Immediate-release Formulation Research Articles

Prediction of pharmacokinetic parameters and dose of pregabalin gastroretentive formulation in healthy adults, healthy pediatrics and renal-impaired geriatrics

IntroductionThe study aimed to predict pregabalin individualized doses in healthy adults, pediatrics and renal impaired geriatric patients by using physiological based pharmacokinetic (PBPK) model for gastroretentive formulation producing comparable pharmacokinetics to that of the immediate release (IR) formulation to obtain doses on basis of their physiological needs. MethodologyThe PBPK model of pregabalin was developed for a healthy adult, healthy pediatrics, healthy and renal impaired geriatric (with creatinine clearance, CLcr = 90, 60, 30, 15 ml/min) at different once daily doses of the IR and GR formulations. In PBPK adult model, PK parameters were also predicted in fasting and fed condition after administration of pregabalin 300 mg of IR and 330 mg of sustained release (SR) formulations. The doses in the renal impaired geriatrics and healthy pediatric population were computed by a dose decremental method and were selected at which the comparable pharmacokinetics parameters to that of the reported values in healthy adults were obtained. ResultsIn healthy adults, comparable PK parameters were obtained after administration of pregabalin 300 mg of IR and 330 mg of SR formulation in fasting and fed state and there was no effect of food on the bioavailability of pregabalin. In neonates to infants and toddlers, the same AUC0-48 to that of the adults was obtained with a 40–82 mg dose of GR formulation of pregabalin. For pre-schooled and schooled virtual populations, a dose of 40–170 mg and for adolescents, 40–330 mg produced the comparable AUC0-48 as that of the normal adults, 42.20 ± 32 μg h/ml. The predicted doses of gastroretentive formulation in renal impaired geriatric with CLcr, 60, 30, and 15 ml/min were 220–330, 110 to 220 and 55–85 mg, respectively to achieve the same level of PK parameters as elder individual with normal CLcr (90 ml/min) after administration of 330 mg of gastroretentive formulation. ConclusionPBPK models effectively predicted dose for the modified GR pregabalin formulations in special populations such as pediatrics and elder renal impaired individuals.

Evaluation of a Modified Flow-Through Method for Predictive Dissolution and In Vitro/In Vivo Correlations of Immediate Release and Extended Release Formulations

The present study evaluated the ability of a modified flow-through method for predicting in vivo performance of immediate release (IR) and extended release (ER) formulations. In vitro dissolution of two model drugs, paracetamol IR tablets and felodipine ER tablets, was investigated under tuned conditions using the modified flow-through method and compared with the compendial quality control (QC) basket method. The in vivo absorption properties of paracetamol IR tablets and felodipine ER tablets were investigated in healthy volunteers. In vitro-in vivo correlation (IVIVC) analysis was performed based on the obtained in vitro and in vivo data. Our results demonstrated that the compendial QC method was not able to reflect in vivo actual absorption, while satisfactory discriminatory power and comparable in vitro dissolution/in vivo absorption were achieved for both paracetamol IR tablets and felodipine ER tablets by the modified flow-through method. This study indicated that the modified flow-through method is a potential tool to reflect in vivo performance of the IR and ER formulations.

Dynamic flowsheet model development and digital design of continuous pharmaceutical manufacturing with dissolution modeling of the final product

The integration of continuous unit operations imposes a challenge on the pharmaceutical companies aspiring to achieve plant-wide continuous manufacturing due to the additional complexity of the dynamic interactions, process control and quality assurance. To overcome this challenge, flowsheet modeling emerged as a viable tool to gain deeper process knowledge. In this work, the dynamic model of the integrated continuous manufacturing of acetylsalicylic acid (ASA) was formed based on real continuous unit operations. Furthermore, the surrogate model of the in vitro dissolution test of ASA capsules was integrated into the flowsheet model the first time to analyze the integrated manufacturing in light of the dissolution specifications of an immediate-release formulation. Systematic optimization studies were performed on the integrated process and on the continuous unit operations step-by-step, which clearly revealed the impact of the plant-wide dynamic modeling, as the integrated approach resulted in the threefold increase in the overall productivity and the parallel decrease in the required reactant excess. Sensitivity analyses of the operating conditions and the kinetic parameters were also performed. The crystallization temperature emerged as one of the most critical parameters, which variation could even result in the failure of the dissolution specification. Moreover, by calculating the time-varying sensitivity indices, the dynamics of the error propagation could be studied. These results could facilitate the integration of existing continuous units, the development of the control strategy, and encourage the implementation of dissolution surrogate models into process flowsheet simulations.

Development and evaluation of physical and release properties of a tablet formulation containing dry hydroethanolic extract from Lippia alba leaves

The development of an immediate-release solid formulation which contains natural products is a challenge considering several variables. These include the physical properties of the drug, the complex composition of the herbal extracts, and its ability to be released in the body. The present study describes the development and characterization of an immediate-release tablet formulation of a hydroethanolic extract of Lippia alba (Mill.) N. E. Br. dried leaves which possess potential gastroprotective properties and sedative effects. L. alba is a Brazilian herb known as “cidreira,” and the ethnopharmacological use of the leaf infusion has been reported in many South and Central America countries. However, no study has considered phytotherapeutics containing extracts of this herb. To achieve this goal, 14 solid formulations were produced using direct compression, wet granulation, or dry granulation. These were characterized by physical tests, such as average weight, friability, hardness, and disintegration tests. The tablet formulation produced by the dry granulation of 100 mg of the L. alba extract exhibited better physical properties, and it was characterized using acteoside (verbascoside) as a chemical marker, presenting 6.9 % w/w of acteoside content per tablet, corresponding to 41.3 mg of this constituent per unit. This formulation dissolves rapidly in simulated gastric fluid without enzymes, achieving amounts >80 % after 20 min. Thus, an immediate-release tablet formulation with L. alba extract was successfully prepared.

Assessing Food Effects on Oral Drug Absorption Based on the Degree of Renal Excretion.

Food intake influences the pharmacokinetics of orally administered drugs by altering drug absorption, metabolism, and excretion. A drug which is mainly excreted into urine as parent drug is usually highly water-soluble and metabolically stable. Food intake is not expected to significantly affect its extent of oral absorption, metabolism, and excretion. Therefore, we hypothesize that an orally administered drug with significant renal excretion should not have a dramatic food effect (FE). To test our hypothesis, we summarized the FE for orally administered immediate-release (IR) and modified-release (MR) formulations approved by the US FDA from 1998 to 2019, focusing on drugs undergoing significant renal excretion. Totally, 98 active pharmaceutical ingredients (APIs) in IR formulations and 34 APIs in MR formulations were selected. The results demonstrate that the area-under-the-curve (AUC) for IR drug products with fur_unchanged_po > 10% is unlikely to be affected by food, although the peak plasma concentration (Cmax) may increase or decrease by up to 50%. Compared with IR drug products with fur_unchanged_po > 10%, MR drug products with fur_unchanged_po > 10% tend to have more significant FE. Although our proposed approach cannot substitute a clinical FE study, it could be a useful addition to early drug development to get an initial sense of the potential for FE for a drug candidate.

Changes in utilization of immediate-release, extended-release, and liquid formulation medications relative to bariatric surgery: a segmented regression analysis.

Changes in gut anatomy following bariatric surgery impacts medication absorption, often requiring changes in medication formulations. To assess changes in utilization of extended-release (ER), immediate-release (IR), and liquid formulations 360 days before and after bariatric surgery. Large U.S. administrative claims database of privately insured beneficiaries, January 2005 through December2018. We included patients aged ≥18 years with 360 days of continuous enrollment before and after date of bariatric surgery (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy [SG]). The proportion of each formulation (ER, IR, or liquid) of oral prescription medications filled during the study period were assessed in twelve 30-day windows before and after bariatric surgery and stratified by bariatric surgery type. Segmented regression analysis was used to assess filled medication categorized by formulation before and after bariatric surgery overall and RYGB relative to SG. Among 122,866 included patients, there were increases in the proportion of patients on each formulation before and after surgery attributed to proton pump inhibitors, opioids, antiemetics, and ursodiol. After removing these acutely used medications, we found a 40% immediate reduction in patients on ER medications (P < .0001), 15% immediate reduction in patients on IR medications (P < .0001), and a nonsignificant increase in patients on liquid formulations (P = .1340). Despite reductions in ER formulations, many patients continued on this formulation which may potentially contribute to poor outcomes.

Quality by Design Applied Development of Immediate-Release Rabeprazole Sodium Dry-Coated Tablet.

The aim of this study was to develop immediate-release oral rabeprazole sodium tablets with rapid efficacy and gastric stability for the treatment of gastroesophageal reflux disease. Rabeprazole sodium is a commonly prescribed proton pump inhibitor; however, it is extremely unstable and degrades in acidic environments. Hence, it has been manufactured and supplied only in enteric-coated tablet form, while immediate-release (IR) formulations for this drug are very limited. In this study, we applied the quality by design (QbD) approach to formulate and optimize an IR dry-coated tablet containing rabeprazole sodium as an inner core with an outer sodium bicarbonate layer to stabilize the active pharmaceutical ingredient at gastric pH. We also investigated the stability of the pharmaceutical dosage form and its pharmacokinetic profile. The results show that the developed tablets are stable for approximately 12 months and have a high dissolution rate, greater than or equal to 90% at 30 min. Further, in vivo beagle pharmacokinetics confirmed that the newly developed IR tablet had an AUCt which is bioequivalent to the existing delayed-release rabeprazole tablet; however, its Tmax was 0.5 h, which is up to seven times faster than that of the existing tablet. Moreover, the IR tablet was found to immediately absorb in the stomach. Hence, the development of IR tablets can be used as a platform to overcome the technical and commercial limitations currently associated with various proton pump inhibitors used to treat patients with gastroesophageal reflux disease that require immediate therapeutic relief.

Pharmacokinetics and Pharmacodynamics of Esomeprazole/Sodium Bicarbonate Immediate-Release Capsules in Healthy Chinese Volunteers: A Cross-Over, Randomized Controlled Trial.

Esomeprazole delayed release tablets (ESO) are one of the most effective treatments for acid-related disorders. The purpose of this study is to compare the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of an immediate-release capsule formulation containing esomeprazole 20mg and sodium bicarbonate 1100mg (IR-ESO) compared to those of the esomeprazole delayed release tablet 20mg (ESO). In addition, the impact of CYP2C19 gene polymorphisms on PK and PD was evaluated. A single-center, open-label, randomized, 2-treatment, 2-sequence, and 2-period crossover study was conducted in 40 healthy Chinese subjects. Subjects received either IR-ESO or ESO for 5days. After single- and multiple-dosing administration, blood samples were collected for PK analysis, and intragastric pH was assessed by 24-h pH monitoring. The CYP2C19 gene polymorphisms were analyzed by Sanger sequencing. The geometric mean ratios (90% confidence interval) [GMR (95%CI)] of IR-ESO/ESO for AUCinf [single dose: 103.60% (96.58%, 111.14%), multiple doses: 101.65% (97.88%, 105.57%)] were within the range of 80.00-125.00%. The AUCinf showed an increasing trend between CYP2C19 extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) after single-dose and multiple-dose administration (p<0.05). The GMR (95%CI) of IR-ESO/ESO for 24-h integrated gastric acidity from baseline [single dose: 101.07% (96.56%, 105.78%), multiple doses: 101.24% (97.74%, 104.86%)] were within the range of 80.00-125.00%. The percentage changes in 24-h integrated gastric acidity from baseline was significant difference between EM, IM, and PM after single-dose IR-ESO and ESO (p<0.05). Drugs were all well tolerated, and there were no significant differences in adverse events between IR-ESO and ESO. This study showed that IR-ESO can inhibit the secretion of gastric acid rapidly and continuously, and that the PK and PD of IR-ESO are affected by CYP2C19 genotypes. The GMR (95% CI) of IR-ESO/ESO for AUCinf and the percentage changes in 24-h integrated gastric acidity from baseline were all within the range of 80.00-125.00%. Chinese Clinical Trial Registry: ChiCTR1900024935.

Once-Daily Extended-Release Levetiracetam Improves Medication Compliance in Adolescent Epilepsy Patients

Purpose Since pharmacologic agents are the mainstay of epilepsy treatment, drug compliance is one of the most important factors in seizure control. Once-daily levetiracetam (LEV) has been proven to have the same efficacy as that of an immediate-release (IR) formulation. A reduced number of doses may improve drug compliance and patient satisfaction. The aim of this study was to assess drug compliance and patient satisfaction when changing from IR to an extended-release (ER) formulation. Methods Adolescent patients diagnosed with epilepsy who were taking LEV from 2018 to 2020 were included in this study. Compliance charts were reviewed retrospectively. We compared the frequency of seizure occurrence with the frequency of skipping doses and adverse effects before and after changing formulations. Changes in subjective compliance and satisfaction were also investigated. Results Among 585 patients taking LEV, 44 were included in this study. The average age of the included patients was 16.4±2.0 years. There was no significant change in the average seizure frequency (P=0.491) after switching formulations. Objective compliance based on chart records significantly improved after switching formulations (P=0.021). Additionally, 26 of 44 patients mentioned how they felt about switching formulations, of whom 25 (96.2%) were satisfied with the ER formulation. Thirteen of 24 patients (54.2%) reported better compliance. Conclusion Our study shows that the efficacy of LEV ER was similar to that of the IR formulation. The reduced number of medication doses improved patient satisfaction and medication compliance. LEV ER may be preferable in adolescent epilepsy patients. Keywords: Compliance; Delayed-action preparations; Levetiracetam; Epilepsy

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin’s effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Exploring the performance-controlling tablet disintegration mechanisms for direct compression formulations

The design and manufacture of tablets is a challenging process due to the complex interrelationships between raw material properties, the manufacturing settings and the tablet properties. An important factor in formulation and process design is the fact that raw material and tablet properties drive the disintegration and dissolution performance of the final drug product. This study aimed to identify the mechanisms which control tablet disintegration for 16 different immediate-release placebo formulations based on raw material and tablet properties. Each formulation consisted of two fillers (47% each), one disintegrant and a lubricant. Tablets were manufactured by direct compression using four different combinations of the fillers microcrystalline cellulose (MCC), mannitol, lactose and dibasic calcium phosphate anhydrous (DCPA). The disintegration mechanism was primarily driven by the filler combination, where MCC/lactose tablets were identified as wettability controlled, MCC/mannitol tablets as dissolution controlled and DCPA-based tablets (MCC/DCPA and lactose/DCPA) as swelling controlled. A change of 2% in porosity for the wettability controlled tablets (MCC/lactose) caused a significant acceleration of the disintegration process (77% reduction of disintegration time), whereas for swelling controlled tablets (MCC/DCPA) the same porosity change did not considerably impact the disintegration process (3% change in disintegration time). By classifying these formulations, critical formulation and manufacturing properties can be identified to allow tablet performance to be optimised.

PHARMACOKINETIC STUDY OF OLOPATADINE 10 MG EXTENDED RELEASE TABLET IN COMPARISON WITH OLOPATADINE 5 MG IMMEDIATE RELEASE TABLET IN INDIAN POPULATION

Objective: This study was designed to assess the pharmacokinetics of single dose of olopatadine hydrochloride 10 mg extended release (ER) tablet of Ranbaxy laboratories limited (two test formulations) with two doses of Allelock® 5 mg immediate release (IR) tablets of Kyowa Hakko Kogyo Co. Ltd. (reference formulation R), in healthy, adult, Indian male subjects under fed condition.&#x0D; Methods: Fifteen healthy male volunteers, 26.07±6.62 y in age and 57.17±6.68 kg in body weight, were divided into three groups and received either olopatadine hydrochloride 10 mg ER tablet or two doses of Allelock® 5 mg tablets in each period. Blood samples were taken at predetermined time points and plasma concentrations of olopatadine were monitored by liquid chromatography mass spectrometric (LCMS/MS). Pharmacokinetic (PK) parameters AUC0-t, AUC0-24, AUC0-∞, and Cmax were calculated for olopatadine using WinNonlin. A statistical analysis was performed on PK data using SAS system.&#x0D; Results: The ER formulations showed a similar AUC as compared to the IR formulation and there was no statistically significant difference in AUC of test formulation A and B and reference R. The ratios of AUC0-t, AUC0-24 and AUC0-∞ for A/R were 91.08, 94.90 and 91.32 and for B/R were 89.63, 93.95 and 89.63 respectively. The ER formulations reported a higher Cmax value as compared to IR formulation. The ratios of Cmax for A/R and B/R were 151.09 and 167.96 respectively. But these higher Cmax values did not pose any safety issue as there were no serious adverse events reported during the study.&#x0D; Conclusion: In conclusion, we can say that though the study drugs did not meet the bioequivalence criteria set by regulatory agencies, but this study gave an insight about PK properties of olopatadine extended release formulation and given an idea about effect of smoking on the PK profile of olopatadine which can be studied in future.

Biorelevant Dissolution Method Development For Dutasteride/Tamsulosin Hydrochloride Modified Release Capsule - A Prognostic Tool For Oral Drug Absorption

The research work was aimed to develop a biorelevant dissolution method for fixed dose combination containing Dutasteride 0.5 mg in immediate-release form and Tamsulosin 0.4 mg in modified-release form. Mean plasma concentration achieved after oral administration to human under pre-prandial condition are deconvoluted using Wagner-Nelson deconvolution method, to achieve target dissolution profile. The dissolution profile observed using office of generic drugs recommended dissolution media was observed to be faster than the target dissolution profile. Tamsulosin being a modified-release multiparticulate system, biorelevant dissolution method was developed with Fasted state simulated change over dissolution media, using USP Apparatus 3 (reciprocating cylinder). Dutasteride being an immediate-release form, dissolution method was developed with single dissolution media, by extending the dissolution run time upto C max . Dissolution media, media volume and Dips Per Minute (DPM) are optimized by performing full factorial design of experiment. The ANOVA result interprets the biorelevant dissolution media for Tamsulosin part is 250 ml of Fasted state simulated change over dissolution media with 15 DPM, based on desirability factor of 0.7768 and for Dutasteride part 250 ml of pH 6.5 Fasted state simulated intestinal fluids with 7 DPM, based on desirability factor of 0.8988. The regression co-efficient (R 2 ) value of 0.999 and 0.996 demonstrates a very good in-vitro/in-vivo correlation under pre-prandial condition for Tamsulosin and Dutasteride respectively. The developed method shall be used as a predictive in-vitro tool for evaluation of in-vivo performance under pre-prandial condition.

Evaluation of partial area under the curve in bioequivalence studies using destructive sampling design.

Product blood-level in vivo bioequivalence (BE) studies typically involve complete blood concentration-time profiles generated for each subject. Accordingly, each subject provides the estimates of the rate and extent of drug absorption. However, repeated blood draws are not always feasible for studies using small animals because of handling or blood volume (e.g., fish or in toxicokinetic studies when only single samples can be taken per animal). Although several proposals have been published for comparing the product extent of absorption, the issue of comparative absorption rates remains unresolved. In this paper, we propose to apply the Bailer-Satterthwaite-Fieller confidence interval for estimating the ratio of partial area under the curve in studies that use a destructive sampling design (one blood sample per subject). To characterize the behavior of this alternative approach, we examine the impact of partial area cutoff time, blood sampling schedule, and the number of subjects included at each sampling time. Using simulated situations reflective of the issues encountered with immediate-release veterinary formulations, we compare BE conclusions resulting from the use of this approach with simulated results that assuming repeated blood draws from each study subject.

'Doctor, will this medicine give me cancer?': Lessons from nitrosamines and extended-release metformin.

The withdrawal in the USA of metformin extended-release formulations [1,2] due to a contaminant with carcinogenic potential has raised concerns. An impurity from the manufacturing process has been implicated, which has been found only in the extended-release and not in the immediate-release metformin formulations.

Real-World Evidence to Contextualize Clinical Trial Results and Inform Regulatory Decisions: Tofacitinib Modified-Release Once-Daily vs Immediate-Release Twice-Daily for Rheumatoid Arthritis.

IntroductionTofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To provide additional clinical evidence in regulatory submissions for a modified-release (MR) once-daily (QD) tofacitinib formulation, we compared real-world adherence and effectiveness between patients initiating the MR QD formulation and patients initiating an immediate-release (IR) twice-daily (BID) formulation.MethodsTwo noninterventional cohort studies were conducted. First, adherence and two effectiveness proxies were compared between patients with RA who newly initiated tofacitinib MR 11 mg QD or IR 5 mg BID in the IBM® MarketScan® Commercial and Medicare Supplemental US insurance claims databases (March 2016–October 2018). Second, using data collected in the Corrona US RA Registry (February 2016–August 2019), two Clinical Disease Activity Index (CDAI)-based measures of effectiveness were compared between tofacitinib MR 11 mg QD and IR 5 mg BID, and against noninferiority criteria derived from placebo-controlled clinical trials of the tofacitinib IR formulation. Multiple sensitivity analyses of the registry data were conducted to reassure regulators of consistent results across different assumptions.ResultsIn each study, approximately two-thirds of patients initiated the MR formulation. In the claims database study, improved adherence and at least comparable effectiveness were observed with tofacitinib MR vs IR over 12 months, particularly in patients without prior advanced therapy. In the registry study, the noninferiority of tofacitinib MR vs IR was demonstrated for both CDAI outcomes at ~6 months; this finding was robust across multiple sensitivity analyses.ConclusionThese results demonstrate the value of real-world evidence from complementary data sources in understanding the impact of medication adherence with a QD formulation in clinical practice. These analyses were suitable for regulatory consideration as an important component of evidence for the comparability of tofacitinib MR 11 mg QD vs IR 5 mg BID in patients with RA.Trial RegistrationClaims database study: ClinicalTrials.gov identifier NCT04018001, retrospectively registered July 12, 2019. Corrona US RA Registry study: ClinicalTrials.gov identifier NCT04267380, retrospectively registered February 12, 2020.Electronic supplementary materialThe online version of this article (10.1007/s12325-020-01501-z) contains supplementary material, which is available to authorized users.

Systematic Development of Bicalutamide Immediate Release Pellets Using Aeroperl and Non-MCC Extruder Aid

Background: The Microcrystalline Cellulose is called as a gold standard for the manufacture of pellets. The poor disintegration leads to incomplete drug release that restricts the use of MCC in the immediate-release formulation. Objective: The present work aims to explore non-MCC extruder aid for pellet formulation and solubility modulation potential of Aeroperl® 300 Pharma. Methods: Bicalutamide (BCL) was selected as a model BCS class-II drug. The solubility of BCL was assessed in different vehicles such as polyethylene glycol, propylene glycol, and Tween by carrying out phase solubility study. The suitable vehicle was selected based on the higher solubility of BCL. The vehicle was further adsorbed on newer adsorbent Aeroperl® 300 Pharma to formulate liquisolid granules. The liquisolid granules were further incorporated into the pellet using mannitol and microcrystalline cellulose as an extruder aid. Box-Behnken design was adopted for the optimization of formulation considering MCC: mannitol ratio, the concentration of HPMC and spheronizer speed as independent factors whereas drug release at 30 min, disintegration time and aspect ratio were selected as dependent variables. The pellets were evaluated for different evaluation parameters. Results: Propylene glycol was selected for the formulation of liquisolid technique based on the results of the phase solubility study. Propylene glycol containing BCL was adsorbed on Aeroperl 300 Pharma. The optimized batch was selected exploring the Design-Expert software by considering the limits of different responses. Pellet had excellent flowability. Friability was found to be within the range (&lt;1%). Pellets were found to be spherical and had pores on the surfaces. Conclusion: Liquisolid granules containing newer solubilizer Aeroperl was found to be a promising approach for the improvement in the solubility of the drug. The use of mannitol with MCC has a profound effect on disintegration time, without altering flow property and other parameters. No patents were reported on the combination of Bicalutamide, mannitol and Aeroperl. The critical finding of the present work is to use mannitol as an extruder aid to fasten the disintegration leads to complete drug release within a short period of time. Aeroperl and Mannitol, MCC: mannitol ratio, the concentration of HPMC and spheronizer speed were found to be significant and had the potential effect in pellet formulation.

Efficacy and Safety of Ivabradine Once-Daily Prolonged-Release versus Twice-Daily Immediate-Release Formulation in Patients with Stable Chronic Heart Failure with Systolic Dysfunction: A Randomized, Double-Blind, Phase 3 Non-Inferiority (PROFICIENT) Study.

IntroductionDosing frequency is an important factor influencing medication compliance in patients with heart failure (HF), which in turn is imperative in achieving the desired therapeutic outcome. Here we assessed the efficacy and safety of ivabradine prolonged-release (PR) once-daily (test) vs. ivabradine immediate-release (IR) twice-daily (reference) formulations in patients with stable chronic HF with systolic dysfunction.MethodsPatients with sinus rhythm and heart rate (HR) ≥ 50 bpm, left ventricular ejection fraction ≤ 40% (HF with reduced ejection fraction), on guideline-based standard care, receiving a stable dose of ivabradine IR 5/7.5 mg twice daily for ≥ 1 month were enrolled in this randomized, double-blind, phase 3 non-inferiority study. Patients were randomly assigned 1:1 to ivabradine PR (10 mg/15 mg) based on the ivabradine IR dosage or continued ivabradine IR (5 mg/7.5 mg). The primary endpoint was change in resting ECG HR from baseline to the end of 3 months, assessed by 12-lead ECG. Safety assessments and 24-h Holter HR monitoring (in a subgroup of patients) were also performed. Non-inferiority was concluded if the upper limit of the 95% CI of the difference between the test and reference was less than the margin of 6.5 bpm in the per-protocol set.ResultsA total of 169 out of 180 randomized patients (93.9%) completed the study (PR = 84; IR = 85). The least-square mean (standard error [SE]) for change in HR from baseline to 3 months was 0.76 (1.188; 95% CI −1.59:3.11) in ivabradine PR vs. ivabradine IR, which was within the pre-specified margin of 6.5 bpm, confirming the non-inferiority of ivabradine PR. The change from baseline to 3 months was comparable between the treatment groups for 24-h Holter ECG monitoring (p = 0.3701), mean HR awake (p = 0.3423), and mean HR asleep (p = 0.1501). Thirty-nine treatment-emergent adverse events (TEAEs) were reported; the majority in both groups were of mild or moderate severity and were subsequently resolved. Seven serious adverse events were reported (ivabradine PR = 2; ivabradine IR = 5), of which one was fatal (ivabradine IR group). The bradycardia events reported were comparable between groups.ConclusionIvabradine PR was found to be non-inferior to ivabradine IR in the management of patients with stable CHF, with a comparable safety profile. Once-daily ivabradine PR effectively maintained the HR in patients shifted from the ivabradine IR twice-daily regimen, and thus may aid in improving treatment compliance.Trial RegistrationCTRI/2018/04/013464 (Trial Registered Prospectively on 24/04/2018)

Biliary Excretion-Mediated Food Effects and Prediction.

Many orally administered drugs with negative food effects (i.e., lower exposure under fed conditions) are often primarily or partially eliminated by biliary excretion. The aim of this study is to assess the potential correlation between a negative food effect and biliary excretion. Correlation analysis was conducted using a training dataset containing 27 drugs which met the following criteria: (1) immediate-release formulations, (2) shows a negative food effect, (3) > 10% biliary clearance, and (4) does not undergo extensive metabolism. A correlation between fed-state biliary clearance (CLb,fed) and fasted-state biliary clearance (CLb,fast) (y = 1.81*x, R2 = 0.68) was observed. The 1.8-fold increase in biliary clearance was then used as a correction factor to improve physiologically based pharmacokinetic (PBPK) prediction of food effects for 12 test drugs. The mean deviations of predicted fed/fasting AUC ratio and Cmax ratio from clinically observed values were reduced from 32.4 to 17.2% and from 63.3 to 54.3%, respectively. In contrast to the positive food effects on most biopharmaceutics classification system (BCS) class II drugs for which food-stimulated bile flow increases drug solubility and absorption, our results suggest that the elimination of biliary excreted drugs is increased by food-stimulated bile flow, resulting in negative food effects.

Pharmaceutical opioids utilisation by dose, formulation, and socioeconomic status in Queensland, Australia: a population study over 22years.

Background Prescription opioids are a central aspect of pain management and as the prevalence of pain is increasing so is the rate of use of prescription opioids. Increased opioid prescriptions increases the risk of deaths and morbidity. Objective To (a) describe the 22-year trend of prescription opioid dispensing in Queensland, (b) examine the effect of opioid dose, formulation and socioeconomic status on the number of prescriptions dispensed. Design/setting Retrospective analysis of data from the Monitoring of Drugs of Dependence system of the Monitored Medicines Unit of Queensland Health, Australia. Participants Queensland residents (3.3 million) from 18years old dispensed 18.8 million opioid prescriptions from January 1997 to December 2018. Results Opioid prescriptions dispensed annually increased to over two million in 2018 from about 150,000 prescriptions in 1997. The number of prescriptions for modified-release formulations dispensed annually was three times higher compared to the immediate-release formulations. Oxycodone accounted for over 60% of prescriptions for pharmaceutical opioids since 2013. There was an increase in the number of prescriptions dispensed as socioeconomic status decreased and modified-release opioid formulations positively affects the pattern of dispensing. The highest increase in number of prescriptions dispensed (for all opioids) was observed among the high socioeconomic status (IRR = 1.25, 95% CI 1.25, 1.26). The disparities in the annual number of prescriptions across dose categories are wider in the modified-release than the immediate-release formulations. Conclusion The dispensing of opioids increased significantly in Queensland. There was a positive relationship between the increased dispensing of opioids and locations of lower socioeconomic status.