of CD-LD IR (n = 393) was 2.20 h. Patients randomized to double-blind treatment with CD-LD IR (n = 192) experienced an increase in mean ON time per dose from baseline to EOS from 2.24 h to 2.38 h. In comparison, patients randomized to double-blind treatment with CD-LD ER (n = 201) experienced an increase in mean ON time per dose from baseline (on CD-LD IR) to EOS (on CD-LD ER) from 2.17 h to 3.55 h. Conversion and optimization with CD-LD ER increased ON time per dose by 1.21 h more than optimization of CD-LD IR (p < 0.0001). Similarly, CD-LD ER increased ON time WoTD per dose by 1.16 h more than CD-LD IR (p < 0.0001).Conclusion: In the ADVANCE-PD trial, CD-LD ER significantly increased ON time per dose compared to CD-LD IR (+1.21 h, p < 0.0001) and provided significantly more ON time per dose (3.55 h vs 2.38 h, p < 0.0001). [ABSTRACT FROM AUTHOR]

Background: Wax microsphere bound oxycodone was developed as an abuse-deterrent opioid and maintains a similar pharmacokinetic profile whether administered with or without an intact capsule. We hypothesized that microsphere oxycodone could be utilized for extended release analgesia in patients undergoing radiation (RT) for head-and-neck cancer (HNC) and would not need to be discontinued due to dysphagia or gastrostomy tube dependence. Methods and materials: We performed a prospective trial that enrolled participants > 18 years with histologically confirmed HNC who were scheduled to receive RT. Analgesia was prescribed in accordance with the WHO pain ladder. Microsphere oxycodone was initiated when total daily opioid dose exceeded 30 mg of morphine sulfate equivalent and was titrated weekly during RT. Pain level and effect on quality of life were assessed using the Brief Pain Inventory. The primary feasibility endpoint was frequency of microsphere oxycodone discontinuation within 3 months of RT for reasons other than pain resolution. Results: Twenty-six eligible patients were enrolled. Microsphere oxycodone was initiated in 16 (61.5%) patients. Six (23.1%) patients utilized a gastrostomy tube to administer microsphere oxycodone during all or part of RT. Microsphere oxycodone was discontinued in 1 (7.6%) patient due to perceived inefficacy. No patients were discontinued due to toxicity or difficulty with administration. Ratings for average pain was 3.1 (± 3.4) at enrollment, 4.0 (± 2.4) at week 6 of RT, and 1.8 (± 2.2) at 3-month follow-up. Conclusions: These results support the feasibility and safety of microsphere oxycodone for extended release analgesia among patients with HNC undergoing RT. [ABSTRACT FROM AUTHOR]

Background: In the REST-ON clinical trial (NCT02720744), mean sleep latency on the Maintenance of Wakefulness Test (MWT) was significantly improved with extended-release once-nightly sodium oxybate (ON-SXB) vs placebo ( P  < 0.001) in participants with narcolepsy. This post hoc analysis assessed response to treatment and improvement in excessive daytime sleepiness., Methods: Participants with narcolepsy aged ≥16 years were randomized 1:1 to receive ON-SXB (4.5 g, week 1; 6 g, weeks 2-3; 7.5 g, weeks 3-8; and 9 g, weeks 9-13) or placebo. Mean sleep latency on the MWT was measured across 5 trials of ≤30 min each. Post hoc assessments included percentage of participants whose sleep latency improved ≥5, ≥10, ≥15, and ≥20 min and with a mean sleep latency of 30 min., Results: Significantly more participants receiving ON-SXB vs placebo experienced increased mean sleep latency ≥5 min (all doses P  < 0.001), ≥10 min (all doses P  < 0.001), ≥15 min (6 and 7.5 g, P  < 0.001; 9 g, P  < 0.01), and ≥20 min (6 g, P  < 0.01; 7.5 g, P  < 0.001; 9 g, P  < 0.05). More participants receiving ON-SXB had mean sleep latency of 30 min vs placebo (6 g, 5.7 % vs 0 %, respectively [ P  < 0.05]; 7.5 g, 10.5 % vs 1.3 % [ P  < 0.05]; 9 g, 13.2 % vs 5.1 % [ P  = 0.143])., Conclusions: Significantly more participants who received ON-SXB experienced increased mean sleep latency ≥5 to ≥20 min; at the 2 highest doses, >10 % remained awake for the entirety of the MWT. ON-SXB offers a once-at-bedtime treatment option for adults with narcolepsy., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michael J. Thorpy reports a relationship with Axsome Therapeutics that includes: consulting or advisory. Michael J. Thorpy reports a relationship with Balance Therapeutics that includes: consulting or advisory. Michael J. Thorpy reports a relationship with Eisai that includes: consulting or advisory. Michael J. Thorpy reports a relationship with Avadel Pharmaceuticals that includes: consulting or advisory. Michael J. Thorpy reports a relationship with Harmony BioSciences that includes: consulting or advisory. Michael J. Thorpy reports a relationship with 10.13039/100011096Jazz Pharmaceuticals that includes: consulting or advisory. Michael J. Thorpy reports a relationship with NLS Pharmaceuticals that includes: consulting or advisory. Michael J. Thorpy reports a relationship with Suven Life Sciences Ltd. that includes: consulting or advisory. Michael J. Thorpy reports a relationship with 10.13039/100008373Takeda Pharmaceutical Co that includes: consulting or advisory. Clete A. Kushida reports a relationship with Avadel Pharmaceutical that includes: consulting. Clete A. Kushida reports a relationship with XW Pharma that includes: consulting. Richard Bogan reports a relationship with WaterMark Medical and Health Humming LLC that includes: equity or stocks. Richard Bogan reports a relationship with WaterMark Medical that includes: board membership. Richard Bogan reports a relationship with 10.13039/100011096Jazz Pharmaceuticals that includes: consulting or advisory, funding grants, and speaking and lecture fees. Richard Bogan reports a relationship with Harmony BioSciences that includes: consulting or advisory and speaking and lecture fees. Richard Bogan reports a relationship with 10.13039/100008373Takeda Pharmaceutical Co. that includes: consulting or advisory and funding grants. Richard Bogan reports a relationship with Avadel Pharmaceuticals that includes: consulting or advisory and funding grants. Richard Bogan reports a relationship with Oventus that includes: consulting or advisory. Richard Bogan reports a relationship with BresoTec that includes: funding grants. Richard Bogan reports a relationship with 10.13039/100004326Bayer that includes: funding grants. Richard Bogan reports a relationship with 10.13039/501100016198Idorsia that includes: funding grants. Richard Bogan reports a relationship with Suven Life Sciences Ltd. that includes: funding grants. Richard Bogan reports a relationship with Balance Therapeutics that includes: funding grants. Richard Bogan reports a relationship with 10.13039/100010902Vanda that includes: funding grants. Richard Bogan reports a relationship with 10.13039/100004334Merck that includes: funding grants. Richard Bogan reports a relationship with 10.13039/501100003769Eisai that includes: funding grants and speaking and lecture fees. Richard Bogan reports a relationship with Fresca that includes: funding grants. Richard Bogan reports a relationship with 10.13039/100013410LivaNova that includes: funding grants. Richard Bogan reports a relationship with 10.13039/100004337Roche that includes: funding grants. Richard Bogan reports a relationship with Sommetrics that includes: funding grants. John Winkelman reports a relationship with Avadel Pharmaceuticals that includes: consulting or advisory. John Winkelman reports a relationship with Emalex Biosciences that includes: consulting or advisory. John Winkelman reports a relationship with Noctrix Health that includes: consulting or advisory. John Winkelman reports a relationship with Disc Medicine that includes: consulting or advisory. John Winkelman reports a relationship with 10.13039/501100016198Idorsia Pharmaceuticals that includes: consulting or advisory. John Winkelman reports a relationship with 10.13039/100004334Merck & Co. that includes: funding grants. John Winkelman reports a relationship with 10.13039/100016473American Regent that includes: funding grants. John Winkelman reports a relationship with 10.13039/100000026NIDA that includes: funding grants. John Winkelman reports a relationship with 10.13039/100004087RLS Foundation that includes: funding grants. John Winkelman reports a relationship with Baszucki Brain Research Fund that includes: funding grants. Maurice M. Ohayon reports a relationship with Avadel Pharmaceuticals that includes: consulting or advisory. Maurice M. Ohayon reports a relationship with 10.13039/100008373Takeda Pharmaceutical Co. that includes: consulting or advisory. Maurice M. Ohayon reports a relationship with Jazz Pharmaceuticals that includes: consulting or advisory. Colin M. Shapiro reports a relationship with Avadel Pharmaceuticals that includes: consulting or advisory and speaking and lecture fees. Colin M. Shapiro reports a relationship with 10.13039/100011096Jazz Pharmaceuticals that includes: consulting or advisory and speaking and lecture fees. Jennifer Gudeman reports a relationship with Avadel Pharmaceuticals that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Abstract Background The study was to develop an extended release (ER) encapsulated and compacted pellets of Atenolol using hydrophobic (wax based and polymeric based) and high viscosity grade hydrophilic matrix formers to control the release of this highly water soluble drug by extrusion/spheronization (ES). Atenolol is used for cardiovascular diseases and available as an immediate release (IR) tablet dosage form. The lipids, Carnauba wax (CW), Glyceryl monostearate (GMS) and cellulose based i.e. Hydroxypropyl methylcellulose (HPMC) and Ethyl cellulose (EC) were used in preparing Atenolol ER pellets. Thermal sintering and compaction techniques were also applied to control the burst release of Atenolol. Method For this purpose, thirty-six trial formulations (F1-F36) were designed by Response Surface Methodology (RSM), using Design-Expert 10 software, keeping (HPMC K4M, K15 M & K100 M), (EC 7FP, 10FP & 100FP), waxes (GMS, & CW), their combinations, sintering temperature and duration, as input variables. Dissolution studies were performed in pH, 1.2, 4.5 and 6.8 dissolution media. Drug release kinetics using different models such as zero order, first order, Korsmeyer-Peppas, Hixon Crowell, Baker-Lonsdale and Higuchi kinetics were studied with the help of DDsolver, an excel based add-in program. Results The formulations F35 and F36 showed compliance with Korsmeyer-Peppas Super case II transport model (R2 = 0.975–0.971) in dissolution medium pH 4.5. No drug excipient interaction observed by FTIR. Stereomicroscopy showed that sintered combination pellets, (F35), were highly spherical (AR = 1.061, and sphericity = 0.943). The cross-sectional SEM magnification (at 7000X) of F34 and F35 showed dense cross-linking. The results revealed that the optimized formulations were F35 (sintered pellets) and F36 (compacted pellets) effectively controlling the drug release for 12 h. Conclusion Extended-release encapsulated, and compacted pellets were successfully prepared after the combination of lipids CW (10%) and GMS (20%) with EC (10FP 20% & 100FP 20%). Sintering and compaction, in addition, stabilized the system and controlled the initial burst release of the drug. Extended release (ER) Atenolol is an effective alternative of IR tablets in controlling hypertension and treating other cardiovascular diseases.

Abstract Background Febuxostat immediate release (IR), a xanthine oxidase inhibitor, is indicated for the management of hyperuricemia in patients with gout by lowering urate levels. An extended release (XR) formulation of febuxostat was developed to provide equal or superior efficacy on urate lowering compared with the IR formulation and potentially lower the risk of treatment-initiated gout flares due to an altered pattern of drug exposure. The present study evaluated the efficacy and safety of febuxostat XR and IR formulations in patients with gout and moderate renal impairment (estimated glomerular filtrate rate ≥ 30 and

Reinforced edible gluten film was successfully prepared by the addition of polylactic acid (PLA) nano-fibers to improve their mechanical and barrier properties. Scanning electron microscopy (SEM) of the transverse cross-section of gluten film was performed to investigate the binding of PLA fibers to the surface of gluten film. It was observed that the nano-fibers attached to the surface of the gluten film could improve by 13.9% in the barrier properties and up to 29.3% in the mechanical properties compared to the control gluten film. The effect of ultraviolet light exposure on the tensile strength and water vapor barrier properties, as well as the stability of lycopene encapsulated in PLA nano-fibers, was investigated. It was shown that PLA nano-fibers in gluten film reduce UV light's harmful effect on the water vapor barrier properties by up to 6.8% and on the tensile strength up to 23.5% compared to the control film. The results also showed that the treatment of lycopene with ultraviolet light, unlike the control sample (55.7% degradation in lycopene), had no destructive effect on the antioxidant activity of lycopene. Finally, the rate of release of lycopene was studied in fatty food simulants. It was observed in gluten/PLA film that the encapsulation of lycopene in PLA nano-fibers has a much lower rate of release than the direct addition of lycopene to gluten film. Gluten film containing electrospun nano-fibers showed a release rate of lycopene about 31.8% at approximately 90 h. However, the sample of nano-fibers-free gluten film had a release rate of 48.5% at the same time. This result is beneficial for active food packaging because it allows food to be stored for longer in the packaging. [ABSTRACT FROM AUTHOR]

Long acting injectable formulations have been developed to sustain the action of drugs in the body over desired periods of time. These delivery platforms have been utilized for both systemic and local drug delivery applications. This review gives an overview of long acting injectable systems that are currently in clinical use. These products are categorized in three different groups: biodegradable polymeric systems, including microparticles and implants; micro and nanocrystal suspensions and oil-based formulations. Furthermore, the applications of these drug delivery platforms for the management of various chronic diseases are summarized. Finally, this review addresses industrial challenges regarding the development of long acting injectable formulations. Unlabelled Image [ABSTRACT FROM AUTHOR]

The development of modified‐release (MR) drug products aims to address a clinical need such as improving patient compliance. There are multiple pathways and development strategies for the registration and approval of MR products. The development strategy of an MR product is usually dependent on the availability and pharmacokinetic/pharmacodynamics (PK/PD) characteristics of the reference drug product, that is, an immediate‐release (IR) product or a reference MR. Compared with a reference IR product, an MR product is likely to have a different PK profile over the least common dosing time due to unequal dosing intervals. In case of differences in PK profiles between the MR product and the reference product, confirmatory efficacy and safety studies may be needed to support registration. In some cases, however, a thorough clinical PK/PD characterization may provide sufficient basis to support the approval of the proposed MR product without the need for additional safety and efficacy studies. This article summarizes the US Food and Drug Administration experience and the regulatory considerations supporting the approval of MR products in the past 6 years and discusses cases in which clinical pharmacology and PK/PD information were leveraged to support approval without the need for additional clinical studies. Details of all these cases are available in the public domain. In 2 cases a well‐characterized exposure‐response relationship provided sufficient justification that differences in the shape of the PK profiles were not clinically relevant. In the remaining 3 cases a thorough characterization of the PK profile along with a risk‐based approach provided bases for approval. [ABSTRACT FROM AUTHOR]

Purpose: When establishing IVIVC, a special problem arises by interpretation of averaged in vivo profiles insight of considerable individual variations in term of time and number of mechanical stress events in GI-tract. The objective of the study was to investigate and forecast the effect of mechanical stress on in vivo behavior in human of hydrophilic matrix tablets. Methods: Dissolution profiles for the marketed products were obtained at different conditions (stirring speed, single- or repeatable mechanical stress applied) and convoluted into C-t profiles. Vice versa, published in vivo C-t profiles of the products were deconvoluted into absorption profiles and compared with dissolution profiles by similarity factor. Results: Investigated hydrophilic matrix tablets varied in term of their resistance against hydrodynamic stress or single stress during the dissolution. Different scenarios, including repeatable mechanical stress, were investigated on mostly prone Seroquel® XR 50 mg. None of the particular scenarios fits to the published in vivo C-t profile of Seroquel® XR 50 mg representing, however, the average of individual profiles related to scenarios differing by number, frequency and time of contraction stress. When different scenarios were combined in different proportions, the profiles became closer to the original in vivo profile including a burst between 4 and 5 h, probably, due to stress-events in GI-tract. Conclusion: For establishing IVIVC of oral dosage forms susceptible mechanical stress, a comparison of the deconvoluted individual in vivo profiles with in vitro profiles of different dissolution scenarios can be recommended. [ABSTRACT FROM AUTHOR]

Background: Carbidopa (CD) and levodopa (LD) extended release (CD-LD ER) capsules are designed to combine both immediate and extended release pharmacokinetics. In the phase 3, randomized, double-blind, ADVANCE-PD trial, patients randomized to CD-LD ER experienced a 1.17-hour greater reduction in OFF time compared to patients randomized to CD-LD IR (p < 0.0001). Objective: To compare CD-LD IR optimization to CD-LD ER conversion based on patient dyskinesia status at baseline using data from the ADVANCE-PD trial. Methods: This was a retrospective analysis of the ADVANCE-PD study. Patients were categorized by dyskinesia status at baseline into 1) those who had No Dyskinesia (ND), 2) those who had Non-Troublesome Dyskinesia Only (NTDO), and 3) those who had Troublesome Dyskinesia (TD). Results: Comparative reductions in OFF time favoring CD-LD ER over CD-LD IR were similar for the ND (–1.08 h, p = 0.0071, n = 183) and NTDO (–1.12 h, p = 0.0104, n = 131) groups, and smaller for the TD group (–0.82 h, p = 0.2382, n = 79). Reductions in OFF time for both CD-LD ER conversion and CD-LD IR adjustment were largest within the ND group and smallest within the TD group (CD-LD ER: ND –2.86 h, NTDO –2.11 h, TD –1.36 h; CD-LD IR: ND –1.78 h, NTDO –0.99 h, TD –0.55 h). Conclusion: Responses to both CD-LD IR adjustment and CD-LD ER conversion depended on baseline dyskinesia status. Significant reductions in OFF time with CD-LD ER compared to CD-LD IR were observed in the ND and NTDO groups. In the TD group, comparing CD-LD ER conversion to CD-LD IR optimization, benefits were still observed, but there was less reduction in OFF time, less reduction in troublesome dyskinesia, and fewer patients self-rated themselves much or very much improved than in the ND and NTDO groups. These data suggest that in clinical practice, the best chances for success with conversion from CD-LD IR to CD-LD ER are in patients without TD. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate cellulose acetate butyrate (CAB) as a carrier for extended-release alcohol-resistant matrix tablet. Powder blends were either directly compressed or granulated before compression. The drug release from CAB matrix tablet was robust to formulation/process parameters such as compression force (10−20 kN), granular size (0.15−1.40 mm), and drug content (50–70%). In addition, release medium variables such as ionic strength, pH, and agitation rate had no effect on the drug release. CAB matrix tablet was more robust than ethylcellulose matrix tablet; the release from CAB matrix tablet was not affected by ethanol content (up to 20% v/v) in the release medium irrespective of agitation. CAB is a promising polymer for formulating of alcohol-resistant extended-release matrix tablet. [ABSTRACT FROM AUTHOR]

Introduction: Ambroxol is used in the treatment of acute and chronic respiratory conditions characterized by abnormal mucus secretion and impaired mucus transport and is available in a variety of formulations. This study aimed to compare the steady-state (SS) pharmacokinetic characteristics of extended-release (ER) 75-mg retard capsules with two immediate-release (IR) formulations (60-mg effervescent tablets and 30-mg tablets) over a 24-h period. Methods: An open-label, randomized, three-period, six-sequence crossover study was conducted in healthy volunteers aged 18–45 years who had a normal body mass index. The test (ER 75-mg retard capsule once daily) and reference treatments (half of IR 60-mg effervescent tablet twice daily or 30-mg IR tablet twice daily) were administered on days 1–5 of each treatment period. Meals were standardized and concomitant therapy was prohibited. Blood samples for pharmacokinetic assessment were collected on day 5 (SS) of each treatment period. The co-primary endpoints were exposure (AUCSS 0–24) and maximum plasma level (Cmax SS). Results: Twenty-four participants received ambroxol (male n = 13, 54.2%; mean ± standard deviation [SD] age 25.0 ± 6.4 years) and 23 completed the study. ER retard capsules provided similar AUCSS 0–24 compared to IR tablets (geometric means ratio [GMR] 110.7%; 90% confidence interval [CI] 99.8%, 122.7%) and effervescent tablets (GMR 106.9%; 90% CI 100.3%, 114.0%). ER retard capsules provided similar Cmax SS compared to IR tablets (GMR 84.7%, 90% CI 77.0%, 93.3%), and lower Cmax SS compared to effervescent tablets (GMR 80.9%, 90% CI 73.9%, 88.6%). Time to Cmax SS (tmax SS) was longer with ER retard capsules (6.0 h) than with IR tablets (2.0 h) or effervescent tablets (1.0 h). Conclusions: ER ambroxol 75-mg retard capsules given once daily showed a similar pharmacokinetic profile to IR ambroxol formulations and therefore can be used instead of these in the treatment of respiratory conditions. ClinicalTrials.gov identifier: NCT02036775. Plain Language Summary: Ambroxol is used to relieve the symptoms of respiratory conditions in which abnormal mucus secretion is a problem, including the common cold, acute and chronic bronchitis, and chronic obstructive pulmonary disease. Different formulations of ambroxol are available, including tablets and effervescent tablets that release the drug as soon as they are digested, but need to be taken twice a day, or extended release (retard) capsules that release the drug slowly over 24 h and can be taken once a day. This randomized, three-period, six-sequence crossover study in 24 healthy volunteers compared the pharmacokinetics of three formulations of ambroxol: tablets, effervescent tablets, and retard capsules. The amount of drug in the bloodstream over 24 h was similar with all three formulations, but (as expected) the time to reach peak plasma concentration was longer with the retard capsules than both forms of tablet. These results show that people who take ambroxol for respiratory conditions will receive the same amount of ambroxol whether they take retard capsules, standard tablets, or effervescent tablets. [ABSTRACT FROM AUTHOR]

Objective: Validation of a prospective new therapeutic concept in a proof of concept study is costly and time-consuming. In particular, pharmacologically active tool compounds often lack suitable pharmacokinetic (PK) properties for subsequent studies. The current work describes a PLGA-based formulation platform, encapsulating different preclinical research compounds into extended release microparticles, to optimize their PK properties after subcutaneous administration. Significance: Developing a PLGA-based formulation platform offers the advantage of enabling early proof of concept studies in pharmaceutical research for a variety of preclinical compounds by providing a tailor-made PK profile. Methods: Different model compounds were encapsulated into PLGA microparticles, utilizing emulsification solvent evaporation or spray drying techniques. Formulations aiming different release rates were manufactured and characterized. Optimized formulations were assessed in in vivo studies to determine their PK properties, with the mean residence time (MRT) as one key PK parameter. Results: Utilizing both manufacturing methods, tested tool compounds were encapsulated successfully, with a drug load between 5% and 40% w/w, and an extended release time up to 250 h. In the following PK studies, the MRT was extended by a factor of 90, resulting in prolonged coverage of the required target through level. This approach was confirmed to be equally successful for additional internal compounds, verifying a general applicability of the platform. Conclusion: For different active pharmaceutical ingredients (API), an optimized, tailor-made PK profile was obtained utilizing the described formulation platform. This approach is applicable for a variety of pharmacologically active tool compounds, reducing timelines and costs in preclinical research. [ABSTRACT FROM AUTHOR]

Ondansetron HCl (OSH) is a 5-HT3 receptor antagonist indicated for the prevention of nausea and vomiting associated with radiotherapy (adults: 8 mg, t.i.d) and/or chemotherapy (adults: 8 mg, b.i.d to t.i.d) and prevention of postoperative nausea and/or vomiting (adults: 8 mg, b.i.d). In elderly subjects, bioavailability may be somewhat higher (65%) and lower clearance, presumably due to reduced hepatic first-pass metabolism. OSH is extensively distributed in the body; about 70–75% of the drug in plasma is protein-bound and terminal elimination half-life is about 3 h after oral administration. The study was aimed to develop Push–pull Osmotic Pump (PPOP) bi-layered tablets for Ondansetron HCl ER tablets. The granulation was carried out using non-aqeous solvents followed by compression, seal coating, semi permeable coating, laser drilling (0.6 mm), and drug film coating with loading dose. The drug release was controlled by swelleable osmotic polymers of pull layer and push layer and orifice on the surface of tablet. The formulations were optimized for its core composition, extended release coating (Semipermeable membrane) polymer as to plasticizer ratio and orifice diameter. Optimized formulations were evaluated for micromeritic properties and in vitro drug release. The analytical methods were developed and validated to estimate in vitro drug potency, drug release, and in vivo pharmacokinetic parameters. Stability studies were done as per the ICH guidelines. The results of in vivo study concludes that the once OSH ER dose consistently maintains plasma concentration of drug within the therapeutic window over a period of 24 h. [ABSTRACT FROM AUTHOR]

The main objective of the present study was to explore the potential of matrix tablets as extended release dosage form of tianeptine, using HMPC K100 as a polymer. HPMC K100 extended the release of the drug from formulation due to the gel-like structure. Direct compression method was adopted to compress the tablets using different concentrations of polymer. Tablets were evaluated for pre-compression and post-compression parameters. Drug release study showed that tablet extends the release of drug with the increasing concentration of polymer. Drug, polymers and tablets were analyzed and/or characterized for compatibility, degradation, thermal stability, amorphous or crystalline nature via FTIR, DSC, TGA, XRD studies. SEM study predicted that tablets had a uniform structure. HPMC K100 based tablets were similar to that of the reference product. Acute toxicity study conducted on Swiss albino mice showed that matrix tablets were safe and non-toxic, as no changes in physical activity and functions of organs were observed. Biochemical and histopathological study revealed lack of any kind of abnormality in liver and renal function. Moreover, necrotic changes were absent at organ level. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of age on the safety and tolerability of ALO-02, an abuse-deterrent opioid formulation consisting of oxycodone hydrochloride and sequestered naltrexone hydrochloride, in patients with chronic pain.Methods: Data from two clinical studies in patients with chronic low back pain or chronic non-cancer pain were analyzed. Patients aged ≥18 years who required continuous around-the-clock opioid analgesia for an extended period were grouped into ≥65 years and <65 years age groups. Treatment-emergent adverse events (TEAEs), use of concomitant medications, clinical laboratory measurements, and occurrences of opioid withdrawal using reported adverse events (AEs) and Clinical Opiate Withdrawal Scale (COWS) scores assessed safety. Data pooling was employed for the titration and maintenance phases of both studies.Results: Respectively 805 and 436 patients received ≥1 dose of ALO-02 in the titration and maintenance phases; 121 (15.0%) and 83 (14.6%) patients, respectively, were aged ≥65 years in the titration and maintenance phases. Average doses of ALO-02 were lower in the older patients in both phases. Incidences of TEAEs were comparable between age groups in both phases and generally lower in the maintenance phase. Concomitant medications were taken more often by patients aged ≥65 years. Incidences of potentially clinically significant laboratory results were low in both phases with no clinically important differences between age groups. There were few reports of opioid withdrawal events as assessed by reported AEs and COWS scores. One patient aged ≥65 years experienced an AE of opioid withdrawal.Conclusions: The safety and tolerability of ALO-02 is similar in those aged ≥65 years and those aged <65 years with chronic pain.ClinicalTrials.gov identifiers: NCT01571362, NCT01428583. [ABSTRACT FROM AUTHOR]

The crosslinking of the polymer matrix with compatible macromolecules results in a three-dimensional network structure that offers an enhancement in the controlled release properties of the material. In this sense, this work aimed to improve the release profile of mefenamic acid (MAC) through crosslinking strategies. κ-Carrageenan/sericin crosslinked blend was obtained by covalent and thermal crosslinking and the different formulations were characterized. The gastroresistant potential and release profile were evaluated in the dissolution assay. The effect and characterization of the particles were investigated. Multiple units presented high entrapment efficiency (94.11–104.25), high drug loading (36.50–47.50 %) and adequate particle size (1.34–1.57 mm) with rough surface and visually spherical shape. The Weibull model showed that drug release occurred by relaxation, erosion and Fickian diffusion. Material stability and absence of MAC -polymer interactions were demonstrated by FTIR and thermogravimetric analysis. DSC showed a stable character of MAC in the drug-loaded beads. Moreover, the application studies of κ-Car/Ser/carboxymethylcellulose in the in vitro intestine mode showed that the crosslinked blend increased cell viability (>85 %), while free MAC exhibited a cytotoxic effect. Finally, the crosslinked k-Car/Ser blend MAC -loaded showed promising properties of a sustained release form of anti-inflammatory drug. [Display omitted] • κ-carrageenan/sericin with covalent and thermal crosslinking approach • kCAR/SER/MAC/CA with high entrapment efficiency (>94 %) and drug loading (>36 %) • Blend crosslinked with CMC increased the release time of mefenamic acid (MAC). • Crosslinked κ -carrageenan/sericin blend with pH-dependent behavior • CMC-crosslinked blend increased the cell viability of MAC (>85 %). [ABSTRACT FROM AUTHOR]

Abstract Background Antiemetic agent Meclizine HCl, widely prescribed in vertigo, is available only in immediate release dosage forms. The approved therapeutic dose and shorter elimination half-life make Meclizine HCl a potential candidate to be formulated in extended release dosage form. This study was aimed to develop extended release Meclizine HCl pellets by extrusion spheronization using natural and synthetic lipids. Influence of lipid type, drug/lipid ratio and combinations of different lipids on drug release and sphericity of pellets were evaluated. Methods Thirty two formulations were prepared with four different lipids, Glyceryl monostearate (Geleol®), Glyceryl palmitostearate (Precirol®), Glyceryl behenate (Compritol®) and Carnauba wax, utilized either alone or in combinations of drug/lipid ratio of 1:0.5–1:3. Dissolution studies were performed at variable pH and release kinetics were analyzed. Fourier transform infrared spectroscopy was conducted and no drug lipid interaction was found. Results Sphericity indicated by shape factor (eR) varied with type and concentration of lipids: Geleol® (eR = 0.891–0.997), Precirol® (eR = 0.611–0.743), Compritol® (eR = 0.665–0.729) and Carnauba wax (eR = 0.499-0.551). Highly spherical pellets were obtained with Geleol® (Aspect ratio = 1.005–1.052) whereas irregularly shaped pellets were formed using Carnauba wax (Aspect ratio = 1.153–1.309). Drug release was effectively controlled by three different combinations of lipids: (i) Geleol® and Compritol®, (ii) Geleol® and Carnauba wax and (iii) Geleol®, Compritol® and Carnauba wax. Scanning electron microscopy of Compritol® pellets showed smooth surface with pores, whereas, irregular rough surface with hollow depressions was observed in Carnauba wax pellets. Energy dispersive spectroscopy indicated elemental composition of lipid matrix pellets. Kinetics of (i) Geleol® and Compritol® pellets, explained by Korsmeyer-Peppas (R2 = 0.978–0.993) indicated non-Fickian diffusion (n = 0.519-0.597). Combinations of (ii) Geleol® and Carnauba wax and (iii) Geleol®, Compritol® and Carnauba wax pellets followed Zero-order (R2 = 0.991–0.995). Similarity test was performed using combination of Geleol® and Compritol® (i) as a reference. Conclusions Matrices for the extended release of Meclizine HCl from extruded-spheronized pellets were successfully formed by using three lipids (Geleol®, Compritol® and Carnauba wax) in different combinations. The encapsulated pellets of Meclizine HCl can be effectively used for treatment of motion sickness, nausea and vertigo for extended period of time.

ObjectivesTo compare gabapentin extended-release, a gastro-retentive formulation, in relieving postamputation pain among gabapentin-experienced and gabapentin-naïve patients.DesignOpen-labeled pilot study.SubjectsSixteen patients with postamputation pain (8 patients in the gabapentin-experienced and 8 patients in the gabapentin-naïve groups).MethodsPatients 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).ResultsPatients 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).ConclusionOnce-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.