Fixed Dose Single Tablet Formulation with Differential Release of Amlodipine Besylate and Simvastatin and Its Pharmacokinetic Profile: QbD and Risk Assessment Approach.

PURPOSE: A differential release fixed dose matrix tablet of amlodipine besylate (AML-B) and simvastatin (SIM) was formulated to enhance patient compliance. MATERIAL AND METHOD: In the first phase, release controlling parameters of AML-B and SIM granules were identified and in the second phase a fixed dose AML-B and SIM tablet formulation was prepared and optimized for a differential release of the drugs using a quality by design (QbD) and risk assessment approach. A validated HPLC method was employed for simultaneous determination of AML-B and SIM for FDC formulation. A pharmacokinetics of the above drugs was studied in healthy dogs in the third phase. RESULTS: In QbD-based optimized formulation, Eudragit® RSPO-dicalcium phosphate (DCP) blend controlled the release of AML-B over 8 h, though this diffusion-controlled release assumed first order kinetics. DCP and Eudragit® RS 100 also retarded release of SIM causing SIM release over 8 h after AML-B release from the optimized FDC tablet formulation. The HPLC retention times of AML-B and SIM were 2.10 and 15.52 min, respectively. Linearity for AML-B was 5.0-50 ng/mL and 0.01-2.0 µg/mL for SIM with percent recoveries of 92.85-101.53% and 94.51-117.75% for AML-B and SIM. AUC0-∞ of AML-B was increased 3 fold, while AUC0-∞ of SIM was decreased 2 fold. The tmax values for AML-B and SIM were 12 and 6 h, respectively. AML-B was absorbed without any lag time (tlag) while tlag was 6.33 ± 0.81 h for SIM, thus met the study objective. CONCLUSION: The pharmacokinetic study showed an immediate absorption of AML-B while that of SIM was withheld for 6 h, close to the desired delay time of 8 h.

Optimization, characterization, and in vitro assessment of alginate-pectin ionic cross-linked hydrogel film for wound dressing applications.

Natural polymer-based hydrogel films have great potential for biomedical applications and are good candidates for wound dressings. In this study, we aimed to develop simvastatin-loaded crosslinked alginate-pectin hydrogel films by ionic crosslinking to improve the mechanical characteristics, wound fluid uptake and drug release behavior. Alginate-pectin hydrocolloid films were chemically crosslinked by immersing in different concentrations of CaCl2 (0.5-3% w/v) for 2-20min. The degree of crosslinking was influenced by both contact time and CaCl2 concentration. The optimized conditions for crosslinking were 0.5% and 1% (CaCl2) for 2min. The optimized hydrogel films were then characterized for their physical, mechanical, morphological, thermal, in vitro drug release, and cytocompatibility profiles. Crosslinking improved the mechanical profile and wound fluid uptake capacity of dressings. The hydrogel films were able to maintain their physical integrity during use, and the best results were obtained with the film in which the extent of crosslinking was low (0.5%). Thermal analysis confirmed that the crosslinking process enhanced the thermal stability of hydrogel films. Sustained, slow release of simvastatin was obtained from the crosslinked films and in vitro cytotoxicity assay demonstrated that the hydrogel films were non-toxic.

Assessment of simvastatin niosomes for pediatric transdermal drug delivery.

The prevalence of childhood dyslipidemia increases and is considered as an important risk factor for the incidence of cardiovascular disease in the adulthood. To improve dosing accuracy and facilitate the determination of dosing regimens in function of the body weight, the proposed study aims at preparing transdermal niosomal gels of simvastatin as possible transdermal drug delivery system for pediatric applications. Twelve formulations were prepared to screen the influence of formulation and processing variables on critical niosomal characteristics. Nano-sized niosomes with 0.31 µm number-weighted size displayed highest simvastatin release rate with 8.5% entrapment capacity. The niosomal surface coverage by negative charges was calculated according to Langmuir isotherm with n = 0.42 to suggest that the surface association was site-independent, probably producing surface rearrangements. Hypolipidemic activities after transdermal administration of niosomal gels to rats showed significant reduction in cholesterol and triglyceride levels while increasing plasma high-density lipoproteins concentration. Bioavailability estimation in rats revealed an augmentation in simvastatin bioavailability by 3.35 and 2.9 folds from formulation F3 and F10, respectively, compared with oral drug suspension. Hence, this transdermal simvastatin niosomes not only exhibited remarkable potential to enhance its bioavailability and hypolipidemic activity but also considered a promising pediatric antihyperlipidemic formulation.

Bioavailability assessment of hydroxymethylglutaryl coenzyme A reductase inhibitor utilizing pulsatile drug delivery system: a pilot study.

Chronotherapy or pulsatile drug delivery system could be achieved by increasing drug plasma concentration exactly at the time of disease incidence. Cholesterol synthesis shows a circadian rhythm being high at late night and early in the morning. Simvastatin (SIM) inhibits hydroxymethylglutaryl coenzyme A reductase, which is responsible for cholesterol synthesis. In this study, SIM lipid-based formulation filled in gelatin capsules and coated with aqueous Eudragit® S100 dispersion was prepared for chronotherapeutic treatment of hypercholesterolemia. The pharmacokinetic parameters of SIM capsules were studied in human volunteers after a single oral dose and compared with that of Zocor® tablets as a reference in a randomized cross-over study. Pharmacokinetic parameters such as AUC0-∞, Cmax, Tmax, t1/2 and elimination rate constant were determined from plasma concentration-time profile for both formulations. The tested formulation had the ability to delay drug absorption and provide higher drug concentrations from 3 up to 10 h after oral administration compared to that of commercial tablets. The data in this study revealed that the prepared formulation could be effective in chronotherapeutic treatment of hypercholesterolemia. Moreover, the tested formulation was found to enhance SIM bioavailability by 29% over the reference tablets.

Rational formulation development and in vitro assessment of SMEDDS for oral delivery of poorly water soluble drugs.

The aims of this study were to formulate a self-microemulsifying drug delivery system (SMEDDS) by a rational formulation approach using mixture experimental design and to derive general concepts that make the development of such systems more feasible. Various types of oils and surfactants were systematically combined and the phase behaviour upon dilution with simulated gastric fluid examined by construction of phase diagrams. The systems solubilising the highest amount of simulated gastric fluid in the continuous microemulsion area were selected for investigation and optimisation of drug solubility. Simvastatin was added as a poorly water-soluble, lipophilic model drug. Two different mixture experimental designs using D-optimal design were set up and used to investigate the solubility of simvastatin in the SMEDDS before and after dilution with simulated gastric fluid respectively. The solubility in each mixture region was analysed by fitting quadratic models using partial least squares analysis. The established models revealed the influence of mixture components on phase behaviour and drug solubility and gave the rationale for formulation optimisation. This study demonstrated that the development of complex self-emulsifying formulations with sufficient solubilisation capacity for poorly water-soluble drugs upon oral administration can be more feasible when using experimental design.

Comparison of simvastatin tablets from the US and international markets obtained via the Internet.

BACKGROUND: Convenient access to prescription drugs produced outside the US has been facilitated by the Internet. Of greatest concern to clinicians and policymakers is product quality and patient safety. The Food and Drug Administration has issued warnings to potential buyers that the safety of drugs purchased through the Internet cannot be guaranteed and may present consumers with a health risk from substandard products. OBJECTIVE: To determine whether generic simvastatin tablets and capsules obtained via the Internet from international markets are equivalent to the US innovator product regarding major aspects of pharmaceutical quality. METHODS: Twenty simvastatin tablets and capsules were obtained for pharmaceutical analysis: 19 generic samples from international Internet pharmacy Web sites and the US innovator product. Tablet samples were tested according to US Pharmacopeial (USP) guidelines where applicable, using high-performance liquid chromatography, disintegration, dissolution, weight variation, hardness, and assessment of physical characteristics. These tests are often used to detect formulation defects of drug products during the manufacturing process. RESULTS: Several international samples analyzed were not comparable to the US product in one or more aspects of quality assurance testing, and significant variability was found among foreign-made tablets themselves. Five samples failed to meet USP standards for dissolution and 2 for content uniformity. Among all samples, variability was observed in hardness, weight, and physical characterization. CONCLUSIONS: Results suggest that manufacturing standards for the international generic drug products compared with the US innovator product are not equivalent with regard to quality attributes. These findings have implications for safety and effectiveness that should be considered by clinicians to potentially safeguard patients who choose to purchase foreign-manufactured drugs via the Internet.

"Insight" into drug quality: comparison of simvastatin tablets from the US and Canada obtained via the Internet.

BACKGROUND: Recently, there has been much debate in the US concerning drug importation from Canadian Internet pharmacies. The Food and Drug Administration and US drug manufacturers assert that drugs obtained from international markets via the Internet present a health risk to consumers from substandard products. The public's perception is that drugs from Canada are as safe as those from the US. OBJECTIVE: To determine whether simvastatin tablets obtained via the Internet from Canadian generic manufacturers are comparable in blend uniformity, a major attribute of tablet quality, with the US innovator product. METHODS: Generic simvastatin tablets from 4 Canadian Internet pharmacy Web sites and the US innovator product were obtained for pharmaceutical analysis. Tablet samples were analyzed using near-infrared spectroscopic imaging techniques, which are designed to detect formulation defects of drug products during the manufacturing process. Digital images were created, revealing the tablets' internal structures. RESULTS: The blend uniformity of the active pharmaceutical ingredient in the tablet samples from Canada was determined and compared with that of the US innovator product. Results indicated that there is little significant difference in blend uniformity among US innovator and Canadian generic tablets. CONCLUSIONS: Results of this study suggest comparable quality assurance manufacturing standards for the US innovator product and the Canadian generic drug products tested. These findings have clinical, legal, and economic implications that should be addressed by policy makers to safeguard consumers who choose to purchase Canadian-manufactured drugs via the Internet.