Aly Nada

Solid State and Dissolution Rate Characterization of Co-Ground Mixtures of Nifedipine and Hydrophilic Carriers

ABSTRACT Co-ground powders of the poorly water-soluble drug nifedipine and a hydrophilic carrier, [partially hydrolyzed gelatin (PHG), polyvinylpyrrolidone (PVP), sodium dodecyl sulfate (SDS), hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), urea or Pluronic F108] were prepared in order to improve the dissolution rate of nifedipine. The effects of type of grinding equipment, grinding time, and type of hydrophilic carrier on the crystallinity of nifedipine (x-ray diffraction and differential scanning calorimetry) on the interaction between drug and carriers (differential scanning calorimetry), on the particle size and appearance (scanning electron microscopy), on the wettability (contact angle measurements), and on the drug release were investigated. Grinding nifedipine together with these carriers improved the dissolution rate. PHG-ground mixtures resulted in the fastest dissolution rate followed by PVP, SDS, HPMC, Pluronic, urea, and PEG. This effect was not only due to particle size reduction, which increased in the order PHG < PEG = SDS < Pluronic < drug < urea < HPMC < PVP, but also resulted from the ability of some carriers (PVP and HPMC) to prevent reaggregation of the finely divided drug particles. PVP, HPMC, and PHG formed a powder with amorphous drug. The carriers improved the wettability of the ground products in the order HPMC < drug < urea < PVP < SDS < PHG < PEG < Pluronic. Differential scanning calorimetry (DSC) measurements gave valuable information about the nature of drug crystallinity and the interactions with the carriers within the ground mixtures.

Physicochemical characterization of gliclazide–macrogol solid dispersion and tablets based on optimized dispersion

Background: This study investigated the physical interaction of gliclazide (GLC) with a hydrophilic carrier, that is, macrogol [polyethylene glycol (PEG)]. Different molecular weights of PEG (4000, 10,000, and 20,000) were used in different drug : carrier weight ratios (1 : 1, 1 : 2, 1 : 5, and 1 : 10). Method: Preliminary screening was done by phase solubility studies to characterize the liquid state interaction between the drug and the carrier. Solid dispersions (SDs) of GLC and PEG in different ratios were prepared by fusion technique and by physical mixing. The solid-state interaction between the drug and the carrier was examined by performing differential scanning calorimetry and Fourier transform infrared spectroscopic studies. SD with satisfactory characteristics was selected for the formulation of tablets by wet granulation method and compared with the commercial brand for in vitro dissolution. Results: It was evident from phase solubility studies that the drug solubility increased linearly with increasing PEG concentrations. In vitro dissolution of GLC improved significantly in the SDs prepared by fusion method as compared with the original drug and physical mixtures. Scanning electron microscopy images showed well-defined changes in the surface topography of GLC, thus confirming the effective formation of a fused binary system. The SD tablets showed a significant improvement in the drug release profile than that of the commercial brand. Conclusion: It was thus concluded that SD formulations of GLC can be successfully used to design a solid dosage form of the drug, which would have significant advantages over the current marketed tablets.

Preparation and evaluation of fast-release mephenamic acid microspheres.

Mephenamic acid is characterized by low solubility, which affects its dissolution rate and bioavailability. The objective of this study was to develop fast-release microspheres of ammonium salt of the drug (AMM) by emulsion congealing.The effect of polymer, drug to polymer ratio, surfactant, type and volume of oil phase, stirring rate, microsphere size, encapsulation efficiency and stability of the microspheres were investigated. The results pointed out a good yield (69–98%) and encapsulation efficiency (71–100%). Optimum conditions include moderate molecular weight PEG, inclusion of Tween 20 and/or Span 80, high ratio of PEG (1 : 4, drug : PEG), use of mineral oil and high stirring rate (2000 rpm). Dissolution efficiency ranged between 57% and 90%. Effect of ageing on drug content and release revealed that the microspheres prepared remained stable throughout 1 year of storage. The described method was simple, efficient and resulted in stable microspheres with enhanced drug release.

Development of Novel Formulations to Enhance in Vivo Transdermal Permeation of Tocopherol

Tocopherol represents a big challenge for transdermal permeation owing to its extreme hydrophobicity and large molecular mass. The aim of the present study was to develop alpha-tocopherol (T) topical formulations and evaluate their ex vivo and in vivo permeation. Franz diffusion cells were used for ex vivo permeation, and neonatal rats were used for in vivo permeation. Seven gel formulations and 21 liquid formulations were investigated for physical stability, viscosity and permeation of T. Analysis of T was performed by a validated HPLC method using a UV detector. The ex vivo permeation from gel and emulsion formulations was very poor (0.001-0.015 %). Highest permeation was observed from monophasic liquid formulations containing dimethyl sulfoxide (DMSO), tocopheryl polyethylene glycols (TPGs), propylene glycol, ethanol and 9.5 % T. The in vivo results demonstrated higher retention in the epidermis compared to subcutaneous tissues, 1377 and 1.13 μg g-1, respectively. Increasing T concentration from 4.8 to 9.5 % did not increase the amount permeated or % of T retained. It was concluded that simple solutions of T in the presence of DMSO and TPGs were more promising systems for effective transdermal permeation compared to gel, emulsion or oleaginous systems.

Comparative Bioavailability of Norfloxacin Tablets Based on Blood and Urine Data

Objective: To assess the bioavailability of norfloxacin from urinary excretion relative to plasma concentration. Materials and Methods: Twelve healthy volunteers (22–33 years) participated in the study. Each received a previously developed (M), a local (L) and a multinational (Noroxin®) tablet (Ref), 400 mg each, according to a random balanced three-way crossover design on 3 different days. Blood samples were collected over a 12-hour period and urine over a 24-hour period. Norfloxacin concentrations were analyzed by a validated HPLC method. Results: An initial estimate of bioequivalence of the three products was obtained using analysis of variance on transformed data and based on confidence interval calculation. Elimination pharmacokinetic parameters (half-life and renal clearance) calculated from plasma concentration and urinary excretion data (mean values, n = 36) were comparable to reported values for norfloxacin. Interproduct differences in elimination parameters (mean values, n = 12) were statistically insignificant (F values, ANOVA). Strong association was found between the mean of plasma concentration and urinary excretion rates for many volunteers (F values, regression analysis). Relative bioavailability values calculated for the local and previously developed products relative to Noroxin were higher than 85% based on area under the curve and urinary excretion. Bioequivalence could not be established among the three tested products based on calculated 90% confidence intervals. Conclusion: Urinary excretion of norfloxacin may be a useful noninvasive tool for bioavailability assessment of norfloxacin oral formulations.

Preparation and in vitro/in vivo evaluation of metformin hydrochloride rectal dosage forms for treatment of patients with type II diabetes

Abstract Background: Metformin hydrochloride (MtHCL) is an oral antidiabetic drug and has many other therapeutic benefits. It has poor bioavailability, narrow absorption window and extensive liver metabolism. Moreover, children and elders face difficulty to swallow the commercial oral tablets. Objectives: Preparation, in vitro/in vivo evaluation of MtHCL suppositories for rectal administration to solve some of these problems. Methods: Suppository fatty bases (Witepsol®, Suppocire® and Massa®; different grades) and PEG bases 1000, 4000 and 6000 (different ratios), were used to prepare rectal suppository formulations each containing 500 mg drug. These were characterized for manufacturing defects, and pharmacotechnical performance and formulations showing superior results were subjected to bioavailability testing in human volunteers compared with the commercial oral tablet (Ref) applying LC–MS/MS developed analytical technique. Results: The preparation method produced suppositories with satisfactory characteristics and free of manufacturing defects. The fatty bases were superior compared with PEG bases regarding the physical characteristics. Three formulations were chosen for bioavailability testing and the results showed comparable bioavailability compared to the Ref. Conclusions: The fatty bases showed superior characteristics compared with the PEG bases. MtHCL formulated in selected fatty bases could be a potential alternative to the commercial oral tablets particularly for pediatric and geriatric patients.

Enantioselective penetration enhancing effect of carvone on the in vitro transdermal permeation of nicorandil.

The objective was to investigate the difference in penetration enhancing effect of R-carvone, S-carvone and RS-carvone on the in vitro transdermal drug permeation. In vitro permeation studies were carried out across neonatal rat epidermis from 2%w/v HPMC (hydroxypropyl methylcellulose) gel containing 4%w/v of nicorandil (a model drug) and a selected concentration (12%w/v) of either R-carvone, S-carvone or RS-carvone against a control. The stratum corneum (SC) of rats was treated with vehicle (70%v/v ethanol-water) or ethanolic solutions of 12%w/v R-carvone, S-carvone or RS-carvone. The enhancement ratio (ER) of R-carvone, S-carvone and RS-carvone when compared to control was about 37.1, 31.2 and 29.9, respectively indicating enantioselective penetration enhancing effect of carvone enantiomers. Furthermore, there was a significant decrease in the lag time required to produce a steady-state flux of nicorandil with S-carvone when compared to R-carvone and RS-carvone. DSC and FT-IR studies indicate that the investigated enantiomers of carvone exhibit a difference in their ability to affect the cellular organization of SC lipids and proteins thereby showing enantioselective transdermal drug permeation. It was concluded that R-carvone exhibited a higher penetration enhancing activity on transdermal permeation of nicorandil when compared to its S-isomer or racemic mixture.

Preparation and in-vitro evaluation of meloxicam co-ground mixtures

I Farmacologica y Biofarmaceutica, SAPI de CV (IFaB) is a market-leading clinical research organization (CRO– Authorized Third Party) that focuses on bioavailability and bioequivalence testing studies in the Mexican healthcare market. The company is comprised by a group of highly qualified and renowned professionals in various areas of expertise related to the pharmaceutical industry who have worked together as a team for over ten years. IFaB is certified by the Mexican Federal Commission for the Protection against Health Risks (COFEPRIS–Ministry of Health) and the Brazilian National Health Advisory Agency (ANVISA) the only Mexican company to have this certification. The company s client base includes first-rate international and local pharmaceutical companies. Over the past 10 years, the bioequivalence market has witnessed a boom derived from new regulation aiming to renewal legacy drug licenses in Mexico. It is estimated that every year 300-350 bioequivalence studies are conducted, which represent a total market of

In vitro/in vivo Correlation of Fast Release Mephenamic Acid Microspheres in Humans

40 million dollars. With IFaB s dual strategy, the Brazilian and Mexican regulatory requirements are fulfilled, and with this pharmaceutical companies can obtain licenses in Brazil, Mexico, Chile, Colombia, Peru, and several Central American countries–covering approximately 80% of the Latin American market with just one BE study. The pharmaceutical industry is experiencing significant changes: Biosimilar products provide cost savings, increases in patient access and innovations. The company believes that it can add value by developing new and complex products that can differentiate IFaB from competitors and increase its portfolio services with oncologicals, inhalables–combining complex drugs with sophisticate medical devices, patches–innovative alternative for controlled drug delivery through the skin, and biotechnological products including monoclonal antibodies, etc.T vasoconstrictor assay (VCA) method published in FDA’s 1995 Guidance on bioequivalence of topical dermatologic corticosteroids is currently the only pharmacodynamic method approved by FDA for demonstrating bioequivalence of topical corticosteroid products (gels, creams, lotions, ointments, foams, tapes and sprays). The Guidance recommends a pilot dose durationresponse study to determine the appropriate dose duration for use in the pivotal study. In general, evaluation of bioequivalence by the VCA method has worked well over the last 20 years, but there remain several challenges in design and data analysis. For example, for the dose-response study the fit of the simple Emax model is not always optimal with low potency products, with products that show delayed vasoconstrictor (skin blanching) response, or with subjects that have low skin blanching (low Emax); for the pivotal study a too short or very long ED50 duration products can pose operational challenges. Furthermore, the sample size recommendation in the Guidance of 40-60 qualifiers for pivotal studies may be too low for those products that show high intra-subject variability in vasoconstrictor response. Successful bioequivalence studies depend on the clinic’s ability to recruit a fair-skinned population of subjects that show high and consistent skin blanching to even low potency topical steroids so that within-subject variability in vasoconstrictor response is minimized. This presentation will discuss approaches for minimizing operational issues, estimating sample size, and evaluating reliability of blanching profiles for pivotal studies and will provide examples of design and data analysis challenges for dose-response and pivotal studies.

In vitro and in vivo Permeation of Vitamin E and Vitamin E Acetate from Cosmetic Formulations

Objectives: The objectives of this study were to assess the bioavailability of an optimized mephenamic acid (MFA) microspheres (test) against a Ponstan® capsule (reference) in healthy volunteers, and to establish a correlation with in vitro parameters. Subjects andMethods: Four subjects received the test and reference (250 mg MFA each) in a randomized crossover design, separated by a 1-week washout period. The drug was analyzed in plasma by a specific high-performance liquid chromatographic method. The relevant pharmacokinetic parameters [maximum plasma concentration (Cmax), time of peak concentration (Tmax), area under plasma concentration-time curves from 0 to 12 h (AUC0–12) and area under plasma concentration-time curves from zero to ∞ (AUC0–∞)] were calculated from the plasma drug concentration-time data. Results: The test product exhibited faster absorption (Tmax of 1.87 ± 0.482 vs. 2.14 ± 0.20 h; Cmax of 5.91 ± 0.604 vs. 3.58 ± 0.671 µg/ml) when compared to the reference. The relative bioavailability of the test compared to the reference capsule was 172%. Good correlations were established between the in vitro 90% dissolution (T90) and each of the AUC0–12 and Tmax, as well as between the percentage of drug released and plasma concentrations. Conclusion: The formulation of MFA microsphere with polyethylene glycol improved the dissolution rate and bioavailability of MFA, as evidenced by a higher Cmax, AUC0–12 and AUC0–∞, and shorter Tmax values. Good correlations between T90 and both AUC0–12 and Tmax as well as between the percentage of drug released and plasma concentrations were achieved.