Bappaditya Chatterjee

Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view

Abstract Self-emulsifying drug delivery system (SEDDS) is an isotropic mixture of lipid, surfactant and co-surfactant, which forms a fine emulsion when comes in contact of an aqueous medium with mild agitation. SEDDS is considered as a potential platform for oral delivery of hydrophobic drug in order to overcome their poor and irregular bioavailability challenges. In spite of fewer advantages like improved solubility of drug, bypassing lymphatic transport etc., SEDDS faces different controversial issues such as the use of appropriate terminology (self-microemulsifying drug delivery system; SMEDDS or self-nanoemulsifying drug delivery system; SNEDDS), presence of high amount of surfactant, correlation of in vitro model to in vivo studies, lack of human volunteer study and effect of conversion of SEDDS to final administrable dosage form on pharmacokinetic behavior of the drug. In this review, potential issues or questions on SEDDS are identified and summarized from the pharmacokinetic point of view. Primarily this review includes the conflict between the influences of droplet size, variation in correlation between in vitro lipolysis or ex-vivo intestinal permeation and pharmacokinetic parameters, variation in in vivo results of solid and liquid SEDDS, and potential challenges or limitation of pharmacokinetic studies on human volunteers with orally administered SEDDS. In the past decades, hundreds of in vivo studies on SEDDS have been published. In the present study, only the relevant article on in vivo pharmacokinetic studies with orally administered SEDDS published in past 5–6 years are analyzed for an up to date compilation.

Pharmacokinetic and Pharmacodynamic Features of Nanoemulsion Following Oral, Intravenous, Topical and Nasal Route

BACKGROUND Most of the active pharmaceutical ingredients discovered recently in pharmaceutical field exhibits poor aqueous solubility that pose major problem in their oral administration. The oral administration of these drugs gets further complicated due to their short bioavailability, inconsistent absorption and inter/intra subject variability. METHODS Pharmaceutical emulsion holds a significant place as a primary choice of oral drug delivery system for lipophilic drugs used in pediatric and geriatric patients. Pharmacokinetic studies on nanoemulsion mediated drugs delivery approach indicates practical feasibility in regards to their clinical translation and commercialization. RESULTS This review article is to provide an updated understanding on pharmacokinetic and pharmacodynamic features of nanoemulsion delivered via oral, intravenous, topical and nasal route. CONCLUSION The article is of huge interest to formulation scientists working on range of lipophilic drug molecules intended to be administered through oral, intravenous, topical and nasal routes for vivid medical benefits.

Development and validation of an LC-ESI-MS/MS method for simultaneous quantitation of olmesartan and pioglitazone in rat plasma and its pharmacokinetic application

A simple, high-throughput and specific high-performance liquid chromatography tandem mass spectrometry method has been developed and validated according to the FDA guidelines for simultaneous quantification of olmesartan and pioglitazone in rat plasma. The bioanalytical method consists of liquid-liquid extraction and quantitation by triple quadrupole mass spectrometry using electrospray ionization technique, operating in multiple reaction monitoring and positive ion modes. The compounds were eluted isocratically on a C(18) column with a mobile phase consisting of a mixture of methanol and water (containing 0.5% formic acid) in a ratio of 9:1. The response to olmesartan and pioglitazone was linear over the range 0.01-10 µg/mL. The validation results demonstrated that the method had satisfactory precision and accuracy across the calibration range. Intra- and inter-day precisions ranged from 0.66 to 3.32 and from 0.94 to 2.93% (%CV), respectively. The accuracy determined at three quality control levels was within 91.27-107.28%. There was no evidence of instability of the analytes in rat plasma following the stability studies. The method proved highly reproducible and sensitive and was successfully applied in a pharmacokinetic study after single dose oral administration of olmesartan and pioglitazone to the rat.

Development and validation of a high-performance liquid chromatographic method for bioanalytical application with rimonabant

A simple and feasible high-performance liquid chromatographic method with UV detection was developed and validated for the quantification of rimonabant in human plasma. The chromatographic separation was carried out in a Hypersil BDS, C(18) column (250 mm x 4.6mm; 5 microm). The mobile phase was a mixture of 10 mM phosphate buffer and acetonitrile (30:70, v/v) at a flow rate of 1.0 ml/min. The UV detection was set at 220 nm. The extraction recovery of rimonabant in plasma at three quality control (QC) samples was ranged from 84.17% to 92.64%. The calibration curve was linear for the concentration range of 20-400 ng/ml with the correlation coefficient (r(2)) above 0.9921. The method was specific and sensitive with the limit of quantification of 20 ng/ml. The accuracy and precision values obtained from six different sets of QC samples analyzed in separate occasions ranged from 88.13% to 106.48% and 0.13% to 3.61%, respectively. In stability tests, rimonabant in human plasma was stable during storage and assay procedure. The method is very simple, sensitive and economical and the assay was applied to human plasma samples in a clinical (pharmacokinetic) study of rimonabant.

Development and validation of a high throughput LC–MS/MS method for simultaneous quantitation of pioglitazone and telmisartan in rat plasma and its application to a pharmacokinetic study

Management of cardiovascular risk factors in diabetes demands special attention due to their co-existence. Pioglitazone (PIO) and telmisartan (TLM) combination can be beneficial in effective control of cardiovascular complication in diabetes. In this research, we developed and validated a high throughput LC–MS/MS method for simultaneous quantitation of PIO and TLM in rat plasma. This developed method is more sensitive and can quantitate the analytes in relatively shorter period of time compared to the previously reported methods for their individual quantification. Moreover, till date, there is no bioanalytical method available to simultaneously quantitate PIO and TLM in a single run. The method was validated according to the USFDA guidelines for bioanalytical method validation. A linear response of the analytes was observed over the range of 0.005–10 µg/mL with satisfactory precision and accuracy. Accuracy at four quality control levels was within 94.27%–106.10%. The intra- and inter-day precision ranged from 2.32%–10.14 and 5.02%–8.12%, respectively. The method was reproducible and sensitive enough to quantitate PIO and TLM in rat plasma samples of a preclinical pharmacokinetic study. Due to the potential of PIO-TLM combination to be therapeutically explored, this method is expected to have significant usefulness in future.

Polymeric behavior evaluation of PVP K30-poloxamer binary carrier for solid dispersed nisoldipine by experimental design.

Abstract Context: High melting point polymeric carrier without plasticizer is unacceptable for solid dispersion (SD) by melting method. Combined polymer–plasticizer carrier significantly affects drug solubility and tableting property of SD. Objective: To evaluate and optimize the combined effect of a binary carrier consisting PVP K30 and poloxamer 188, on nisoldipine solubility and tensile strength of amorphous SD compact (SDcompact) by experimental design. Materials and methods: SD of nisoldpine (SDnisol) was prepared by melt mixing with different PVP K30 and poloxamer amount. A 32 factorial design was employed using nisoldipine solubility and tensile strength of SDcompact as response variables. Statistical optimization by design expert software, and SDnisol characterization using ATR FTIR, DSC and microscopy were done. Results: PVP K30:poloxamer, at a ratio of 3.73:6.63, was selected as the optimized combination of binary polymeric carrier resulting nisoldipine solubility of 115 μg/mL and tensile strength of 1.19 N/m2. Discussion: PVP K30 had significant positive effect on both responses. Increase in poloxamer concentration after a certain level decreased nisoldipine solubility and tensile strength of SDcompact. Conclusion: An optimized PVP K30–poloxamer binary composition for SD carrier was developed. Tensile strength of SDcompact can be considered as a response for experimental design to optimize SD.

Current regulatory requirements and practical approaches for stability analysis of pharmaceutical products: A comprehensive review

&NA; Different regulatory guidelines recommend establishing stability profile of pharmaceuticals at the time of drug development. The expiry date, retesting period and storage conditions of active drugs or products are established through stability analysis. Several regulatory guidelines exist for stability testing of pharmaceuticals. Mostly, ICH stability guidelines are followed in practice. This guideline recommends to validate stability indicating method using forced degradation samples that contains all possible degradation impurities. ICH guidelines provide general recommendations for inclusion of stability indicating parameters in a stability testing protocol. However, those guidelines do not provide specific requirements and experimental methodology to be followed for stability studies. Due to this gap, often confusion arises in the scientific community in designing stability testing protocol. Therefore, significant variations are observed in reported literature in selection of stability indicating parameters. Procedural dissimilarity amongst reported stability studies is also evident. This review discusses the regulatory guidelines and procedures to follow in performing stability testing of pharmaceuticals. Scope of this review also includes recommendations on practical approaches for designing stability testing protocol to fulfill current regulatory requirements for drug substances and their formulations. Graphical abstract Figure. No caption available.

Bioequivalence study of a fixed dose combination tablet containing rabeprazole and diclofenac sodium in healthy Indian subjects

The pharmacokinetics of rabeprazole (CAS 117976-89-3) and diclofenac sodium (CAS 15307-79-6) has been extensively evaluated in adult human volunteers individually after oral administration of tablet formulation. However, no published data is available regarding the combined pharmacokinetics and bioavailability of this particular fixed dose combination. In light of the above, a clinical study was designed to evaluate the bioequivalence of two fixed dose combination (FDC) products (reference and test) of two manufacturers containing rabeprazole 20 mg and diclofenac sodium 100 mg slow release (SR) tablet in healthy Indian male volunteers. Each subject received a test FDC and a reference FDC in a randomized, single dose, fasting state, two period, and crossover study design with a one-week washout period between the doses. Extraction of the drugs from the plasma was carried out by the precipitation method. Analysis of rabeprazole and diclofenac sodium from plasma samples was done by a simple and sensitive HPLC method using a UV detector. An analysis of variance was performed on the pharmacokinetic parameters of Cmax, tmax, AUC(0-t), and AUC(0-infinity), using general linear model (GLM) procedures in which sources of variation were subject, formulation and period. The results of this study indicated that there were no statistically significant differences between the logarithmically transformed AUC(0-infinity) and Cmax values of the two preparations. The 90% confidence interval for the ratio of logarithmically transformed AUC(0-t), AUC(0-infinity) and Cmax were within the bioequivalence limit of 0.80-1.25 and the relative bioavailability of rabeprazole and diclofenac sodium were found to be 98.6% and 98.9% respectively in the test product. Thus, these findings clearly indicated that the two products are bioequivalent in terms of rate and extent of drug absorption.

Transdermal delivery of raloxifene HCl via ethosomal system: Formulation, advanced characterizations and pharmacokinetic evaluation

&NA; Raloxifene HCl belongs to a class of selective estrogen receptor modulators (SERMs) which is used for the management of breast cancer. The major problem reported with raloxifene is its poor bioavailability which is only up to 2%. The main objective of the present work was to formulate raloxifene loaded ethosomal preparation for transdermal application and compare it with an oral formulation of the drug. Five ethosomal formulations with different concentrations of ethanol and a conventional liposomes formulation were prepared by rotary evaporation method. The prepared systems were characterised by high resolution transmission electron microscopy (HRTEM), force emission electron microscopy (FESEM), atomic force microscopy (AFM), X‐ray diffraction (XRD) and 31P NMR study. All these advanced characterization study established that the ethosome formulation was well defined by its size, shape and its bilayer formation. Transdermal flux of the optimized ethosome formulation was 22.14 ± 0.83 &mgr;g/ml/cm2 which was 21 times higher when compared to the conventional liposomes. Confocal microscopy study revealed an enhanced permeation of coumarin‐6 dye loaded ethosomes to much deeper layers of skin when compared with conventional liposomes. The gel was found to be pseudoplastic with elastic behaviour. In‐vivo studies on rats showed a higher bioavailability of RXL (157% times) for ethosomal formulation when compared with the oral formulation. In conclusion, RXL loaded ethosomal formulation via transdermal route showed superior drug delivery properties as compared to oral formulation.

Assessment of preclinical pharmacokinetics and acute toxicity of pioglitazone and telmisartan combination

ABSTRACT The prevalence of hypertension is very common amongst the diabetic patients and is reported as the major cause of mortality in diabetes. Pioglitazone reported to have an ability to alter the blood cholesterol level and cardioprotective efficiency along with its antidiabetic activity. Telmisartan, through activation of PPAR‐&ggr; receptor exerts insulin sensitizing property in addition to its primary cardioprotective efficiency. Theoretically, a combination of pioglitazone and telmisartan may be beneficial to effectively control the high blood glucose level and management of coexisting cardiovascular complication in diabetes. The aim of this research was to experimentally evaluate the pharmacokinetic interaction of pioglitazone and telmisartan when are coadministered in rat. Pioglitazone and telmisartan were administered orally as a single dose individually and in combination to the rats. The plasma samples of the pharmacokinetic study were analyzed using a validated LCMS method. The acute toxicity of the combination with a high dose in rats was also evaluated as a part of the determination of its safety profile. There was no significant change in pharmacokinetic parameters were resulted due to the coadministration of pioglitazone and telmisartan in rat. Absence of major toxicological effect supports the in vivosafety of the combination. HighlightsPharmacokinetics of pioglitazone and telmisartan combination was evaluated in rat.No significant changes in pharmacokinetics was evidenced.Acute toxicity study of the combination with high dose was performed.Histopathological or any other abnormal changes were not observed.