Vehicle effects on in vitro release of tiaprofenic acid from different topical formulations

The aim of the present study was to investigate the in vitro release properties of tiaprofenic acid (TA) from different topical vehicles. Carbopol 940 gel, chitosan gel, two types of emulsion-based ointment formulations (o/w and w/o) and hydrophilic petrolatum USP were prepared with 2% drug content. Drug release from all vehicles through a standard cellophane membrane was evaluated by using Franz-type diffusion cells. In vitro release study results showed that the diffusion coefficients of the drug from vehicles rank according to the following order: Carbopol 940 gel (D = 3.11 x 10(-7) +/- 0.54 cm(2)/s) > chitosan gel (D = 0.27 x 10(-7) +/- 0.08 cm(2)/s) > emulsion-based ointment (o/w) (D = 0.18 x 10(-7) +/- 0.05 cm(2)/s) > emulsion-based ointment (w/o) (D = 0.13 x 10(-7) +/- 0.02 cm(2)/s) > hydrophilic petrolatum USP (D = 0.02 x 10(-7) +/- 0.01 cm(2)/s). Carbopol 940 gel base showed significantly higher drug release than other vehicles (P < 0.001). These results indicated that Carbopol 940 gel base is a good candidate for the topical delivery of TA, giving significantly higher drug release than the other vehicles.     

Lecithin vesicles for topical delivery of diclofenac.

Skin penetration of topically applied diclofenac is important for the treatment of rheumatic diseases and actinic keratoses. We have studied the permeation of diclofenac across human cadaver epidermis in-vitro from four lecithin vesicle formulations and a few marketed semi-solid preparations. The lecithin vesicle formulations were prepared by dissolving the lipid contents (lecithin and sodium cholate) in a 1:1 mixture of methanol-chloroform, evaporating the solvents under vacuum, and hydrating the lipid layer with the drug solution in water or 10% ethanol. The vesicles were sonicated for 5 min to reduce the vesicle size and their size and Zeta potential were characterized. The cumulative amount and maximum flux of diclofenac was 69.7+/-40.3 micrograms and 4.77+/-3.16 micrograms/hcm(2) from lecithin vesicles containing sodium cholate and 10% ethanol, and is the highest of all formulations studied. The cumulative amount and mean maximum flux obtained from other formulations were in the range of 2.46+/-1.98-29.9+/-10.1 micrograms and 0.53+/-0.46-3.61+/-0.86 micrograms/hcm(2). Based on the results, lecithin vesicles of diclofenac appear to be advantageous for the topical delivery of diclofenac.     

The percutaneous absorption of diclofenac

The percutaneous absorption of diclofenac diethylammonium 1.16% (w/w) in a combination of emulsion cream and gel (Voltaren Emulgel) and of diclofenac sodium 1% (w/w) in a cream formulation (Voltaren cream) was investigated in guinea-pig, rabbit and man. The percutaneous absorption of diclofenac sodium in guinea-pig was 3 to 6% of the dose when the cream formulation in doses of 320, 100 or 40 mg was applied on 10 cm2 of occluded skin and left in place for 6 h. The transdermal delivery of 14C-labelled diclofenac yielded plateau plasma concentrations of radiotracer from 1.5 h after application until removal of the residual cream. Subsequently the steady state drug depots in the skin and muscle tissue were depleted promptly. During daily administration the steady state levels in the muscle tissue in proximity to the application site were about 3 times higher than in distant muscle tissue. By topical application on knee joints of rabbits diclofenac penetrated into the patellar ligament, the adipose corpus and the synovial fluid. In man the percutaneous absorption was 6% of the dose when the Emulgel formulation was spread by 5 mg/cm2 and left for 12 h on non-occluded skin. The pattern of metabolites of diclofenac in human urine was the same after topical and oral administration. In man, upon daily topical administration of 3 times 2.5 g cream formulation (10 mg/cm2) the diclofenac steady state plasma levels were 20 to 40 nmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Topical diclofenac: clinical effectiveness and current uses in osteoarthritis of the knee and soft tissue injuries

Background: Diclofenac is a commonly used non-steroidal anti-inflammatory drug (NSAID) for symptom control in osteoarthritis (OA) of the knee and soft tissue injuries. Although treatment with oral diclofenac is associated with serious adverse effects involving both the gastrointestinal and renal systems, these adverse effects are thought to be limited with topical diclofenac formulations without loss of efficacy. Objective: The aim of this review is to explore the available evidence in relation to the pharmacokinetics, efficacy and reported adverse effects of the topical diclofenac formulations available. Results/conclusions: In the majority of studies examined, topical diclofenac formulations with sodium lotion, lecithin or epolamine gel, patch or plaster were either superior or equivalent to oral diclofenac formulations or placebo. Topical diclofenac significantly reduced pain and morning stiffness and improved physical function and patient global assessment without major adverse effects reported in patients with OA of the knee; and provided significant pain relief in patients with sports and soft tissue injuries involving the ankle, knee or shoulder. In the majority of studies, the predominant adverse effect involved pruritus or rash at the site of application, or nausea. The principle outcome of these studies is that topical diclofenac is a safe and practical alternative as a method of treatment in OA of the knee or as an alternative treatment for sports and soft tissue injury.     

Liposomal formulations of serratiopeptidase: in vitro studies using PAMPA and Caco-2 models

The feasibility of using liposomes as a potential oral delivery system for the systemic delivery of other peptides and protein-based pharmaceuticals has been studied. Serratiopeptidase, a proteolytic enzyme, was used as a model drug. Liposomes were prepared by a thin film hydration method using various lipids, namely, soya lecithin, DMPC and DMPE. It was further investigated whether the liposomal formulations of serratiopeptidase altered the permeability/absorption of the drug using PAMPA, a non-cell-based assay, and Caco-2 assay, a cell monolayer system, mimicking in vivo GI epithelium cells. The entrapment efficiency of the formulations was found to be 62%, 84% and 86% for the liposomes of soya lecithin, DMPC and DMPE respectively. The effectiveness of the liposomal formulations against the pure drug in terms of permeability/absorption was compared. The effective permeability (log Pe) values from PAMPA study varied from -7.47 to -6.5 cm/s whereas for the serratiopeptidase it was -7.72 cm/s. The apparent permeability values calculated from Caco-2 assay varied from 1.25 x 10(-6) to 1.61 x 10(-6) cm/s whereas for the serratiopeptidase it was 1.25 x 10(-6) cm/s. The flux was found to be 3.88-4.96 microg/cm (2)/h for the formulations when compared to 3.208 microg/cm(2)/h for serratiopeptidase. The results obtained indicated that in comparison with the pure drug, incorporation of drug into liposomes improved the permeability. Thus it could be concluded that the liposomal formulations would improve the oral absorption of serratiopeptidase.     

Biodistribution of diclofenac following repeated topical applications of two diclofenac sodium formulations to minipigs

This study evaluated diclofenac concentrations in plasma, selected hind limb tissues and synovial fluid after repeated topical applications of two diclofenac formulations. Group 1 Gottingen minipigs (n = 18) were administered diclofenac sodium 2.0% topical solution twice daily on days 1–6 and once on day 7. Group 2 minipigs (n = 18) were administered diclofenac sodium 1.5% topical solution four times daily on days 1–6 and twice on day 7. Approximately 20 mg of diclofenac was applied daily to a 10 × 15 cm dosing site centered over the patella of the right knee. Plasma and tissue samples were collected throughout and analysed for diclofenac concentrations using liquid chromatography with tandem mass spectrometry. On day 1, diclofenac sodium 2.0% topical solution produced higher plasma concentrations compared with the 1.5% formulation; however, after 24 h and throughout the remainder of the dosing period, plasma concentrations appeared similar, except at the 72 h time point. Twenty‐four hours after the final application, skin treated with diclofenac sodium 2.0% topical solution retained a significantly (p < 0.02) greater amount of diclofenac than the 1.5% formulation. Generally, both formulations produced similar diclofenac concentrations in synovial fluid, underlying muscle, tendon and bone 24 h after the last application. The 2.0% diclofenac formulation applied twice daily delivered similar amounts of diclofenac as the 1.5% formulation administered four times daily. The skin retained a significant portion of the applied dose to serve as a depot for continuous diffusion of diclofenac into underlying tissues and systemic circulation. Copyright © 2013 John Wiley & Sons, Ltd.     

Diclofenac metabolic profile following in vitro percutaneous absorption through viable human skin.

The extent of metabolism of diclofenac sodium in excised viable human skin was investigated using combination HPLC and radioactivity assay. In an earlier diffusion experiment using an in vitro flow-through diffusion system, radiolabelled diclofenac sodium in either lotion (Pennsaid) or aqueous solution was applied to viable human skin, either as single dose or multiple dose (8 times over 2 days). In this study, the receptor fluid samples from the diffusion experiment were subjected to extraction and the aliquot was analysed using HPLC to separate diclofenac and authentic metabolites. Based on the radioactivity of each HPLC fraction, the collection time of the fractions was compared with the retention time of diclofenac and metabolites in standard solutions. The samples from a single or multiple dose application of lotion showed radioactivity in mainly one fraction, whose retention time corresponded with diclofenac. Other HPLC fractions showed none or only small amounts of radioactivity within the error range of the assay. The same results were obtained with the pooled samples from the application of the lotion or of aqueous solution. The results suggest that diclofenac sodium does not undergo metabolism in viable human epidermis during percutaneous absorption in vitro. Hence, with topical application to human skin in vivo, diclofenac will be delivered with minimal, if any, metabolism.     

Fourier transform infrared spectroscopy for the analysis of neutralizer-carbomer and surfactant-carbomer interactions in aqueous, hydroalcoholic, and anhydrous gel formulations

The objective of the present study is to evaluate the polymer-surfactant and polymer-neutralizer interactions in topical aqueous, anhydrous, and hydroalcoholic gel formulations using Fourier transform infrared (FTIR) spectroscopy. The gels were prepared by dispersing Carbomer (Carbopol 980) in water and ethanol for aqueous and anhydrous systems, respectively. Glycerol and propylene glycol were also added to ensure that the compositions of gels closely resembled those used in typical topical gel formulations. Comparisons of the spectra of Carbopol dispersions in aqueous, anhydrous, and hydroalcoholic systems, performed for the first time, show Carbopol-neutralizer and Carbopol-surfactant interactions vary depending on the nature of the solvents used for gel formation. Analysis of the spectra of aqueous gel formulations indicates significant presence of ionized carboxyl groups only at higher pH (approximately 8.0). Drying of the aqueous gels causes a shift in the carbonyl stretch band toward higher energy, suggesting changes in polymer-neutralizer interaction. Anhydrous gels exhibit 2 different carbonyl stretch bands: the one at approximately 1653 cm(-1) is related to the carboxyl group that is hydrogen bonded and is akin to hydrous gels; the second one at approximately 1717 cm(-1) is indicative of free carbonyl groups. The carbonyl bands of dried gels appear at different energy levels than the solvated gels. This shift resulting from solvent evaporation, reported for the first time, indicates changes in hydrogen bond characteristics. The results show that FTIR can be a good technique compared with other more time-consuming means of analysis for topical formulations.     

Psyllium and copolymers of 2-hydroxylethylmethacrylate and acrylamide-based novel devices for the use in colon specific antibiotic drug delivery

In order to utilize the psyllium husk, a medicinally important natural polysaccharide, to develop the hydrogels meant for the drug delivery, we have prepared psyllium 2-hydroxylethylmethacrylate (HEMA) and acrylamide (AAm)-based polymeric networks by using N,N'-methylenebisacrylamide (N,N'-MBAAm) as crosslinker and ammonium persulfate (APS) as initiator. The polymeric networks thus formed [psy-cl-poly(HEMA-co-AAm)] were characterized with FTIR and swelling studies which were carried out as a function of crosslinker concentration, time, pH and [NaCl] of the swelling medium. The swelling kinetics of the hydrogels and in vitro release dynamics of model drug (tetracycline hydrochloride) from these hydrogels has been studied for the evaluation of swelling mechanism and drug release mechanism from the hydrogels. The values of the diffusion exponent 'n' have been obtained 0.5 for both swelling kinetics and drug release dynamics. This value shows that the Fickian type diffusion mechanism has occurred for the swelling of the polymers and for the release of drug from the polymers in different release mediums. The values of the initial diffusion coefficients (10.6 x 10(-4), 13.1 x 10(-4), 14.0 x 10(-4))cm(2)/min, average diffusion coefficients (22.2 x 10(-4), 25.7 x 10(-4), 27.0 x 10(-4))cm(2)/min and late diffusion coefficients (1.68 x 10(-4), 2.15 x 10(-4), 2.28 x 10(-4))cm(2)/min for the release of tetracycline HCl respectively in distilled water, pH 2.2 buffer and pH 7.4 buffer from the drug loaded samples shows that in the initial stages, the rate of release of drug from the hydrogels is slow and rate of diffusion of drug increases with time.     

Topical Delivery of Flurbiprofen from Pluronic Lecithin Organogel

The purpose of this research is to formulate and evaluate the suitability of pluronic lecithin organogels containing flurbiprofen for topical application. Four formulations were developed using flurbiprofen, lecithin, Pluronic F127, isopropyl palmitate, water, sorbic acid and potassium sorbate were coded as FL1, FL2, FL3 and FL4. All the formulations carried 30% w/w of lecithin phase and 70% w/w of Pluronic phase. The formulated organogels were evaluated for appearance and feel psychorheologically, in vitro diffusion study, drug content, viscosity and pH. Release of flurbiprofen from all formulations was monitored via dialysis membrane-70 and Wistar rat skin as a semipermeable membrane into phosphate buffer saline (0.2 M, pH 7.4) using Keshary-Chien diffusion cell. The viscosities of different formulations were determined by using Brookfield Viscometer at 25°. An attempt has been made to explore the potential of pluronic lecithin organogels for topical delivery of flurbiprofen.     

First-principles, structure-based transdermal transport model to evaluate lipid partition and diffusion coefficients of hydrophobic permeants solely from stratum corneum permeation experiments

To account for the effect of branched, parallel transport pathways in the intercellular domain of the stratum corneum (SC) on the passive transdermal transport of hydrophobic permeants, we have developed, from first-principles, a new theoretical model-the Two-Tortuosity Model. This new model requires two tortuosity factors to account for: (1) the effective diffusion path length, and (2) the total volume of the branched, parallel transport pathways present in the SC intercellular domain, both of which may be evaluated from known values of the SC structure. After validating the Two-Tortuosity model with simulated SC diffusion experiments in FEMLAB (a finite element software package), the vehicle-bilayer partition coefficient, K(b), and the lipid bilayer diffusion coefficient, D(b), in untreated human SC were evaluated using this new model for two hydrophobic permeants, naphthol (K(b) = 225 +/- 42, D(b) = 1.7 x 10(-7) +/- 0.3 x 10(-7) cm(2)/s) and testosterone (K(b) = 92 +/- 29, D(b) = 1.9 x 10(-8) +/- 0.5 x 10(-8) cm(2)/s). The results presented in this paper demonstrate that this new method to evaluate K(b) and D(b) is comparable to, and simpler than, previous methods, in which SC permeation experiments were combined with octanol-water partition experiments, or with SC solute release experiments, to evaluate K(b) and D(b).     

New, simple and validated UV-spectrophotometric methods for the estimation of gatifloxacin in bulk and formulations

New, simple and cost effective UV-spectrophotometric methods were developed for the estimation of gatifloxacin in bulk and pharmaceutical formulations. Gatifloxacin was estimated at 286 nm in 100 mM phosphate buffer (pH 7.4) and 292 nm in 100 mM hydrochloric acid (pH 1.2). Linearity range was found to be 1-18 mug ml(-1) (regression equation: absorbance=0.0684 x Concentration in microg ml(-1) + 0.0050; r2 = 0.9998) in the phosphate buffer (pH 7.4) and 1-14 microg ml(-1) (regression equation: absorbance = 0.0864 x Concentration in microg ml(-1) + 0.0027; r2 = 0.9999) in hydrochloric acid medium (pH 1.2). The apparent molar absorptivity was found to be 2.62 x 10(4) l mol(-1) cm(-1) in the phosphate buffer and 3.25 x 10(4) l mol(-1) cm(-1) in hydrochloric acid media. In both the proposed methods sandell's sensitivity was found to be about 0.01 microg cm(-2)/0.001A. These methods were tested and validated for various parameters according to ICH guidelines and USP. The quantitation limits were found to be 0.312 and 0.3 microg ml(-1) in the phosphate buffer and hydrochloric acid medium, respectively. The proposed methods were successfully applied for the determination of gatifloxacin in pharmaceutical formulations (tablets, injection and ophthalmic solution). The results demonstrated that the procedure is accurate, precise and reproducible (relative standard deviation <2%), while being simple, cheap and less time consuming and can be suitably applied for the estimation of gatifloxacin in different dosage forms and dissolution studies.     

Transdermal drug delivery using microemulsion and aqueous systems: influence of skin storage conditions on the in vitro permeability of diclofenac from aqueous vehicle systems

The objective of this study was to evaluate the transdermal delivery potential of diclofenac-containing microemulsion system in vivo and in vitro. It was found that the transdermal administration of the microemulsion to rats resulted in 8-fold higher drug plasma levels than those obtained after application of Voltaren Emulgel. After s.c. administration (3.5 mg/kg), the plasma levels of diclofenac reached a peak of 0.94 microg/ml at t=1 h and decreased rapidly to 0.19 microg/ml at t=6 h, while transdermal administration of the drug in microemulsion maintained constant levels of 0.7-0.9 microg/ml for at least 8 h. The transdermal fluxes of diclofenac were measured in vitro using skin excised from different animal species. In three rodent species, penetration fluxes of 53.35+/-8.19 (furry mouse), 31.70+/-3.83 (hairless mouse), 31.66+/-4.45 (rat), and 22.89+/-6.23 microg/cm(2)/h (hairless guinea pig) were obtained following the application of the microemulsion. These fluxes were significantly higher than those obtained by application of the drug in aqueous solution. In contrast to these results, a 'flip-flop' phenomenon was observed when frozen porcine skin (but not fresh skin) was significantly more permeable to diclofenac-in-water than to the drug-in-microemulsion. In fact, the drug penetration from the microemulsion was not affected by the skin storage conditions, but it was increased when an aqueous solution was applied. However, this unusual phenomenon observed in non-freshly used porcine skin places a question mark on its relevancy for in vitro penetration studies involving aqueous vehicle systems.     

Preparation and rectal absorption of highly concentrated glycyrrhizin solution

We developed a simple method for preparing a highly concentrated solution of glycyrrhizin monoammonium salt (GZ) at low viscosity with no surfactants nor organic solvents and investigated the absorption profile after rectal administration to rats. GZ (200 mg/ml) was dissolved in phosphate buffered solution, pH 7.0; over 350 mM concentration was maintained for the aqueous solution without gel-formation. When glycerin was used as a non-aqueous formulation, GZ did not form gel. Apparent permeability coefficients of GZ obtained from 350 mM phosphate buffered solution (pH 7.0) and glycerin solution through rat rectal mucosa estimated by in vitro parallel diffusion chamber technique were 0.686 x 10(-6) and 0.379 x 10(-6) cm/s, respectively. On the other hand, the area under plasma concentration-time curves of GZ in 400 mM phosphate buffer (pH 7.0) and glycerin formulations after rectal administration to the rat were significantly higher than that in polyethylene glycol 400/propylene glycol (55 : 5) formulation. Maximum plasma concentrations of these formulations were dependent on the apparent permeability coefficients of GZ. Increased absorption observed by phosphate buffered formulation accompanied no pronounced histological damage in mucosa. These results demonstrate that addition of a highly concentrated phosphate salts is effective not only for lowering the viscosity of a highly concentration of GZ solution, but also for improving the mucosal GZ absorption.     

Diclofenac systemic exposure is not increased when topical diclofenac is applied to ultraviolet-induced erythema

Objectives Diclofenac is a non-steroidal anti-inflammatory drug used for a variety of painful and inflammatory conditions. A new low-dose, topical-gel form of diclofenac sodium (diclofenac-Na) has been developed for pain relief and redness reduction after sunburn. The objective was to compare exposure to oral diclofenac-Na with the systemic exposure to diclofenac after application of the new topical diclofenac-Na 0.1% Emulgel gel (diclofenac-Na gel) to normal skin and to that with ultraviolet-induced erythema relative. Methods This study was an open, single-centre, three-period, non-randomised trial in 18 healthy Caucasian subjects. During the first period, 12.5 g gel (12.5 mg diclofenac-Na) was applied twice on a single day to normal skin. During the second period, a 25-mg diclofenac-Na, enteric-coated tablet was given orally three times in a single day. During the third period, the diclofenac-Na gel was applied, as in the first period, but during the early phase of an erythema induced by three times the ultraviolet minimal erythema dose, i.e. a first-degree sunburn associated with pain. During each period, venous blood samples were collected over 24 h and urine was collected over 72 h after first administration for the determination of diclofenac in plasma and urine and of 4-OH-diclofenac in urine. Results The systemic exposure after topical application of 25 mg diclofenac-Na on sunburned skin was less than 3% that of 75 mg oral diclofenac-Na and was not increased to that measured on normal skin. Conclusion The diclofenac-Na 0.1% Emulgel gel can be applied safely to sunburned skin (superficial sunburn, i.e. first degree) as well as to normal skin.     

In Vitro Cutaneous Disposition of a Topical Diclofenac Lotion in Human Skin: Effect of a Multi-Dose Regimen

Purpose. This study determines comparative bioavailability of diclofenac sodium lotion compared to an aqueous solution after topical application to viable human skin in vitro. In addition, the difference between a single dose and multiple doses (8 times) was also determined. Methods. An in vitro flow-through diffusion cell system was employed, using radiolabelled diclofenac sodium. Results. Multiple doses of lotion (2 l/cm² and 5 l/cm²) delivered a total of 40.1 ± 17.6 g and 85.6 ± 41.4 g diclofenac, respectively, at 48 h, compared to only 9.4 ± 2.9 g and 35.7 ± 19.0 g absorbed after topical application of diclofenac as an aqueous solution (P < 0.05). A single dose study showed no statistical difference between diclofenac delivered in lotion or an aqueous solution. Over 48 h the total absorption from lotion was 10.2 ± 6.7 g and 26.2 ± 17.6 g (2 l/cm² and 5 l/cm², respectively), compared to 8.3 ± 1.5 g and 12.5 ± 5.7 g from an aqueous solution. Both single doses of lotion and aqueous diclofenac showed decreased diclofenac absorption into the receptor fluid between 12 and 24 h. However, when applied multiple times, absorption from lotion was continually increasing up to 48 h. The total dose accountability ranged from 76.8 ± 8.2% to 110.6 ± 15.1% of the applied dose. Conclusions. Diclofenac lotion exhibited enhanced diclofenac percutaneous absorption rate through human skin (mass, flux and partition coefficient) when applied a multiple number of times and this enhanced absorption was maintained over 48 h. This suggests that a constituent of the lotion (DMSO) will enhance human skin absorption of diclofenac when used in a multi-dose regimen, but not after a single dose.     

Analgesic efficacy of a lecithin-vehiculated diclofenac epolamine gel in shoulder periarthritis and lateral epicondylitis: a placebo-controlled, multicenter, randomized, double-blind clinical trial

Diclofenac epolamine (2-hydroxyethyl-pyrrolidine) (DHEP) is a diclofenac salt endowed with enhanced cutaneous permeation. To optimize its absorption after topical application, a lecithin-enriched DHEP 1.3% gel has been developed (DHEP lecithin gel) and investigated in patients with shoulder periarthritis and lateral epicondylitis in a placebo-controlled, multicenter double-blind clinical trial. One hundred fifty-eight patients were randomized to a 10-day treatment with DHEP lecithin gel or placebo (5 g t.i.d. applied on the painful area). The efficacy criteria were pain measured by visual analog scale (VAS) while performing a specific standardized movement, intake of rescue medication (paracetamol), and the disabilities of the arm, shoulder and hand (DASH) questionnaire. VAS scores indicated a consistently higher analgesic activity of DHEP lecithin gel. At day 3, pain was reduced by -20.1 +/- 20.2 and -9.9 +/- 12.7 mm in the DHEP lecithin gel- and placebo-treated patients, respectively (p < 0.001); at day 6 of treatment, DHEP lecithin gel induced a pain reduction of -33.2 +/- 26.1 mm, while the reduction achieved with placebo was only -21.2 +/- 18.8 mm (p < 0.001). The mean changes in DASH questionnaire indicated that DHEP lecithin gel was more effective than placebo in improving patient well-being and reducing difficulties in performing the activities most severely impaired by rheumatism, while no difference was observed between the two treatments in consumption of rescue medication. In conclusion, these results indicate that DHEP lecithin gel is a topically effective analgesic product in patients with shoulder periarthritis or lateral epicondylitis and provide further evidence on the use of topical nonsteroidal anti-inflammatory drugs as an optimal approach to the treatment of localized musculoskeletal disorders.     

Transdermal application of bupivacaine-loaded poly(acrylamide(A)-co-monomethyl itaconate) hydrogels

Bupivacaine, an amide local anaesthetic agent of long-acting and intense anaesthesia, was incorporated into poly(acrylamide(A)-co-monomethyl itaconate (MMI)) hydrogels. The swelling behaviour of two gel compositions, without drug, 75A/25MMI and 60A/40MMI, through rabbit ear skin, mounted on a modified Franz diffusion cell, was studied. Both gel compositions reach the equilibrium swelling degree (88.9+/-0.7 wt.% for 75A/25MMI and 92.5+/-0.1 wt.% for 60A/40MMI). The swelling kinetics was in accordance with the second Fick's Law; diffusion coefficients indicate faster swelling for gels with lower amount of monomethyl itaconic acid. The skin flux of bupivacaine solution through rabbit ear skin was 105+/-24 microg/cm(2)/h, the effective permeability coefficient was 26 x 10(-3)+/-9 x 10(-3)cm/h, and 77+/-15% of bupivacaine was permeated. Bupivacaine-loaded gels allow the drug was permeated through the skin. 47+/-4% and 36+/-3% of the drug amount included in 75A/25MMI and 60A/40MMI hydrogels, respectively, was permeated. The skin flux of the drug was between 90+/-5 and 16+/-7 microg/cm(2)/h depending on the amount of bupivacaine included in the gel and the gel composition. Skin flux increases with the drug load of the gels. Furthermore, as more MMI in the gel slower skin flux of the drug due to bupivacaine-gel interactions.     

Formulation and evaluation of novel controlled release of topical pluronic lecithin organogel of mefenamic acid

In the present study, pluronic lecithin based organogels (PLO gels) were formulated as topical carrier for controlled delivery of mefenamic acid. Ten organogel formulations were prepared by a method employing lecithin as lipophilic phase and pluronic F-127 as hydrophilic phase in varying concentrations to study various parameters using in vitro diffusion study and in vivo studies. All formulations were found to be off-white, homogenous, and reluctant to be washed easily and have pH value within the range of 5.56–5.80 which is nonirritant. Polymer concentration increased in formulations of F1 to F5 (lecithin) and F6 to F10 (pluronic) resulted in decrease of the gelation temperature, increase of viscosity and reduction of spreadability of gels having polymer tendency to form rigid 3D network. Organogels with higher viscosity were found to be more stable and retard the drug release from the gel. The formulations of F2 and F3 were selected for kinetic studies and stability studies, as they found to have all physical parameters within acceptable limits, highest percent drug content and exhibited highest drug release in eight hours. The order of drug release from various formulations was found to be F2?>?F3?>?F10?>?F4?>?F1?>?F9?>?F8?>?F5?>?F7?>?F6. The optimized formulation F2 was found to follow zero order rate kinetics showing controlled release of the drug from the formulations. In vivo anti-inflammatory activity of optimized mefenamic acid organogel (F2) against a standard marketed preparation (Volini gel) was found satisfactory and significant.     

Assessment of topical non-steroidal anti-inflammatory drugs in animal models

Four commercial gel preparations of topical anti-inflammatory agents have been assessed in six animal models commonly used to determine the biological activity of non-steroidal anti-inflammatory agents for systemic administration. Only UV-induced erythema of the skin, adjuvant induced arthritis and the measurement of vascular permeability proved suitable for differentiation of the potency of the four topical agents. Carrageenin-induced paw oedema, the cotton pellet test and the assessment of the pain threshold according to Randall and Selitto were of little value. The effects of the gel preparation of diclofenac (CAS 15307-86-5) diethylammonium (Voltaren Emulgel) were comparable to two preparations containing 1% and 5% active ingredient, respectively. Gel 4 showed low overall activity. The experiments demonstrated that some of the models used for the assessment of anti-inflammatory agent for systemic administration proved suitable for the testing of topical preparations and that percutaneous absorption was insufficient to elicit anti-inflammatory effect in the animals at sites remote from the site of application.