Extended-release Tablet Formulation Research Articles

Opportunities and Challenges: Process Raman for the Real-Time Release Testing (RTRT) of Extended-Release Formulations

The use of a process analytical technology has been demonstrated using near-infrared spectroscopy for continuous manufacturing of pharmaceutical formulations and is within the scope of the U.S. Food and Drug Administration's real-time release testing initiative. While effective for simple formulations, this preliminary study investigates whether such a spectroscopic surrogate application can replace pharmaceutical dissolution testing for extended-release formulations. In this study, we will assess the use of process Raman spectroscopy for real-time dissolution testing. Extended-release tablet formulations often accomplish the release rate delay through the addition of gelling agents. In this work, hydroxypropyl methylcellulose (HPMC) polymers were used to formulate extended-release niacin tablets. Process Raman spectroscopy was evaluated as a tool to effectively model dissolution profiles to determine if the optical technique has the ability to differentiate HPMC polymers from the background and be selective for the polymer type employed. Our preliminary work indicates that while Raman can effectively detect and monitor the niacin response of the tablet formulations, there are not enough unique spectral features between the different HPMC polymers to selectively resolve their responses. Additional measurements and chemometric analysis might suggest otherwise. Thus, for extended-release tablet applications with continuous manufacturing, further dissolution surrogate development is needed.

Formulation Strategies for Sustained-Release Tablet Dosage Forms

Sustained-release or extended-release tablet formulations are designed to release the active pharmaceutical ingredient at a slower rate and over an extended period compared to conventional immediate-release dosage forms. This controlled drug delivery approach offers several advantages including improved patient compliance, maintenance of therapeutic drug levels, reduced side effects, and protection of drug molecules from degradation. [1,2] Various formulation approaches have been explored for achieving sustained drug release from tablet matrices. This review discusses key formulation aspects like rate-controlling polymers, factors influencing drug release, manufacturing techniques, and recent advances aided by quality-by-design principles and mathematical modeling for optimizing sustained-release profiles. Regulatory considerations for evaluation and approval are also highlighted

Development of Extended-Release Formulations Containing Cyclobenzaprine Based on Physiologically Based Biopharmaceutics Modeling and Bioequivalence Safe Space

The use of physiologically based biopharmaceutics modeling (PBBM) and bioequivalence safe space is increasingly common for immediate-release drug products. However, for extended-release (ER) formulations there are only a few examples of this application. In this study, we developed ER formulations containing cyclobenzaprine 15 mg, supported by PBBM and bioequivalence safe space. Four formulations were prepared, F1, F2, F3 (ER mini-tablet formulations) and F4 (ER tablet formulation), and the dissolution profiles were evaluated. The dissolution profile of the reference drug product was also evaluated and used to set a bioequivalence safe space. A PBBM was set up, evaluated, and used to predict the in vivo behavior of the formulations. The bioequivalence safe space was calculated to be between – 25% and + 75% of the k1 and Tlag values of the dissolution profile of the reference drug product when applying the first-order dissolution kinetic model. All time points of the dissolution profile of the ER mini-tablet formulation F2, were within the safe space, and was approved in 10 of 10 trials of crossover virtual bioequivalence studies. Based on the PBBM strategy and bioequivalence safe space, it was possible to develop an ER mini-tablet formulation virtually bioequivalent to the reference drug product, even though this formulation failed the f2 test.

Formulation and evaluation of extended-release tablets of trimetazidine HCL

The present study was undertaken with an aim to formulate develop and evaluate Trimetazidine HCL extended release matrix tablets using different polymers as release retarding agent. Pre formulation study was done initially and results directed for the further course of formulation. Based on Pre formulation studies different batches of Trimetazidine HCL were prepared using selected excipients. Powders were evaluated for tests Angle of repose, Bulk density, tapped density, compressibility index, and Hausner ratio before being punched as tablets. It was concluded that the tablets of batch F9 had considerable swelling behaviors and in vitro drug release. Percentage drug release in 8 hr is 80.77. It was observed that tablets of batch F9 followed the Huguchi release profiles. From the results and discussion it is concluded that formulation of Extended release matrix tablet of HCL containing HPMC K-15 (19.44%) and Hyper mellose (19.44%), Ethyl cellulose (19.44%) batch F9 can be taken as an ideal or optimized formulation Extended release matrix tablet for 8 hour release as it fulfills the requirements for extended release matrix tablet.

A Bioequivalence Comparison at Steady State between the Newly Developed Once-Daily Extended Release Tablet Formulation and the Approved Twice-Daily Tablet Formulation of Deutetrabenazine (P2-11.015)

<h3>Objective:</h3> To assess the bioequivalence (BE) and relative bioavailability (BA) between a once-daily (QD) extended release formulation of deutetrabenazine and the approved twice-daily (BID) formulation at steady state under fed conditions. <h3>Background:</h3> Deutetrabenazine (Austedo, Teva) in a BID formulation is an approved treatment for tardive dyskinesia and chorea associated with Huntington disease. A QD formulation has been developed. <h3>Design/Methods:</h3> In a phase 1 study (TV50717-BE-10179) using a randomized cross-over design, healthy adult males and females (n=262) received 24 mg QD formulation (test) as a once daily administration and 12 mg BID formulation (reference) as a twice daily administration, each for 7 days in fed state. Safety was assessed throughout the study and pharmacokinetic (PK) blood sampling occurred on days 4–7. Test-to-reference geometric mean ratios (GMRs) and 90%CIs for BE acceptance limits (80.00% to 125.00%) were computed for PK parameters (area under the plasma concentration curve over 24-hours at steady-state [AUC_0–24hr,ss] and maximum plasma concentration at steady-state [C_max,ss]) of deutetrabenazine, active metabolites, deuterated α-HTBZ and β-HTBZ, and total (α+β)-HTBZ. Relative BA was assessed for C_max,ss of the active metabolites (individually and as a total sum). <h3>Results:</h3> The GMRs (90%CIs) for AUC_0–24hr,ss were 115.15% (110.38–120.14%) for deutetrabenazine, 95.40% (94.13–96.69%) for α-HTBZ, 94.13% (92.35–95.94%) for β-HTBZ, and 95.05% (93.67–96.46%) for total (α+β)-HTBZ. GMRs of C_max,ss were 95.09% (90.60–99.80%) for deutetrabenazine, 79.56% (78.21–80.94%) for α-HTBZ, 74.85% (73.13–76.60%) for β-HTBZ and 77.71% (76.26–79.16%) for total (α+β)-HTBZ. No new safety findings emerged in this study. <h3>Conclusions:</h3> At steady state, deutetrabenazine administered as the QD formulation was bioequivalent to the approved BID formulation for both AUC and C_max. The active metabolites at steady state were bioequivalent with regard to AUC between the QD and BID formulation; C_max was slightly lower for the QD formulation compared to the BID formulation. <b>Disclosure:</b> Dr. Sunzel has received personal compensation for serving as an employee of Teva Pharmaceuticals. Dr. Sunzel has stock in Teva Pharmaceuticals. An immediate family member of Dr. Sunzel has stock in Incyte. Laura Rabinovich-Guilatt has received personal compensation for serving as an employee of Teva Pharmaceuticals. Laura Rabinovich-Guilatt has stock in Teva Pharmaceuticals. Ms. Iyengar has received personal compensation for serving as an employee of Teva. Ms. Iyengar has stock in Teva. Mrs. Ruffo has nothing to disclose. Dr. Gutierrez has stock in Teva. Dr. Gordon has received personal compensation for serving as an employee of Teva. Dr. Gordon has stock in Teva. Dr. Ghibellini has received personal compensation for serving as an employee of Teva Pharmaceutical. Dr. Ghibellini has stock in Teva Pharmaceuticals.

Assessment of Dose Proportionality of Three Dose Strengths (6 mg, 12 mg and 24 mg) over the Clinical Dose Range (6–48 mg) of the Newly Developed Once-Daily Extended Release Tablet Formulation of Deutetrabenazine (P2-11.016)

<h3>Objective:</h3> To assess dose proportionality of three dose strengths (6mg, 12mg and 24mg), and across recommended clinical dose range (6mg – 48mg), for the once-daily (QD) extended-release tablet formulation of deutetrabenazine. <h3>Background:</h3> Deutetrabenazine (Austedo, Teva), a twice-daily (BID) formulation, is an approved treatment (daily doses 6–48mg) for tardive dyskinesia and chorea associated with Huntington disease. The new QD formulation has shown to deliver similar daily exposure to the BID formulation. <h3>Design/Methods:</h3> In a randomized phase 1 study (Study TV50717-PK-10175), healthy adult males and females (n=116) received single administrations of the QD formulation in a fed state (2×6mg, 1×12mg, 1×24mg, 2×24mg). Safety was assessed, and pharmacokinetic (PK) blood samples were collected pre-dose and up to 96 hours post-dose. Geometric mean ratios (GMRs) and 90% CIs were computed for PK parameters (maximum plasma concentration [C_max], area under the plasma concentration curve from time 0 to 36 hours [AUC_0–36h] and extrapolated to infinity [AUC_0-inf]) of deutetrabenazine, and active metabolites, deuterated α-HTBZ and β-HTBZ (individually and as a sum). A power model was fitted to describe the relationship between dose and PK parameters using a mixed model with sequence, period, and dose as fixed effects; and subject as random effect. To determine dose proportionality starting at 6mg, relative bioavailability was assessed between 2×6mg and 1×12mg. <h3>Results:</h3> GMRs and 90% CIs for C_max and AUCs fell within the bioequivalence limits of 80.00%–125.00%, demonstrating similarity between 2×6mg and 1×12mg tablets. Dose proportionality was demonstrated for all PK parameters and all analytes for QD formulation dose strengths 6mg, 12mg, and 24mg; and over the clinical dose range (6–48mg), as the 90% CIs for the slopes were contained within 0.839 to 1.161 and 0.839 to 1.107, respectively. <h3>Conclusions:</h3> The QD formulation of deutetrabenazine exhibits dose proportional pharmacokinetics for dose strengths (6mg, 12mg and 24mg), and across the full clinical dose range (6mg – 48mg). <b>Disclosure:</b> Dr. Sunzel has received personal compensation for serving as an employee of Teva Pharmaceuticals. Dr. Sunzel has stock in Teva Pharmaceuticals. An immediate family member of Dr. Sunzel has stock in Incyte. Dr. Ghibellini has received personal compensation for serving as an employee of Teva Pharmaceutical. Dr. Ghibellini has stock in Teva Pharmaceuticals. Ms. Iyengar has received personal compensation for serving as an employee of Teva. Ms. Iyengar has stock in Teva. Dr. Gutierrez has stock in Teva. Mrs. Ruffo has nothing to disclose. Dr. Gordon has received personal compensation for serving as an employee of Teva. Dr. Gordon has stock in Teva. Laura Rabinovich-Guilatt has received personal compensation for serving as an employee of Teva Pharmaceuticals. Laura Rabinovich-Guilatt has stock in Teva Pharmaceuticals.

A QBD WITH THE FRACTIONAL FACTORIAL DESIGN WAS USED TO MATCH THE SIMILARITY BETWEEN RANOLAZINE EXTENDED-RELEASE TABLETS 500 MG AND 1000 MG

Objective: Formulation and development of Ranolazine extended-release Tablets 500 mg and 1000 mg by using QBD with Fractional factorial design to match the similarity with Branded formulation (RANEXA®). Methods: Ranolazine extended-release tablets were developed by using various polymers, Polyquid PA100 and ETHOCEL TMstandard 7 premium and Hypromellose with a wet granulation process. QBD (Quality by Design) approach was used to identify the formulation and process variables that may affect the CQAs (critical quality attributes). Excipient compatibility studies were conducted to identify the interaction between API (active pharmaceutical ingredient) and selected excipients. Additionally, using a two-level, fractional factorial (22+3) design, the DOE (design of experiments) was employed to confirm the impacts of key process factors (fluid uptake and kneading time) on the formulation's ability to match the dissolution (f2) compared to RLD (reference listed drug) and establish a stable formulation. Results: Initial risk assessment was carried out to identify the various attributes such as API flow properties, solubility, PSD, Hygroscopicity, formulation, and process variables to impact the quality of the drug product. Flow properties of API indicate poor flow. Drug and excipients compatible study results indicate that excipients used in the compatibility study are considered compatible with the active ingredient. As per the saturation solubility studies and sink conditions, dissolution media was selected. Significant differences were found among the drug release profile by examining the various levels of polymers and binders. Using a two-level, fractional factorial (22+3) design, optimum process parameters were identified with selected formulation to match the dissolution (f2) similarity with the reference listed drug (RLD); finally, XRD (X-ray diffraction) studies confirm that the crystalline polymorphic forms (Form 1) peaks in optimum formulation (F07) comparable to the reference listed drug. Conclusion: Optimized formulation and process were established with QbD (quality by design) that provides the consistent drug release to match the f2 similarities with the extended-release tablets of RANEXA®(Ranolazine) 500 mg and 1000 mg.

Formulation and Evaluation of Extended-Release Tablets of Oxybutynin HCL by Push-Pull Technology

The objective of this study was to formulate and evaluate Extended-release oxybutynin chloride tablets using a push-pull osmotic pump system. Oxybutynin HCL is a muscarinic antagonist used for the treatment of overactive bladder with symptoms of urinary incontinence, urgency, and frequency. PPOP are used to deliver drugs that are highly soluble in water. The drug is located in the upper compartment along with osmogent while the lower compartment consists of polymeric osmotic agents. The push pull technique has been formulated in the form of double-layer tablets by wet granulation. The nine formulations were prepared using oxybutynin chloride, HPMC, polyethylene oxide, Nacl, and other excipients, lubricants, and colouring agents. The tablets are coated with a semi-permeable membrane (cellulose acetate), followed by a film coating. The pre-compression parameters (Bulk density, tapped density, Carr’s index, Hausner ratio, and angle of repose) and post-compression parameters of the extended-release tablets (Hardness, friability, weight variation, thickness, and drug content) were all within limits. An FTIR study showed no interaction between API and HPMC and all excipients at the molecular level. In vitro release studies in 0.1 N HCl, and 6.0 phosphate buffer showed that the optimized F5 formulation extended the drug release by 93% after 24 h and the release profile was similar to a product from an innovator.

Optimization of the Preformulation and Formulation Parameters in the Development of New Extended-Release Tablets Containing Felodipine

Herein, new extended-release tablets containing felodipine were developed. For the orally administered formulations, optimization of the preformulation and formulation parameters was performed to assess the performance of the dosage form. Initially, the morphological and physical characterization of two forms of felodipine (microcrystalline and macrocrystalline) using Fourier transform infrared spectroscopy, differential scanning calorimetry and optical microscopy was performed. The pharmaco-technical properties of the two felodipine forms were also determined. Subsequently, formulation studies for felodipine extended-release tablets were performed. Mathematical modelling of release kinetics of felodipine from developed formulations using a power law model was also performed. Based on the influence of formulation factors on the in vitro availability of felodipine in experimental tablets, a new extended-release tablet formulation was established.

Formulation and Evaluation of Cefaclor Extended-Release Tablet

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.&#x0D; 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 ƛ max value at different concentrations.&#x0D; 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.&#x0D; Keywords: Extended release, Cefaclor, Higuchi diffusion mechanism, PBP, bacterial cell wall synthesis.

The Effect of pH dependent and pH independent polymers on the drug release of anti-ischemic agent :

The objective of current study is to study the effects of combination of pH independent (HPMCK100M) and dependent (partially neutralized; Eudragit L 100-55) polymers on the drug release of Ranolazine form extended release tablet formulation. Ranolazine, an anti-ischemic or anginal agent. Mainly used for treating exercise induced; variant and stable chronic angina pectoris along with myocardial infarction. Anti-ischemic effect exhibited by Ranolazine is independent of haemodynamic effects, due to this benefit; it was useful for treating patients, who were not responded to other anti-anginals. Extended release tablets of Ranolazine were prepared using various proportions of Eudragit L 100-55,HPMCK100M in by direct compression technique. 9 formulations were developed and characterized for pharmacopoeial limits. Data obtained from the dissolution study fitted well to kinetic modeling, kinetic parameters were determined. EHR5 containing 31.25 mg of Eudragit L 100-55& 31.25 mg of HPMCK100M, is the best formulation showing similarity f2=85.77, f1= 2.31 with the marketed product (RANOLAZ). Formulation EHR5 follow zero order, whereas release mechanism found to be nonfickian type (n= 0.653).

FORMULATION AND OPTIMIZATION OF NATURAL GUM BASED EXTENDED RELEASE TABLETS OF LOSARTAN USING D-OPTIMAL MIXTURE DESIGN

Objective: Losartan potassium is one of the widely prescribed antihypertensive drugs administered orally and its extended-release tablet formulations are essentially required for the long-acting effect at reduced dosage frequency. The present research was aimed for the development and optimization of an extended-release tablet of losartan potassium, exploring natural gums, i.e., xanthan gum and guar gum as drug release modifiers.&#x0D; Methods: The tablet formulation was prepared by wet granulation method and the formulation optimization was done by D-optimal mixture design using Design Expert® software. The independent variables studied were xanthan gum (X1), guar gum (X2) and lactose (X3) taking various combinations of the total amount of gum and ratio of xanthan gum to guar gum under the given constraint range. The dependent (response) variables studied were % drug release in 1h (Y1), 4h (Y2), 7h (Y3) and 10h (Y4). The developed tablets were evaluated for physical properties, i.e., hardness, friability, weight variation as well as the in vitro drug release profiles. For optimization studies, the polynomial equations and response surface plots were generated and the optimized formulation was selected on the basis of maximum desirability value.&#x0D; Results: The developed tablet formulation was found to possess all physical properties within the desired range and showed sustained release profile with ~80% drug release in 10 h duration. The model fitting studies demonstrated best fit in the zero-order model and the slope value of Korsmeyer–Peppas plot was ˃0.89, suggesting case II transport as a drug release mechanism.&#x0D; Conclusion: The findings suggested that natural gums-based matrix tablets of losartan could be successfully developed and natural gums can be explored as platform technology as release retardants and in the development of sustained-release matrix tablets of other drugs.

INFLUENCE OF CELLULOSE AND ACETATE-BASED POLYMERS ON THE RELEASE OF CIPROFLOXACIN HCL FROM EXTENDED RELEASE MATRIX TABLETS PREPARED BY DIRECT COMPRESSION TECHNIQUE

The objectives of the current study were to investigate the influence of different types and concentration of polymers on release of ciprofloxacin HCl as well as to formulate an extended release tablets of ciprofloxacin hydrochloride by direct compression method. Twelve formulations (F1–F12) were manually designed using different proportions (10–30%) of Hydroxypropyl methylcellulose (HPMC), Ethylcellulose (EC) and Kollidon SR polymers. Avicel PH101, talc and magnesium stearate were used in a constant quantity of 2% in all the formulations. Multiple point dissolution was carried out in different media. Dissolution profiles indicated that formulations F1, F4, F8 and F11, extended the drug release up to 12 hrs, while, other formulations failed to retard the drug release up to desired period. DDSolver software was used to analyze the dissolution profile data for drug release kinetics such as first order, Zero-order, Korsmeyer–Peppas and Higuchi models. Drug polymers compatibility was assessed using Fourier Transformed Infrared (FTIR) spectroscopy. Selected formulations were placed in the stability chamber at accelerated temperature (40±2°C and RH 75±5%) for six months and re-evaluated after 3 and 6 months as per ICH guidelines. The present study accomplished that ethylcellulose alone or in combination with HPMC was found to be an excellent rate controlling agent for ciprofloxacin and may be used successfully to develop extended release tablet formulations.

Bioequivalence of Two Oral Ciprofloxacin Extended-Release Formulations in Healthy Mexican Volunteers

Introduction. Oral ciprofloxacin extended-release formulation decreases the risk of treatment failure and prevents the development of antimicrobial resistance. However, non-equivalent formulations lead to subtherapeutic plasma drug concentrations, increasing the risk of such problems. Objective. To determine the bioequivalence of two oral ciprofloxacin extended-release tablet formulations (1,000 mg) in healthy Mexican volunteers. Material and Methods. In this open-label 2 × 2 crossover design study, 26 healthy volunteers were randomly allocated to receive a single dose of the reference drug Cipro XR® (Bayer, Mexico) and the test formulation Ciproflox DM® (Senosiain Laboratories, Mexico). Blood samples were obtained for 24 hours. Ciprofloxacin plasma levels were quantified using a validated liquid chromatography method. Pharmacokinetic parameters were obtained by standard non-compartmental analysis. In order to determine bioequivalence, log-transformed test/reference ratios of Cmax, AUC0-t, and AUC0-inf were compared by an analysis of variance, followed by the 90 % confidence intervals and the Schuirmann bilateral test. Results. The 90 % confidence intervals ranged from 85.69 to 114.31 % for Cmax, 85.16-115.84 % in AUC0-t, and 85.39-114.61 % for AUC0-inf, all cases were within bioequivalence acceptance criteria (80-125 %). Schuirmann test verified the probability that the values were within these criteria (p &lt; 0.05). No side-effects were observed with any treatment. Conclusions. The results obtained demonstrate bioequivalence between the analyzed formulations.

INFLUENCE OF CELLULOSE AND ACETATE-BASED POLYMERS ON THE RELEASE OF CIPROFLOXACIN HCL FROM EXTENDED RELEASE MATRIX TABLETS PREPARED BY DIRECT COMPRESSION TECHNIQUE

The objectives of the current study were to investigate the influence of different types and concentration of polymers on release of ciprofloxacin HCl as well as to formulate an extended release tablets of ciprofloxacin hydrochloride by direct compression method. Twelve formulations (F1–F12) were manually designed using different proportions (10–30%) of Hydroxypropyl methylcellulose (HPMC), Ethylcellulose (EC) and Kollidon SR polymers. Avicel PH101, talc and magnesium stearate were used in a constant quantity of 2% in all the formulations. Multiple point dissolution was carried out in different media. Dissolution profiles indicated that formulations F1, F4, F8 and F11, extended the drug release up to 12 hrs, while, other formulations failed to retard the drug release up to desired period. DDSolver software was used to analyze the dissolution profile data for drug release kinetics such as first order, Zero-order, Korsmeyer–Peppas and Higuchi models. Drug polymers compatibility was assessed using Fourier Transformed Infrared (FTIR) spectroscopy. Selected formulations were placed in the stability chamber at accelerated temperature (40±2°C and RH 75±5%) for six months and re-evaluated after 3 and 6 months as per ICH guidelines. The present study accomplished that ethylcellulose alone or in combination with HPMC was found to be an excellent rate controlling agent for ciprofloxacin and may be used successfully to develop extended release tablet formulations.

Bioavailability and Pharmacokinetics of Once-Daily Amantadine Extended-Release Tablets in Healthy Volunteers: Results from Three Randomized, Crossover, Open-Label, Phase 1 Studies.

IntroductionIn February 2018, OS320—an amantadine extended-release (ER) tablet formulation with once-daily morning administration—was approved for the treatment of Parkinson’s disease and drug-induced extrapyramidal reactions in adults. The purpose of this study was to describe three phase 1 studies that assessed the pharmacokinetics (PK) and bioavailability of amantadine ER in healthy adult volunteers.MethodsStudy 1 was an open-label, four-treatment, single-dose, crossover study comparing amantadine ER 129, 193, and 258 mg tablets with an equivalent dose of immediate-release (IR) amantadine 40 mg/5 mL syrup. Study 2 was an open-label, single-dose, crossover food-effect study with amantadine ER 258 mg. Study 3 was an open-label, multiple-dose, crossover study comparing amantadine ER and amantadine IR syrup.ResultsAmantadine ER displayed a steady release of amantadine, with the peak amantadine concentration occurring at ~ 7.5 h postdose or in the middle of the day (following a morning dose) with steady-state administration. Administration of amantadine ER 258 mg with a high-fat meal did not affect amantadine bioavailability. Amantadine plasma exposure increased proportionally with increasing doses, and at steady state, amantadine exposure from an amantadine ER 258-mg tablet was bioequivalent to twice-daily 129-mg amantadine IR syrup.ConclusionThe PK profile of amantadine ER 129-mg, 193-mg, and 258-mg tablets allows for once-daily dosing in the morning; the 24-h average amantadine plasma concentration is equivalent to that for the same daily dose of IR amantadine administered twice daily.FundingOsmotica Pharmaceutical US LLC.

Application of artificial neural networks for Process Analytical Technology-based dissolution testing.

This work proposes the application of artificial neural networks (ANN) to non-destructively predict the in vitro dissolution of pharmaceutical tablets from Process Analytical Technology (PAT) data. An extended release tablet formulation was studied, where the dissolution was influenced by the composition of the tablets and the tableting compression force. NIR and Raman spectra of the intact tablets were measured, and the dissolution of the tablets was modeled directly from the spectral data. Partial Least Square (PLS) regression and ANN models were developed for the different spectroscopic measurements individually as well as by combining them together. ANN provided up to 3% lower root mean square error for prediction (RMSEP) than the PLS models, due to its capability of modeling non-linearity between the process parameters and dissolution curves. The ANN model using reflection NIR spectra provided the most accurate predictions with 6.5 and 63 mean f1 and f2 values between the computed and measured dissolution curves, respectively. Furthermore, ANN served as a straightforward data fusion method without the need for additional preprocessing steps. The method could significantly advance data processing in the PAT environment, contribute to an enhanced real-time release testing procedure and hence the increased efficacy of dissolution testing.

Evaluating the Clinical Impact of Formulation Variability: A Metoprolol Extended-Release Case Study.

The objective of this research was to evaluate the impact of changes in the formulation of metoprolol extended-release (ER) tablets on dissolution, pharmacokinetic, and exercise-induced heart rate (EIHR) using a combined physiologically based absorption pharmacokinetic, and population pharmacokinetic/pharmacodynamic modeling and simulation approach. Using a previously developed physiologically based absorption pharmacokinetic model in DDDPlus and GastroPlus, we simulated the changes in drug release and exposure as the result of quantitative changes in the release-controlling excipient, hydroxylpropylmethylcellulose, for 50 and 200 mg. The similarity of dissolution profiles was assessed using the f2 test, and bioequivalence was tested on the simulated pharmacokinetic profiles. We used the simulated concentration-time profiles following formulation changes as pharmacokinetic input into a population pharmacokinetic/pharmacodynamic model newly developed in NONMEM to determine if changes in pharmacokinetics lead to clinically significant changes in pharmacodynamics. Pharmacodynamic assessment was based on the percentage reduction in the EIHR from baseline. Therapeutic effect was considered similar when the model-predicted EIHR was within 50% to 85% of the average maximum EIHR of healthy 30-year-old subjects. A 40% or more increase in the release rate constant resulted in dissimilarity in dissolution profiles and bioINequivalence in pharmacokinetics for both 50 and 200 mg. Formulation-related differences in drug release of metoprolol ER tablets can lead to differences in pharmacokinetics. However, the evaluated pharmacokinetic differences do not lead to clinically meaningful differences in EIHR, suggesting that EIHR may not be sensitive enough to detect changes in pharmacokinetics of metoprolol ER products.

DEVELOPMENT AND VALIDATION OF HPTLC METHOD FOR QUANTITATIVE ESTIMATION OF PALIPERIDONE

A planar chromatography (HPTLC) method has been developed and validated for quantitative estimation of the atypical antipsychotic drug paliperidone, which is weakly basic and poorly water soluble. The Camag HPTLC system, operated by software winCATS (ver.1.4.1.8), was used. Sample application was facilitated by Linomat 5 applicator. After sample application, plates were subjected to ascending development in twin trough chamber of size 10 cm x10 cm, using about 10 mL of mobile phase. The optimized mobile phase was composed of ethyl acetate:chloroform:toulene:methanol (2.5:2.5:2.5:2.5 v/v/v/v). In post development, the plates were air dried and then scanned densitometrically using a UV detector at 278 nm in absorbance mode. In HPTLC densitogram, well defined peak was obtained for paliperidone with starting position at 0.27 Rf, max position at 0.31 Rf and end position at 0.34 Rf. The optimal Rf value for paliperidone was found to be 0.31. Performance characteristics of proposed and newly developed HPTLC method were statistically validated as per recommendations of ICH guidelines of analytical method validation. The HPTLC method was found to be linear across the range from 20 to 140 ng/band. The LOD and LOQ values were found to be 1.288 and 3.905ng/band, respectively. The method was found to be accurate, precise, robust and economical for the determination of paliperidone from bulk and its extended release tablet formulation.

Role of guaifenesin in the management of chronic bronchitis and upper respiratory tract infections

Guaifenesin, a mucoactive drug, acts by loosening mucus in the airways and making coughs more productive. It is used for relief of wet cough and chest congestion due to the common cold, and remains the only legally marketed expectorant in the US (per OTC Monograph). An ingredient in numerous over-the-counter (OTC) cough/cold medications, guaifenesin has a secondary indication for use in stable chronic bronchitis (professional indication). Clinical pharmacology and patient studies support the clinical utility of guaifenesin in respiratory conditions where mucus hypersecretion is prevalent: acute upper respiratory tract infections (URTIs), stable chronic bronchitis, and possibly rhinosinusitis. Guaifenesin has a well-established and favorable safety and tolerability profile in adult and pediatric populations. Its dosing range (200–400 mg 4-hourly, up to 6× daily) allows flexible dose titration to allow an increase of plasma concentrations. Multiple daily doses are needed to maintain 24-h therapeutic effect with immediaterelease formulations. Extended-release guaifenesin tablet formulations are available, providing convenience with 12-hourly dosing and portability compared to liquids. Guaifenesin is considered as a safe and effective expectorant for the treatment of mucus-related symptoms in acute URTIs and stable chronic bronchitis. Its clinical efficacy has been demonstrated most widely in chronic respiratory conditions, where excess mucus production and cough are more stable symptoms. Progress is being made to establish clinical models and measures that are more appropriate for studying symptomatic relief with guaifenesin in acute respiratory infections. This will help generate the up-to-date and high-quality data needed to optimize guaifenesin’s effectiveness in established uses, and in new respiratory indications associated with mucus hypersecretion.