The pharmaceutical applications of a biopolymer isolated from Trigonella foenum-graecum seeds: Focus on the freeze-dried matrix forming capacity.

The aim of the present study was to evaluate the funtion of fenugreek seed mucilage (FSM) as potential matrix forming agent for orodispersible pharmaceutical lyophilisates. The FSM was isolated and characterized. FSM colloidal dispersions were prepared and the rheological evaluation was performed. Oral lyophilisates (OLs) with different FSM concentrations, containing meloxicam as model drug were prepared by freeze drying method. The OLs were characterized and compared to gelatin containing tablets, prepared under the same conditions. The FSM dispersions revealed shear thinning flow type. Based on colloidal dispersions' rheological properties, five FSM concentrations were taken forward to the lyophilization step. Completely dry and elegant tablets were obtained. Texture analysis indicated highly porous structures, confirmed by SEM analysis, which explain the fast disintegration properties. All the prepared tablets disintegrated in less than 47 s. The disintegration process was prolonged by the increase in FSM content, due to the high viscosity the polymer creates in aqueous media. FSM tablets presented longer disintegration times, as compared to gelatin tablets, but also higher crushing strength. Considering the fast disintegration and the high crushing strength, FSM is a good candidate as matrix forming agent for fast disintegrating dosage forms or other freeze-dried preparations.

Defining the design space for freeze-dried orodispersible tablets with meloxicam.

OBJECTIVE: This work focused on simultaneously investigating formulation variables and freeze-drying parameters when preparing orodispersible tablets with meloxicam (Mel), by a Quality by Design (QbD) approach. MATERIALS AND METHODS: Methylcellulose (MC) was selected as a matrix forming agent and mannitol (Man) as cryoprotectant, both at two concentration levels. The freezing regime was also varied between fast and shelf-ramped, to find out how it affects the final products. The tablet formulations were characterized for their disintegration time, wetting properties, mechanical properties, morphology and in vitro dissolution. Response Surface Modeling completed the statistical analysis that assessed the effects of independent variables on the responses. RESULTS: All the responses showed good fitting to the chosen model. The increase in MC content determined a positive effect on disintegration time, wetting time, mechanical strength and a negative effect on Mel dissolution. High levels of Man-determined brittle products with low-absorption capacity and fast Mel dissolution. The freezing rate had an important effect on the structure of tablets: fast freezing determined slightly thicker pore walls with smooth surfaces, while shelf-ramped freezing led to a multiple-layer structure with increased hardness. Still, shelf-ramped freezing yielded higher Mel release, due to physical changes of the active substance during the freeze-drying process. CONCLUSION: From the generated design space, an optimal formulation was obtained and the results validated the experimental design. The QbD approach was an efficient manner of understanding formulation and process parameters at the freeze-dried orodispersible tablets preparation.

Effect of fluvoxamine on the pharmokinetics of zolpidem: a two-treatment period study in healthy volunteers.

1. Our objective was to evaluate a possible pharmacokinetic interaction between zolpidem and fluvoxamine in healthy volunteers. 2. The study consisted of two periods: Period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem; and Period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 100 mg fluvoxamine. Between the two periods, the subjects were treated for 6 days with a single daily dose of 100 mg fluvoxamine. 3. Pharmacokinetic parameters of zolpidem given in each treatment period were calculated using non-compartmental analysis and the data from two periods were compared to determine statistically significant differences. 4. In the two periods of treatments, the mean peak plasma concentrations (C(max)) were 56.4 ± 25.6 ng/mL (zolpidem alone) and 67.3 ± 25.8 ng/mL (zolpidem after pretreatment with fluvoxamine). The t(max), times taken to reach C(max), were 0.83 ± 0.44 and 1.26 ± 0.74 h, respectively, and the total areas under the curve (AUC(0-∞)) were 200.9 ± 116.8 and 512.0 ± 354.6 ng h/mL, respectively. The half-life of zolpidem was 2.24 ± 0.81 h when given alone and 4.99 ± 2.92 h after pretreatment with fluvoxamine. 5. Fluvoxamine interacts with zolpidem in healthy volunteers and increases its exposure by approximately 150%. The experimental data showed the pharmacokinetic interaction between zolpidem and fluvoxamine, and suggest that the observed interaction might be clinically significant, but its relevance has to be confirmed.

Development and in vitro evaluation of multiparticulate sustained release carbamazepine formulation.

The objective of the present study was the development and the in vitro evaluation of extended release multiparticulate dosage forms with carbamazepine, starting from drug crystals of established granulometry as cores and using Eudragit NE aqueous dispersions as coating film polymer in a bottom spray fluid bed coating system. The chosen independent variables, i.e., the quantity of film coating (Eudragit NE) and the % of hydrophilic polymer in film coating that act as pores generating (hydroxypropyl methylcellulose ratio) were optimized with a two-factor, three-level central composite experimental design. The chosen dependent variables were cumulative percentage values of carbamazepine released after 1, 2, 4, 6, 8 and 12 h and Peppas kinetic release equation parameters (k and n). Based on the experimental design, different carbamazepine formulations were proposed and their release profiles were determined. The second-order polynomial model coefficients and response surface plots were used to analyze the relation between the dependent and the independent variables. The optimized formulation prepared according to computer-determined levels provided a release profile which was close to the predicted values. The dissolution profile of carbamazepine from the coated crystals and tablets prepared with them were similar, and were unchanged after storage for 3 months under controlled conditions.

Pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers.

Our objective was to evaluate a possible pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers. The study consisted of two periods: Period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem and Period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 500 mg ciprofloxacin. Between the two periods, the subjects were treated for 5 days with a single daily dose of 500 mg ciprofloxacin. Plasma concentrations of zolpidem were determined during a 12-hour period following drug administration. Pharmacokinetic parameters of zolpidem administered in each treatment period were calculated using non-compartmental analysis and the data from two periods were compared to determine statistically significant differences. In the two periods of treatments, the mean peak plasma concentrations (Cmax) were 75.73±28.34 ng/ml (zolpidem alone) and 80.58±22.40 ng/ml (zolpidem after pre-treatment with ciprofloxacin). The tmax, times taken to reach Cmax, were 0.91±0.42 and 1.44±0.61 h, respectively, and the total areas under the curve (AUC0-∞) were 300.2±115.5 and 438.1±142.6 ng h/ml, respectively. The half-life of zolpidem was 2.39±0.53 h when administered alone and 3.34±0.87 h after pre-treatment with ciprofloxacin. These differences were statistically significant for Cmax, tmax, AUC0-∞, half-life and mean residence time. Ciprofloxacin interacts with zolpidem in healthy volunteers, raising its bioavailability by about 46%. This magnitude of effect is likely to be clinically significant.

Pharmacokinetic interaction between fluoxetine and omeprazole in healthy male volunteers: a prospective pilot study.

BACKGROUND: Fluoxetine is an inhibitor of the main metabolizing enzymes (cytochrome P450 [CYP] 2C19 and CYP3A4) of omeprazole and thus might influence that drug's pharmacokinetics. The changes in omeprazole's pharmacokinetics may have clinical significance concerning efficacy and tolerability of the treatment. OBJECTIVE: The aim of this study was to assess the pharmacokinetic interaction of fluoxetine with omeprazole in healthy volunteers. METHODS: The study enrolled healthy adult men and consisted of 2 periods. In the first period, all subjects received a single 40-mg dose of omeprazole. This was followed by an 8-day period during which fluoxetine monotherapy (60 mg/d) was administered as a single oral daily dose. At the end of those 8 days, the subjects were administered a 40-mg dose of omeprazole with a 60-mg dose of fluoxetine. Plasma concentrations of omeprazole were determined at 0.5, 1, 1.33, 1.66, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 12 hour(s) after study drug administration. Omeprazole plasma concentrations were determined by a validated HPLC method. Pharmacokinetic parameters of omep-razole were calculated using noncompartmental analysis. Adverse events were assessed throughout the study duration. RESULTS: Eighteen healthy male volunteers (mean [SD] age, 22.11 [2.52] years [range, 18-26 years]; body mass index, 23.34 [2.31] kg/m(2) [range, 19.1-27.1 kg/m(2)]) were enrolled and completed the study. In the 2 periods of treatment, the mean Cmax of omeprazole was 730.8 ng/mL (omeprazole monotherapy) and 1725.5 ng/mL (combination treatment with fluoxetine). The observed AUC0-∞ was 1453.3 and 5072.5 ng/mL/h and AUC0-t was 1465.0 and 5185.3 ng/mL/h, respectively. The Tmax was 1.30 and 1.63 hours and the elimination rate constant was 0.753 and 0.482 hr(-1). The t½ was 0.96 and 1.47 hours, whereas the mean residence time was 2.33 and 3.35 hours, respectively. Statistically significant differences were observed for all parameters between periods 1 and 2 (all, P < 0.001). CONCLUSION: The data found in this prospective pilot study suggest a pharmacokinetic interaction between fluoxetine and omeprazole in these healthy volunteers, but its relevance has to be confirmed.

High-throughput LC/MS/MS analysis of ruscogenin and neoruscogenin in Ruscus aculeatus L.

A new, sensitive LC/MS/MS method was developed for the quantification of ruscogenin and neoruscogenin in hydrolyzed extracts from Ruscus aculeatus L. (Liliaceae). The two sapogenins were separated on a Zorbax SB-C18 column under isocratic conditions. The detection was performed in the multiple reaction monitoring mode using an ion trap mass spectrometer with an electrospray ionization source operated in positive ionization mode. For the quantification of the ruscogenin and neoruscogenin, calibration curves were constructed over the range of 2-1000 ng/mL. This is the first reported LC/MS/MS method for the simultaneous analysis of ruscogenin and neoruscogenin, and it showed superior sensitivity when compared with other assays described in the literature. The method has been successfully applied to quantify the two sapogenins in aerial (phylloclades) and underground parts (rhizomes, roots) of Ruscus aculeatus L.

A new, high-throughput high-performance liquid chromatographic/mass spectrometric assay for therapeutic level monitoring of digoxin in human plasma.

A new, high-throughput HPLCIMS assay for the quantification of digoxin in human plasma was developed and validated. The separation was performed on a Zorbax SB-C18 column under isocratic conditions using a 55 + 45 (v/v) mixture of methanol and 0.1% (v/v) formic acid in 10 microM sodium acetate as the mobile phase at 45 degrees C with a flow rate of 1 mL/min. The detection of digoxin was performed in the selected ion monitoring mode (m/z 803.5). The human plasma samples (0.2 mL) were deproteinized with 7% perchloric acid in water, and aliquots of 20 microL from supernatants obtained after centrifugation were directly injected into the chromatographic system. The method showed good linearity (r > 0.9926), precision (CV > 18.9%), and accuracy (bias > 5.6%) over the range of 0.5-50 ng/mL plasma. The lower LOQ was 0.5 ng/mL, and the recovery was between 92 and 106%. The method is not expensive, it needs a minimum time for plasma sample preparation, and it has a run time of 2.3 min for instrument analysis (the retention time of digoxin was 1.9 min). The developed and validated high-throughput method is very simple, rapid, and efficient, with wide applications in clinical level monitoring, pharmacokinetics, and bioequivalence studies.

Determination of loratadine and its active metabolite in human plasma by high-performance liquid chromatography with mass spectrometry detection.

A new sensitive and selective liquid chromatography coupled with mass spectrometry (LC/MS/MS) method for quantification of loratadine (LOR) and its active metabolite descarboethoxyloratadine (DSL) in human plasma was validated. After addition of the internal standard, metoclopramide, the human plasma samples (0.3 ml) were precipitated using acetonitrile (0.75 ml) and the centrifuged supernatants were partially evaporated under nitrogen at 37 degrees C at approximately 0.3 ml volume. The LOR, DSL and internal standard were separated on a reversed phase column (Zorbax SB-C18, 100 mmx3.0 mm i.d., 3.5 microm) under isocratic conditions using a mobile phase of an 8:92(v/v) mixture of acetonitrile and 0.4% (v/v) formic acid in water. The flow rate was 1 ml/min and the column temperature 45 degrees C. The detection of LOR, DSL and internal standard was in MRM mode using an ion trap mass spectrometer with electrospray positive ionisation. The ion transitions were monitored as follows: 383-->337 for LOR, 311-->(259+294+282) for DSL and 300-->226.8 for internal standard. Calibration curves were generated over the range of 0.52-52.3 ng/ml for both LOR and DSL with values for coefficient of determination greater than 0.994 by using a weighted (1/y) quadratic regression. The lower limits of quantification were established at 0.52 ng/ml LOR and DSL, respectively, with an accuracy and precision less than 20%. Both analytes demonstrated good short-term, long-term, post-preparative and freeze-thaw stability. Besides its simplicity, the sample treatment allows obtaining a very good recovery of both analytes, around 100%. The validated LC/MS/MS method has been applied to a pharmacokinetic study of loratadine tablets on healthy volunteers.

Piecewise function parameters as responses of the design of experiment in the development of a pulsatile release chronopharmaceutical system.

The aim of this work was to develop a pulsatile release system with metoprolol for chronotherapeutical use by coating swellable mini-tablets with Eudragit RS. To study the influence of the formulation factors (amount of coating polymer, plasticizer percentage in film coating and swelling agent percentage in mini-tablets), a Box-Behnken design of experiment (DoE) was used. To evaluate the influence of the studied factors on the sigmoid shape of the dissolution profile, piecewise function parameters were used as the responses of DoE. The results show that higher concentrations of coating polymer and higher concentrations of plasticizer polymer led to a thicker and more elastic polymeric film, which led to a delay in drug release. Using the parameters of the piecewise function as DoE responses, an optimum formulation with a sigmoid shape dissolution profile and a 2.5-h lag time followed by rapid drug release were obtained.

Development of a reservoir type prolonged release system with felodipine via simplex methodology.

BACKGROUND AND AIMS: Felodipine is a dihydropyridine calcium antagonist that presents good characteristics to be formulated as prolonged release preparations. The aim of the study was the formulation and in vitro characterization of a reservoir type prolonged release system with felodipine, over a 12 hours period using the Simplex method. METHODS: The first step of the Simplex method was to study the influence of the granules coating method on the felodipine release. Furthermore the influence of the coating polymer type, the percent of the coating polymer and the percent of pore forming agent in the coating on the felodipine release were studied. Afterwards these two steps of the experimental design the percent of Surelease applied on the felodipine loaded granules and the percent of pore former in the polymeric coating formulation variables were studied. The in vitro dissolution of model drug was performed in phosphate buffer solution (pH 6.5) with 1% sodium lauryl sulfate. The released drug quantification was done using an HPLC method. The release kinetics of felodipine from the final granules was assessed using different mathematical models. RESULTS: A 12 hours release was achieved using granules with the size between 315-500 µm coated with 45% Surelease with different pore former ratios in the coating via the top-spray method. CONCLUSION: We have prepared prolonged release coated granules with felodipine using a fluid bed system based on the Simplex method. The API from the studied final formulations was released over a 12 hours period and the release kinetics of the model drug substance from the optimized preparations fitted best the Higuchi and Peppas kinetic models.

Optimization of the sonication process for meloxicam nanocrystals preparation.

BACKGROUND AND AIMS: Meloxicam, a widely recommended AINS, presents poor water solubility, which limits its bioavailability and effect onset. The objective of this study is the investigation of the most important factors that influence the efficiency of sonication in the preparation of meloxicam nanocrystals. METHODS: The effects of crucial technological sonication parameters (amplitude, time and applied cycle) on the crystal sizes and dissolution were investigated using a central composite experimental design with three factors and three levels. Different mathematical models were applied for the evaluation of the influence of each factor on the measured responses. RESULTS: The amplitude and the time were found as the most important variables. Their increase determined significant size reduction and homogeneity due to cavitation phenomenon, while the applied cycle was less important. The crystal size greatly influenced dissolution; a strong correlation was noted between small crystals and fast dissolution after freeze-drying the nanosuspensions. The optimal formulation was obtained by sonication at 100% amplitude, for 45 minutes and cycle 1, conditions which led to 600 nm crystals with 0.521 polydispersion index. The morphological analysis revealed small, round-shaped crystals with narrow size distribution. CONCLUSIONS: The results provided the optimal sonication conditions needed to obtain meloxicam nanosuspensions with high drug dissolution capacity.

Selecting oral bioavailability enhancing formulations during drug discovery and development.

INTRODUCTION: The role of chemical structure, lipophilicity, physico-chemical, absorption, distribution, metabolism, excretion, toxicity (ADMET) and biopharmaceutical properties of compounds including bioavailability are critical in drug discovery and drug dosage forms design. AREAS COVERED: The authors discuss a number of parameters including computational approaches used for selected chemical structures with biological activity for lead optimization and chemogenomics and preclinical studies for ADMET process development of ligand properties. The authors also look at a number of other parameters including: early drug product formulations with method selection based on the biopharmaceutical classification system (BCS); in vitro-in vivo correlation (IVIVC) and different formulation strategies to enhance solubility; dissolution rate and permeability; bioavailability evaluation and quality by design as an opportunity to develop 'safe space' regions, where bioavailability is unaffected by pharmaceutical variations. EXPERT OPINION: The biopharmaceutical requirements for absorption are solubility and permeability. Both are influenced by lipophilicity, but in the opposite way. The genomic methodology, coupled with combinatorial chemistry, high-throughput screening, structure-based design and in silico ADMET would yield parameters as a starting point for the biopharmaceutical properties determination in further preclinical and clinical studies. Consecutive stages in drug discovery and development are irreplaceable, but pharmacokinetics is the critical step. Selection of drug formulations based on the BCS, IVIVC are the principal aspects to enhance the solubility and dissolution rate, while a rationale management of pharmaceutical and technological factors will enhance the bioavailability.

Subcellular drug targeting, pharmacokinetics and bioavailability.

Effective treatment of diseases at the molecular level is possible by directing the drug substance (micromolecular, protein or peptide drugs, DNA, oligonucleotides, siRNA) with the aid of a specialized nanoparticulate carrier, for safe and effective transport to the specific site of action in the cytosol and its organelles including nuclear targeting. To achieve efficient cytosolic delivery of therapeutics or nuclear targeting, different drug delivery systems (DDS) have been developed (macromolecular drug conjugates, chemically or genetically modified proteins, and particulate drug carriers) capable of subcellular internalization overcoming the biological barriers, by passive targeting and especially by active targeting (receptor-targeted delivery). The success depends on the physicochemical nature of DDS, intracellular barriers that these systems need to overcome, the bioavailability of the bioactive drug, biodistribution, the intracellular pharmacokinetics and its influence on the pharmacodynamic effect. Models necessary for this purpose exist but they need to be more developed especially with quantitative treatments, after the development of the means of highlighting the evolution of the drug substance in biophase or at the level of the target cellular organelle by quantitative assays. It is expected that intracellularly targeted drug delivery approaches will be clinically useful using specialized DDSs belonging to the pharmaceutical nanotechnologies.

Investigation into the role of Cu/Zn-SOD delivery system on its antioxidant and antiinflammatory activity in rat model of peritonitis.

BACKGROUND: The current study evaluated the role of delivery system (solution, conventional liposomes and PEG-ylated liposomes) on superoxide dismutase (SOD) antioxidant and antiinflammatory properties in a rat model of lipopolysaccharide (LPS)-induced peritonitis. METHODS: Fifty male albino rats (Wistar-Bratislava) were divided into five groups (n=10). Control group received saline and the other four groups received intraperitoneal injections of LPS (5mg/kg). Among the LPS-injected groups, one was LPS control group and the other three groups received the endotoxin injection 30min after receiving the same dose of SOD (500U/kg, ip) in different delivery systems: saline solution (SOD-S), conventional liposomes (SOD-L) or PEG-ylated liposomes (SOD-PL). The animals were euthanized 6h after LPS injection, blood samples were collected and acute phase response (total and differential leukocytes count; tumor necrosis factor α), antioxidants (total antioxidants; reduced glutathione), oxidative stress (total oxidants; lipid peroxidation) and nitrosative stress (nitric oxide metabolites; nitrotyrosine) were evaluated. RESULTS: Intraperitoneal administration of LPS to rats induced a marked inflammatory and oxidative response in plasma. On the other hand, all SOD formulations had protective effect against endotoxin-induced inflammation and oxidative/nitrosative stress, but PEG-ylated liposomes had the most significant activity. Thus, SOD-PL administration significantly reduced the effects of LPS on bone marrow acute phase response, the oxidative status and production of nitric oxide metabolites, while increasing the markers of antioxidant response in a significant manner. CONCLUSION: SOD supplementation interferes both with inflammatory and oxidative pathways involved in LPS-induced acute inflammation, PEG-ylated liposomal formulation being of choice among the tested delivery systems.

Systemic and biophase bioavailability and pharmacokinetics of nanoparticulate drug delivery systems.

The development of the vectorized delivery systems combining advantages of the colloidal carriers, with active targeting to the receptors sites suggests that nanoparticles have a considerable potential for treatment after biophase internalization and pharmacokinetics, as for example gene therapy. Two major mechanisms can be distinguished for addressing the desired sites for drug release: (i) passive and (ii) active targeting. Examples of passive targeting were presented: organ targeting by the Enhanced Permeability and Retention (EPR) effect; targeting the mononuclear phagocitic system; organ targeting by chemoembolization or local (organ) administration;sterical stabilization of nanoparticles (PEGylation). A strategy that could allow active targeting involves the surface functionalization of drug carriers with ligands that are selectively recognized by receptors on the surface of the cells of interest. The source for biophase bioavailability can be the systemic bioavailability following common routes of administration (generally for systemic delivery of medicines), or directly the site specific biophase bioavailability for the formulations capable of cellular or nuclear drug internalization where the drug release only will take place (for nanoparticulate drug delivery systems, DDS). Once the pharmaceutical nanosystem was internalized, begins the release of the active moiety by different mechanisms, as for example the escape from endosome, or biodegradation of the polymer carrier or liberation of the active peptide or gene from a biological construct in the nucleus, etc. The presentation will discusses the pharmacokinetics of drugs after systemic administration but especially the biophase bioavailability and pharmacokinetics after the administration of biotechnology origin of therapeutic proteins like monoclonal antibodies, gene transfer products, plasmid DNAs, nucleotides, antisense oligonucleotides (AODNs) or small interfering RNAs (siRNA).

Quantification of ascorbic acid and sodium ascorbate in powder blends for tableting and in vitamin C chewable tablets by NIR-chemometry.

The paper proposes a near infrared method able to directly and simultaneously quantify ascorbic acid and sodium ascorbate in powder blends for tableting and in vitamin C chewable tablets without any sample preparation. In the first step, calibration models for the quantification of ascorbic acid and sodium ascorbate in powder blends for tableting and subsequently in chewable vitamin C tablets (corresponding to 80-120 % active substance) were developed according to an experimental design with 2 variables and 5 levels. Then, using the best calibration models, the methods were fully validated in terms of recovery, precision and accuracy for both powder blends and vitamin C chewable tablets. The validated concentration range was 15.14-18.51 % for ascorbic acid and 12.06-14.49 % for sodium ascorbate in powder blends and 91.85-111.03 mg per tablet for ascorbic acid and 71.01-84.50 mg per tablet for sodium ascorbate in tablets. Validation results showed good precision and accuracy.

Drug delivery systems with modified release for systemic and biophase bioavailability.

This review describes the most important new generations of pharmaceutical systems: medicines with extended release, controlled release pharmaceutical systems, pharmaceutical systems for the targeted delivery of drug substances. The latest advances and approaches for delivering small molecular weight drugs and other biologically active agents such as proteins and nucleic acids require novel delivery technologies, the success of a drug being many times dependent on the delivery method. All these dosage forms are qualitatively superior to medicines with immediate release, in that they ensure optimal drug concentrations depending on specific demands of different disease particularities of the body. Drug delivery of these pharmaceutical formulations has the benefit of improving product efficacy and safety, as well as patient convenience and compliance. This paper describes the biopharmaceutical, pharmacokinetic, pharmacologic and technological principles in the design of drug delivery systems with modified release as well as the formulation criteria of prolonged and controlled release drug delivery systems. The paper presents pharmaceutical prolonged and controlled release dosage forms intended for different routes of administration: oral, ocular, transdermal, parenteral, pulmonary, mucoadhesive, but also orally fast dissolving tablets, gastroretentive drug delivery systems, colon-specific drug delivery systems, pulsatile drug delivery systems and carrier or ligand mediated transport for site specific or receptor drug targeting. Specific technologies are given on the dosage forms with modified release as well as examples of marketed products, and current research in these areas.

Pharmacokinetic interaction between ivabradine and phenytoin in healthy subjects.

BACKGROUND: Phenytoin is an inductor of the main metabolizing enzyme of ivabradine and it could influence its pharmacokinetics. Changes in ivabradine pharmacokinetics could have clinical significance regarding the safety of the treatment. OBJECTIVE: The study objective was evaluation of the pharmacokinetic interaction between ivabradine and phenytoin in healthy subjects. METHODS: A single dose of ivabradine 10 mg was administered alone or in combination with phenytoin 150 mg to 18 healthy subjects in a two-treatment study design, separated by 5 days in which the phenytoin alone was administered at a dose of 150 mg twice daily. Plasma concentrations of ivabradine were determined during a 12-hour period following drug administration, using a high-throughput liquid chromatography coupled with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment were calculated using non-compartmental analysis and compared to determine if the differences were statistically significant. RESULTS: In the two treatment periods, the mean ± SD peak plasma concentrations (C(max)) were 18.6 ± 8.0 ng/mL (ivabradine alone) and 6.5 ± 3.1 ng/mL (ivabradine after pre-treatment with phenytoin). The mean ± SD times taken to reach C(max) (t(max)) were 1.2 ± 0.7 h and 0.8 ± 0.6 h, respectively, and the total areas under the plasma concentration-time curve from time zero to infinity (AUC(∞)) were 62.3 ± 18.7 ng · h/mL and 19.2 ± 17.0 ng · h/mL, respectively. Statistically significant differences were observed for the C(max) and AUC(∞) of ivabradine when administered alone or with phenytoin, whereas for t(max) and the half-life the differences were non-significant. CONCLUSION: This study showed that phenytoin has an important effect on the pharmacokinetics of ivabradine in healthy subjects, reducing its bioavailability by approximately 70%.

Simultaneous quantification of l-α-phosphatidylcholine and cholesterol in liposomes using near infrared spectrometry and chemometry.

This paper describes the development and validation of a multivariate method based on transmittance NIR spectroscopy for simultaneous quantification of l-α-phosphatidylcholine (LPC) and cholesterol (CHO). Method development was based on a D-optimal experimental design consisting of 16 LPC-CHO mixtures. Calibration models were generated by partial least-squares (PLS) and principal component regression (PCR) method followed by leave-one-out cross-validation. Among the spectra pretreatment methods tested, Norris Gap first derivative was the best for both LPC and CHO quantification, combined with PLS multivariate method. The method was validated (trueness, precision, accuracy) for the concentration range 50-150% of the expected concentration in liposomes. This method was successfully applied for the characterization of liposomes prepared using the two excipients.