Design, Development and In vitro Evaluation of Transdermal Patches containing Domperidone Maleate

Irfan Newaz Khan, Md Abdul Motaleb Bhuiya, Kishor Mazumder, Neher Sultana Sherin1, Md Akbar Hossain1 and Md Hassan Kawsar1* Department of Pharmacy, University of Science & Technology, Chittagong
1

Department of Pharmacy, Dhaka International University

*Author for correspondence: Md Hassan Kawsar, hassankawsar@yahoo.com

Abstract
Three matrix type transdermal drug delivery systems (TDDS) of Domperidone Maleate were formulated using blends of three different polymeric combinations of polyvinylpyrrolidone (PVP) and ethylcellulose (EC). No signicant interaction founded in TLC between the drug and polymers used and the SEM photographs also demonstrated this. In vitro dissolution studies showed that the drug distribution in the matrix was homogeneous. It was observed that as the concentration of the hydrophilic polymer PVP increased in the formulation, the rate of dissolution increased subsequently and the best result found for the polymer ratio 3:5. From the study of release mechanism, the higuchi plot showed reasonably straight line with high correlation coefficient. Hence, it can be concluded that Domperidone Maleate can be formulated into the transdermal matrix type patches to sustain its release characteristics and the polymeric composition of PVP and EC was 3:5 found to be the best choice for manufacturing transdermal patches of Domperidone Maleate among the formulations studied.

Introduction
There is a constant need for methods of preparation for the safe and effective administration of physiologically active agents, such as anti-emetics (Domperidone Maleate). For many medications it is important that the administration regime is as simple and non-invasive as possible in order to maintain a high level of compliance by a patient. Oral administration is one administration regime that is commonly used because it is a relatively simple regime to follow. However, the oral administration route is also complicated because of complications associated with gastrointestinal irritation, drug metabolism in the liver and is often impractical if a patient is vomiting or nauseous. Domperidone is a benzimidazole derivative that acts peripherally by dopamine blockade. Domperidone has been approved for the symptomatic management of upper gastrointestinal tract motility disorders associated with chronic and subacute gastritis and diabetic gastroparesis. It may also be used to prevent gastrointestinal symptoms associated with the use of dopamine agonist agents in Parkinson's disease (1). Domperidone is absorbed orally, but bioavailibility is only ~15% due to first pass metabolism (2). This originates the need of an alternative route of administration, which can bypass the first pass metabolism. Transdermal route is an alternative choice of route of administration for such drugs. The drug Domperidone Maleate also possesses the ideal characteristics such as poor bioavailability (~15%), short biological half-life (7.5 h), smaller dose (1040 mg), etc., to be formulated into a transdermal patch. Transdermal patches offer added advantages such as maintenance of constant and prolonged drug level, reduced frequency of dosing, minimization of inter- and intra-patient variability, self administration, and easy termination of medication, leading to patient compliance (3). The aim of the present work was to develop a transdermal matrix patche with varied ratios of polyvinylpyrrolidone (PVP) and ethylcellulose (EC), containing the drug Domperidone Maleate and to study the drug excipients interaction and in vitro release kinetics of the prepared patches. The purpose was to provide the delivery of drug at a controlled rate across intact skin to achieve a therapeutically effective drug level for a longer period of time from transdermal patches An attempt was made to establish the best possible combination of polymeric ratio of formulated transdermal patches with maximum controlled and sustained drug release capability as well as physical stability.

Materials used
Domperidone Maleate (BASF), Ethyl Cellulose (Merck KGaA, Germany), Polyvinylpyrrilidone (Kollidon VA 64, BASF), Di-n-Butyl Pthalate (Merck Limited, Mumbai), Plovinyl alcohol (E. Merck, England), Choloform (E. Merck, England), Menthol (Local source), Aluminium Foil (Local source).

Methods
Preparation of Domperidone Maleate Transdermal Patch: Matrix type transdermal patches containing Domperidone maleate were prepared using the three different ratios of PVP and EC by solvent evaporation technique in cylindrical both sides open glass molds. The ratios are as follows: Formulation Code PVP: EC F1 1:2 F2 1:3 F3 3:5 The bottom of the mold was wrapped with aluminum foil on which the backing membrane was cast by pouring 4% w/v Plovinyl alcohol (PVA) solution followed by drying at 60C for 6 h. The two polymers were weighted in requisite ratio and they were then dissolved in chloroform. Di-n-butyl-pthalate 30% w/w of polymer composition was used as a plasticizer. The drug was added to the 20% w/w of the total weight of polymers, in the homogeneous dispersion, by vortexing. The matrix was prepared by pouring the homogeneous dispersion of drug with different blends of either type of lipophilic polymer (EC or Eudragit) with PVP in chloroform on the backing membrane in glass moulds. The above dispersion was evaporated slowly at 40C for 6 h to achieve a drugpolymer matrix patch. The dry patches were kept in desiccators until use (4). DrugExcipients Interaction Study: The drugexcipients interaction study was performed using silica gelcoated TLC (Thin Layer Chromatography) plates and a mixture of one volume of hydrochloric acid, one volume of water, six volumes of glacial acetic acid, and 11 volumes of ethylacetate as a mobile phase (5). Scanning Electron Microscopy: The external morphology of the transdermal patches was analyzed using a scanning electron microscope (S3400N Hitachi, High-tech Science

System). The samples placed on the stubs were coated finely with gold palladium alloy and examined under the microscope. In-vitro Release Dissolution Studies: The release-rate determinations are one of the most important studies to be conducted for all controlled-release delivery systems. The dissolution studies of patches are very crucial, because one needs to maintain the drug concentration on the surface of stratum corneum consistently and substantially greater than the drug concentration in the body, to achieve a constant rate of drug permeation (6). The dissolution of patches was performed using USP basket type dissolution apparatus. The patches were placed in respective baskets with their drug matrix exposed to phosphate buffer, pH 7.4. All dissolution studies were performed at 320C, at 50 rpm, with each dissolution jar carrying 900ml of buffer. Samples were withdrawn at different time intervals and analyzed using a UV spectrophotometer at 280 nm against blank. The amount of drug released was calculated from previously prepared standard Domperidone maleate calibration curve. Cumulative amounts of drug released was plotted against time for different formulations (7).

Results and Discussions

DrugExcipient Interaction Studies: TLC studies were performed to assess any interaction between the drug and the excipients. The data obtained suggested that there was no interaction between the drug and the excipients because the Rf values of both the drug and the drugexcipient solutions were nearly similar (Table 1). Table 1: Determination of Drug-Excipient Interaction using the TLC method Formulation Code DPT 1 DPT 2 DPT 3 PVP/EC Drug 1:2 1:3 3:5 0.709 0.793 0.794 Rf Value DrugExcipient 0.756 0.793 0.828

Scanning Electron Microscopy: The surface morphology and distribution of the transdermal patches was scanned using a Scanning Electron Microscope (S-3400N, Hitachi High-Technologies Europe GmbH, Germany) (Figure 1 3). From these figures it can be concluded that the formulation containing PVP and EC ratio 3:5 shows the comparatively uniform distribution of drugs in the polymer matrix.

Figure 1: SEM photograph of Domperidone maleate matrix patch containing the polymer PVP & EC (1:2)

Figure 2: SEM photograph of Domperidone maleate matrix patch containing the polymer PVP & EC (1:3)

Figure 3: SEM photograph of Domperidone maleate matrix patch containing the polymer PVP & EC (3:5) In-Vitro Dissolution Studies: Dissolution studies are important for ensuring the sustained release performance and the reproducibility of rate and duration of drug release. It was observed from the study that as the concentration of hydrophilic polymer, PVP, increased in the formulations, the rate of dissolution increased subsequently and the best result found in the polymer ratio 3:5. The results are shown in Figure 4.
F1
100 90 80 % Drug Release 70 60 50 40 30 20 10 0 0 60 120 180 240 300 360 420 480 540 600 660 720 Time(mimutes)

F2

F3

Figure 4: In-vitro dissolution profiles of Domperidone maleate containing different matrix prepared by using different ratios of PVP & EC with menthol at pH 7.4. Data shows mean SE (n = 3)

Release Kinetics Study: The release kinetics was also studied to identify the best possible release mechanism of the drug. In figure 5, the percentage of Domperidone Maleate was plotted against time to get the zero order plots. In addition the percentage of release was plotted against Square Root of Time in Minutes to get higuchi plot. Again the log remaining was plotted against time in figure 6 to get the first order plot. The higuchi plot showed reasonably straight line with high correlation coefficient.
90 80 70 60 50 40 30 20 10 0 -10 0 5 10 15 20 25 30
F1 F2 F3

Figure 5: Higuchi plot for release profiles of Domperidone maleate containing different matrix films prepared by using different ratios of PVP & EC with menthol at pH 7.4. Data shows mean SE (n = 3)
2.5 2 1.5
F1 F2 F3

1 0.5 0 0 200 400 600 800

Figure 6: First order plot for release profiles of Domperidone maleate containing different matrix films prepared by using different ratios of PVP & EC with menthol at pH 7.4. Data shows mean SE (n = 3)

Conclusion
In this study, the prepared matrix type transdermal patches containing Domperidone Maleate were studied using different ratio of polyvinylpyrrilidone (PVP) and ethylcellulose (EC) by solvent evaporation technique. The drug matrix film of PVP and EC was casted on a polyvinyl alcohol (PVA) backing membrane and it was observed that as the concentration of hydrophilic polymer PVP increased in the formulations, the rate of dissolution increased subsequently and the best result found for polymer ratio 3: 5. The release kinetics was also studies to identify the best possible release mechanism of the drug and the Higuchi plot showed reasonably straight line with high correlation coefficient Finally from the study it was found that Domperidone Maleate could be given as Transdermal Patch with polymeric combination of PVP & EC preferably the 3:5 ratio.

References
1. Domperidone (Motilium) Tablets (product monogr), Janssen Pharmaceutica, Mississauga, Ont, 1985 2. Essentials of Medical Pharmacology, KD Tripathi, Jaypee, 4th Edition; Page No. 650 3. Polymer matrix consideration for transdermal devices. Keith AD. 1983. Drug Dev Ind Pharm 9:605621. 4. P. Arora, B. Mukherjee, Design, development, physicochemical and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt, J. Pharm. Sci. 91 (2002) 20762089. (Procedure of manufac) 5. Baichwal RW. 1983. Advances in drug delivery systems. Bombay: MSR Foundation, pp 136147. 6. Devi K, Paranjothy KLK. 1999. Pharmacokinetic prole of a new matrix type transdermal delivery system: Diclofenac diethyl ammonium patch. Drug Dev Ind Pharm 25:695700. 7. Johnson ME, Blankschtein D, Linger R. 1997. Evaluation of solute permeation through the stratum corneum: Lateral bilayer diffusion as the primary transport mechanism. J Pharm Sci 86:11621172.