CONTROLLED RELEASE FORMULATION AND CHARACTERIZATION OF CARVEDILOL TRANSDERMAL FILM
U.D. Shivhare*, V.P. Dorlikar, B.N. Mirani, V.B. Mathur, K.P.Bhusari
*Sharad Pawar College of Pharmacy, Wanadongri, Hingna Road,
Transdermal films of carvedilol were prepared using Eudragit RL 100 (ERL) and ERL in combination with Eudragit RS 100 (ERS), Hydroxypropyl methyl cellulose (HPMC) and Ethyl cellulose (EC) in different proportion. Characterisation of polymeric films were performed by evaluating the factors like moisture absorption (MA), moisture loss (ML), moisture content (MC), folding endurance, film thickness, mass variation, water vapour transmission rate (WVTR) and drug content. Drug release kinetics and drug diffusion kinetics showed that the formulation A5 containing ERL:ERS:HPMC:EC in the ratio of 6.5:1.25:1.25:1.25 followed the drug release mechanism governed by Peppas model while the drug diffusion rate followed zero order kinetics.
Carvedilol is widely used for the therapeutic management of hypertension, congestive heart failure. It is a drug of choice for hypertension but it has several drawbacks such as short biological half-life of about 2-8 hours, it is readily metabolized in liver primarily by cytochrome P 450 isoenzyme, CYP 206 and CYP209 and has oral bioavailability as 30%. These factors in addition to its low molecular weight (406.05) and low melting point (117o) necessitate the formulation of sustained release transdermal drug delivery system for carvedilol,.
Water soluble polymer like hydroxypropyl methylcellulose (HPMC) and water insoluble polymers like Eudragit RL 100 (ERL ), Eudragit RS 100 (ERS ), and ethyl cellulose (EC), were selected as carriers in which the drug was incorporated to form matrix transdermal films. The films were evaluated for their physicochemical properties like effect of polymer ratios on patch flatness, thickness, water vapour transmission rate (WVTR), percentage moisture loss (ML), percentage moisture absorption (MA), percentage moisture content (MC), drug content, folding endurance. In-vitro drug release and drug permeation studies using artificial permeation membrane were performed ( Arora P. et al, 2002 ).
MATERIAL AND METHODS
Carvedilol was obtained as a gift sample from Cipla Ltd., Patalganga. Eudragit RL 100 (15 cps) and Eudragit RS 100 (15 cps) were procured from Rohm Pharma, West Germany . ERL and ERS are copolymers of acrylic and methacrylic acid esters containing 10 and 5% trimethylammonium methacrylate chloride, respectively. HPMC (K 15 LV) and EC (20 cps) were purchased from SD fine chemicals. All the other chemicals, reagents and solvents used were of AR grade.
Preparation of the transdermal films
The matrix-type transdermal patches containing carvedilol were prepared using ERL and different ratios of ERS, HPMC and EC. The polymers in selected ratios were weighted (300 mg) and dissolved in ethanol. Carvedilol (13 mg), was added slowly to the polymer solution and mixed thoroughly to obtain a uniform solution. Di-n-butyl phthalate (60 mg), and Di-methyl sulfoxide (60 mg) were incorporated as plasticizer and penetration enhancer respectively.
Table 1: Polymeric ratio used in the preparation of transdermal film
The polymeric solution of drug was poured onto the mercury surface and dried at room temperature in a dust-free environment. After 24 h the films were cut into a 5cm2 piece and a backing membrane of Scotch pack 9742 (3M) was glued on. The transdermal films were stored in a dessicator until further use.
Drug -partition coefficient
The partition coefficient study was performed using n-octanol as the oil phase and phosphate buffer pH 6.8 as the aqueous phase.
Investigation of physicochemical compatibility of drug and polymer
The physicochemical compatibility between carvedilol and polymers used in the patches was studied by using thin layer chromatography; differential scanning calorimetric and Fourier transform infrared spectroscopy.
Evaluation of Polymeric Films
1. Percentage moisture absorption (MA)
The films were weighed accurately and placed in the dessicator containing 100 ml of saturated solution of potassium chloride, which maintains 79.50% RH. After 3 days, the films were taken out and weighed. The percentage moisture absorption was calculated using the formula
Percentage moisture absorption=
2. Percentage moisture loss (ML)
The films were weighed accurately and kept in a dessicator containing anhydrous calcium chloride. After 3 days, the films were taken out and weighed. (Bhalla H L. et al, 1986 ) The moisture loss was calculated using the formula
Percentage moisture loss=
3. Moisture content (MC)
The prepared films were marked, then weighed individually and kept in a dessicator containing activated silica at room temperature for 24 h. The films were weighed again and again individually until they showed the constant weight. The percentage of moisture content was calculated using the formula
Percentage of moisture content =
4. Folding endurance
This was determined by repeatedly folding the film at the same place until it broke. The number of times the film could be folded at the same place without breaking/cracking gave the value of folding endurance.
The thickness of film was measured at 3 different points by using Electrometer.
6. Mass variation
The films were subjected to mass variation by individually weighing 5 randomly selected films. Such determinations were carried out for each formulation ( Dehgan G R. et al, 1993 ).
7. Water vapour transmission rate (WVTR)
Glass vials of equal diameter were used as transmission cells. These transmission cells were washed thoroughly and dried in an oven. About 1g anhydrous calcium chloride was placed in the cells and the respective polymer film was fixed over the brim. The cells were accurately weighed and kept in a closed dessicator containing saturated solution of potassium chloride to maintain a humidity of 84%. The cells were taken out and weighed after 12, 24 h of storage.
The amount of water vapours transmitted was found using the formula:
Water vapours transmission rate=
8. Drug content
A film was cut into 4 quadrants and put in a 100 ml buffer (pH 6.8).This was then shaken on a mechanical shaker for 24 h to get a homogeneous solution and filtered. The drug was determined spectroscopically at 240 nm after suitable dilution.
In-vitro drug release (Dissolution studies)
A modified stainless steel disc assembly (USP Apparatus 5, paddle over disc assembly), was used for the assessment of the release of the drug from the patches. The transdermal drug delivery system (TDDS) was mounted on the disc and placed at the bottom of the dissolution vessel. The dissolution medium was pH 6.8 and the apparatus was equilibrated to 32 ± 0.5o. The apparatus was operated at 100 rpm and samples were withdrawn at appropriate time intervals up to 24 h and analysed at 240 nm spectrophotometrically. Cumulative % drug release were calculated and plotted against time.( Costa P. et al, 2001 )
In-vitro permeation studies
The permeation studies were performed in a modified Keshary-Chien cell of capacity 15 mL. using cellophane membrane. The cellophane membrane was activated in phosphate buffer pH 6.8 by boiling in it followed by keeping in it for overnight. A section of membrane was cut, measured, and placed on the dermal side of the membrane in the donor compartment facing the drug matrix side of the patch to the membrane and backing membrane upward. The holder containing the membrane and formulation was then placed on the receiver compartment of the modified diffusion cell, containing phosphate buffer pH 6.8. The donor and receiver compartment were kept in an intimate contact by wrapping paraffin at the junction. The temperature of the diffusion cell was maintained at 320.
This whole assembly was kept on a magnetic stirrer and solution in the receiver compartment was constantly and continuously stirred during the whole experiment using magnetic bead. The samples were withdrawn (1 mL) at different time intervals and an equal amount of phosphate buffer, pH 6.8, was replaced each time. Absorbance of the samples were read spectrophotometrically at 240 nm taking phosphate buffer solution, pH 6.8, as blank. The amount of drug permeated per square centimetre at each time interval was calculated and plotted against time. Release-rate constants for different formulations were also determined.( Chandrashekhar N S. et al, 2005 )
Scanning Electron Microscopy Study (SEM)
The external morphology of the transdermal patches before and after the application were analyzed using Scanning Electron Microscopy. (JSM 6380 JEOL, Tokyo, Japan).
RESULTS AND DISCUSSIONS
The logarithmic value of the partition coefficient of carvedilol (log P) was found to be 2.79 ± 0.03.
The data obtained from TLC and IR studies suggested that there was no interaction between the drug and the excipients because in TLC Rf values of drug in all the cases were same, while the drug peaks in IR remained unchanged.
The DSC analysis of pure carvedilol showed a sharp endothermal peak at 117.48 o, corresponding to the drug’s melting point .The DSC analysis of the formulations revealed a negligible change in the melting point of carvedilol.
Fig.1: DSC thermograms of carvedilol and the physical mixtures
The transdermal film A1 showed maximum MC which can be attributed to hydrophilicity of ERL, while the film A7 showed the least MA, MC and WVTR due to the presence of EC in high quantity. The formulation A8 showed the least ML. The thickness of the patches varied from 28 to 48 μ due to the different percentage of cellulose esters. Mass variation study was varied between the ranges 329-360 mg. Appearance and flatness studies showed that the formulation A4, A5, A7 and A8 were hazy appearances while others were transparent because of the presence of only acrylate polymers. Folding endurance study indicated A2 formulation (19±0.8165) having highest folding endurance.
The study of drug release kinetics showed that majority of the formulations governed by Peppas model and mechanism of release was Fickian mediated, while others followed zero order release equation. Regression analysis of the in-vitro permeation curves was carried out. The slope of the curve obtained after plotting the mean cumulative amount released per patch vs. time was taken as the in-vitro release for carvedilol. All the formulations showed release upto 24 h and above 90% of drug released from each formulation. Formulation A3 showed maximum release as 99.01% while formulation A5 as 98.33%. Formulation A5 has highest zero order rate constant i.e. (k Value= 37.0596) and follows zero order rate release and mechanism of release was Fickian mediated.
The majority of the formulations governed by zero order equation and mechanism of release was anomalous mediated for the formulations A1, A2, A3, A4 and A6 while others followed Peppas model. Regression analysis of the in-vitro permeation curves was carried out.
Surface morphology of the transdermal patches before and after the in-vitro drug release study was scanned using a scanning electron microscope. Fig.2 depicts how the polymer–matrix behaves after the release of drug molecules, it also indicates that the formulation maintains the elastic nature of the film even after the release of drug.
Fig. 2: SEM photograph of the transdermal film
showing the patch behaviour after the release
The log P value of drug indicate that the drug possesses sufficient lipophilicity, which meets the requirements of formulating it into a transdermal patch. The DSC, IR and TLC results suggest that the drug and polymers are compatible with each other.
Formulation A5 has showed maximum release and highest zero order rate constant i.e. (k Value= 11.8113) and followed Peppas model and mechanism of release was Fickian mediated. Hence, the formulation A5 comprising of ERL, ERS, EC and HPMC in the ratio of 6.5:1.25:1.25:1.25 ratio fulfills the requirement of good TDDS.
Authors are grateful to Cipla Ltd. Patalganga, Raigad for providing Carvedilol, Rohm Pharma, West Germany for providing Eudragit RL 100 (15 cps) and Eudragit RS 100 (15 cps) as a gift sample.
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Copyright © Priory Lodge Education Limited 2009
First Published January 2009