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155 FORMULATION AND EVALUATION OF MELOXICAM GELS FOR TOPICAL ADMINISTRATION Nagia A. El-Megrab, Hanan M. El-Nahas* and Gehan F.Balata تم في هذه الدراسة تحضير عقار ميلوكسيكام في شكل مستححلاا قييقتة هيميتة مهيميتا قهتيتة تححتوم علتا متاق ا يتل ( مهيميتا كحوليتة تححتوم علتاhydrogel) مكذلك تم تحضير هيميتا ماييتة.)أمليا أم حامض أمليك (الوسط الدهتي تم قراسة معدل انطيق العقتار متن لتيل ء تا.(topical) كماق إهيمية السحخدامها عن طر ق الجلد940 ماق كربوبول %1 ) التذم ححتوم علتتا7.4 ستيلوفا مكتذلك نذات حتة متن لتيل أللتد ايرنتل فتي محلتول سونستن الكتابج (أ هيتدرمأليتي ) علا لصتاي%1 ، 0.65 ، 0.5( ميد تم قراسة تأثير تركيز الدما الماديي.حجم من ماق كار حا لور ل صوق وم/ مز نذات ة ماق ميلوكسيكام من مسححلاا ماق إ يل أمليا هي أحسن صيغة تم الحصول عليها مقارنتة بتالهيم الحجتارم لعقتار أألر ت قراسة لماق ميلوكسيكام كعقار مضاق ليلحهابا بعد تتامله عن طر تق الذتم مالجلتد للذنترا ممقارنحته. بيرمكسيكام أم تحت هتتذه الدراستة أ أعلتتا معتدل معملتتي نطتتيق التدما مامحصاصتته متن لتتيل الجلتد كتتا متتن.بهتيم بيرمكستتيكام أم تتحت الدراستتة الحتتي أألر تتت علتتا الذنتترا أ هتتيم متتاق. المستتححلل التتدييق الهيمتتي المححتتوم علتتا ا يتتل أمليتتا من ماق ا يل أمليا ) أعطا حما ة كايتر تد االلحهتاق مقارنتة%1 ميلوكسيكام (المسححلل الدييق الهيمي المححوم علا .(feldene®) بهيم ماق بيرمكسيكام For topical administration of meloxicam (ME), microemulsion gels and lipogels containing either ethyl oleate or oleic acid as an oil phase were prepared. In addition, Hydrogel and hydroalcoholic gels containing carbopol 940 as a gelling agent were also prepared. In-vitro drug release through cellophane membrane and permeation through the excised rabbit skin in Sörensen`s phosphate buffer (pH 7.4) containing 1% w/v sodium lauryl sulphate were performed .The influence of initial drug concentration (0.5, 0.65, 1% w/w) was studied. The permeation properties of ME from ethyl oleate microemulsion which is the best formula achieved was studied in comparison to the commercially available piroxicam gel. Moreover, the anti-inflammatory activity of ME after oral and topical administration in rats was studied and compared to that of piroxicam gel. The results of an in-vitro drug release and its percutaneous permeation revealed that the ethyloleate microemulsion gel showed the highest results. Meloxicam gel (ethyl oleate microemulsion gel 1%) showed good protection against inflammation as compared to Feldene® gel in rats. Key words: Meloxicam, lipogels, hydrogels, microemulsion gels, carrageenan. Introduction Meloxicam, a non-steroidal anti-inflammatory drug (NSAID), is a preferential inhibitor of cyclooxygenase-2 and has demonstrated potent analgesic Department of Pharmaceutics. Faculty of Pharmacy . University of Zagazig. Zagazig, Egypt. * To whom correspondence should be addressed. E. mail: [email protected] Saudi Pharmaceutical Journal, Vol. 14, Nos. 3-4, July-October 2006 and anti-inflammatory activity after oral administration (1). NSAIDs have been widely used in the treatment of rheumatoid arthritis and other related conditions. However, they carry the risk of undesirable systemic side effects and gastrointestinal irritation at the usual dose of oral administration (2). Considering the fact that most inflammatory diseases occur locally and near the surface of the body, topical application of NSAIDs on the inflamed site can offer the advantage of delivering a drug 156 EL-MEGRAB ET AL directly to the disease site and producing its local effect. This occurs by avoiding gastric irritation and also reduces adverse systemic effects (3, 4). However, the barrier properties of intact skin limit the permeability of wide variety of substances, including pharmaceutical active agents. To overcome these problems, the development of an optimal vehicle system for rapid skin permeation of ME is required. Currently, microemulsions have been recognized as good vehicles for percutaneous absorption of drugs (5, 6). They are clear or slightly opalescent, isotropic; thermodynamically stable systems of two immiscible liquids. Microemulsions are created by the presence of a suitable surfactant, usually in conjunction with a co-surfactant. They are relatively stable and can solubilize a considerable amount of hydrophobic drugs in their lipophilic domain (7). Recently, lipogels-semisolid ointment like preparations have been investigated as vehicles for topical drug delivery. Lipogels are obtained by gelling an oleaginous phase with a lipophilic substance (8-10). The purpose of this study was to formulate ME in different types of gels, namely, hydrogel, hydroalcoholic gel, microemulsion gel and lipogel using different oils. The second goal was to evaluate the properties of ME gels like in-vitro drug release, percutaneous absorption and comparison antiinflammatory effect of this gel with the marketed piroxicam gel. Experimental Materials: Meloxicam powder was donated as a gift from Delta Pharma, Tenth of Ramadan City, Egypt), Mexicam® tablets were purchased from Delta Pharma, Tenth of Ramadan City, Egypt), Feldene® gel was purchased from (Pfizer Pharm.Co., Cairo, Egypt), Carbopol 940 was purchased from (BF Goodrich Co., OH), Ethyl oleate (EO) was purchased from (Aldrich Chemical, Milwaukee,WI), Oleic acid was purchased from (Fluka, Buchs, CH), Glyceryl monostearate (Henkel, Düsseldorf, Germany), Propylene glycol (PG) was purchased from (Carl Roth, W, Germany), Tween 80 (Polyoxyethylene Sorbitan Monooleate) , Sodium Lauryl sulphate, Potassium dihydrogenorthophosphate, disodiumhydrogen phosphate, sodium chloride and ethanol were purchased from (ElSaudi Pharmaceutical Journal, Vol. 14, Nos. 3-4, July-October 2006 Nasser Pharmaceutical Chemicals, Cairo, Egypt), Triethanolamine was purchased from (Merck, Darmstadt, Germany), Carrageenan and hydroxyl propylmethylcellulose (HPMC) were purchased from (Sigma, St, Louis, MO),all chemicals were analytical grade. Semipermeable Cellophane membrane 30/32 (Fischer Scientific Co., London, England). Distilled water, was used in the experiments. Methods: Preparation of hydrogel and hydroalcoholic gel samples: The gel samples were prepared by dispersing 1% Carbopol 940 in a mixture of water and PG (80: 20 w/w) in case of hydrogel or a mixture of water, ethanol and PG ( 40: 40: 20 w/w) in case of hydroalcoholic gel. ME (1% w/w) was added to the mixtures and kept under magnetic stirring for 12 hrs (Formulas 1 and 2, Table 1). The dispersions were then neutralized (pH 7.4) and their viscosity was improved by adding triethanolamine 0.01% (11). Preparation of microemulsion gel samples: The appropriate amounts of Tween 80, PG and oil (EO or oleic acid) were weighed into screwcapped vial as surfactant, co-surfactant, and oil (50:10:40) respectively. ME was added in a concentration of 1% w/w into the vial. The mixture was shaken by using a magnetic stirrer (1 cm), then the microemulsion gel was formed by the addition of 25 % water with continuous stirring, and it was enhanced by using a vortex mixer for 2 min. The gel of ME samples were stored at 25°C for 24 hrs for equilibration (Formula 3, Table 1). Preparation of lipogel samples: The calculated amount (15% w/w) of monoglyceryl stearate was heated at 70 °C with oil (EO or oleic acid) to complete melting, then 1% ME was dissolved into the melted mass (formula 4 table 1). The mass was then gelled by cooling under stirring (100 rpm) to 50°C until clouding of the melted mass, then allowing to gel at rest. The sample was then maintained at 25 °C for 24 hrs before use (10). Effect of initial drug concentration: Further study was done upon ethyl oleate microemulsion gel as it gave the best results of drug release and skin permeation. The effect of initial ME FORMULATION AND EVALUATION OF MELOXICAM GELS concentration was tested on the permeation properties of that gel by using other two drug concentrations 0.5 and 0.65% besides 1% ME. Solubility measurements: The solubility of ME in either EO or oleic acid was determined by adding excess amount of drug into 10 ml of oil in a screw-capped vial. The vials were equilibrated at 25°C for 72 hrs in a thermostatic shaker water bath. The suspension was centrifuged at 3000 rpm for 15 min, and the supernatant was diluted with ethanol and used for the determination of ME spectrophotometrically at λmax = 362 nm, the blank was EO or oleic acid in ethanol. Viscosity measurements: The different formulations were tested at room temperature using Viscostar viscometer (Fungilab S.A., Spain). The measurements were made using spindle number 5 at 2 rpm. In-Vitro drug release: A one gram sample of each formulation was accurately weighed and placed on a semipermeable cellophane membrane (previously immersed in sörencen`s phosphate buffer, pH 7.4 for 20 hrs) to occupy a circle of 2.9 cm diameter. The loaded membrane was stretched over the lower open end of a glass tube of 2.9 cm diameter and made water tight by rubber band. The tube was immersed in a beaker containing 150 ml of Sörencen’s phosphate buffer pH 7.4. Sodium lauryl sulphate 1% w/w was added to the medium to ensure sink condition. The system was maintained for 4 hrs at 32°C in a thermostatic shaker water bath at 100 rpm (Figure1). Samples 3 ml were withdrawn at intervals of 15, 30, 45, 60, 90, 120, 180, and 240 min, the volume of each sample was replaced by the same volume of fresh buffer to maintain constant volume, samples were analyzed without dilution or filtration for ME content spectrophotometrically at λmax = 362 nm. In case of Feldene® gel, samples were analyzed for piroxicam content at λmax = 358 nm. In-Vitro permeation studies: In-vitro permeation studies with excised rabbit skin (13) were performed as follows: Abdominal full-thickness skin of male rabbit was obtained from white New Zealand rabbits weighing 3-4 kg. The skin was carefully removed from animals and the hair was clipped without damaging the skin. The fat Saudi Pharmaceutical Journal, Vol. 14, Nos. 3-4, July-October 2006 157 was removed with the aid of scissor and skin was washed and soaked over night in 0.9 % sodium chloride solution. The excised skin was used as a permeation membrane with the epidermal surface upward, the stratum corneum was facing the donor side of the cell and the dermal side of the skin was allowed to be in contact with a buffer solution (Figure 1). The procedure for the release test described above was used except that the receptor medium contained 150 ml 0.9% sodium chloride of pH 7.4 with the addition of sodium lauryl sulphate (1% w/v). Samples of 3 ml were withdrawn periodically for 9 hrs and replaced with an equal volume of fresh receptor solution. ME and piroxicam were assayed spectrophotometrically at 362 nm and 358nm, respectively. Calculation of cumulative drug release: The amount of ME in the total receptor solution was determined from a calibration curve. The cumulative drug permeated (Qn) corresponding to the time of the nth sample was calculated from the following equation (14): n-1 Qn = VRCn + Σ VsCi i=0 Where Cn and Ci are the drug concentrations of the receptor solution at the time of the nth sample and the i ( the first) sample, respectively and VR and VS are the volumes of the receptor solution and the sample, respectively. Calculation of permeation parameters: The permeation profiles of ME across rabbit skin from different gel formulations were constructed by plotting the total cumulative amount of ME penetrated per unit surface area (μg/cm2) versus time (hour) as shown in figure 4. Meloxicam steady state flux (Jss) was calculated as the slope of linear regression line at the steady state phase for each experimental run. Permeability coefficient (Kp) was calculated using the relation derived from Fick’s first law of diffusion, which described in the following equation: Jss = Kp /Co where, Co is the initial drug concentration in the donor (15). 158 EL-MEGRAB ET AL Anti-inflammatory activity of Meloxicam gel: Acute inflammatory activity model, carrageenan induced rat paw edema method (16) was applied in this study. The rats weighing about 200 gm were divided into 6 groups, each group containing 4 rats. The animals of groups 1, 2 and 3 received 1ml oral suspension of meloxicam (0.2 mg/kg) in 0.9 % sodium chloride (17), 200 mg of EO microemulsion gel topically and 200 mg of feldene® gel topically, respectively. The gels were applied to the surface of the right hind paw, then the treated area was immediately covered by thin vinyl sheet and gauze. Two hours later, the covers were removed and 0.1 ml of 1% carrageenan solution was injected subcutaneously into both treated area and the left hind paw. The animals of control groups 4,5 and 6 were treated with sodium chloride solution orally, microemulsion placebo gel topically and HPMC placebo gel topically respectively. The carrageenan was injected in the same manner as above. Three hours later, the thickness of the right and left paws was measured using a dial micrometer and the percentage inhibition of edema was calculated (18). The data were reported as mean ± SEM (n=4) and statistical analysis was carried out using ANOVAtest at a level of significance of P< 0.05. Results and Discussion In-Vitro Drug Release and Permeation Studies Effect of gel type: The data obtained from release and permeation studies were shown in Figures 2-5 and Table 2. The amount of ME released from all gel formulations show a linear relationship with the square root of time (r >0.9), therefore, the release rate of the test drug followed Higuchi theoretical model (19). It was observed that the in-vitro release data as well as the permeation studies were superior from EO microemulsion gel. The cumulative amounts permeated at 9 hrs were 616.1, 295.15, 141.5 and 235.2 μg/cm2 for EO microemulsion gel, EO lipogel, carpobol gel and hydroalcoholic carpobol gel respectively. These results were in agreement with El-Laithy and El-Shaboury, Who reported that maximum fluconazole permeation and 1.5 fold improvement in drug release were achieved from microemulsion prepared with jojoba oil in comparison to its corresponding lipogel (20). Thacharodi and Panduranga (7) explained the Saudi Pharmaceutical Journal, Vol. 14, Nos. 3-4, July-October 2006 mechanism by which microemulsions enhance the percutaneous absorption of drugs on the basis of the combined effect of both the lipophilic and hydrophlilic domains of microemulsion. The lipophilic domain of the microemulsion can interact with the stratum corneum in many ways. The drug dissolved in the lipid domain of a microemulsion can directly partition into the lipid of the stratum corneum or lipid vesicles themselves can intercalate between the lipid chains of stratum corneum, thereby destabilizing its bilayer structure. These interactions will lead to increased permeability of the lipid pathway to the drugs. On the other hand, the hydrophilic domain of the microemulsion can hydrate the stratum corneum to a greater extent. When the aqueous fluid of the microemulsion enters the polar pathway, it will increase inter lamellar volume of stratum corneum lipid bilayer, resulting in the disruption of its interfacial structure. Since, some lipid chains are covalently attached to corneocytes, hydration of these proteins will also lead to the disorder of lipid bilayers. Similarly, swelling of the intercellular proteins may also disturb the lipid bilayers; a lipophilic penetrant like ME can then permeate more easily through the lipid pathway of stratum corneum. It was observed that the type of oil affect the release and permeation properties of ME from microemulsion gels and lipogels. The cumulative amounts of ME permeated From EO microemulsion gel and lipogel were 616.1 and 295.1 μg/cm2 respectively, compared with 260.5 and 248.8 μg/cm2 from oleic acid microemulsion gel and lipogel, respectively. This may be due to increased solubility of ME in oleic acid where it was 0.35 mg/ml and 2.42 mg/ml in EO and oleic acid respectively (Table 3), which lead to decreased partitioning of ME into the skin and hence decreased permeation (21). Our investigation revealed that meloxicam gels have greater viscosity in oleic acid formulation than EO formulation (Table 4). Consequently there was a decreased release and permeation of ME from oleic acid gels than EO gels. The result is in agreement with that previously mentioned by Hüttenrauch et al (22) and Ugri-Hunyavari and Erös (23). They stated that, gel having a compact and close structure may have a slower release rate than one of lower consistency. The enhanced drug release and permeation properties from the hydroalcoholic carbopol gel compared to the hydrogel, could be ascribed to two FORMULATION AND EVALUATION OF MELOXICAM GELS Feldene gel EO lipogel EO microemulsion gel Oleic acid microemulsion gel Oleic acid lipogel 500 400 2 Amount released (ug/cm ) factors; first, ethanol is a vehicle known to increase the permeation of drugs through the skin either by attacking the dense barrier structure of the skin (24) or by augment the solubility and partitioning of the drug in stratum corneum (25 ). Second, ethanol decreases the viscosity of carpobol gel (Table 4) which lead to improved drug release and permeation from the gel (Figures 3 and 5). The results are in agreement with the previous investigation performed by Chi and Jun (26), who demonstrated that the enhancement effect of ethanol in ketoprofen gel formulations is due to decrease of viscosity and increased solubility of drug in the gel. Comparison of the results (Figures 2 and 3) indicated that although there is a better in-vitro release of piroxicam than meloxicam from their formulations, figure 4 and 5 reflect inferior skin permeation of the former. These results can be attributed to the physicochemical properties of drugs such as partition coefficient, vehicle solubility and molecular weight which determine there permeation through the complicated structure of the skin (27,28). 159 300 200 100 0 0 0.5 1 1.5 2 2.5 Time1/2(hrs) Figure 2. Release profiles of meloxicam from different microemulsion gels and lipogels across standard cellophane membrane in comparison with feldene® gel. (n=3, mean + SE). Feldene gel Carbobol gel Hydroalcoholic carbobol gel 500 Rabbit skin loaded with sample (donor) Cover with a small open 250 ml beaker Shaking water bath → Figure 1. Cross-sectional diagram of the drug permeation apparatus (Thermostatic shaker water bath). Saudi Pharmaceutical Journal, Vol. 14, Nos. 3-4, July-October 2006 400 2 Amount released (ug / cm ) Effect of initial drug concentration: Figure 6 and Table 2 show the effect of initial drug concentration (0.5, 0.65, 1% w/w) on the release and permeation of ME from EO microemulsion gel. The results revealed that increasing the drug concentration, results in increasing the cumulative amount permeated. The cumulative amounts permeated at 9 hrs were 133.6, 208.5 and 616.1 μg/cm2 for gel prepared with 0.5, 0.65, and 1% ME, respectively. A close parallel results were reported by Fergany (29). 300 200 100 0 0 0.5 1 1.5 Time 1/2 2 2.5 (hrs) Figure 3. Release profiles of meloxicam from two carbopol gels across standard cellophane membrane in comparison with Feldene gel. Anti-inflammatory activity of meloxicam gel: Table 5 shows the inhibitory effects of ME gel on the carrageenan- induced paw edema compared with oral Mexicam® and Feldene® gel (0.5% piroxicam). The data were reported as mean ± SEM (n=4) and statistical analysis was carried out using ANOVA-test at a level of significance of P< 0.05. ME gel (EO microemulsion) produced significant inhibitory effects, with a 42.37% inhibition after 4 hrs and the activity was approximately equivalent to that of Mexicam® oral tablet, while more effective 160 EL-MEGRAB ET AL Feldene gel Carbopol gel Hydroalcoholic carbopol gel 300 2 Amounte permeated (ug/cm ) than that of Feldene® gel. In this experiment, the normal saline and the placebo gel had no effect on carrageenan edema. ME gel significantly inhibited inflammation in the treated paw and had also some influence on edema of non-applied paw. While, Feldene had no influence on edema of non-applied paw indicating absence of any systemic effects. These results were in agreement with that previously mentioned by Gupta et al (1). They reported that, meloxicam gel (1%w/w) showed increased protection against inflammation as compared to piroxicam (0.5 % w/w) and diclofenac (1% w/w) gels. 250 200 150 100 50 0 0 2 4 6 8 10 Time (hr) Feldene gel EO lipogel EO microemulsion gel Oleic acid microemulsion gel Oleic acid lipogel Amount permeated (ug/cm2) 600 500 400 300 200 100 0 0 1 2 3 4 5 6 7 8 9 10 Time (hrs.) meloxicam permeated (ug/cm2) Figure 5. Permeation profiles of meloxicam from two carbopol gels across abdominal rabbit skin in comparison with Feldene® gel. 800 700 600 500 400 300 200 100 0 0 0.2 0.4 0.6 0.8 1 1.2 meloxicam concentration (W/W%) Figure 4. Permeation profiles of meloxicam across abdominal rabbit skin from different microemulsion gels and lipogels in comparison with feldene® gel. (n=3, mean + SE). Figure 6. Effect of initial drug concentration on the amount of meloxicam permeated from EO microemulsion gel through abdominal rabbit skin. Table 1: Components of different gel formulations. Formula Formula 1 Carbopol hydrogel Formula 2 Carbopol hydroalcoholic gel Formula 3 Microemulsion gel Formula 4 Lipogel Quantities by grams required to prepare 10 grams of gel 0.1 g corbopal, 9.9g (80 : 20%w/w) water : PG 0.1 g carbopol , 9.9g (40:40:20%w/w) water : PG : EOH 5g Tween80, 1g PG, 4g ethyl oleate or oleic acid, 2.5g water 1.5g monoglyceryl stearate, 8.5g ethyl oleate or oleic acid Saudi Pharmaceutical Journal, Vol. 14, Nos. 3-4, July-October 2006 FORMULATION AND EVALUATION OF MELOXICAM GELS 161 Table 2: Percutaneous permeation parameters of ME through abdominal rabbit skin from various formulations (Mean ± SE, n = 3) Formulation Higuchi model (r) Microemulsion gel: EO Oleic acid Lipogel: EO Oleic acid Feldene® (0.5% piroxicam gel) Meloxicam (%) 0.5 0.65 1 Carbopol gel Hydro alcoholic carbopol gel Cumulative amount at 9hrs (Q9h, μg/cm2) Permeability Coefficient (Kp, Cm/hr × 10 -5) 0.98 0.98 616.1± 59.73 260.5±49.98 25.88±0.051 14.65±3.91 258.8±0.51 146.5±39.1 0.99 0.99 295.15 ±102.2 248.8 ± 35.85 15.2 ±10.7 17.23 ± 5.44 152 ±107 172.3 ± 54.4 0.98 198.1 ± 1.2 11.89 ± 0.559 237.8 ± 11.18 0.99 0.98 0.98 133.6± 1.34 208.5± 15.77 616.1 ± 59.73 4.38± 0.05 6.1± 0.997 25.88 ± 0.051 87.6 ± 1.00 93.8 ± 19.94 258.8 ± 0.51 0.98 0.98 141.5 ± 9.99 235.2 ± 19.93 6.34 ± 1.38 15.81 ± 0.655 63.4 ± 13.8 158.1 ± 6.55 Table 4: Viscosity measurements of different gel bases (Mean ± SE, n=3) Table 3: Solubility of ME in the oils. Oil Flux (Jss, μg/cm2/hr) Gel base Microemulsion gel: EO Oleic acid Lipogel: EO Oleic Acid Carbopol gel Hydroalcoholic carbopol gel Feldene® gel Solubility (mg/ml) Ethyl oleate 0.355 Oleic acid 2.42 Viscosity (cp) 32313 ± 2899 74843± 5838 39403 ± 10946 144596 ± 1998 220612 ± 1156 131030 ± 7554 148080 ± 5071 Table 5: Evaluation of the anti-inflammatory activity of meloxicam microemulsion gel (Mean ± SE, n=4). Sample % Swelling (mean SEM) % inhibition Control 1 57.45 ± 3.95 - Meloxicam tablet 33.54* ± 10.25 41.62 Treated foot Non treated foot Treated foot Non treated foot Control 2 46.28 ± 9.97 63.66 ±18.53 EO microemulsion 26.67 ± 5.54* 50.73 ± 13.3 Control 3 55.78 ± 5.53 51.78 ± 8.52 42.37 24.79 20.31 Zero Feldene® gel 41.95 ± 9.51* 59.34 ± 8.94 Control 1 = animals administered normal saline. Control 2 = animals treated with placebo microemulsion gel. Control 3 = animals treated with placebo HPMC gel. P*< 0.05 compared with the control. 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