Formulation & Invitro Evaluation of Drug Reservoir Transdermal Patches of Piroxicam Using Polymers HPMC E15, PVP K30 & Eudragit L100

Transcription

1 Formulation & Invitro Evaluation of Drug Reservoir Transdermal Patches of Piroxicam Using Polymers HPMC E15, PVP K30 & Eudragit L100 Jadhav Jaydatt 1*, Sreenivas S.A. 2, 1 Research scholar, JJT University, Jhunjhunu, Rajasthan, India 2 Guru Nanak Institute of Pharmacy, Khanapur, Hydrabad, (AP) ABSTRACT The purpose of this research work was to formulate and evaluate drug reservoir Transdermal Patches containing Piroxicam with different ratios of hydrophilic and hydrophobic polymeric combinations by the solvent casting technique. The physicochemical compatibility of the drug and the polymers were studied by Fourier transfer infrared spectroscopy. The results suggested no physicochemical incompatibility between the drug and the polymers. Transdermal patch formulations consists of hydroxy propyl methylcellulose E15, Polyvinyl pyrrolidone K30 and Eudragit L100 in the various ratios respectively were prepared. All formulations contained Oleic acid as penetration enhancer and Polyethylene glycol 400 as plasticizer in dichloromethane and methanol (1:1) as solvent system. The prepared Transdermal patches were evaluated for in vitro studies such as moisture absorption, moisture loss and mechanical properties. The diffusion studies were performed by using Franz diffusion cells. The formulation, F6 with combination of polymers showed maximum release of in 24 hrs. Hence, it can be practically concluded that Piroxicam can be formulated into the Transdermal drug reservoir patches to sustain its release characteristics. Key words: Transdermal Patches, drug reservoir, Piroxicam, HPMC E15 and Eudragit L100 INTRODUCTION There are two traditional designs for transdermal patches. With the membrane, or reservoir, system, a membrane that lies between the drug and the skin controls the rate of release from a reservoir. This patch design can provide a true zero-order release pattern to achieve a constant serum drug level. These devices are used when drug permeation rate is rapid and absorption should therefore be controlled by controlling drug release (R1< R2). It is also suitable for potent drugs with low therapeutic indices where monitoring drug levels in a narrow range is essential. The drug is usually contained within the reservoir as a suspension in a liquid (such as silicone) or gel carrier. The ratecontrolling thin polymeric membrane is made of oleinic polymers and copolymers, cellulosic esters, polyamides or PVC. When applied on skin, the device shows a rapid. Release at first (initial burst effect) *Corresponding Author Jadhav Jaydatt 67 P a g e

2 followed by a constant zero-order release as long as the solution inside the reservoir is saturated. In this system the drug reservoir is embedded between an impervious backing layer and a rate controlling membrane. The drug releases only through the rate controlling membrane, which can be micro porous or non porous. In the drug reservoir compartment, the drug can be in the form of a solution, suspension, gel or dispersed in a solid polymer matrix. Hypoallergenic adhesive polymer can be applied as outer surface polymeric membrane which is compatible with drug [1, 2, 3]. Controlled drug release can be achieved by Transdermal drug delivery systems which can deliver medicines via the skin portal to systemic circulation at a predetermined rate over a prolonged period of time [4, 5, 6]. Transdermal drug delivery systems has gained a lot of interest during the last decade as it offers many advantages over the conventional dosage forms and oral controlled release delivery systems notably avoidance of hepatic first pass metabolism, less frequency of administration, reduction in gastrointestinal side effects and improves patient compliance [7]. EXPERIMENTAL Material Piroxicam was received as gift from Zydus cedilla, Verna, Goa, India. Hydroxy propyl methyl cellulose E15, Polyvinyl pyrrolidone K30, and Eudragit L100 was received from Colorcon Pharmaceuticals Pvt. Ltd., Goa. Polyethylene Glycol 400, Oleic acid and Dichloromethane was received from Themis laboratory, Mumbai. All the other chemicals and solvents were of Pharmaceutical grade. Method for preparation of Transdermal Drug reservoir patches Reservoir type transdermal patches were prepared using solvent casting technique. The backing membrane was cast by pouring a 5% solution of polyvinyl alcohol into a Petri plate of diameter 9 Centimetre and dried at 65 0 c. Primary polymeric layer prepared by using HPMC E15 and PVP K30, Eudragit L100 as secondary polymeric layer and propylene glycol as plasticizer. Primary polymer was added to 25 ml of the solvent mixture (dichloromethane and methanol, 1:1) and allowed to stand for 2 hrs to swell. Piroxicam was dissolved in 5 ml of solvent mixture and added to the polymeric solution. Measured quantity of oleic acid (10% v/v) was added as penetration enhancer. This was poured on backing membrane set aside for 4-5 hrs. To remove entrapped air, then transferred to a Petri plate of diameter 9 Centimetre and dried at room temperature and The secondary polymeric solution was prepared by dissolving weighed Eudragit L100 and 90 μl of propylene glycol 400 in 15 ml of solvent mixture and poured on the primary polymer layer and allowed to dry at room temperature. The formulated patches were removed carefully, cut to size (each having an area of 4 cm 2 ), and stored in a desiccators [8-10]. EVALUATION OF TRANSDERMAL PATCHES Physical appearance All the prepared patches were visually inspected for colour, clarity, flexibility and smoothness. 68 P a g e

3 Thickness The thickness of films was measured by digital Vernier calipers with least count 0.001mm. The thickness uniformity was measured at five different sites and average of three readings was taken with standard deviation [11, 12]. Weight uniformity For each formulation, three randomly selected patches were used. For weight variation test, 3 films from each batch were weighed individually and the average weight was calculated [13]. Drug content determination The patches at 4 cm 2 were cut and added to a beaker containing 100ml of Phosphate buffered solution of ph 7.4. The medium was stirred with a Teflon coated magnetic bead for 24 hrs. The solution was later filtered and analyzed for drug content with proper dilution at 334 nm spectrophotometrically [14]. Folding endurance The folding endurance was measured manually for the prepared films. A strip of film (2 x2cm) was cut and repeatedly folded at the same place till it broke. The number of times the film could be folded at the same place without breaking/cracking gave the value of folding endurance [15]. Flatness Longitudinal strips were cut out from the prepared medicated film the lengths of each strip were measured. Then variation in the length due to the non-uniformity in flatness was measured. Flatness was calculated by measuring constriction of strips and a zero percent constriction was considered to be equal to a hundred percent flatness [16]. L1 - L2 Constriction (%) = 100 L2 Where, L1- initial length of strip L2 - final length of strip Percentage moisture absorption The percent moisture absorption test was carried out to check the physical stability and integrity of the films at high humid conditions. In the present study the moisture absorption capacities of the films were determined in the following manner. The films were weighed accurately and placed in the desiccators containing 100 ml of saturated solution of potassium chloride, which maintains 80-90% RH after 3 days, the films were taken out and weighed. The study was performed at room temperature. The percentage moisture absorption was calculated using the formula [17, 18] : (W f W i ) % Moisture absorption = 100 Where, W i - initial weight W f - final weight W i Percentage moisture loss Percentage moisture loss was carried out to check the (physical stability) moisture sensitiveness during storage of patch. The films were weighed accurately and kept in a desiccators containing anhydrous calcium chloride. After 3 days, the films were taken out and weighed. The moisture loss was calculated using the formula [17, 18] : 69 P a g e

4 (W f W i ) % Moisture loss = 100 W i Moisture vapours transmission rate Glass vials of 5 ml capacity were washed thoroughly and dried to a constant weight in an oven. About 1 g of fused calcium chloride was taken in the vials and the polymer films of 4 cm 2 were fixed over the brim with the help of an adhesive tape. Then the vials were weighed and stored in a humidity chamber of % RH condition for a period until it show constant weight gain [7 days]. The vials were removed and weighed at 24 h time intervals to note down the weight gain [19]. (W f W i ) Transmission rate = 100 (Area x Time) Tensile Strength The tensile strength was determined by the apparatus designed such that it had horizontal wooden platform with fixed scale and attachments for two clips that holds Transdermal patch under test. Out of the two clips one was fixed and other was movable. Weights were hanged to one end of pulley and the other end of pulley was attached with movable clip. The wooden platform was such fitted that it would not dislocate while the test is running. Three strips of patch were cut having 2cm length and 1cm breadth. The thickness and breadth of strips were noted at three sites and average value was taken for calculation. Weights were gradually added to the pan to increase the pulling force till the film was broken 20. The tensile strength was calculated by using following formula. Tensile stress = Applied force Cross sectional area m x g = b x t Where, m- Mass in kg g- Acceleration due to gravity 9.8 N/m 2 b- Breath of specimen in mm t Thickness of specimen in mm. Diffusion studies Transdermal Drug reservoir patches A. Preparation of skin A full thickness of skin was excised from dorsal site of dead rat and skin was washed with water. The skin was kept in normal saline solution in refrigerator until skin was used for diffusion study. Prior to use, the skin was allowed to equilibrate with room temperature. Then skin was mounted between donor and receptor compartment of cell. The skin was clamped in such a way that the dermal side will be in contact with receptor medium. B. Diffusion cell In this work, The Franz Diffusion cells used generally it comprise two compartments, one containing the active Compartment (donor compartment) and the other containing receptor solution (receptor compartment) separated by barrier i.e. rat abdominal skin and The cell 70 P a g e

5 consisted of sampling port and temperature maintaining jacket and The outlet and inlet was connected with latex tube so the jacket had stagnant water inside and heat was provided by hot plate. Taflon coated magnetic bead was used to stir the receptor solution using magnetic stirrer. Dead rat dorsal site skin was placed on receptor compartment and both compartments held tight by clamps. (Prior to study the membrane was kept in phosphate buffer solution 7.4 for 24 hr.). Phosphate buffer ph 7.4 was used as receptor solution and the volume of diffusion cell was 20 ml and stirred with magnetic bead. The temperature was maintained at 37 ± 1 C with the help of hot plate. It was carried out for 24 hours and 0.5 ml sample was withdrawn at 1 hour interval. The same volume of phosphate buffer ph 7.4 was added to receptor compartment to maintain sink conditions and the samples were analyzed at 334 nm [21, 22]. Stability Studies of Piroxicam Drug reservoir Transdermal patch In any rationale design and evaluation of dosage forms, the stability of the active component must be major criteria in determining their acceptance or rejection. During the stability studies the product is exposed to normal conditions of temperature and humidity. However the studies will take a longer time and hence it would be convenient to carry out the accelerated stability studies where the product is stored under extreme conditions of temperature. In the present study, stability Studies were carried out on optimized formulation. The patches were stored at temp 40 0 C±2 0 C & RH 75 % ± 5% for duration of Six month. After an interval of two months sample was withdrawn and tested for drug diffusion [23]. RESULTS AND DISCUSSION In this work an attempt was made to formulated and evaluated drug reservoir transdermal patches Piroxicam by solvent casting method. The main objective of formulating the transdermal system was to prolong the drug release time, reduce the frequency of administration and to improve patient compliance. The Standard Calibration Curve of Piroxicam at ph 7.4 shown in table and figure 1 and FTIR Spectrum figure 2. The compatibility parameters characterization was done by FTIR method shown in figure 3, 4, and 5. Ten formulations were prepared using different polymers in different ratios and combinations, along with plasticizers and penetration enhancer. Petri dish was used as a substrate for pouring the polymeric solution shown in table 2. The patches were evaluated for uniformity of thickness, weight variation, drug content, folding endurance, tensile strength, % flatness, % moisture absorption, Moisture vapor transmittance rate shown in table 3 and 4. In vitro diffusion studies using Franz diffusion cell. Dead rat skin was used for the diffusion study table 5 and figure 6. Stability studies for drug diffusion of optimized batch F6 at 40 o C ± 2 0 C and 75% ± 5% RH for 180 days table no.6 and figure no. 7 The weight variation was found in the range of ± 0.47 to ± 0.94 mg. Thickness of transdermal patch was 71 P a g e

6 measured by digital Vernier calipers. The thickness of the films varies between 0.42± 0.32 to 0.45± 0.85 mm. The tensile strength of the films was found vary with the nature of the polymer. It was found to vary between 5.13±0.580 to 5.67±0.217 N/mm 2. Flatness of all prepared patches was found to be 100%. Folding endurance of the transdermal patches was measured and it was varied between 102 ±1.86 to 137±1.05. The drug content uniformity was determined for all the ten formulations by spectrophotometric method and found in between ± 0.56 to ± 0.84 %. The % moisture absorption at 75% RH for all the formulations was in the range of 2.46 ± 0.29 to 4.72 ± 0.22 %. The % moisture absorption at 84% RH for all the formulations was in the range of 4.12 ± 0.68 to 5.72 ± 0.15 %. Moisture vapour transmission rate for all formulation was in the range of 1.21 ± 0.19 to 2.73 ± 0.12 %. The In vitro diffusion study was carried out in phosphate buffer ph 7.4 for 24hours. It was considered that the drug is dispersed uniformly throughout the film. The fabricated transdermal patches of Piroxicam were subjected to Invitro permeation study across excised rat skin using modified Franz diffusion cell having a receptor volume of 50 ml and an effective surface area of 4 cm 2. This study was carried out for 24 hours and cumulative percent permeated was calculated based on the amount of drug originally present in the patch. The batch F6 was optimised batch of Piroxicam transdermal patches prepared Showed good physical properties and ideal release kinetics. The formulation F6 showed the maximum diffusion through the membrane for 24 hours. It showed the diffusion of 94.81%. Conclusion: Finally we conclude that the formulated reservoir transdermal patches of Piroxicam showed good thickness, drug content uniformity and tensile strength. The polymers HPMC E15 and PVP K30 and Eudragit L100 can be used to develop reservoir type transdermal patches. As concentrations of hydrophilic and hydrophobic polymers increases in primary and secondary layer respectively, the folding-endurance and tensile-strength also increases, increased folding endurance and tensile strength shows the good film consistency. In moisture uptake study the moisture uptake is going decreases as the concentration of Eudragit L100 in secondary layer were increases. From drug diffusion study, here concluded, concentration of HPMC E15 decreases and PVP K30 increases in primary layer the Invitro drug diffusion rate were decreases. There is scope for the further study and development of the Piroxicam reservoir type transdermal patches. REFERENCES: 1. Brahmankar.D.M, Jaiswal.S.B, Biopharmaceutics and pharmacokinetics A Treatise. Vallabh Prakashan, Delhi1995, Jain.N.K, Controlled and novel drug delivery, first edition, CBS publishers and distributors, New Delhi Aulton.M.E, Pharmaceutics; The science of dosage form design, second edition, Churchill Livingston, Harcourt publishers P a g e

7 4. Das M. K. Bhattacharya A. Ghoshal S.K. Transdermal delivery of trazodone hydrochloride from acrylic films prepared from aqueous latex. Ind.J.pharm.Sci. 2006; 68 (1): Shivraj A. Selvam R.P. Mani T.T. Shivkumar T. Design and evaluation of transdermal drug delivery of ketoprofen fumarate, Int. J. Pharm Biomed Res. 2010; 1(2): Patel D. Patel N. Parmar M. Kaur N. Transdermal drug delivery system: Review, Int. J. Biopharmaceutical & Toxicological Research 2011; 1(1): Prausnitz M.R. Langer R. Transdermal drug delivery system: Nat Biotechnol 2008; 26(11); Saritha Thatikonda, Shiva kumar yellanki, Formulation and evaluation of reservoir type selegiline transdermal delivery system, Asian journal of pharmaceutical and clinical research, Vol 5, suppl. 4, 2012, Shravani.P, Vinod K.R, Teja B.B, David Banji, Designing and characterization of reservoir type transdermal formulation of fulvestrant, international journal of pharmaceutical sciences review and research, volume 5, issue 3, November December 2010,pp, Babu RJ, Pandit JK., Effect of penetration enhancers on the release and skin permeation of bupranolol from reservoir-type transdermal delivery systems. Int J Pharm Jan 20; 288(2): Shankar M.S. Kulkarni S.V. Sandeep H.N. Ranjit Kumar. P. Someshwar Rao B. Ashok Kumar P. Development and evaluation of Aceclofenac transdermal patches using hydrophilic and hydrophobic polymers, Journal of Global Pharma Technology. 2010; 2(4): Amnuaikit C. Ikeuchi I. Ogawara K. Higaki K. Kimura T. Skin permeation of propranolol from polymeric film containing terpene enhancers for transdermal use. Int. J. Pharm. 2005; 289: Verma P.R.P. Iyer S.S. Transdermal delivery of propranolol using mixed grades of Eudragit: design and invitro and in vivo evaluation. Drug Dev. Ind. Pharm. 2000; 26: Biswajit M. Sushmita M. Ritu G. Balaram P. Amit T. Priyanka A. comparision between povidoneethylcellulose and povidone-eudragit transdermal dexamethasone matrix patches based on in vitro skin permeation. Eur.J.Pha and Bio. 2005; 59: Rakesh P. Formulation and Evaluation of Transdermal Patch of Aceclofenac. Int.J.Drug Del. 2009;1: Krishna R. Pandit J.K. Transdermal delivery of propranolol. Drug Dev. Ind. Pharm. 1994; 20: Seth A.K. Agarwal G.P. Saini T.R. Evaluation of free films. Indian drugs. 1985; 23(1): Garala K. C. Shinde A. J. Shah P. H. Formulation and in-vitro characterization of monolithic matrix Transdermal systems using 73 P a g e

8 hpmc/eudragit100 polymer blends. International journal of pharmacy and pharmaceutical sciences2009; 1(1): Chein Y.W. Rate-controlled drug delivery systems. Indian J Pharm Sci. 1988; 50(2): Chein Y.W. Development of Transdermal drug delivery systems. Drug Dev. Ind. Pharm., 1987; 13: Gye J.R. Jong S.W. Sung J H. Young W.L. Chang H.L. Topical oleohydrogel preparation of Ketoprofen with enhanced skin permeability. Drug Dev. Ind.Pharm. 1999; 25(6): Dey S. Malgope A. Preparation of Carvedilol transdermal patch and the effect of propylene Glycol on permeation. International journal of pharmacy and pharmaceutical sciences 2010; 2(1): Kanvinde S. A. Kulkarni M. S. Stability of transdermal product A global perspective, Pharma Times, May 2005; 37 (5): Table 1: Standard Calibration Curve of Piroxicam at ph 7.4 S. N. Concentration (μg /ml) Absorbance at 336 nm P a g e

9 Table 2: The Composition of Drug Reservoir Transdermal Patches of Piroxicam Drug Primary Layer Secondary Layer Batches Piroxicam (mg) HPMC E15 (mg) PVP K30 (mg) PEG 400 (μl) Oleic acid (μl) Eudragit L100 (mg) PEG 400 (μl) F F F F F F F F F F Where, HPMC E15: Hydroxy propyl Methyl Cellulose, PVP K30: Polyvinyl pyrrolidone K30.PEG 400: Polyethylene glycol 400. Table3: Weight variation, thickness, drug content, flatness, of Piroxicam Drug Reservoir Transdermal patches. Batch No. Weight variation (mg) Thickness (um) Drug Content (%) Flatness % F ± ± ± F ± ± ± F ± ± ± F ± ± ± F ± ± ± F ± ± ± F ± ± ± F ± ± ± F ± ± ± F ± ± ± P a g e

10 Table 4: Tensile strength, folding endurance, MVRT, %moisture content and moisture absorption of Piroxicam Drug Reservoir Batch No. Tensile strength (N/mm 2 ) Folding endurance MVTR (%) Moisture content (%) Moisture Absorption (%) 75%RH 85%RH F1 5.13± ± ± ± ± ± 0.24 F2 5.47± ± ± ± ± ± 0.41 F3 5.50± ± ± ± ± ± 0.53 F4 5.55± ± ± ± ± ± 0.49 F5 5.55± ± ± ± ± ± 0.15 F6 5.45± ± ± ± ± ± 0.68 F7 5.49± ± ± ± ± ± 0.15 F8 5.41± ± ± ± ± ± 0.29 F9 5.67± ± ± ± ± ± 0.15 F ± ± ± ± ± ± 0.43 *MVRT: Moisture vapour transmission rate *RH: Relative humidity Table 5: Invitro drug diffusion study of Piroxicam Drug Reservoir Transdermal patches of batches F1 to F10 Time ( hrs) F1 F2 F3 F4 F5 F6 F7 F8 F9 F P a g e

11 Absorbance INTERNATIONAL JOURNAL OF Table 6: Comparative Stability studies for drug diffusion of optimized batch F6 at 40 o C±2 0 C and 75%± 5% RH after 180 days. Time (hrs) % of Piroxicam diffuse % of Piroxicam diffuse after 60 days % of Piroxicam diffuse after 120 days % of Piroxicam diffuse after 180 days Standard calibration curve of Piroxicam Concentration in ug/ml standard calibration curve of Piroxicam Figure 1: Standard Calibration Curve of Piroxicam at ph P a g e

12 Figure 2: FTIR Spectra of Piroxicam Figure 3: FTIR spectrum of mixture of Piroxicam and HPMC E15 78 P a g e

13 Figure 4: FTIR of mixture of Piroxicam and PVP K30 Figure 5. FTIR of mixture of Piroxicam and Eudragit L P a g e

14 Cumulative % drug diffusion Cumulative % Drug Diffusion INTERNATIONAL JOURNAL OF Comparative Diffusion Study of batch F1 to F Time in Hours F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 Figure 6: Comparative Diffusion Study of Drug Reservoir Type Transdermal Patches of Piroxicam Batch F1 to F Comparative stability studies of Batch F Time in hrs Release at 0 day Release after 60 days Release after 120 days Release after 180 days Figure 7: Comparative Stability studies for drug diffusion of optimized batch F6 at 40 o C±2 0 C and 75%± 5% RH after 180 days 80 P a g e