Use of Surfactant in the Dissolution of Medroxyprogesterone Acetate Tablets

Abstract

The use of sodium lauryl sulfate in water and 0.1N HC1 as dissolution medium for medroxyprogesterone acetate tablets is investigated. The FDA's handbook of drug dissolution standards recommends the use of 0.54% sodium lauryl sulfate in water as dissolution medium for medroxyprogesterone acetate tablets to meet the recommended dissolution tolerance limits of not less than 85% in 45 minutes. This study shows that these tolerance limits can be achieved by using smaller quantities of 0.1% sodium lauryl sulfate in 0.1N HC1 as dissolution medium.     

High-Throughput Evaluation of Non-Swellable Controlled Release Matrix Tablets

Abstract

Drug release from controlled-release (CR) matrix tablets involves the permeation and diffusion of water through the system. In this study, a new methodology is proposed for the measurement of water permeation and simultaneous drug release from the inert, non-swellable CR matrix tablet of diltiazem (DLT) and a correlation is made between these two processes. Cylindrical matrices were readily prepared by direct compression of pellets obtained by extrusion-spheronization. Water transport was studied using tritiated water (HTO) as a permeant in a Franz-diffusion cell and simultaneously drug release was measured. Further, dissolution was performed on USP XXI/XXII dissolution apparatus I using demineralized water. Matrices showed a steady water-uptake up to 6 h and the steady state for HTO permeation lasting from 6-h to 24-h Flux of water permeated and flux of drug released correlated well. Thus, HTO permeation through the matrix tablet and the proposed methodology can be used as a tool and/or surrogate marker for evaluation of controlled release matrix tablets. This methodology can be coined as “high-throughput” in terms of amount of labor and resources required in comparison to that of dissolution.     

Influence of Surfactants on the In-Vitro release and Permeation of Lorazepam from Tablets

Sodium lauryl sulfate, tween 80, sodium taurocholate and sodium tauroglycocholate were included into lorazepam tablet formulations to increase the dissolution and permeation of the drug. The increasing concentration of the surfactants has increased the dissolution and permeation of the drug. The fractional quantity remained to be permeated versus time plots show the exponential decay.     

Optimization of Slow-Release Tablet Formulations Containing Montmorillonite II. Factors Affecting Drug Release

Abstract

The influence of electrolytes, surfactants in the dissolution medium, and particle size of drug and montmorillonite on the in vitro release of the soluble model drug sodium sulfathiazole from directly compressed slow-release tablets containing 20% drug and 30% magnesium aluminum silicate was investigated. The presence of electrolytes in the dissolution media decreased the release from the tablets. A decrease in release was also observed in deionized water when sodium chloride was included in the tablet formulation. The surface tension of the media appeared to have little influence on the dissolution rate of the drug. Varying the particle size of the drug had a greater effect on release rates than varying the particle size of the montmorillonite clay.     

Development of Sustained-Release Tablets Containing Sodium Valproate: In Vitro and In Vivo Correlation

ABSTRACT

We have developed a 200 mg and 400 mg sustained-release sodium valproate tablet that allows effective blood concentration of the active drug with once-a-day dosing. The controlled dissolution or sustained release of the drug was attained by a membrane-controlled system. A single-coating system did not adequately control the dissolution rate, and therefore double-coated tablets were prepared and a human pharmacokinetic study was conducted. With the 200 mg VPA-Na tablets, the nonfasting C_max was only 20% higher than the fasting C_max. An in vitro dissolution test was conducted to predict the effects of food on drug dissolution after administration of this tablet. A relatively good correlation was observed between the absorption profiles and the dissolution profiles of the drug.     

Improved oral bioavailability of valsartan using proliposomes: design,characterization and in vivo pharmacokinetics

Abstract

The objective of our investigational work was to develop a proliposomal formulation to improve the oral bioavailability of valsartan. Proliposomes were formulated by thin film hydration technique using different ratios of phospholipids:drug:cholesterol. The prepared proliposomes were evaluated for vesicle size, encapsulation efficiency, morphological properties, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug-release studies were performed in simulated gastric fluid (pH 1.2) and purified water using dialysis bag method. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA), Caco-2 monolayer and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague Dawley (SD) rats. Among the proliposomal formulations, F-V was found to have the highest encapsulation efficiency of 95.6?±?2.9% with a vesicle size of 364.1?±?14.9?nm. The in vitro dissolution studies indicated an improved drug release from proliposomal formulation, F-V in comparison to pure drug suspension in both, purified water and pH 1.2 dissolution media after 12?h. Permeability across PAMPA, Caco-2 cell and everted rat intestinal perfusion studies were higher with F-V formulation as compared to pure drug. Following single oral administration of F-V formulation, a relative bioavailability of 202.36% was achieved as compared to pure valsartan.     

Clinical pharmacokinetic study for the effect of glimepiride matrix tablets developed by quality by design concept

Objective: Implementation of a new pharmaceutical technique to improve aqueous solubility and thus dissolution, enhancement of drug permeation, and finally formulation of a controlled release tablet loaded with glimepiride (GLMP).

Significance: Improve GLMP bioavailability and pharmacokinetics in type II diabetic patients.

Methods: Different polymers were used to enhance aqueous GLMP solubility of which a saturated polymeric drug solution was prepared and physically adsorbed onto silica. An experimental design was employed to optimize the formulation parameters affecting the preparation of GLMP matrix tablets. A compatibility study was conducted to study components interactions. Scanning electron microscope (SEM) was performed before and after the tablets were placed in the dissolution medium. An in vivo study in human volunteers was performed with the optimized GLMP tablets, which were compared to pure and marketed drug products.

Results: Enhancement of GLMP aqueous solubility, using the polymeric drug solution technique, by more than 6–7 times when compared with the binary system. All the studied formulation factors significantly affected the studied variables. No significant interaction was detected among components. SEM illustrated the surface and inner tablet structure, and confirmed the drug release which was attributed to diffusion mechanism. The volunteer group administered the optimized GLMP tablet exhibited higher drug plasma concentration (147.4?ng/mL), longer time to reach maximum plasma concentration (4?h) and longer t_1/2 (7.236?h) compared to other groups.

Conclusions: Matrix tablet loaded with a physically modified drug form could represent a key solution for drugs with inconsistent dissolution and absorption profiles.     

Design and Evaluation of a Lorazepam Transdermal Delivery System

Abstract

The aim of this work was to study the release and the permeation rate of lorazepam, in order to develop a transdermal therapeutic system (TTS) containing that drug. Only a small number of drugs are by themselves able to permeate the skin at a useful rate in order to achieve a therapeutic effect. The lorazepam permeation rate did not reach that value and required a skin permeation enhancer to increase the skin's permeability. Three permeation enhancers (Tween 80, sodium lauryl sulfate, and benzalkonium chloride) were investigated in two different concentrations: 1% and 5% of the amount of lorazepam. The best permeation enhancement results were obtained using benzalkonium chloride in concentration of 5%.     

The Effect of pH and Ionic Strength on the Release of Quinine Adsorbed on to an Insoluble Sodium Polyphosphate

Abstract

The preparation and evaluation of a potential prolonged-release drug delivery system with the model drug quinine HCl adsorbed onto an insoluble sodium polyphosphate (Maddrell's phosphate type II) is described. The delivery system was prepared by equilibration of the drug with a suspension of the polyphosphate and then compressing the dried adsorbed complex into disks. It was shown that the extraction of the drug from the loose powder was enhanced by increasing the sodium ion concentration and by reducing the pH. The effect of sodium ion concentration upon release of the drug from compressed dish depended upon the pH of the dissolution fluid. At low pH, which slowly dissolved the disks, the zero-order release of quinine was reduced as the ionic strength of the dissolution medium was increased. At near-neutral pH, the release of quinine was first-order at sodium concentrations greater than 0.025 M and was zero-order at sodium concentrations lower than 0.025 M. The release was promoted by an increase in the ionic strength.     

Some Factors Influencing the Release of Drdg from Nondisintegrating Slow Release Tablets

Abstract

The purpose of this study was to investigate some factors that control the drug release from non disintegrating cylindrical slow release tablets using sodium salicylate as a model drug. The in vitro release of sodium salicylate was described adequately by a previously published cubic equation. It was found that the release of the drug from a nondisintegrating tablet is controlled by the factors such as porosity (e) of the tablet and the mass of drug present (A) per unit tablet volume. On the other hand, pH of the dissolution fluid had no influence on the release of sodium salicylate.     

Fast- and Slow-Release Tablets for Oral Administration of Flavonoids: Rutin and Quercetin

ABSTRACT

Many derivatives of rutin (Rt) and its metabolite quercetin (Q) are employed in clinics for cardiovascular chronic pathology, and are also known for their antiulcer behavior in vivo and antiproliferative and antimutagenic activity in vitro. Unfortunately, the absorption of quercetin and rutin from the gastrointestinal tract is slow and irregular, probably due to their very slight solubility in water and slow dissolution rate.

In this work the dissolution rate of the drugs from oral formulations has been improved using some enhancers such as cross-linked sodium carboxymethylcellulose (CMC-XL), sodium carboxymethylstarch (E), and cross-linked polyvinylpyrrolidone (P). The drugs were loaded on the hydrophilic carriers by different techniques such as mixing or co-milling. The in vitro dissolution profiles of the mixed or co-milled drug/polymer systems, obtained in various media with different pH, were compared. The results show that the drug dissolution rate from the co-milled drug/carrier systems is faster than that from mixed systems, and CMC-XL and sodium carboxymethylstarch systems are able to enhance the dissolution rate. For this reason, these co-milled drug/carrier systems were used for the production of both fast- and slow-release tablets. The co-milled drug/CMC-XL system was used for the preparation of fast-release tablets containing rutin, while three different fast-release tablets were formulated and tested using respectively Q/CMC-XL, Q/E, and Q/P co-milled systems.

The effect of the presence of sodium lauryl sulfate in the aqueous medium on the dissolution profile of flavonoids alone was also studied.

The prolonged-release formulations have been developed using hydroxypropylmethylcellulose (HPMC) of different viscosity grades as retarding polymer. An extended release of the drugs for times ranging from 6 to 14 hr could be obtained, depending on the type and viscosity of the HPMC used.     

Optimization of the Ussing chamber setup with excised rat intestinal segments for dissolution/permeation experiments of poorly soluble drugs

Context: Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments.

Objective: The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media.

Methods: The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIF_mod) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant.

Results: Fa/FeSSIF_mod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations.

Discussion: The compatibility of Fa/FeSSIF_mod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo.

Conclusion: The optimized setup uses FaSSIF_mod as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B.     

Modified Drug Release From Beads Prepared with Combinations of Two Grades of Microcrystalline Cellulose

Abstract

In previous work, the use of binary drug diluent mixtures with various grades or types of microcrystalline cellulose were shown to exhibit varying degrees of release from beads prepared by extruder/marumerizer technology.

In this work beads of suitable physical appearance were prepared with varying proportions of two grades of microcrystalline cellulose (Avicel PH-101 and Avicel RC-581) and 10% drug. In-vitro dissolution results varied with the proportion and the grade of the microcrystalline cellulose and with the dissolution medium utilized. Microcrystalline cellulose beads remained intact in water or in acid, but beads with the microcrystalline cellulose/carboxymethylcellulose sodium product exhibited gel structures in water and remained as beads in acid. The quantity of gel formation increased with an increasing level of the carboxymethylcellulose sodium product.     

Enhanced Oral Bioavailability of Piroxicam in Rats by Hyaluronate Microspheres

ABSTRACT

To enhance the dissolution and oral bioavailability of poorly water soluble piroxicam, the piroxicam-loaded hyaluronic microspheres were prepared with various ratios of piroxicam, sodium hyaluronate and polyethylene glycol 4000 (PEG) using a spray dryer, and their physicochemical properties such as shape, size, drug-loading efficiency and dissolution were investigated. The pharmacokinetic study of piroxicam-loaded hyaluronic micropheres in rats was then performed compared to piroxicam powder. The piroxicam-loaded hyaluronic microspheres, spherical in shape, had the geometric mean diameters of about 1.5 μm and drug loading efficiency of about 90%, irrespective of ratio of piroxicam/sodium hyaluronate/PEG. The hyaluronic microspheres containing PEG gave significantly higher dissolution rates of drug than did piroxicam powder, PEG-based solid dispersion system and hyaluronic microspheres without PEG, suggesting that the hyaluronic microsphere with sodium hyaluronate and PEG was more useful for improving the dissolution rate of poorly water soluble piroxicam. The piroxicam-loaded hyaluronic microcapsule composed of (piroxicam/sodium hyaluronate/PEG; 2: 20: 1) gave about threefold improved dissolution of drug in water for 4 h compared to piroxicam powder. It showed higher plasma concentrations of drug compared to piroxicam powder. It gave significantly higher AUC and faster T_max of piroxicam than did piroxicam powder. In particular, the AUC of piroxicam from hyaluronic microsphere was about twofold higher than that from piroxicam powder, suggesting that it could enhance the oral bioavailability of piroxicam. Thus, the hyaluronic microsphere developed using spray-drying technique with sodium hyaluronate and PEG was a more effective oral dosage form for poorly water soluble piroxicam.     

Characterization of the Absorption of Theophylline From Immediate- and Controlled-Release Dosage Forms With a Numerical Approach Using the In Vitro Dissolution-Permeation Process Using Caco-2 Cells

After oral administration, drug absorption rate is recognized to be dependent on two major factors: dissolution and intestinal cells permeability. Caco-2 monolayer cells have been largely used as a permeation study model. In this study, a numerical approach funded on an exponential first-order time relationship was tested to compare immediate- and controlled-release tablets of theophylline using a dissolution-permeation system. The dissolution performance using USP II paddle apparatus was coupled to the permeability studies investigated in Caco-2 cell monolayers. The dissolved samples were taken at different times; their pH and osmolarity were adjusted to render them suitable to Caco-2 permeability studies (osmolarity = 300 mosm, pH = 7.4). The experimental data show that the dissolution fits the exponential first-order relationship rate. The permeability values were in a range of 4.45 10^{? 6}–5.28 10^{? 6} cm/s, and percentages of absorbed drug dose were dependent on the fraction initially present in the donor compartment, indicating that absorption of theophylline was dissolution rate limited. Plotting experimental absorbed fractions (F_a) against experimental dissolved fractions (F_d) show that permeation is the rate-limiting step in drug absorption process in the extended release form of theophylline. Our results demonstrate a general agreement between observed F_a/F_d relationships and theoretical F_a/F_d relationships obtained with our approach funded on dissolution and permeation behavior. We concluded that the couple dissolution-caco-2 system could be a useful tool to characterize intestinal permeation for a new formulation of a drug compared with the conventional one.     

Development of novel amisulpride-loaded liquid self-nanoemulsifying drug delivery systems via dual tackling of its solubility and intestinal permeability

Objective: The aim of the current investigation was at enhancing the oral biopharmaceutical behavior; solubility and intestinal permeability of amisulpride (AMS) via development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) containing bioenhancing excipients.

Methods: The components of L-SNEDDS were identified via solubility studies and emulsification efficiency tests, and ternary phase diagrams were constructed to identify the efficient self-emulsification regions. The formulated systems were assessed for their thermodynamic stability, globule size, self-emulsification time, optical clarity and in vitro drug release. Ex vivo evaluation using non-everted gut sac technique was adopted for uncovering the permeability enhancing effect of the formulated systems.

Results: The optimum formulations were composed of different ratios of Capryol? 90 as an oil phase, Cremophor^® RH40 as a surfactant, and Transcutol^® HP as a co-surfactant. All tested formulations were thermodynamically stable with globule sizes ranging from 13.74 to 29.19?nm and emulsification time not exceeding 1?min, indicating the formation of homogenous stable nanoemulsions. In vitro drug release showed significant enhancement from L-SNEDDS formulations compared to aqueous drug suspension. Optimized L-SNEDDS showed significantly higher intestinal permeation compared to plain drug solution with nearly 1.6–2.9 folds increase in the apparent permeability coefficient as demonstrated by the ex vivo studies.

Conclusions: The present study proved that AMS could be successfully incorporated into L-SNEDDS for improved dissolution and intestinal permeation leading to enhanced oral delivery.     

Effect of batch age on potency and dissolution of levothyroxine sodium tablets: impact of BP and USP monograph differences on dissolution results

Controversies surround levothyroxine sodium as a drug and product, and are reflected in compendia (USP vs BP) differences in levothyroxine sodium tablets specifications concerning potency limit and dissolution test conditions, and in lack of consensus on several issues such as whether the drug BCS class I or III. We have recently published a clinical study in patients comparing the efficacy of multisource 100?mcg levothyroxine sodium tablets (three sources, two brands, a total of five batches). Clinical efficacy and dissolution rate data varied among the tablet batches studied and indicated that brand/source interchangeability could not be claimed. The efficacy parameters showed good correlation with dissolution data generated under BP 2014, but not under USP 2014 dissolution test conditions. In the present study, we decided to expand the number of tablet batches studied in vitro to a total of 12, to report potency and content uniformity data missing in the clinical study, and to further examine the discrepancy in dissolution results based on the medium used. The wide range of batch age in the studied samples allowed investigating the effect of batch age on in-vitro tablet performance parameters. Generated potency values indicated the prevalence of super-potent tablet batches. The dissolution data reflected the effect of compendia monograph differences in dissolution medium. The results also indicated an inverse relationship between tablet potency and batch age and, between dissolution and batch age. The possible effect of potency results on the generated dissolution data was discussed. Statistical significance of correlations examined was assessed by linear and non-linear regression analysis. Statistical significance was evident for the relation between batch age and BP 2014 dissolution data, compared to USP 2014 dissolution results.     

The Kinetics of Drug Release from Ethylcellulose Solid Dispersions

Abstract

Sulphadiazine - ethylcellulose (EC) solid dispersions with different drug: carrier ratios were prepared and fractionated. In vitro drug release followed an apparent zero-order kinetics rate constant being dependent on the thickness of the coat which was the rate controlling step in the process. Drug release was found to increase as the granule size was decreased. The amount of drug released was found to be pH dependent thus showing the existence of pores in the coat surrounding the drug particles. Inclusion of polyethylene glycol or sodium lauryl sulphate in the coat material or dissolution medium resulted in increased dissolution, an effect which was attributed to increase in porosity, reduction of interfacial tension and increase in wettability which was associated with the presence of these compounds.     

In vitro models to estimate drug penetration through the compromised stratum corneum barrier

Objectives: The phospholipid vesicle-based permeation assay (PVPA) is a recently established in vitro stratum corneum model to estimate the permeability of intact and healthy skin. The aim here was to further evolve this model to mimic the stratum corneum in a compromised skin barrier by reducing the barrier functions in a controlled manner. Methods: To mimic compromised skin barriers, PVPA barriers were prepared with explicitly defined reduced barrier function and compared with literature data from both human and animal skin with compromised barrier properties. Caffeine, diclofenac sodium, chloramphenicol and the hydrophilic marker calcein were tested to compare the PVPA models with established models. Results and discussions: The established PVPA models mimicking the stratum corneum in healthy skin showed good correlation with biological barriers by ranking drugs similar to those ranked by the pig ear skin model and were comparable to literature data on permeation through healthy human skin. The PVPA models provided reproducible and consistent results with a distinction between the barriers mimicking compromised and healthy skin. The trends in increasing drug permeation with an increasing degree of compromised barriers for the model drugs were similar to the literature data from other in vivo and in vitro models. Conclusions: The PVPA models have the potential to provide permeation predictions when investigating drugs or cosmeceuticals intended for various compromised skin conditions and can thus possibly reduce the time and cost of testing as well as the use of animal testing in the early development of drug candidates, drugs and cosmeceuticals.     

Effect of Formulation Variables on Dissolution Profile of Diclofenac Sodium from Ethyl- and Hydroxypropylmethyl Cellulose Tablets

Abstract

The effects of formulation variables on the release profile of diclofenac sodium from ethyl cellulose (EC) and hydroxypropylmethyl cellulose (HPMC) matrix tablets were investigated. With increase in viscosity of ethyl cellulose used in nonaqueous granulation, a decrease in drug release from the tablets was observed, while the percentage of fines articles passed through 60 mesh) in the granulation had a significant effect on the dissolution profile. Granules containing 15% fines exhibited slow release of the drug in comparison to those containing 30% fines with EC matrices. An analysis of kinetics of drug release from hydrophobic EC matrix showed Fickian diffusion regulated dissolution. Drug release from HPMC tablets followed an apparent zero-order kinetics.