IJRPB 1(5) September October 2013 Page 629

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1 FORMULATION AND EVALUATION OF TRANSDERMAL PATCHES OF ANTI- HYPERTENSIVE DRUG METOPROLOL SUCCINATE Koteswararao P 1*, Duraivel S 1, Sampath Kumar KP 2, Debjit Bhowmik 3 1. Nimra College Of Pharmacy,Vijayawada, Andhrapradesh 2. Coimbatore Medical College,Coimbatore 3. Karpagam University,Coimbatore *Corresponding author: kotipharmanew@gmail.com ABSTRACT The present research work is an attempt to develop and evaluate matrix-type transdermal therapeutic system of metoprolol succinate. It has a relatively greater blocking effect on beta 1-receptors.Transdermal patches of metoprolol succinate were developed with different ratios of hydrophilic - HPMC and hydrophobic EC polymer combinations by solvent evaporation technique. The Fourier transform infrared spectroscopy (FTIR) was used to confirm compatibility and to rule out any possible interactions between drug and polymers. Ten transdermal patch formulations consisting HPMC K 15 M and Ethyl Cellulose were prepared. All formulations carried Dimethyl Sulfoxide as penetration enhancer and Dibutyl Phthalate as plasticizer and dichloromethane and methanol as solvent system. The prepared patches were evaluated for their physicochemical characteristics such as weight variation, thickness, folding endurance, percentage moisture absorption, percentage moisture loss, and drug content and In- vitro drug diffusion studies. Data of In - vitro drug diffusion from patches were fit in to different equations and kinetic models to explain release kinetics. The Cumulative drug release from Formulation K10 was found to be (97.36±1.089), after 24 hrs. So the formulation K10 is emerged as ideal formulation for metoprolol succinate because it showed better release with sustained effect as compared to other formulations. KEY WORDS: Metoprolol Succinate; HPMC and Ethyl Cellulose, Hypertension, First pass metabolism INTRODUCTION Transdermal drug delivery systems are adhesive, drug containing devices of defined surface area that deliver a pre-determined amount of drug to the surface of intact skin at a pre-programmed rate. These systems provide drug systemically at a predictable rate periods of time. Currently transdermal drug delivery is one of the most promising methods for drug application through the skin to the systemic circulation. Transdermal drug delivery system Avoidance the first- pass metabolism and gastro intestinal incompatibility. This Single application has capacity for multi day therapy, thereby improving patient compliance and Self medication is possible with this systems. This is Provides utilization of drugs with short biological half life, narrow therapeutic window and avoiding the fluctuations in drug levels. Metoprolol Succinate dose is ( mg) daily. It used as a treatment of Hypertension, Angina pectoris and cardiac arrhythmias. Metoprolol succinate is a greater blocking effect on beta 1-receptors. It is a white crystalline powder. It is freely soluble in water and soluble in methanol, sparingly soluble in ethanol, slightly soluble in dichloromethane and 2-propanol. The plasma half-life of Metoprolol Succinate is 3 to 7 hours and it is indicating about 50% first-pass metabolism. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Peak plasma concentrations are achieved after 2 3 hours is almost completely absorbed (95%) after oral administration. Therefore Metoprolol Succinate is an ideal drug candidate for transdermal drug delivery system. MATERIALS AND METHODS Metoprolol Succinate was obtained from as gift sample from Zyduscadila, Ahmadabad, Gujarat. HPMC K 15 M and Ethyl Cellulose obtained from Micro advance research center, Banglore, Karnataka. Dibutyl phthalate, Dimethyl sulfoxide and Dichloro methane were purchased from Merk specialities, pvt.ltd.mumbai and methanol from Jianasuhuaxi International trade co.ltd. Made in china. Transdermal patches of metoprolol succinate were prepared by solvent evaporation method. The polymers EC, HPMC-K 15M, were taken in required quantity. About 14ml of solvent mixture of dichloromethane: methanol (1:1) was added and stirred well and after complete solubilization of polymers in mixture of solvent, added required quantity of Dibutyl Phthalate to this mixture, it is act as a plasticizer. Next weighed quantities of metoprolol succinate added to the polymer solution and mixed well and finally add permeation enhancer (Dichloro Methane). It was set-aside for some time to exclude any entrapped air and was then transferred into a previously cleaned Petri plate and then this was kept aside for solvent evaporation. The rate of solvent evaporation was controlled by inverting a glass funnel over the Petri plate. After over night, the dried films were taken out and stored in desiccators. The compositions of Transdermal Patches were shown in table.1. IJRPB 1(5) September October 2013 Page 629

2 Table.1.Composition of Transdermal Patch Ingredients (In mg or ml) K1 K2 K3 K4 K5 K6 K7 K8 K9 K10 Metoprolol succinate HPMC-K 15 M Ethyl cellulose Dibutyl phthalate Dimethyl sulfoxide Methanol: dichloromethane(1:1) EVALUATION OF TRANSDERMAL PATCHES FTIR study: The Infrared (IR) spectra were recorded using an FTIR by the KBr pellet method and spectra were recorded.the spectra obtained for Metoprolol Succinate, polymers, and physical mixtures of Metoprolol Succinate with polymers were compared. Disappearance of metoprolol succinate peaks or shifting of peak in any of the spectra was studied. Thickness: The thickness of films was measured by digital Verniercalipers with least count 0.01mm. The thickness uniformity was measured at five different sites and averages of five readings were taken with standard deviation. Folding Endurance: It was determined by repeatedly folding a small strip of films at the same place till it broke. The number of times, the films could be folded at the same place without breaking gave the value of folding endurance. Weight variation The three patches from each batch weighed on electronic balance for weight variation test. The test was done to check the uniformity of weight and thus check the batchto- batch variation. Percentage of moisture loss: The percent moisture loss was carried out to check the integrity of the film at dry condition. This was carried out in the following manner. The films were weighed accurately and kept in the desiccators containing anhydrous calcium chloride. After 3 days, the films were taken out and weighed. Percentage of moisture loss formula: Percentage of moisture loss Per cent moisture absorption: The patches were accurately weighed and placed in desiccators contains humidity condition of % RH is maintained by using saturated solution of potassium chloride. The patches were kept until uniform weight is obtained then taken out and weighed. The percentage moisture uptake was calculated as the difference between final weight (w2) and initial weight (w1) with respect to initial weight. Percent moisture absorption formula: Percent moisture absorption Drug content Determination: The prepared drug contained patches specified surface area (1 cm 2 ) were cut and dissolved in 100ml of ph 7.4 phosphate buffer, and vigorously shaked for 12hrs, and then sonicated for 15minutes, centrifuged at 5000 rpm for 30 min. Filter the drug contained polymeric solution through 42 number whatsman filter paper, then 1ml of the filtrate was taken in a test tube and dilute it for five times with same solvent by using double beam UV-Visible spectrophotometer to determined drug content at max 223 nm. Respected Placebo patch was taken as a blank solution. In vitro drug release studies: Franz - diffusion cell was used in our studies for in-vitro drug release. The cell consists of two chambers, the donor and the receptor. The donor compartment is open at the top and is exposed to the atmosphere. The receptor compartment is surround contain a water jacket for maintaining the temperature at 37 o C ± 2 and is provided with a sampling port. The diffusion medium was ph7.4 buffer, which was stirred with magnetic beads used a magnetic stirrer. A semipermeable cellophane membrane previously soaked overnight in 0. 1N HCl was placed between the two chambers. The diffusion media was stirred to prevent the formation of concentrated drug solution just beneath the membrane. Samples from the receptor compartment were taken at various intervals of time over a period of 24 hours and the concentration of the drug was determined by UV Spectrophotometric method using the standard curve. Amount of drug diffused at various time intervals was calculated and plotted against time. RESULTS AND DISCUSSION Our present work comprises the formulation and evaluation of Metoprolol Succinate transdermal patches for sustained or extended release for a prolonged period of time. Transdermal patches of metoprolol succinate were prepared by solvent evaporation method. Totally, ten IJRPB 1(5) September October 2013 Page 630

3 % moisture content formulation trials (K1 to K10) were done with the aim to achieve the successful matrix type Metoprolol Succinate transdermal patches. HPMC K 15 M and controlled release Ethyl Cellulose polymers in the formulation of Metoprolol Succinate transdermal patches individually and in combination. Methanol and Dichloromethane used as solvents. Dibutyl phthalate used as plasticizer and dimethyl sulfoxide used as a penetration enhancer.the compatibility study of the drug with excipients indicate no characteristic visual changes and no additional peaks were observed during FTIR studies. All the patches were evaluated for weight variation, thickness, percentage moisture absorption, percentage moisture loss, drug content, folding endurance, and in-vitro drug release. In this thickness study with the help of Digital verneircalipers, the thickness of patches was measured. It was found to be in between 0.15±0.015 to 0.18± All formulations have good film properties. The folding endurance of the patches was found between 84.11±5.03 to 131±4.49, the results indicate, as the HPMC concentration increases the folding endurance of the patches increases. All formulations from K1 to K10 show weight variation in between 1.10± to 1.25± gm. The percentage moisture absorption of the prepared patches results between 0.99 ± to 13.2 ± 1.993, HPMC K 15 M Alone High Moisture Absorption. The percentage moisture Loss of the prepared patches are in following order Percentage Moisture Content Studies K1>K2>K10>K9>K8>K7>K6>K5>K4>K3. The formulation containing HMPC K 15 M alone shows high loss of moisture (14±3.30) when compare to other patches. All formulations show good % drug content in between 90 to 98. From the results of In - vitro drug diffusion studies it is observed that, as the concentration of hydrophilic polymer increases the drug release from the transdermal patch increases. The formulation K1 HPMC alone showed maximum drug release of ± 1.53 % after 8 hrs, even then the formulation K1 cannot be considered as ideal formulation for Metoprolol succinate because it fails to sustain the drug release for 24 hrs. The formulation K2 showed lowest drug release of ± % after 24 hrs. Increase the hydrophilic polymer increase the % drug release, formulas K3 to K10 the % drug release shown order K3 (73.68 ± 1.031), K4 (77.39 ± 0.589), K5 (81.42 ± 0.736), K6 (84.76 ± 0.55), K7 (87.13 ± 1.218), K8 (90.36 ± 1.789), K9 (92.58 ± 0.931), K10 (97.36 ± 1.089) after 24 hrs. The formulation K10 containing HPMC and EC (400:400) is emerged as ideal formulation for Metoprolol succinate because it showed better release with sustained effect as compared to other formulations. The Cumulative drug release from Formulation K10 was found to be (97.36±1.089), after 24 hrs. The drug release kinetics studies showed Non-Fickian diffusion and Zero order release k1 k2 k3 k4 k5 k6 k7 k8 k9 k10 formulation code % moisture absorption % moisture loss Figure.1.Comparison between moisture loss and moisture absorption Table.2.Evaluation of Patches Formulation Thickness Folding Weight uniformity % moisture loss % moisture % drug content code (mm) endurance (gm) absorption K1 0.17± ± ± ± ± ±0.25 K2 0.18± ± ± ± ± ±0.75 K3 0.15± ± ± ± ± ±0.39 K4 0.16± ± ± ± ± ±0.48 K5 0.17± ± ± ± ± ±0.79 K6 0.16± ± ± ± ± ±0.39 K7 0.15± ± ± ± ± ±0.70 K8 0.18± ± ± ± ± ±0.52 K9 0.17± ± ± ± ± ±0.44 K ± ± ± ± ± ±0.43 IJRPB 1(5) September October 2013 Page 631

4 cumulative % drug realease Table.3.In-vitro drug permeation of metoprolol succinate (K1 to K5) Time(hr) Cumulative % drug release 0 K1 K2 K3 K4 K ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0, ± ± ± ± ± ± ± ± ±0.736 Table.4.In-vitro drug permeation of metoprolol succinate (K6 to K10) Time(hr) Cumulative % drug release K6 K7 K8 K9 K ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± In-vitro drug permeation profile time (hr) k1 k2 k3 k4 k5 k6 k7 k8 k9 k10 Figure.2.In- vitro drug permeation profile of Metoprolol succinate IJRPB 1(5) September October 2013 Page 632

5 Figure.3.FTIR Spectrum of pure Metoprolol succinate drug Figure.4.FTIR spectrum of ethyl cellulose Figure.5.FTIR Spectrum of pure Metoprolol succinate drug with ethyl cellulose Figure.6. FTIR spectrum of HPMC K 15 M Figure.7.FTIR spectrum of pure Metoprolol succinate drug with HPMC K 15 M Figure.12.FTIR spectrum of pure Metoprolol succinate drug with ethyl cellulose and HPMC K 15 M IJRPB 1(5) September October 2013 Page 633

6 CONCLUSION Metoprolol succinate is a an anti-hypertensive agent which selected for the preparation of transdermal delivery system as it complies with physicochemical properties required to permeate through skin. The pre formulation studies involving solubility, melting point, partition coefficient and ph of the drug were found to be comparable with the standard. The transdermal films of metoprolol succinate were prepared by solvent evaporation method and were subjected for evaluation parameters such as weight variation, thickness, folding endurance, drug content, percentage moisture absorption, percentage moisture loss and diffusion studies. All the parameters showed by the formulations were within the limits. The transdermal drug delivery system K1 (HPMC K 15 M alone) showed the drug release (95.16±1.534), but lasts only for 8 hrs. The transdermal drug delivery system K2 (EC alone) showed lowest drug release but successfully prolonged the release. Thus, formulations K3 to K10 were developed using different ratios of HPMC K 15 M and EC, in order to achieve better release along with sustained action. All the formulations carried Dibutyl Phthalate as plasticizer and Dimethyl sulfoxide as permeation enhancer. The formulation K10 containing HPMC K 15 M: EC (400:400mg) showed better release (97.36±1.089) for sufficiently long period, up to 24 hrs and emerged as ideal formulation for metoprolol succinate. From this studies improving patient compliance of metoprolol succinate by development of transdermal Drug delivery system using HPMC K 15 M and Ethyl cellulose. REFERENCES Ansari Khushbu, SinghaiAkhlesh Kumar, SaraogiGaurav Kant, PatilSwaraj, Transdermal Drug Delivery of Salbutamol Sulphate with Different Concentration of Polymers, International journal of research in pharmacy and science, 1(3), 2011, Darshan G. Trivedi, Hiren J. Patel, Anand K, Bhandari, Dushyant A Shah, Preparation and evaluation of transdermal patch ofdesloratadine, IJBR, 2(6), 2011, Himansu Bhusan Samal, Suddhasattya Dey, Itishree Jogamaya Das, Development and characterization of transdermal patches of metoprolol Succinate, Journal of Pharmacy Research, 4 (6), 2011, J.R.D.Gupta, R.Irchiayya, N.Garud. Formulation and evaluation of matrix type transdermal patches of Glibenclamide. International Journal of Pharmaceutical Sciences Development and Research, 1(1), 2009, Putta Rajesh Kumar, Rajesh Tatavarthi, Mallikarjuna gouda M, SomashekarShyale, S.M.Shanta Kumar, preparation of monolithic transdermal drug delivery system for arthritis treatment and effect of permeation enhancers on release kinetics, International Journal of Pharmaceutical Sciences Review and Research, 6(2), 2011, Shivakumar H R, vishwanathbhat, Sheshapparai K, ganeshsanjeev, Bhavyab B, Influence of blending of chitosan and pullulan on their drug release behavior: an in-vitro study. International Journal of Pharmacy and Pharmaceutical Sciences, 4(3), 2012, Suvakanta Dash, Kinetic modeling on drug release from controlled drug delivery systems drug research, 67(3), 2010, IJRPB 1(5) September October 2013 Page 634