Absorption Of Diclofenac Research Articles

Photobiomodulation therapy enhances topical diclofenac absorption in healthy volunteers – a randomized placebo-controlled trial: preliminary results

The inflammatory Muscle-skeletal disorders are responsible for a high economic impact on public health and Pharmacological treatments produce important renal and gastric toxicity especially. However, the real effects of topical NSAID’s still controversial. Photobiomodulation therapy has been used to treat musculo-skeletal conditions. The aim of this study was to evaluate the effects of Photobiomodulation on topical absorption of sodium diclofenac in healthy volunteers. Methods. The volunteers were selected after an assessment of their state of health. The study began with 12 volunteers with dark skin and 12 white skin. The study was designed to determinate the pharmacokinetic parameters. The volunteers received during hospitalization 5g diclofenac gel in the presence or not of photobiomodulation, following the randomization. A Laser Cluster with 14 laser diodes (100 mW/diode) delivered 3 Joules of Energy/diode (spot area 0.028 Cm2). Blood samples were taken for determination of plasmatic diclofenac concentration (0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 24h) by tandem mass spectrometry. Low Power Laser Therapy operating at a wavelength of 650 nm was effective to enhance the absorption of diclofenac emulgel in white-skinned individuals but not in black-skinned individuals. Maximum plasma concentrations were higher in the white-skinned group of volunteers who received low-power laser irradiation prior to drug application when compared to the placebo group.

Effects of gastric pH on oral drug absorption: In vitro assessment using a dissolution/permeation system reflecting the gastric dissolution process

The aim of the present study was to evaluate the effects of gastric pH on the oral absorption of poorly water-soluble drugs using an in vitro system. A dissolution/permeation system (D/P system) equipped with a Caco-2 cell monolayer was used as the in vitro system to evaluate oral drug absorption, while a small vessel filled with simulated gastric fluid (SGF) was used to reflect the gastric dissolution phase. After applying drugs in their solid forms to SGF, SGF solution containing a 1/100 clinical dose of each drug was mixed with the apical solution of the D/P system, which was changed to fasted state-simulated intestinal fluid. Dissolved and permeated amounts on applied amount of drugs were then monitored for 2h. Similar experiments were performed using the same drugs, but without the gastric phase. Oral absorption with or without the gastric phase was predicted in humans based on the amount of the drug that permeated in the D/P system, assuming that the system without the gastric phase reflected human absorption with an elevated gastric pH. The dissolved amounts of basic drugs with poor water solubility, namely albendazole, dipyridamole, and ketoconazole, in the apical solution and their permeation across a Caco-2 cell monolayer were significantly enhanced when the gastric dissolution process was reflected due to the physicochemical properties of basic drugs. These amounts resulted in the prediction of higher oral absorption with normal gastric pH than with high gastric pH. On the other hand, when diclofenac sodium, the salt form of an acidic drug, was applied to the D/P system with the gastric phase, its dissolved and permeated amounts were significantly lower than those without the gastric phase. However, the oral absorption of diclofenac was predicted to be complete (96–98%) irrespective of gastric pH because the permeated amounts of diclofenac under both conditions were sufficiently high to achieve complete absorption. These estimations of the effects of gastric pH on the oral absorption of poorly water-soluble drugs were consistent with observations in humans. In conclusion, the D/P system with the gastric phase may be a useful tool for better predicting the oral absorption of poorly water-soluble basic drugs. In addition, the effects of gastric pH on the oral absorption of poorly water-soluble drugs may be evaluated by the D/P system with and without the gastric phase.

Formulation and optimization of dermatological dosage form for comparative in-vitro evaluation of semisolid bases

The aim of this study was to improve the permeation of Diclofenac Sodium. Permeation studies were carried out in - vitro using cellophane membrane. Topical formulations of diclofenac sodium were prepared by using various polymers. Gel, cream and ointment of the drug were prepared with polymers and the formulations were subjected for evaluation. Gel formulations were containing carbopol 940, triethanolamine, and preservatives. Cream was formulated by using stearic acid, glycerin, lanolin and preservatives. Ointment was also formulated by using the ingredients cetostearyl alcohol, hard paraffin, white soft paraffin and wool fat. In-vitro permeation studies by using cellophane membrane in diffusion cell revealed better permeation characteristics of diclofenac sodium. These types of topical dosage forms could give sustained delivery of drug on to the skin, so they are interesting promises to improve skin absorption of non steroidal anti-inflammatory drugs and to prevent side effects associated. The Topical formulations are excellent in the percutaneous absorption of diclofenac or its salts and provide good properties upon use and superior medical effects of diclofenac or its salts.

Rapid absorption of diclofenac and acetaminophen after their oral administration to cattle.

The oral pharmacokinetics of diclofenac (DF) were evaluated in cattle by analyzing plasma concentration-time data after its intravenous and oral administration in order to propose the oral administration of DF as effective route to avoid long withdraw period. DF was intravenously and orally administered at 1 mg/kg to cattle using a crossover design with a 4-week washout period. Plasma concentrations of DF were determined by a HPLC analysis. The mean absorption time (MAT) and absorption half-life (t1/2ka) were 1.61 ± 0.61 and 1.51 ± 0.38 hr, respectively, and bioavailability was nearly 100%. The oral pharmacokinetics of acetaminophen (AAP) were also evaluated in cattle. Plasma concentrations of AAP were determined by a HPLC analysis. MAT and t1/2ka were 2.85 ± 0.93 and 1.53 ± 0.28 hr, respectively, and bioavailability was approximately 70%. In conclusion, the results of the present study indicate that DF and AAP are rapidly absorbed from the forestomach of cattle. Therefore, the appropriate efficacies of these drugs may be achieved via their oral administration, even in cattle.

Advances in NSAID development: evolution of diclofenac products using pharmaceutical technology.

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid class with anti-inflammatory, analgesic, and antipyretic properties. Contrary to the action of many traditional NSAIDs, diclofenac inhibits cyclooxygenase (COX)-2 enzyme with greater potency than it does COX-1. Similar to other NSAIDs, diclofenac is associated with serious dose-dependent gastrointestinal, cardiovascular, and renal adverse effects. Since its introduction in 1973, a number of different diclofenac-containing drug products have been developed with the goal of improving efficacy, tolerability, and patient convenience. Delayed- and extended-release forms of diclofenac sodium were initially developed with the goal of improving the safety profile of diclofenac and providing convenient, once-daily dosing for the treatment of patients with chronic pain. New drug products consisting of diclofenac potassium salt were associated with faster absorption and rapid onset of pain relief. These include diclofenac potassium immediate-release tablets, diclofenac potassium liquid-filled soft gel capsules, and diclofenac potassium powder for oral solution. The advent of topical formulations of diclofenac enabled local treatment of pain and inflammation while minimizing systemic absorption of diclofenac. SoluMatrix diclofenac, consisting of submicron particles of diclofenac free acid and a proprietary combination of excipients, was developed to provide analgesic efficacy at reduced doses associated with lower systemic absorption. This review illustrates how pharmaceutical technology has been used to modify the pharmacokinetic properties of diclofenac, leading to the creation of novel drug products with improved clinical utility.

Systemic absorption and adverse ocular and systemic effects after topical ophthalmic administration of 0.1% diclofenac to healthy cats.

To quantify plasma concentrations and determine adverse ocular, renal, or hepatic effects associated with repeated topical ophthalmic application of 0.1% diclofenac to healthy cats. 8 healthy sexually intact male cats. A randomized, placebo-controlled crossover study was conducted. A topical formulation of 0.1% diclofenac was administered 4 times/d for 7 days to 4 cats, and artificial tear (control) solution was administered to the other 4 cats. After a 12-day washout period, cats received the other treatment. Ophthalmic examinations were performed daily. Plasma samples were obtained on days 1 and 7 for pharmacokinetic analysis. A CBC, serum biochemical analysis, urinalysis, determination of urine protein-to-creatinine ratio, and determination of glomerular filtration rate were performed before the start of the study and after each 7-day treatment period. Mild conjunctival hyperemia was the only adverse ocular effect detected. Maximal drug concentration and area under the curve were significantly higher on day 7 than on day 1. Diclofenac-treated cats had a significantly lower glomerular filtration rate than did control-treated cats after the second but not after the first treatment period, presumably associated with iatrogenic hypovolemia. Topical ophthalmic administration of 0.1% diclofenac was well tolerated in healthy cats, with only mild signs of ocular irritation. Detectable systemic concentrations of diclofenac were achieved with accumulation over 7 days. Systemic absorption of diclofenac may be associated with reduced glomerular filtration rate, particularly in volume-contracted animals. Topical ophthalmic 0.1% diclofenac should be used with caution in volume-contracted or systemically ill cats.

Evaluation of Skin Penetration of Diclofenac from a Novel Topical Non Aqueous Solution: A Comparative Bioavailability Study

Different topical formulations of diclofenac have varying skin penetration profile. Recent advances in science and technology has led to the development of many new formulations of drugs for topical drug delivery. One such technological development has led to the innovation of Dynapar QPS, a novel, non-aqueous, quick penetrating solution (QPS) of diclofenac diethylamine. This study was aimed to measure the total exposure from the drug penetrating the skin in healthy human subjects and comparing the relative systemic bioavailability of Dynapar QPS(®) with diclofenac emulgel. A 200 mg of diclofenac from either Dynapar QPS(®) (5 ml) or emulgel (20 g) was applied on back of subject as per the randomisation schedule. Blood samples were collected up to 16 hours post drug application. Plasma concentration of diclofenac was measured by pre-validated HPLC method. Pharmacokinetic (PK) parameters like Cmax, Tmax, t1/2, AUC0-t, AUC0-∞, and Kel, of diclofenac were determined for both the formulations. Mean Cmax after administration of Dynapar QPS(®) and diclofenac emulgel were 175.93 and 40.04 ng/ml, respectively. Tmax of diclofenac was almost half with QPS compared to emulgel (5.24 hrs versus 9.53 hrs respectively). The mean AUC0-t and AUC0-∞ after administration of Dynapar QPS(®) was higher as compared to diclofenac emulgel (AUC0-t: 1224.19 versus 289.78 ng.h/ml, respectively; AUC0-∞: 1718.21 versus 513.83 ng.h/ml, respectively). None of the subject experienced any adverse event during the study. The results indicate an enhanced penetration and subsequent absorption of diclofenac from Dynapar QPS(®) as compared to diclofenac emulgel. Higher penetration is likely to translate into better pain relief in patients.

Pharmacokinetic Properties and Tolerability of Low-dose SoluMatrix Diclofenac

PurposeThis study compared the pharmacokinetic properties and safety profile of low-dose (18- and 35-mg) diclofenac capsules manufactured using SoluMatrix Fine Particle Technology (Trademark of iCeutica Inc. (Philadelphia, Pennsylvania), and the technology is licensed to Iroko Pharmaceuticals, LLC (Philadelphia, Pennsylvania) for exclusive use in NSAIDs), which produces submicron-sized drug particles with enhanced dissolution properties, to those of diclofenac potassium immediate-release (IR) 50-mg tablets. MethodsThis Phase 1, single-center, randomized, open-label, single-dose crossover study was conducted in 40 healthy volunteers. Subjects received, in randomized order, SoluMatrix diclofenac 18- or 35-mg capsules in the fasting condition, SoluMatrix diclofenac 35-mg capsules under fed conditions, and diclofenac potassium IR 50-mg tablets under fasting and fed conditions. Pharmacokinetic parameters (Tmax, Cmax, AUC0–t, AUC0–∞) were calculated from the concentrations of diclofenac in the plasma. Absorption, food effect, and dose proportionality were determined using a mixed-model ANOVA for Cmax, AUC0–t, and AUC0–∞. Tolerability was assessed by recording adverse events, physical examination findings, vital sign measurements: clinical laboratory test results. FindingsOverall, 35 healthy volunteers aged 18 to 52 years completed the study. The mean age of the subjects was 33.4 years, and approximately half were men (47.5%). Median Tmax values were similar between the low-dose SoluMatrix diclofenac 35-mg capsules and the diclofenac potassium IR 50-mg tablets (both, ~1.0 hour). The mean maximum plasma concentration (Cmax) after the administration of low-dose SoluMatrix diclofenac 35-mg capsules was 26% lower than that with diclofenac potassium IR 50-mg tablets under fasting conditions (868.72 vs 1194.21 ng/mL). The administration of low-dose SoluMatrix diclofenac 35-mg capsules was associated with a 23% lower overall systemic exposure compared with that of diclofenac potassium IR 50-mg tablets under fasting conditions. Food decreased the rate but not the overall extent of absorption of SoluMatrix diclofenac. No serious AEs and no clinically significant abnormalities in physical examination findings, including vital sign measurements, or clinical laboratory test results, were noted during this study. ImplicationsThe pharmacokinetic properties of low-dose SoluMatrix diclofenac capsules in the healthy volunteers in this study suggest rapid diclofenac absorption as measured by Tmax. Low-dose SoluMatrix diclofenac capsules represent a potential option for the management of acute and osteoarthritis-related pain.

The role of individual gastric emptying of pellets in the prediction of diclofenac in vivo dissolution

The objective of the present study was to check for the possibility to successfully predict individual in vivo dissolution/absorption profiles resulting from fasted administration of a diclofenac extended release pellet formulation. For this purpose dissolution profiles were generated with different dissolution setups using a set of media reflecting pH-conditions in the different segments of the gastrointestinal tract. Since gastric emptying of pellets seemed to be a critical factor for in vivo drug release, a set of different gastric residence times was screened in in vitro studies. Subsequently, in vitro release profiles were first directly compared with the individual in vivo absorption profiles and in a second step a mathematical model, which had been developed in a previous study, was applied to calculate predicted individual in vivo release profiles based on in vitro release profiles and individual gastric emptying. The comparison of predicted individual in vivo release profiles and individual in vivo absorption profiles showed a high degree of similarity, thus confirming the suitability of a set of different gastric residence times used in in vitro drug release testing. Additionally, obtained results indicated that a substantial part of variability of diclofenac absorption profiles can be explained by the variability of pellet gastric emptying kinetics.

Skin permeability and pharmacokinetics of diclofenac epolamine administered by dermal patch in Yorkshire-Landrace pigs

PurposeThis study compared the pharmacokinetic profile, and systemic and local absorption of diclofenac, following dermal patch application and oral administration in Yorkshire-Landrace pigs.Patients and methodsTwelve anesthetized, female, Yorkshire-Landrace pigs were randomized to receive either the dermal patch (FLECTOR® patch, 10 × 14 cm; Alpharma Pharmaceuticals, a subsidiary of Pfizer Inc, New York, NY) or 50 mg oral diclofenac (Voltaren®; Novartis, East Hanover, NJ). Tissue (skin area of 2 × 2 cm and underlying muscles approximately 2–3 cm in depth) and blood (10 mL) samples were collected at timed intervals up to 11.5 hours after initial patch application or oral administration. The concentrations of diclofenac in plasma, skin, and muscle samples were analyzed using validated ultra performance liquid chromatography tandem mass spectrometric methods.ResultsPeak systemic exposure of diclofenac was very low by dermal application compared with oral administration (maximum concentration [Cmax] values of 3.5 vs 9640 ng/mL, respectively). Absorption of diclofenac into underlying muscles beneath the dermal patch was sustained, and followed apparently zero-order kinetics, with the skin serving as a depot with elevated concentrations of diclofenac. Concentrations of diclofenac in muscles beneath the patch application site were similar to corresponding tissues after oral administration (Cmax values of 879 and 1160 ng/mL, respectively). In contrast to the wide tissue distribution of diclofenac after oral administration, dermal patch application resulted in high concentrations of diclofenac only on the treated skin and immediate tissue underneath the patch. Low concentrations of diclofenac were observed in the skin and muscles collected from untreated areas contralateral to the site of dermal patch application.ConclusionDermal patch application resulted in low systemic absorption and high tissue penetration of diclofenac compared with oral administration.

Diclofenac potassium 25 mg liquid capsules: earlier and higher exposure to diclofenac. A fasted, single-dose, comparative bioavailability study vs. diclofenac potassium 2 × 12.5 mg tablets

A new liquid capsule formulation of low-dose diclofenac-K in 12.5 mg and 25 mg dosages has been developed to provide the patient with an easier to swallow form than the current low-dose tablets. The new formulation is expected to have a faster rate of absorption and comparable overall bioavailability compared with the tablet formulations. To compare the systemic bioavailability of diclofenac from the new 25 mg liquid capsule vs. the currently registered diclofenac-K 2 × 12.5 mg tablets, and to evaluate the safety of the 25 mg liquid capsule. In this randomized, open-label, crossover, comparative bioavailability study, 42 healthy subjects (mean age 23.2 years) were given a single dose of diclofenac-K 25 mg liquid capsule or 2 × 12.5 mg tablets over 1-day treatment periods, separated by a washout period of 14 days. The total systemic exposure to diclofenac, as measured by the mean AUCs, was equivalent between treatments. However, the geometric mean Cmax for the 25 mg liquid capsule was almost double that of 2 × 12.5 mg tablets (1,058.2 vs. 564.5 ng/ml), while the median tmax was 5 minutes faster with the 25 mg liquid capsule and the geometric mean AUCtmax ref for the 25 mg liquid capsule (133.0 ng×h/ml) was much higher than for 2 × 12.5 mg tablets (91.6 ng×h/ml). The estimated AUCtmax ref ratio of 25 mg liquid capsule to 2 × 12.5 mg tablets was 143.1%, indicating much higher early exposure to diclofenac from the 25 mg liquid capsule. Both formulations were very well tolerated and only one adverse event was considered drug related (headache after taking the diclofenac-K 25 mg liquid capsule). Diclofenac-K 25 mg liquid capsule was equivalent to diclofenac-K 2 × 12.5 mg tablets in terms of overall systemic exposure to diclofenac. However, the rate of absorption of diclofenac was much faster from the liquid capsule than from the tablets, with a much greater early exposure to diclofenac. Both formulations were very well tolerated.

Diclofenac potassium 12.5 mg liquid capsules: earlier and higher exposure to diclofenac. A fasted, single-dose, comparative, bioavailability study versus diclofenac potassium 12.5 mg tablets

A fast-release liquid capsule formulation of low-dose diclofenac- K is available, which aims to improve patient convenience and compliance. The new formulation is a soft gelatin capsule designed to facilitate faster absorption of diclofenac versus the tablet form with anticipated overall comparable bioavailability. To compare the bioavailability of diclofenac-K 2 × 12.5 mg liquid capsules versus diclofenac- K 2 × 12.5 mg tablets. This randomized, open-label crossover, single-dose study was conducted in 42 healthy subjects (mean age 23.5 years) given diclofenac-K 2 × 12.5 mg liquid capsules or tablets over two 1-day treatment periods separated by a 14-day washout period. Diclofenac-K 12.5 mg liquid capsules were equivalent to the tablets in terms of total systemic exposure (mean AUCt ratio = 112%, 2-sided 90% CI = (107%, 116%)). However, the mean Cmax for the liquid capsules (1,090 ng/ml) was almost double that of the tablets (583 ng/ml) (mean Cmax ratio = 196%, 2-sided 90% CI = (169%, 227%)). Median tmax was ~ 10 min faster with the liquid capsules (0.42 h) compared with the tablets (0.58 h) and AUCtmax ref for the liquid capsules (294 ng×h/ml) was almost double the value for the tablets (158 ng×h/ml). This indicated a faster absorption of diclofenac from the liquid capsules compared to the tablet. There were no differences between the two treatments regarding safety, and both drugs were well tolerated. This study demonstrated equivalent overall systemic exposure to diclofenac but a faster absorption and substantially greater early exposure to diclofenac from diclofenac-K liquid capsules compared with the tablets, which may lead to a more rapid analgesic effect in patients.

Increased absorption rate of diclofenac from fast acting formulations containing its potassium salt.

Diclofenac (CAS 15307-86-5) is a non-steroidal anti-inflammatory drug largely used, mainly to relief pain of various origin. Diclofenac is present on the market as free acid, as sodium salt (CAS 15307-79-6) and as potassium salt (CAS 15307-81-0). The last salification form has shown a prompter absorption rate and a faster onset of analgesic activity than the acid form and sodium salt. This paper extensively reviews three trials carried out on healthy volunteers, where potassium salt of diclofenac present in three fast-acting formulations, namely sachets (Trial 1), tablets (Trial 2) and oral drops (Trial 3), were compared to reference tablet formulations from the market. A very fast absorption rate was encountered with the three test formulations, with the peak reached in one case 5 min and in most cases within 10-15 min after dosing. The quick absorption rate of test formulations was attributed to the special combination of the salt of diclofenac with a dynamic buffering agent, namely bicarbonate, present in the test formulations and covered by an international patent. The prompt absorption of diclofenac from the new fast-acting formulations was accompanied by the presence of only one peak, whereas the reference formulations produced in most cases two peaks, as widely described in literature. This finding suggested the hypothesis that the absorption of test formulations should occur in a shorter tract of the gut. The faster absorption of diclofenac from the three fast-acting formulations is expected to produce a faster onset of analgesic action, which highlights these new formulations as particularly indicated to relief pain of any origin.

Determination of the Transdermal Bioavailability of a Newly Developed Diclofenac Sodium Patch in Comparison with a Reference Preparation

Two different transdermal diclofenac (CAS 15307-86-5) formulations (Olfen Patch 140 mg diclofenac sodium as test preparation and 180 mg diclofenac epolamine plaster, equivalent to 140 mg diclofenac sodium, as reference preparation) were investigated in 24 healthy male and female volunteers in order to compare the transdermal bioavailability between both treatments following topical multiple dose administration. Subjects were applied 2 plasters of test and reference formulation at a dose interval of 12 h for 4 consecutive days. Test and reference preparation were administered in randomised sequence at a marked spot at the left upper arm under non-fasting conditions. For determination of diclofenac concentrations, pre-dose (trough) values were taken during steady-state build-up and during the period of switch-over between both preparations on days 1-3 and 5-7. Blood samples for pharmacokinetic profiling were taken on days 4 and 8 at pre-defined time points up to 24 h following drug administration (after the 7th resp. 15th dose). Treatments were not separated by a wash-out phase. Considering the short half-life of diclofenac, it was appropriate that a switch-over design was chosen without wash-out periods between treatments. Diclofenac plasma concentrations were determined by means of a validated LC-MS/MS method (limit of detection: 0.06 ng/ml; lower limit of quantification: 0.15 ng/ml). For the test preparation, maximum plasma concentrations of 3.36 ng/ml (C(max, 0-12)), 3.73 ng/ml (C(max, 12-24)) and 3.84 ng/ml (C(max, 0-24)) as well as areas under the plasma concentration-time curve (AUC) of 31.11 ng x h/ml (AUC(0-12), 34.83 ng x h/ml (AUC(12.24)) and 65.94 ng x h/ml (AUC(0-24)) were determined. For the reference preparation, these values were 1.55 ng/ml (C(max, 0-12)), 1.45 ng/ml (C(max, 12-24) and 1.57 ng/ml (C(max, 0-24)) as well as 13.28 ng x h/ml (AUC(0-12)), 12.68 ng x h/ml (AUC(12-24)) and 25.96 ng x h/ml (AUC(0-24)). For the test preparation, peak-to-trough fluctuations (% PTF) of 34.78% (% PTF(0-12)), 38.50% (% PTF(12-24)) and 43.68% (% PTF(0-24)) were observed. Corresponding values for the reference preparation were 35.82% (% PTF(0-12), 31.36% (% PTF(12-24)) and 40.55% (% PTF(0-24)). In order to evaluate comparable bioavailability of both preparations, 90% confidence intervals of the test/reference ratios were determined. Thereby, for all dose intervals considered and all AUC parameters calculated, the extent of diclofenac absorption from the test preparation markedly exceeds those values obtained for the reference preparation. Likewise, maximum plasma concentrations, as a measure for the rate of absorption, were higher after the test preparation. With respect to peak-to-trough fluctuation of plasma diclofenac levels, both plaster preparations were comparable for the morning dose interval 0-12 h as well as for the 0-24 h period.

Effect of itraconazole on the pharmacokinetics of diclofenac in beagle dogs.

The objective of this study was to investigate the potential effect of itraconazole on the pharmacokinetics of diclofenac potassium in beagle dogs after oral coadministration. Five male beagle dogs received a single oral 50 mg dose of diclofenac potassium alone in phase I, and along with a single oral 100 mg dose of itraconazole in phase II. Blood samples obtained for 8.0 hours post dose were analysed for diclofenac concentration using a validated high performance liquid chromatography (HPLC) assay method. The area under plasma concentration-time curve (AUC0–∞), maximum plasma concentration (Cmax), time to reach Cmax (Tmax) and elimination half-life (t1/2), were calculated for diclofenac before and after itraconazole administration. The coadministration of itraconazole with diclofenac potassium has resulted in a significant reduction in AUC0–∞ and Cmax of diclofenac, which was about 31 and 42%; respectively. No statistically significant differences were observed for Tmax and t1/2 of diclofenac between the two phases. Therefore, it could be concluded that oral coadministration of itraconazole may have the potential to affect the absorption of diclofenac as indicated by the significant reduction in its AUC and Cmax in beagle dogs.

Topical Diclofenac Solution

Topical diclofenac solution (Pennsaid) is a liquid formulation containing the NSAID diclofenac sodium (1.5% w/w). The solution base contains 45% w/w dimethyl sulfoxide (DMSO) to enhance the absorption of diclofenac through the skin. Topical diclofenac solution is applied directly to the knee for treatment of symptoms associated with osteoarthritis of the knee. In well designed 4- to 12-week trials in patients with primary osteoarthritis of the knee, topical diclofenac solution (40 drops four times daily) was significantly more effective than placebo or vehicle control (carrier solution without diclofenac) for improving Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain and physical function, and improving patient global assessment (PGA) and/or patient overall health assessment scores from baseline to the final assessments. Topical diclofenac solution (50 drops three times daily) was as effective as oral diclofenac 150 mg/day for improving WOMAC pain and physical function and PGA scores in a 12-week double-blind study in patients with osteoarthritis of the knee. Topical diclofenac solution was generally well tolerated. The most common treatment-emergent adverse event experienced by topical diclofenac solution recipients was dry skin at the application site. Gastrointestinal adverse events and abnormal laboratory parameters were less common with topical diclofenac solution than with oral diclofenac.

Bicellar systems for in vitro percutaneous absorption of diclofenac

This work evaluates the effect of different bicellar systems on the percutaneous absorption of diclofenac diethylamine (DDEA) using two different approaches. In the first case, the drug was included in bicellar systems, which were applied on the skin and, in the second case, the skin was treated by applying bicellar systems without drug before to the application of a DDEA aqueous solution. The characterization of bicellar systems showed that the particle size decreased when DDEA was encapsulated. Percutaneous absorption studies demonstrated a lower penetration of DDEA when the drug was included in bicellar systems than when the drug was applied in an aqueous solution. This effect was possibly due to a certain rigidity of the bicellar systems caused by the incorporation of DDEA. The absorption of DDEA on skin pretreated with bicelles increased compared to the absorption of DDEA on intact skin. Bicelles without DDEA could cause certain disorganization of the SC barrier function, thereby facilitating the percutaneous penetration of DDEA subsequently applied. Thus, depending on their physicochemical parameters and on the application conditions, these systems have potential enhancement or retardant effects on percutaneous absorption that result in an interesting strategy, which may be used in future drug delivery applications.

Bioequivalence study of low-dose diclofenac potassium tablet formulations

Diclofenac is a nonsteroidal antiinflammatory drug with potent analgesic and anti-inflammatory properties. An immediate-release formulation containing a low dose of 12.5 mg diclofenac-potassium (-K) is marketed as over the counter (OTC) medication in most European countries. An immediate-release formulation containing 25 mg diclofenac-K has now also been approved for OTC use. This study assessed the bioequivalence of two immediate-release diclofenac formulations when administered at the same dose. A randomized, crossover, open-label study was conducted in 29 healthy volunteers to assess the bioequivalence of single 25 mg dose of diclofenac-K in two formulations: 2 x 12.5 mg as film-coated tablets and 1 x 25 mg as sugar-coated tablet. Blood samples for pharmacokinetic analyses were obtained over 10 hours post administration. Plasma time courses of diclofenac were similar for the tested formulations. Mean AUC yen was 798 +/- 281 ng x h/ml (mean +/- SD) for the film-coated and 776 +/- 249 ng x h/ml for the sugar-coated formulation, respectively. The 2-sided 90% confidence interval for the mean test/reference ratio of AUCinfinity (95.5 - 107.5) fell within the predetermined equivalence range of 80 - 125%. Both formulations were rapidly absorbed; median time to maximal plasma concentration was 35 min in each group. Adverse events (peripheral erythema on the hand, headache, hypoesthesia) reported during the study were of mild severity and were considered as unlikely to be drug-related. The two diclofenac-K immediate release formulations were pharmacokinetically similar. It can be concluded that the new sugar-coated tablet formulation is equivalent to the available film-coated tablet formulation with respect to the extent of diclofenac absorption.

Transdermal penetration of diclofenac in the presence of AAPH-derived peroxyl radicals

In vitro transdermal delivery of diclofenac across pig skin in the presence of AAPH-derived peroxyl radicals (2,2′-azo-bis(2-amidinopropane)dihydrochloride) has been studied. The transdermal absorption of diclofenac was estimated using high-performance liquid chromatography after its incubation in vertical cells. The diclofenac transdermal penetration was highly modified by peroxyl radicals. In the presence of AAPH, lower diclofenac absorption was observed. This effect was inhibited by ferulic acid. This could be explained by diclofenac–peroxyl radical interactions. In the pretreatment skin with AAPH, lower diclofenac absorption was higher than control experiments. This behavior should be considered in the topical administration of pharmaceutical preparations containing diclofenac.

Diclofenac-hydrotalcite: In vitro and in vivo release experiments

Solutions of the anti-inflammatory drug diclofenac in ethanol and ethanol–water were prepared and mixed with hydrotalcite and hydrotalcite heated at 500 °C. Hydrotalcite pretreated at 500 °C showed a higher adsorption of diclofenac. Diclofenac-hydrotalcites were used for in vitro release experiments to evaluate the percutaneous absorption of diclofenac, using sets of eight Franz cells with membranes of stratum corneum epidermis obtained from human skin; a 2% diclofenac hydroalcoholic gel was used for comparison. Hydrotalcite pretreated at 500 °C is less suitable for release procedures, despite its higher adsorption capacity, whereas diclofenac adsorbed from ethanolic solution by untreated hydrotalcite presents the most efficient sample and shows the best permeation profiles. This sample was selected for the in vivo experiments. Ten healthy volunteers participated on the in vivo experiments: the diclofenac-hydrotalcite appeared to be useful for an efficient application on human skin as inhibitor of the UV-induced erythemas, also better than the usual gel samples.