Preparation of Piroxicam nanosuspensions by high pressure homogenization and evaluation of improved bioavailability.

OBJECTIVE: Inflammation is a natural response of the organism, involving events responsible for releasing chemical mediators and requiring treatments of symptoms such as pain, redness, heat, swelling, and loss of tissue function. Piroxicam (PRX) is a non-steroidal anti-inflammatory drug with the effect of nonselective COX inhibitor activity; however, it shows poor bioavailability caused by the poor and slow water solubility. In this study, we developed PRX nanosuspensions with 200-500 nm in diameter to increase the bioavailability of PRX by improving its solubility. METHODS: PRX nanosuspensions were fabricated by High pressure homogenization method with PVA, SDS and Tween 80. The nanosuspensions were characterized by XRD, FTIR, DSC, and in vitro release. In vivo pharmacokinetic properties and anti-inflammatory effects were also investigated in rabbits. RESULTS: PRX nanosuspensions significantly increased the solubility (14.89 ± 0.03 mg/L for pure PRX and 16.75 ± 0.05 mg/L for PRX nanosuspensions) and dissolution rate as compared to the pure PRX (p < 0.05). Orally administered PRX nanosuspension (AUC 0-t is 49.26 ± 4.29 µg/mL × h) significantly improved the bioavailability of PRX (AUC 0-t is 28.40 ± 12.11 µg/mL × h). The anti-inflammatory effect of PRX nanosuspension was also investigated in rabbits and it was observed that PRX nanosuspension treatment significantly improved the inhibition of COX-2 and NFκB expression as compared to the PRX treatment (p < 0.05). CONCLUSIONS: The results in this study indicate that PRX nanosuspension is a promising nanomedicine for enhancing the anti-inflammatory activity of PRX and has a high potential for the treatment of inflammation.

The Power of Carbon Nanotubes on Sensitive Drug Determination Methods.

Nowadays, carbon nanotubes (CNTs) due to their inorganic conducting, semiconducting, and organic π-π stacking properties are becoming innovative materials. CNTs have an adjustable size, large surface area, and other significant chemical properties. Due to their excellent electrical, optical, and mechanical properties, CNTs play an important role in various application fields. In the past decade, many unique intrinsic physical and chemical properties have been intensively explored for pharmaceutical, biological, and biomedical applications. The functionalization of CNTs results in a remarkably reduced cytotoxicity and at the same time increased biocompatibility. The toxicity studies reveal that highly water-soluble and serum stable nanotubes are biocompatible, nontoxic, and potentially useful for biomedical applications. Ultrasensitive drug determination from its dosage form and/or biological samples with carbon nanotubes can be realized after surface modification. The main purpose of this review is to present recent achievements on CNTs which are investigated in electrochemical and chromatographically sensing technologies.

Evaluation of bacterial uptake, antibacterial efficacy against Escherichia coli, and cytotoxic effects of moxifloxacin-loaded solid lipid nanoparticles.

Moxifloxacin (MOX) is an important antibiotic commonly used in the treatment of recurrent Escherichia coli (E. coli) infections. The aim of this study was to investigate its antibacterial efficiency when used with solid lipid nanoparticles (SNLs) and nanostructured lipid carriers (NLCs) as delivery vehicles. For this purpose we designed two SLNs (SLN1 and SLN2) and two NLCs (NLC1 and NLC2) of different characteristics (particle size, size distribution, zeta potential, and encapsulation efficiency) and loaded them with MOX to determine its release, antibacterial activity against E. coli, and their cytotoxicity to the RAW 264.7 monocyte/macrophage-like cell line in vitro. With bacterial uptake of 57.29 %, SLN1 turned out to be significantly more effective than MOX given as standard solution, whereas SLN2, NLC1, and NLC2 formulations with respective bacterial uptakes of 50.74 %, 39.26 %, and 32.79 %, showed similar activity to standard MOX. Cytotoxicity testing did not reveal significant toxicity of nanoparticles, whether MOX-free or MOX-loaded, against RAW 264.7 cells. Our findings may show the way for a development of effective lipid carriers that reduce side effects and increase antibacterial treatment efficacy in view of the growing antibiotic resistance.

Current Status of Drug Delivery Approaches and Assay of Anti-Migraine Drugs.

Migraine is a chronic, painful, neurological disorder that affects approximately 15% of the population worldwide. It is a form of neurovascular headache: a disorder in which neural events result in the dilation of blood vessels that, in turn, results in pain and further nerve activation. The pathogenesis of migraine is not completely understood, but it is thought that both central and peripheral stimulations can play a role in migraine. Experimental pharmacological evidence suggests that some drugs can have actions in migraine treatment and oral drug delivery is the first choice for these drugs. However, the oral absorption of many drugs is delayed during migraine attacks. Therefore, there may be an advantage to other drug delivery routes, such as parenteral and intranasal. Moreover, nanoparticles can be used for improved drug delivery of anti-migraine agents as they can protect the encapsulated drug from biological and/or chemical degradation, and extracellular transport by P-gp efflux proteins. Various analytical studies have been performed to sensitive and selective assays of antimigraine drugs from commercial and real samples. Anti-migraines, either single or combined with other drugs, can be easily detected by several analytical methods, such as ultraviolet spectrometry, visible spectrometry, high-performance liquid chromatography, liquid chromatography-mass spectrometry, and high-performance thin layer chromatography. This review focuses on the status of antimigraine drug delivery technologies and possible routes for drug delivery. Moreover, it will present their analytical assays with different methods.

Investigation of the mucoadhesivity, swelling, and drug release mechanisms of indomethacin buccal tablets: effect of formulation variables.

The purpose of this study was to investigate the effect of formulation variables on properties related to critical functionality for their use in indomethacin buccal tablets. Chitosan (CH), carbopol (PAA), and hydroxypropyl methyl cellulose (HPMC) concentration and filler type were evaluated as parameters for describing tablet hardness, swelling index, indomethacin release, and mucoadhesion in controlled release buccal tablets. Moreover, a 32 full factorial design was employed to study the effect of each polymer ratio in CH and PAA combination, which significantly influenced characteristics. A slower indomethacin release and a considerably larger degree of swelling were found for different concentrations of PAA or CH (p < 0.05). The buccal tablets formed a continuous gel layer while in contact with the aqueous medium undergoing a combination of swelling and erosion. In vitro drug release in simulated saliva (pH 6.75) appears to occur both by diffusion and a swelling-controlled mechanism, exhibiting anomalous, Case II type transport or Super Case II type transport. The diluent present in all study samples, mannitol (MAN), spray-dried lactose (SDL), and microcrystalline cellulose (MC) were believed to contribute minimally to hydrogel formation and drug release regulation. The dissolution values for the three co-excipients were decreasing order mannitol, spray-dried lactose, and microcrystalline cellulose. In conclusion, the type and concentration of all polymers seem to change the functionality of buccal tablets and it seems important to understand and characterize these excipients to fully predict the drug release, mucoadhesion, and swelling of buccal tablets.

Development, optimization and in vitro evaluation of oxaliplatin loaded nanoparticles in non-small cell lung cancer.

BACKGROUND: Platinum-based chemotherapy in non-small cell lung cancer (NSCLC) has been demonstrated as a promising approach by many researchers. However, due to low bioavailability and several side effects, drug targeting to lungs by intravenous administration is not a common route of administration. OBJECTIVE: In this study, oxaliplatin loaded polycaprolactone (PCL) nanoparticles were prepared to overcome the limitations of the drug. 33 factorial design was used to evaluate the combined effect of the selected variables on the nanoparticle characteristics and to optimize oxaliplatin loaded PCL nanoparticles. METHODS: The factorial design was used to study the influence of three different independent variables on the response of nanoparticle particle size, polydispersity index (PDI), zeta potential, and encapsulation efficiency. The cellular uptakes of oxaliplatin loaded nanoparticles with different molecular weights of PCL were evaluated. Moreover, optimized nanoparticles were evaluated for their efficacy in non-small lung cancer using the SK-MES-1 cell line. RESULTS: In factorial design, it is found that the homogenization speed and surfactant ratio represented the main factors influencing particle size and PDI and did not seem to depend on the PCL ratio. While the cytotoxicity of free oxaliplatin and oxaliplatin loaded nanoparticles were similar in low drug doses (2.5 and 25 µg/mL), the cytotoxicity of oxaliplatin loaded nanoparticles on SK-MES-1 cell was found higher in higher doses (p < 0.05). Moreover, oxaliplatin nanoparticles formulated with different molecular weights of PCL did not show significant differences in cellular uptake in 1 h and 2 h. However, the uptake of PCL80000 NPs was found significantly greater than free oxaliplatin at 4 h (p < 0.05). CONCLUSION: Hence, the development of oxaliplatin loaded PCL nanoparticles can be a useful approach for effective NSCLC therapy. Development, optimization and in vitro evaluation of oxaliplatin loaded nanoparticles in non-small cell lung cancer.

Development of Gemcitabine Loaded PLGA/Lecithin Nanoparticles for Non-Small Cell Lung Cancer Therapy.

BACKGROUND: Compared to polymeric nanoparticles prepared using non-lipid surfactants, lecithin addition forms larger nanoparticles and exhibits higher drug loading and the stability of nanoparticles can be conferred by adding Vitamin E Polyethylene Glycol Succinate (TPGS) into the formulation. AIM: The aim of this study is to prepare Gemcitabine (Gem) loaded lecithin/PLGA nanoparticles. Moreover, the effect of TPGS and sodium cholate (SK) on the preparation of lecithin/PLGA nanoparticles was compared. METHODS: It was found that while PC addition into PLGATPGS nanoparticles formed larger particles (251.3± 6.0 nm for Gem-PLGATPGS NPs and 516,9 ± 3.9 nm for Gem-PLGA-PCTPGS NPs), the particle size of PLGASK nanoparticles was not affected by lecithin addition (p>0.05;). RESULTS: In cytotoxicity studies, it was found that the SK-MES-1 cell inhibition rates of Gem-PLGATPGS NPs, Gem-PLGA-PCTPGS NPs, Gem-PLGASK NPs, Gem-PLGA-PCSK NPs were similar with free Gem (p>0.05;). In cytotoxicity studies, it was found that the encapsulation into nanoparticles did not change the cytotoxicity of the drug. However, higher cellular uptake has been observed when the lecithin was used in the preparation of PLGA nanoparticles. CONCLUSION: Compared with free Gem, the Gem-loaded nanoparticles enhanced the uptake of the drug by SK-MES-1 cells which can increase the effect of gemcitabine for non-small cell lung cancer therapy.

In vitro evaluation of two different types of obidoxime-loaded nanoparticles for cytotoxicity and blood-brain barrier transport.

Nerve agents (NA) are chemical warfare munitions and their exposure causes a progressive inhibition of acetylcholinesterase (AChE). This inhibition causes NA-induced brain damage in central nervous system (CNS). Oximes reactivate AChE in both the peripheral nervous system and the CNS. Transport of the oxime across the blood-brain barrier (BBB) in the existed therapeutic concentrations at the brain parenchyma determines the effectiveness of antidote therapy on respiratory depression and NA-induced brain damage. However, oximes could not cross the BBB in therapeutic concentrations. The aim of this study was to load AChE reactivator obidoxime chloride to PLGA and PEG-b-PLGA nanoparticles and to improve the BBB transport of the molecule. Brain microvascular endothelial cells were used as the BBB model. 79.3 ± 4.2% of obidoxime was released from PLGA nanoparticles and 88.2 ± 4.4% of obidoxime was released from PEG-b-PLGA nanoparticles within 24 h. It was found that PEG-b-PLGA nanoparticles were ideal drug carrier because of its low tissue toxicity, few side effects, and controllable drug release profile. Transport efficiency of obidoxime across the BBB is a major challenge in the prevention of the CNS, the effectiveness of NA poisoning and new strategies like using obidoxime-loaded PEG-b-PLGA nanoparticles could overcome this challenge for the management of NA-induced brain damage.

Effect simultaneous delivery with P-glycoprotein inhibitor and nanoparticle administration of doxorubicin on cellular uptake and in vitro anticancer activity.

Multidrug resistance (MDR) is the most common problem of inadequate therapeutic response in tumor cells. Many trials has been developed to overcome drug efflux by P-glycoprotein (P-gp). For instance, co-administration of a number of drugs called chemosensitizers or MDR modulators with a chemotherapeutic agent to inhibit drug efflux. But for optimal synergy, the drug and inhibitor combination may need to be temporally colocalized in the tumor cells. In this study, we encapsulated the Ver and Dox in PLGA nanoparticles to inhibit the P-gp drug efflux in breast cancer. Moreover, the effect of either Dox solution (DoxS), Dox nanoparticles (DoxNP), DoxS + VerS, DoxNP + VerS, DoxNP + VerNP or Dox-VerNP was evaluated. It was found that co administration of DoxNP with VerNP (70.76%) showed similar cellular uptake of Dox to Dox/Ver combination solution (70.62%). However it is observed that DoxNP + VerNP has the highest apoptotic activity (early apoptotic 13.52 ± 0.06%, late apoptotic 53.94 ± 0.15%) on human breast adenocarcinoma (MCF 7) cells. Hence, it is suggested that DoxNP + VerNP is a promising administration for tumor therapy.

In vitro and in vivo evaluation of linezolid loaded electrospun PLGA and PLGA/PCL fiber mats for prophylaxis and treatment of MRSA induced prosthetic infections.

In this study, it was aimed to formulate linezolid loaded electrospun PLGA and PCL fiber mats doing controlled drug release, to be used in the treatment and prophylaxis of the prosthesis related infections. The effect of PLGA concentration, PLGA to PCL ratio and the amount of linezolid on the fiber and mat properties were examined. Fiber diameter has been shown to increase with increasing amount of PLGA and linezolid. Increase in PLGA amount resulted in reduced linezolid release, whereas increase in linezolid amount resulted in increased drug release. All PLGA fiber mats have shown to have favorable encapsulation efficiency (≥73%) and mechanical properties. Encapsulation efficiency and the mechanical properties deteriorated with the addition of PCL to the formulations. PLGA fiber mats have shown a biphasic controlled release and in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), pattern up to one month. The formulation selected as the optimum has been evaluated in vivo on the infected rats, which had prosthetic implantation after bone fracture. Consequently, it has been demonstrated microbiologically and histopathologically that a more efficient therapy and prophylaxis have been achieved with a 37-fold lower dose of linezolid.

Development and in vitro/in vivo evaluation of dihydroergotamine mesylate loaded maltodextrin-pullulan sublingual films.

Dihydroergotamine mesylate (DHE), ergotamine derivative, has been offered for clinical use to stop or treat symptoms of an emerging migraine as injection for more than a half century. It is shown that bioavailability of DHE greatly changes between the subjects and up to 99% of the orally absorbed dose may be cleared by first pass metabolism. The aim of this study was to design and optimize DHE fast-dissolving sublingual films for migraine treatment. For this purpose pullulan and maltodextrin was chosen as film-forming polymers and propylene glycol as plasticizer. For optimization process Box Behnken design was used. The formed films were free from air bubbles, cuttings, or cracks. Disintegration, mechanical strength and dissolution of films were compared. It is found that pullulan and maltodextrin formed films with the most desired properties at the concentration of 1.5% and 2%. The application of optimum formulation to rabbits showed that bioavailability of formulation is about 23.35% with a tmax 20 min. Due to this fast onset of action and higher bioavailability than oral administration, it is suggested that the polymer combinations of pullulan and maltodextrin formed successful films and were considered as an alternative dosage form for DHE in migraine therapy.

Evaluation of a novel oxiconazole nitrate formulation: The thermosensitive gel.

Superficial fungal infections caused by Candida species are common skin diseases. Therefore, this study aimed to develop a new formulation containing oxiconazole nitrate, which is an azole group derivative for antifungal treatment, as a thermosensitive gel since there has been no literature study until now. MIC value of the novel thermosensitive formulation against three Candida species was calculated and time-dependent antifungal activity analysis was performed. Viscosity, transition temperature Tsol-gel (°C) and gelation time of the thermosensitive gel formulation were also determined in the viscometer. The measurements performed on the tensilometer device were analyzed for adhesion hardness and elongation percentages of the formulation. In the FT-IR spectrometer, the spectrum of solution and gel state was compared between 650 and 4000 cm-1 and it was found that there is no difference between them. It was found that the temperature is reversible on the formulation and did not cause any disruption of its components. Characterization parameters of the thermosensitive gel formulation containing oxiconazole nitrate and time-dependent activity against Candida species was observed to be the same as those of the solution containing only oxiconazole nitrate. MIC, MFC and time-dependent antifungal analysis did not show any particular difference between formulation and oxiconazole nitrate itself. Thermosensitive gel formulation containing oxiconazole nitrate was found to be effective on superficial fungal infections. We believe it is also appropriate for in vivo usage, but it is necessary to perform animal and human research. It is also needed to evaluate the formulation against other etiologic agents of superficial fungal infections.

Development of assay for determination of eletriptan hydrobromide in loaded PLGA nanoparticles.

Eletriptan Hydrobromide is a serotonin 5-HT1 receptor agonist and it used for the treatment of migraine headaches with or without aura. Even if the drug is well absorbed after oral administration, it has some drawbacks like first pass metabolism and decrease in bioavailability after migraine attacks. Encapsulation of drug into polymeric nanoparticles is one of the methods for protecting the drug against degradation. The present work described a preparation of Eletriptan Hydrobromide loaded poly (d,l-lactide-co-glycolide) nanoparticles prepared using o/w single emulsion solvent evaporation method. In order to determine the factors affecting the physicochemical properties of the nanoparticles on the particle size of poly (d,l-lactide-co-glycolide) nanoparticles, D-Optimal design is used. Moreover, novel, simple, sensitive, selective, and fully validated chromatographic technique for the quantification of Eletriptan Hydrobromide from Eletriptan Hydrobromide loaded poly(d,l-lactide-co-glycolide) nanoparticles was developed. Poly(d,l-lactide-co-glycolide) concentration, sonication time and sonication energy were found as significant factors (p<0.05) on particle size of nanoparticles. Limit of detection and limit of quantification values were calculated as 0.28µgmL-1and 0.86µgmL-1, respectively.

Effect of different polymers and their combinations on the release of metoclopramide HCl from sustained-release hydrophilic matrix tablets.

Metoclopramide HCl (MTC) is commonly used for the management of gastrointestinal disorders. It has a short biological half-life and is usually administered four times daily to maintain effective concentrations throughout the day. The aim of this study is to develop sustained-release hydrophilic matrix tablet formulations of drug to achieve reproducible and predictable release rates, extended duration of activity, decreased toxicity, reduction of required dose, optimized therapy, and improved patient compliance. Hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose sodium (NaCMC), chitosan and Carbopol 981 were incorporated in the matrix system separately or in combinations as release controlling factor by direct compression technique. Compatibility among the formulation components was assessed by DSC and FTIR analysis. MTC release from matrix was evaluated by using the US Pharmacopeia dissolution apparatus II. All formulations met the criteria of pharmacopeial requirements. Dissolution studies show that polymer type and concentration are important parameters on drug release. Chitosan, carbopol and NaCMC formulations exhibited pH-dependent drug release profile whereas HPMC did not. All the formulations containing 1:1 ratio of HPMC and chitosan exhibited desired drug release showing that all active substance releases progressively in a period of whole dissolution time and therefore it can be regarded as worthy of consideration for the manufacture of sustained-release MTC product.

Formulation of zolmitriptan sublingual tablets prepared by direct compression with different polymers: in vitro and in vivo evaluation.

First-pass metabolism can be overcome by sublingual drug delivery, and quick drug entry into the systemic circulation can be obtained. In certain diseases such as migraine therapy, taking fast pharmacological response is an important criteria. In this study, zolmitriptan sublingual tablets were prepared by direct compression method using different mucoadhesive polymers such as hydroxypropyl methyl cellulose, chitosan and sodium carboxy methyl cellulose at a concentration range of 0.5-5% to reduce flushing action of saliva and provide enough time for drug to be absorbed. Tablets were evaluated for the physical properties, and optimum formulations were chosen for in vivo studies to carry on sheep model. The tablets disintegrated rapidly, and dissolution tests revealed that zolmitriptan was dissolved from the formulation within the compendial limits. This especially showed us that the concentration range of polymers is in acceptable limit. It was also concluded that microcrystalline cellulose, spray-dried lactose and sodium starch glycolate are the appropriate excipient and formulated in good proportions. In vivo studies indicated that formulation containing 5% chitosan has the maximum C(max) and AUC and minimum t(max) values (p<0.05). As a result, sublingual tablet administration of zolmitriptan formulated with appropriate excipients and especially with chitosan seems promising alternative to traditional routes.

The development and in vitro evaluation of sustained release tablet formulations of benzydamine hydrochloride and its determination.

A novel oral controlled delivery system for benzydamine hydrochloride (BN) was developed and optimized. Hydrophilic matrix tablets of BN were prepared by using hydroxypropylmethylcellulose (HPMC) and chitosan as polymer substance to achieve required sustained release profile. The matrix tablets were prepared both direct compression and wet granulation method. The influence of matrix forming agents and binary mixtures of them on BN release was investigated. The formulated tablets were characterized by hardness, friability, thickness, weight variation and in vitro drug release. The formulated tablets had acceptable physicochemical characters. The quantity of BN present in the tablets and the release medium were estimated by a simple, sensitive, rapid and validated HPLC method. The dissolution results show that increased amount of polymer resulted in reduced and extended drug release. F7 formulation containing 12.5% HPMC and 12.5 % chitosan with direct compression method is the optimum formulation due to its better targeting profile in terms of release. Higuchi (diffusion) and Hixon-Crowell (erosion) kinetic profiles were achieved and this codependent mechanism of drug release was established. This formulation may provide an alternative for oral controlled delivery of BN and be helpful in the future treatment of primary normoreactive types of inflammation.

Nasal administration of metoclopramide from different dosage forms: in vitro, ex vivo, and in vivo evaluation.

Nasal drug delivery is an interesting route of administration for metoclopramide hydrochloride (MTC) in preventing different kind of emesis. Currently, the routes of administration of antiemetics are oral or intravenous, although patient compliance is often impaired by the difficulties associated with acute emesis or invasiveness of parenteral administration. In this perspective, nasal dosage forms (solution, gel, and lyophilized powder) of MTC were prepared by using a mucoadhesive polymer sodium carboxymethylcellulose (NaCMC). In vitro and ex vivo drug release studies were performed in a modified horizontal diffusion chamber with cellulose membrane and excised cattle nasal mucosa as diffusion barriers. The tolerance of nasal mucosa to the formulation and its components were investigated using light microscopy. In vivo studies were carried out for the optimized formulations in sheep and the pharmacokinetics parameters were compared with oral solution and IV dosage form. The release of MTC from solution and powder formulations was found to be higher than gel formulation (p < 0.05). Histopathological examination did not detect any severe damage. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) used in powder formulations was found to be effective for enhancing the release and absorption of MTC. In contrast to in vitro and ex vivo experiments nasal bioavailability of gel is higher than those of solution and powder (p < 0.05). In conclusion, the NaCMC gel formulation of MTC with mucoadhesive properties with increased permeation rate is promising for prolonging nasal residence time and thereby nasal absorption.

Increased oxidative/nitrosative stress and decreased antioxidant enzyme activities in prostate cancer.

OBJECTIVES: The study was aimed to evaluate the oxidative/nitrosative stress status in prostate cancer (CaP) and benign prostatic hyperplasia (BPH). DESIGN AND METHODS: 312 men from two different populations were included: 163 men from Macedonia (73 CaP patients, 67 BPH patients and 23 control subjects) and 149 men from Turkey (34 prostate cancer patients, 100 BPH patients and 15 control subjects). We measured erythrocyte malondialdehyde (MDA) levels, erythrocyte activities of superoxide dismutase (CuZn-SOD), glutathione peroxidase (GPX) and catalase (CAT); plasma nitrite/nitrate (NO(2)(-)/NO(3)(-)), cGMP and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. RESULTS: A similar pattern of alteration in the oxidative/nitrosative stress-related parameters was found in both, Macedonian and Turkish studied samples: higher MDA concentrations with lower GPX and CuZn-SOD activities in CaP patients versus controls and BPH groups. The CAT activity was decreased in the CaP patients versus controls in the Turkish studied sample. Furthermore, CaP patients had increased plasma NO(2)(-)/NO(3)(-) and cGMP levels versus controls and BPH groups in both studied samples. CONCLUSIONS: This study has confirmed an imbalance in the oxidative stress/antioxidant status and revealed an altered nitrosative status in prostate cancer patients.

In vitro and ex vivo permeation studies of etodolac from hydrophilic gels and effect of terpenes as enhancers.

Etodolac, a highly lipophilic anti-inflammatory drug, is widely used in rheumatoid arthritis usually at an oral dose of 200 mg twice daily. The commonest side effects during therapy with etodolac is generally gastrointestinal disturbances these are usually mild and reversible but in some patients are peptic ulcer and severe gastrointestinal bleeding. To eliminate these side effects and obtain high drug concentration at the application side, dermal application of etodolac seems to be an ideal route for administration. Hydrophilic gel formulations of etodolac were prepared with carboxymethylcellulose sodium. The effect of different terpenes (anethole, carvacrol, and menthol) as an enhancer on the percutaneous absorption of etodolac was also investigated. Permeation studies were carried out with unjacketed modified horizontal diffusion cells through cellulose membrane and rat skin. In vitro studies with cellulose membrane showed that all formulations presented the same drug release profile (p > 0.05). Ex vivo studies with excised rat skin revealed that etodolac was released and penetrated into rat skin quickly. Anethole, a hydrophobic terpene, enhanced the absorption of etodolac significantly (p < 0.05). This result is consistent with the fact that hydrophobic terpenes are effective on the percutaneous absorption of lipophilic drugs. Menthol and carvacrol, hydrophilic terpenes, did not enhance the absorption of etodolac. The lipophilicity of the enhancers seems an important factor in promoting penetration of etodolac through the skin. Since etodolac creates gastrointestinal disturbances, topical formulations of etodolac in gel form including 1% anethole could be an alternative.