Plasma Drug Concentration-time Profile Research Articles

GastroPlus- and HSPiP-Oriented Predictive Parameters as the Basis of Valproic Acid-Loaded Mucoadhesive Cationic Nanoemulsion Gel for Improved Nose-to-Brain Delivery to Control Convulsion in Humans.

Oral and parenteral delivery routes of valproic acid (VA) are associated with serious adverse effects, high hepatic metabolism, high clearance, and low bioavailability in the brain. A GastroPlus program was used to predict in vivo performance of immediate (IR) and sustained release (SR) products in humans. HSPiP software 5.4.08 predicted excipients with maximum possible miscibility of the drug. Based on the GastroPlus and HSPiP program, various excipients were screened for experimental solubility, nanoemulsions, and respective gel studies intended for nasal-to-brain delivery. These were characterized by size, size distribution, polydispersity index, zeta potential, morphology, pH, % transmittance, drug content, and viscosity. In vitro drug release, ex vivo permeation profile (goat nasal mucosa), and penetration studies were conducted. Results showed that in vivo oral drug dissolution and absorption were predicted as 98.6 mg and 18.8 mg, respectively, from both tablets (IR and SR) at 8 h using GastroPlus. The predicted drug access to the portal vein was substantially higher in IR (115 mg) compared to SR (82.6 mg). The plasma drug concentration-time profile predicted was in good agreement with published reports. The program predicted duodenum and jejunum as the prime sites of the drug absorption and no effect of nanonization on Tmax for sustained release formulation. Hansen parameters suggested a suitable selection of excipients. The program recommended nasal-to-brain delivery of the drug using a cationic mucoadhesive nanoemulsion. The optimized CVE6 was associated with the optimal size (113 nm), low PDI (polydispersity index) (0.26), high zeta potential (+34.7 mV), high transmittance (97.8%), and high strength (0.7% w/w). In vitro release and ex vivo permeation of CVE6 were found to be substantially high as compared to anionic AVE6 and respective gels. A penetration study using confocal laser scanning microscopy (CLSM) executed high fluorescence intensity with CVE6 and CVE6-gel as compared to suspension and ANE6. This might be attributed to the electrostatic interaction existing between the mucosal membrane and nanoglobules. Thus, cationic nanoemulsions and respective mucoadhesive gels are promising strategies for the delivery of VA to the brain through intransal administration for the treatment of seizures and convulsions.

PBPK modeling of ivermectin-Considerations for the purpose of developing alternative routes to optimize its safety profile.

Although single-dose ivermectin has been widely used in mass-drug administration programs for onchocerciasis and lymphatic filariasis for many years, ivermectin may have utility as an endectocide with mosquito-lethal effects at dosages greater and longer than those used to treat helminths. The final physiologically-based pharmacokinetic (PBPK) model for ivermectin described here was able to capture, with reasonable accuracy, observed plasma drug concentration-time profiles and exposures of ivermectin after a single oral dose of the drug in healthy male (dose range 6-30 mg) and female subjects, in both fasted and fed states, in African patients with onchocerciasis (150 μg/kg) and in African children. The PBPK model can be used for further work on lactation, pediatric dosing (considering CYP3A4 and Pg-p ontogenies), and pregnancy, especially if nonstandard doses will be used. The key findings of our study indicate that absorption of ivermectin may be highly dependent on bile micelle-mediated solubility. The drug is highly lipophilic and permeable, and its plasma exposure appears to be associated with the body mass index of an individual. These are all factors that need to be considered when extrapolating to more complex oral formulations or alternative routes of administration. Administering lower doses over a longer period may attenuate the dependence on bile micelle-mediated solubility. With relevant inputs, the verified PBPK model developed here could be used to simulate plasma exposures following administration of ivermectin by complex generics in development.

Nanocrystallization Improves the Solubilization and Cytotoxic Effect of a Poly (ADP-Ribose)-Polymerase-I Inhibitor.

Olaparib (OLA) is an anticancer agent that acts by inhibiting the poly (ADP-ribose)-polymerase-I (PARP-I). Due to its low solubility and low permeability, it has been placed as a BCS Class-IV drug and hence its clinical use is limited. In this study, we develop the nanocrystals of OLA as a way to improve its solubility and other performances. The OLA-NCs were prepared by antisolvent precipitation method through homogenization and probe sonication technique using a novel amphiphilic polymeric stabilizer (Soluplus®). Particle characterization resulted approximately 103.13 nm, polydispersity-index was 0.104 with positive zeta-potential of +8.67 mV. The crystal morphology by SEM of OLA-NCs (with and without mannitol) exhibited nano-crystalline prism-like structures as compared to the elongated OLA-pure. The DSC, XRD and FTIR were performed to check the interaction of Soluplus, mannitol and OLA did not exhibit any physical interaction among the OLA, Soluplus® and mannitol that is indicated by the presence of parent wave number peak. Two-fold increased solubility of OLA was found in PBS with Soluplus® from the NCs (69.3 ± 6.2 µgmL-1) as compared to pure drug (35.6 ± 7.2 µgmL-1). In vitro release of drug from OLA-NCs was higher (78.2%) at 12 h at pH 6.8 and relatively lower (53.1%) at pH 1.2. In vitro cellular cytotoxicity and anticancer effects were examined on MCF-7 cells. OLA-NCs were found effectively potent to MCF-7 cells compared with OLA-pure with approximately less than half IC50 value during MTT assay. Estimation of p53, Caspase-3 and Caspase-9 in MCF-7 cells indicated that OLA-NCs have significantly (p < 0.05) increased their expressions. After single oral dose in rats, 12 h plasma drug concentration-time profile indicated approximately 2.06-, 2.29-, 2-25- and 2.62-folds increased Cmax, AUC0-12 h, AUC0-∞ and AUMC0-∞, respectively, from the NCs as compared to OLA-pure. Storage stability indicated that the OLA-NCs was physically and chemically stable at 4 °C, 25 °C and 40 °C up to 6-months. Overall, OLA-NCs were deliberated; its potential feasibility to overwhelm the formulation challenges related to poorly soluble drugs and its future clinical applications.

Pharmacokinetics and bioequivalence of generic etoricoxib in healthy volunteers

Introduction/Study Objectives: A bioequivalence study was performed to compare the pharmacological profile of innovator etoricoxib (ETO) with a newly developed generic ETO, both in a 120 mg tablet formulation. A dissolution study was conducted to optimize the formulation process before evaluating physical changes in the active pharmaceutical ingredient and the formulated product. Methods: This was a randomized, open-label, balanced, two-treatment, two-period, two-sequence, single-dose, two-way crossover, truncated bioequivalence study involving a washout period of ten days. A total of 26 healthy male volunteers were recruited. The pharmacokinetic profile of the test formulation was compared with the reference formulation. Results/Discussion: The pharmacokinetic parameters of ETO were calculated based on the plasma drug concentration-time profile using non-compartmental analysis to determine its safety profile and tolerability. The Test/Reference (T/R) ratio of ETO was 104.36% (90% confidence interval (CI): 98.30%–110.80%) for area under curve (AUC)0-72 while the T/R ratio of maximum concentration (Cmax) was 101.39% (92.15%–111.56%). The 90% CI of the Cmax and AUC0-72 of ETO were within acceptable bioequivalence limits of 80%–125%. All values were within the predetermined limits of the Association of Southeast Asian Nation (ASEAN) bioequivalence guidelines. Conclusion: The test formulation was found to be bioequivalent with respect to the reference drug, according to ASEAN bioequivalence guidelines.

Pharmacokinetics and Bioequivalence Study of a New Branded Generic Moxifloxacin Tablet Among Healthy Volunteers.

A newly developed branded generic of a moxifloxacin (MOX) 400-mg tablet formulation was manufactured prior to this study. A bioequivalence (BE) study was done to assess the pharmacokinetics of the formulation using a randomized, open-label, 2-period crossover, 2-sequence, and single-dose experiment. Thirty healthy male volunteers were recruited. The test formulation, Flonoxin 400 mg, was compared with the reference formulation, Avelox 400 mg. The pharmacokinetic parameters of MOX were calculated based on the plasma drug concentration-time profile. Noncompartmental analysis was performed to determine its safety and tolerability. The 90% confidence intervals (CIs) were 88.5%-104.6%, 96.1%-101.1%, and 96.8%-100.7% for Cmax , AUC0-t , and AUC0-inf , respectively. All CIs were within the 80.0%-125.0% boundary, thus fulfilling the acceptable BE criteria according to the ASEAN guidelines.

Relative bioavailability study of cefuroxime axetil tablets

The study was to assess the bioequivalence of two cefuroxime axetil tablets. The test product was Cefxin tablet; the reference product was Zinnat tablet. Twelve healthy adult male volunteers participated in the study. Every subject received each formulation according to a completely double-blind randomized cross-over design with a one-week washout period before the second dose. Following oral administration of two cefuroxime axetil tablets, blood samples were drawn thirteen times over a period of ten hours. These samples were analyzed for cefuroxime concentrations using a sensitive and specific high performance liquid chromatography. Statistical assessments were performed, including ANOVA, power analysis and 90% confidence interval of ratio on various pharmacokinetic parameters derived from the plasma drug concentration-time profiles. The results indicated that the AUC(0-t), AUC(0- inf), peak concentration and mean resident time for the two products were not statistically significant different, i.e., the two products showed no difference in the rate and extent of drug absorption. Namely, there is no statistically significant difference between the bioavailability of Cefxin and Zinnat.

Preparation and evaluation of captopril loaded gastro-retentive zein based porous floating tablets.

In this study, gastro-retentive porous floating tablets of captopril based on zein are reported using l-menthol as a porogen. Tablets were prepared by the direct compression method. Removing of l-menthol through sublimation process generated pores in tablets, which decreased the density to promote floating over gastric fluid. Prepared tablets showed no floating lag time and prolong total floating time (>24h). Drug release was found dependent upon porosity of tablets, an increase in porosity of tablets resulted in increased drug release, so it can be tuned by varying concentration of l-menthol. In addition to floating and sustained release properties, porous tablets showed robust mechanical behavior in wet conditions, which can enable them to withstand real gastric environment stress. In vivo studies using New Zealand rabbits also confirmed the prolonged gastric retention (24h) and plasma drug concentration-time profile showed sustained release of captopril with higher Tmax and MRT as compared to marketed immediate-release tablets. Overall, it was concluded that effective gastric retention can be achieved using porous zein tablets using l-menthol as a porogen.

Brain Distribution of Drugs: Pharmacokinetic Considerations.

It is crucial to understand the basic principles of drug transport, from the site of delivery to the site of action within the CNS, in order to evaluate the possible utility of a new drug candidate for CNS action, or possible CNS side effects of non-CNS targeting drugs. This includes pharmacokinetic aspects of drug concentration-time profiles in plasma and brain, blood-brain barrier transport and drug distribution within the brain parenchyma as well as elimination processes from the brain. Knowledge of anatomical and physiological aspects connected with drug delivery is crucial in this context. The chapter is intended for professionals working in the field of CNS drug development and summarizes key pharmacokinetic principles and state-of-the-art experimental methodologies to assess brain drug disposition. Key parameters, describing the extent of unbound (free) drug across brain barriers, in particular blood-brain and blood-cerebrospinal fluid barriers, are presented along with their application in drug development. Special emphasis is given to brain intracellular pharmacokinetics and its role in evaluating target engagement. Fundamental neuropharmacokinetic differences between small molecular drugs and biologicals are discussed and critical knowledge gaps are outlined.

PHARMACOKINETIC COMPARISON OF MONTELUKAST SODIUM FORMULATIONS AFTER A SINGLE ORAL DOSE IN HEALTHY GUINEA PIGS

Objective: Pharmacokinetic evaluation of montelukast sodium chronomodulated capsules (sustained-release solid dispersion of drug enclosed in pH-sensitive film-coated hard gelatin shell) and marketed tablets has been carried out in this study.
 Methods: A single oral dose of prepared capsules and marketed conventional tablets was administered in healthy male Dunkin-Hartley albino guinea pigs. Blood samples were collected at different time intervals and plasma concentration of drug was determined by reversed-phase high-performance liquid chromatography. Different pharmacokinetic parameters were assessed from plasma drug concentration-time profile by one-compartment model, first-order kinetics.
 Results: Pharmacokinetic parameters such as time to reach maximum concentration, elimination rate constant, elimination half-life, and mean residence time data indicates that drug release from chronomodulated capsules is significantly prolonged with initial release lag time of 3.5–4 h in comparison with marketed conventional tablets. However, maximum drug plasma concentration, area under the concentration-time curve, and apparent volume of distribution values show non-significant difference between capsules and marketed tablets.
 Conclusion: The findings specified that capsules were providing time controlled delivery of drug at a desired rate for prolonged time, which may be helpful for the prevention of episodic attack of asthma in early morning hours.

Applicability of in vitro-in vivo translation of cathepsin K inhibition from animal species to human with the use of free-drug hypothesis

The correlation of in vitro inhibition of cathepsin K (CatK) activity and in vivo suppression of collagen I biomarkers was examined with three selective CatK inhibitors to explore the potential translatability from animal species to human. These inhibitors exhibited good in vitro potencies toward recombinant CatK enzymes across species, with IC50 values ranging from 0.20 to 6.1nM. In vivo studies were conducted in animal species following multiple-day dosing of the CatK inhibitors to achieve steady-state plasma drug concentration-time profiles. Measurement of urinary bone resorption biomarkers (cross-linked N-terminal telopeptide and helical peptide of type I collagen) revealed drug concentration-dependent suppression of biomarkers, with EC50 values estimated to be 12 to 160nM. Marked improvement in the correlation between in vitro and in vivo CatK activities was observed with the application of unbound (free) fraction in plasma, consistent with the conditions stipulated by the free-drug hypothesis. These results indicate that the in vitro-in vivo translation of CatK inhibition observed in animal species can translate to humans when the unbound fraction of the inhibitor is considered. Interestingly, residual levels of urinary bone resorption marker were detected as the suppression reached saturation (at an average of 82% inhibition), an apparent phenomenon observed regardless of the species, biomarker, or compound examined. Since cathepsin enzymes other than CatK were reported to catalyze cleavage of collagen I, it is hypothesized that CatK-mediated degradation of collagen I in bone represents ~82% of overall collagen I turnover in the body.

Fluconazole dosing predictions in critically-ill patients receiving prolonged intermittent renal replacement therapy: a Monte Carlo simulation approach.

Fluconazole is a renally-eliminated antifungal commonly used to treat Candida species infections. In critically-ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic (PK) data are available to guide fluconazole dosing. We used previously-published fluconazole clearance data and PK data of critically-ill patients with acute kidney injury to develop a PK model with the goal of determining a therapeutic dosing regimen for critically-ill patients receiving PIRRT. Monte Carlo simulations were performed to create a virtual cohort of patients receiving different fluconazole dosing regimens. Plasma drug concentration-time profiles were evaluated on the probability of attaining a mean 24-hour area under the drug concentration-time curve to minimum inhibitory concentration ratio (AUC24h : MIC) of 100 during the initial 48 hours of antifungal therapy. At the susceptibility breakpoint of Candida albicans (2 mg/L), 93 - 96% of simulated subjects receiving PIRRT attained the pharmacodynamic target with a fluconazole 800-mg loading dose plus 400 mg twice daily (q12h or pre and post PIRRT) regimen. Monte Carlo simulations of a PK model of PIRRT provided a basis for the development of an informed fluconazole dosing recommendation when PK data was limited. This finding should be validated in the clinical setting.

Controlled release of dutasteride from biodegradable microspheres: in vitro and in vivo studies.

The aim of the present work was to study the in vitro/in vivo characteristics of dutasteride loaded biodegradable microspheres designed for sustained release of dutasteride over four weeks. An O/W emulsion-solvent evaporation method was used to incorporate dutasteride, which is of interest in the treatment of benign prostatic hyperplasia (BPH), into poly(lactide-co-glycolide) (PLGA). A response surface method (RSM) with central composite design (CCD) was employed to optimize the formulation variables. A prolonged in vitro drug release profile was observed, with a complete release of the entrapped drug within 28 days. The pharmacokinetics study showed sustained plasma drug concentration-time profile of dutasteride loaded microspheres after subcutaneous injection into rats. The in vitro drug release in rats correlated well with the in vivo pharmacokinetics profile. The pharmacodynamics evaluated by determination of the BPH inhibition in the rat models also showed a prolonged pharmacological response. These results suggest the potential use of dutasteride loaded biodegradable microspheres for the management of BPH over long periods.

Vecuronium Pharmacokinetics in Patients With Major Burns

Abstract Background Burn patients develop resistance to non-depolarizing neuromuscular blocking agents (NDNMBAs) and require a significantly large dose to produce a desired clinical response. Pathophysiological changes related to burn injury may alter pharmacokinetics (PK) and pharmacodynamics of NDNMBAs. The purpose of this study was to compare vecuronium PK in burns vs non-burns. Methods Twenty adults, aged 23–58 yr, with 27–81% total body surface area (TBSA) burn, were studied at 4–57 post-burn days and compared with age- and sex-matched, non-burn controls. Vecuronium 0.12 mg kg −1 was given i.v. as a single bolus within 10 s. Blood samples ( n =20) were collected over 12 h at predetermined time points. NONMEM was used to describe plasma drug concentration–time profiles for burns and non-burns. Results A three-compartment model best described vecuronium concentration–time profiles. Burn patients showed enhanced distributional clearance at the terminal phase (0.12 vs 0.095 litre min −1 , P vs 6.6 h, P Conclusions The altered drug distribution between tissues may partially explain the known resistance to vecuronium in patients with major burns.

Amalgamation of solid dispersion and adsorption technique

The objective of present investigation was to improve dissolution of ritonavir (RTV), a BCS Class II drug. Amalgamation of solid dispersion and melt adsorption technology was utilized for developing the formulation. Solid dispersion adsorbate (SDA) was prepared using combination of Lutrol F127, Transcutol HP and Labrasol as carriers and Neusilin as an adsorbent and flow inducer. The concept of design of experiments (DoE) was used in identifying the critical formulation factors. The optimised SDA was characterised by Fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis and X-ray diffraction studies. From the results obtained, it can be concluded that improvement in dissolution of RTV was due to hydrogen bonding of drug with Neusilin, micellar solubilisation of drug in carrier, improved wettability and reduction in the crystallinity. The dissolution efficiency value of optimised SDA is 41.68 % at 10 min time point which is three times the release of untreated drug. Convolution modelling was employed to get a predicted plasma drug concentration time profile.

Multiscale Tumor Spatiokinetic Model for Intraperitoneal Therapy

This study established a multiscale computational model for intraperitoneal (IP) chemotherapy, to depict the time-dependent and spatial-dependent drug concentrations in peritoneal tumors as functions of drug properties (size, binding, diffusivity, permeability), transport mechanisms (diffusion, convection), spatial-dependent tumor heterogeneities (vessel density, cell density, pressure gradient), and physiological properties (peritoneal pressure, peritoneal fluid volume). Equations linked drug transport and clearance on three scales (tumor, IP cavity, whole organism). Paclitaxel was the test compound. The required model parameters (tumor diffusivity, tumor hydraulic conductivity, vessel permeability and surface area, microvascular hydrostatic pressure, drug association with cells) were obtained from literature reports, calculation, and/or experimental measurements. Drug concentration-time profiles in peritoneal fluid and plasma were the boundary conditions for tumor domain and blood vessels, respectively. The finite element method was used to numerically solve the nonlinear partial differential equations for fluid and solute transport. The resulting multiscale model accounted for intratumoral spatial heterogeneity, depicted diffusive and convective drug transport in tumor interstitium and across blood vessels, and provided drug flux and concentration as a function of time and spatial position in the tumor. Comparison of model-predicted tumor spatiokinetics with experimental results (autoradiographic data of 3H-paclitaxel in IP ovarian tumors in mice, 6 h posttreatment) showed good agreement (1% deviation for area under curve and 23% deviations for individual data points, which were several-fold lower compared to the experimental intertumor variations). The computational multiscale model provides a tool to quantify the effects of drug-, tumor-, and host-dependent variables on the concentrations and residence time of IP therapeutics in tumors.

Effects of Peritoneal Dialysis on Pharmacotherapy: A Deductive Pharmacokinetic-model Approach to Predict Drug Concentration Profiles in Plasma and Peritoneal Fluid

The aim of this study was to present a deductive compartment pharmacokinetic (PK) model to predict the concentration profiles of drugs in plasma and peritoneal fluid in peritoneal dialysis (PD) rats. PK parameters of model drugs in normal and experimentally induced acute renal failure (ARF) rats not undergoing PD were obtained inductively in a common regression manner with a two-compartment model. In PD normal and ARF rats, PK parameters relating to the transfer of drugs to the peritoneal dialysate and the progress of renal failure were deductively modified to simulate the drug concentration-time profiles in plasma and in the peritoneal fluid in PD rats. The deductively introduced modifiers were the volume of distribution in the peripheral compartment, plasma protein binding, and solvent movement factor to the peritoneal fluid. Predicted profiles of tolbutamide, propranolol and cefazolin in PD normal and ARF rats were compared with the corresponding observed data. This minimal deductive approach yielded satisfactory accuracy in the prediction of both the plasma and peritoneal fluid concentrations of tolbutamide and propranolol.

Differences in Cytochrome P450-Mediated Pharmacokinetics Between Chinese and Caucasian Populations Predicted by Mechanistic Physiologically Based Pharmacokinetic Modelling

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines emphasize the need for better understanding of the influence of ethnicity on drug response to minimize duplication of clinical studies, thereby expediting drug approval. We have developed a Chinese database for the prediction of differences in the population kinetics of drugs mainly metabolized by cytochromes P450 (CYPs) relative to Caucasian populations. Such predictions should help to inform the need for duplication of in vivo pharmacokinetic studies in the two ethnic groups and the design of such studies. Demographic and physiological data for Chinese, along with information on CYP abundances and the frequencies of associated genetic polymorphisms in Chinese, were collated from literature sources and incorporated within the Simcyp Population-based Simulator(®) (v11.1). Default Simcyp parameter values for a virtual Caucasian population and for model compounds metabolized principally by specific CYPs were used as the point of reference. The drugs and the main CYPs involved in their metabolism were phenacetin (CYP1A2), desipramine (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), and alprazolam and midazolam (CYP3A). Hydroxy bupropion formation was used as a more sensitive marker of CYP2B6 activity than bupropion kinetics. Observed plasma drug concentration-time profiles and pharmacokinetic parameters after oral and, where possible, intravenous dosing were obtained from published in vivo studies in both Chinese and Caucasian subjects. Virtual subjects generated within Simcyp were matched to the subjects used in the in vivo studies with respect to age, sex, dosage and, where possible, CYP phenotype frequency. Predicted and observed plasma drug concentrations and weight-normalized clearances were compared between the ethnic groups. Significant differences were identified between Chinese and Caucasian populations in the frequency of CYP2C19 poor metabolizers (PMs) [Chinese 13%; Caucasian 2.4%], CYP2D6 PMs and intermediate metabolizers (IMs) [Chinese PMs 0.3%, IMs 39%; Caucasian PMs 8%, IMs <1%], the hepatic abundance of CYP2C19 (mean values: Chinese 8pmol/mg; Caucasian 14pmol/mg) and liver weight (mean values: Chinese 1198 g; Caucasian 1603 g). The observed plasma drug concentration-time profiles and weight-normalized clearances were predicted with reasonable accuracy (100% within twofold; 89% within 1.5-fold) in both ethnic groups. The predicted phenacetin, tolbutamide, omeprazole, desipramine, midazolam (intravenous), midazolam (oral), alprazolam (intravenous) and alprazolam (oral) clearances were 36, 25, 51, 43, 24, 17, 21 and 22% lower, respectively, in Chinese than in Caucasians; the observed clearances were 28, 2, 75, 42, 19, 62, 20 and 21% lower, respectively. Predicted and observed formation of hydroxy bupropion was lower in Caucasians than in Chinese (6 and 20%, respectively). Differences between ethnic groups were less after normalization for body weight. The results of this study indicate the value of simulation based on mechanistic physiologically based pharmacokinetic modelling (PBPK) in anticipating the likely extent of any differences in the kinetics of CYP substrates in Chinese and Caucasian populations arising from demographic, physiological and genetic differences.

Preparation of acetaminophen capsules containing beads prepared by hot-melt direct blend coating

Twelve hydrophobic coating agents were assessed for their effects on drug release after coating sugar cores by a flexible hot-melt coating method using direct blending. Drug-containing pellets were also produced and used as cores. The cores were coated with single or double wax layers containing acetaminophen (APAP). The harder the wax, the slower the resultant drug releases from single-coated beads. Wax coating can be deposited on cores up to 28% of the beads final weight and reaching 58% with wax and drug. Carnauba-coated beads dissolved in approximately 6 h releasing 80% of the loaded drug. Applying another wax layer extended drug release over 20 h, while still delivering 80% of the loaded drug. When drug-containing pellets (33–58% drug loading) were used as cores, double wax-coated pellets exhibited a near zero-order drug release for 16 h, releasing 80% of the loaded drug delivering 18 mg/h.The simple process of hot-melt coating by direct blending of pellet-containing drug-coated formulations provides excellent options for immediate and sustained release formulations when higher lipid coating or drug loading is warranted. Predicted plasma drug concentration time profiles using convolution and in vitro drug release properties of the beads were performed for optimal formulations.

A review of the pharmacokinetic profile of transmucosal fentanyl formulations

Background and objectives:Breakthrough pain (BTP) is a transitory flare of moderate-to-severe pain that occurs in patients with stable, controlled persistent pain. Management of BTP episodes is difficult because frequency, time-to-peak intensity, and duration of episodes vary both within and between individuals.Formulations of fentanyl that use a buccal, sublingual, or nasal transmucosal route of administration have been developed for the treatment of BTP in opioid-tolerant patients with cancer. These formulations allow rapid passage into the bloodstream and avoid first-pass metabolism and, therefore, are more likely to match the time-course of BTP episodes than are oral formulations.The purposes of this analysis were to identify and review published data describing the pharmacokinetic properties of rapid-onset fentanyl formulations and to evaluate these properties in view of the temporal dynamic characteristics of BTP in order to help guide medical practice.Methods:Relevant publications were searched in the PubMed database from 1998. The plasma drug concentration–time profile of each formulation obtained from the identified studies was adjusted to a consistent scale for comparison.Results:The data revealed that the various transmucosal formulations resulted in three typical plasma fentanyl concentration profiles: (1) type 1: a very rapid rise and short duration; (2) type 2: a rapid increase and sustained intensity; and (3) type 3: a slower onset and longer duration.Conclusions:Given the substantial variability of BTP episodes experienced by patients, these pharmacokinetic differences may provide useful information for a physician who is selecting a rapid-onset opioid medication for a patient.

A Technique to Estimate In Vivo Dissolution Profiles Without Data from a Solution

Dissolution tests are expected to ensure adequate in vivo product performance. Given the recent progress in the ability to predict of human permeability, it is possible to synthesize the plasma drug concentration-time profile from human permeability predictions and the results of the first-in-human trial and use these data to synthesize a pharmacokinetic profile for a solution and provide an initial estimate of the in vivo dissolution profile. This manuscript provides details of such a deconvolution methodology in order to provide an initial estimate of in vivo dissolution. Plasma metoprolol concentration-time data from a previously published study examining the pharmacokinetics of three metoprolol formulations (100 mg), slow, moderate, and fast releasing, and an oral solution (50 mg) were used to estimate in vitro dissolution profiles. A one-compartment unit impulse function was used, and the absorption rate was estimated from animal permeability data (synthetic solution method). The results were compared to those obtained using a unit impulse function estimated from the oral solution data. In vivo dissolution profiles estimated from animal permeability data were similar to those estimated from the oral solution data. Ratios of absorption rate constants (synthetic solution method/oral solution) ranged from 1 to 1.3. The synthetic solution method offers a way to estimate in vivo dissolution profile through deconvolution. It is applicable in cases where it is not possible or feasible to obtain data from a solution. It performs best in cases where dissolution is the rate-limiting step in the absorption process.