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Transdermal drug delivery system TDDS was designed to sustain the release and improve the bioavailability of drug and patient compliance. Among the various types of transdermal patches, matrix dispersion type systems disperse the drug in the solvent along with the polymers and solvent is allowed to evaporate forming a homogeneous drug-polymer matrix. The objective of the present study was to design and formulate TDDS of topiramate TPM and to evaluate their extended release in vitro and ex vivo.
In the present study, an attempt has been made to develop a matrix-type transdermal therapeutic system comprising TPM with different ratios of hydrophilic and hydrophobic polymeric combinations using solvent casting technique.
The physicochemical compatibility of the drug and the polymers was studied by Fourier transform infrared spectroscopy. The results obtained showed no physical-chemical incompatibility between the drug and the polymers. The patches were further subjected to various physical evaluations along with the ex vivo permeation studies using pig ear skin. On the basis of results obtained from the physical evaluation and ex vivo studies the patches containing the polymers, that is, Eudragit L and polyvinylpyrrolidone, with oleic acid as the penetration enhancer were considered as the best formulations for the transdermal delivery of TPM.
Transdermal drug delivery system TDDS is a widely accepted means of drug delivery, and transdermal patches are devised to treat various diseases. They can even avoid gastrointestinal problems associated with drugs and low absorption. Sulfoxides- dimethyl sulfoxide,[ 5 ] azone,[ 6 ] pyrrolidines-N-methylpyrrolidone,[ 7 ] fatty acids lauric acid, capric acid, myristic acid, oleic acid,[ 8 ] terpenes and essential oils-menthol, eugenol,[ 9 ] oxazolidinonesdecyloxazolidinone,[ 10 ] surfactants - tween 80, span 20[ 11 ] are the various classes of penetration enhancers used in TDDS.
Nicotine patches were the first transdermal success raising the market value of TDDS in medicine to newer heights. Estradiol, fentanyl, testosterone, lidocaine, and some other drug combinations are the TDDS available in the present pharma market. Combination drugs such as theophylline-salbutamol sulfate,[ 17 ] and ketoprofen fumarate-salbutamol sulfate[ 18 ] TDDS were also formulated and evaluated in vitro.
Topiramate TPM is a novel antiepileptic drug derived from the naturally occurring monosaccharide D-fructose. It is not structurally related to other antiepileptic drugs and was originally synthesized as the part of a search for fructose-related compounds with hypoglycemic activity.
Polyvinyl alcohol was purchased from Himedia, Mumbai. Polyvinylpyrrolidine, cellulose acetate phthalate CAP , carbopol , tween 80, chloroform, dichloromethane were purchased from Accord labs, Secunderabad.
All chemicals and reagents used in the present study were of analytical reagent grade AR grade. Before formulating the drug substance into a transdermal patch dosage form , preformulation studies were carried out to establish the physicochemical characteristics of a drug TPM and its compatibility with different excipients.
Compatibility study of drug with the excipients was determined by Fourier transform infrared FTIR spectroscopy Shimadzu Wavelength maximum of TPM was found to be Aliquotes of standard drug solution ranging from 1 to 8 ml were transferred into 10 ml volumetric flask and were diluted up to the mark with phosphate buffer pH 7. The absorbance of each solution was measured at A plot of concentrations of the drug versus absorbance was plotted.
The linear regression analysis was applied. A weighed amount of PVA 2. Backing membrane was used as a support for drug-polymer matrix. The polymers in different ratios as given in Table 1 were dissolved in the respective solvents. Then, the drug was added slowly in the polymeric solution and stirred with the help of magnetic stirrer to obtain a uniform solution. Propylene glycol PG was used as a plasticizer. Oleic acid and tween 80 were used as the penetration enhancer.
All the prepared formulations were subjected for preliminary screening to check the effect of various polymer combinations.
Microscopic pictures of all the formulations were observed using an electronic microscope with digital camera to determine the surface of the films formed and uniform dispersion of drug and polymer. In addition to microscopic study, transdermal patches were evaluated for their physicochemical characteristics.
The thickness of the prepared transdermal films was measured by screw gauge with least count at five different sites, and the average was calculated with an SD.
The folding endurance of patches was determined by repeatedly folding a strip of film at the same place till it tends to break. It is determined as the number of times the film is folded at the same place either to break the film or to develop visible cracks. The patches were subjected to weight variation by individually weighing ten selected patches randomly and the average was calculated.
Each patch from different formulations patch size of 1 cm 2 , equivalent to 25 mg of drug was dissolved in phosphate buffer pH 7. In vitro drug release studies were carried out using the paddle over disc method. The plate was then placed in a mL phosphate buffer pH 7.
The paddle was then set at a distance of 2. The experiment was performed in triplicate, and the mean value was calculated. Based on physicochemical characterization and drug release patterns, F17, F9, and F5 formulations were selected to which permeation enhancers like oleic acid and tween 80 were incorporated, and resultant new formulations with permeation enhancers were labeled from F26 to F31 and details were given in Table 2.
For all six formulations, ex vivo diffusion studies were performed using pig ear skin. Composition of formulations of transdermal patches of topiramate with permeation enhancers. An in vitro permeation study was carried out by using Franz diffusion cell. The skin samples were washed with phosphate buffer pH 7.
The prepared skin was mounted between donor and recipient compartments of diffusion cell. Then the formulated patches were positioned over the skin by placing the patch on the stratum corneum side of the skin toward the donor compartment, and dermis side was facing toward receptor compartment. The receptor compartment of the diffusion cell was filled with phosphate buffer pH 7.
Drug release kinetics were analyzed by various mathematical models such as a zero-order and first-order kinetic models; Higuchi and Korsmeyer—Peppas models to ascertain the kinetics of drug release. Where Q is the amount of the drug dissolved in time t , Q is the initial amount of drug in the solution most times, Q 50 and K is the zero order release constant. Where Q t is the amount of drug released in time t , Q 0 is the initial amount of drug in the solution and K is the first order release constant.
Where Q t is the amount of drug released in time t , K H is release rate constants. The model independent mathematical approach proposed by Moore and Flanner for calculating a similarity factor f 2 was used as a basis for comparison between dissolution profiles of different samples. The release profiles are considered to be similar when f 2 is between 50 and The release profile of products was compared using an f 2 which is calculated from following formula.
Where n is the release time and R t and T t are the reference and test value at time t. Transdermal patches of TPM were prepared by matrix type solvent casting method to achieve a controlled release, improved bioavailability of the therapeutic drug and to reduce the toxicity. This is the first report on transdermal drug delivery of TPM and found to be effective compared to previously reported dosage forms of TPM.
Calibration curve of TPM was constructed and found to be leniar and microscopic pictures of formulations with different polymers were compared. However, above-mentioned parameters were also studied for optimized formulations with permeation enhancers, but no significant change was found in these parameters with permeation enhancers. The release characteristics of all prepared formulations were studied in vitro and compared.
Based on these results, F17, F9, and F5 were taken as optimized formulations. The in vitro release data of F17, F9, and F5 formulations was fitted well into the zero order and first order equations. Korsmeyer-Peppas and highuchi models were also applied to test the release mechanism, and results are shown in Table 4. T 50 and T 90 of transdermal formulations of TPM without permeation enhancers were calculated from respective graphs.
Comparative drug release profiles of transdermal drug delivery system with Eudragit L Comparative drug release profiles of transdermal drug delivery system with ethylcellulose. Comparative drug release profiles of transdermal drug delivery system with cellulose acetate phthalate.
T 50 and T 90 of transdermal formulations of TPM with permeation enhancers were calculated from respective graphs. Comparative drug permeation profiles of transdermal drug delivery system without permeation enhancer. Comparative drug permeation profiles of transdermal drug delivery system with oleic acid.
Comparative drug permeation profiles of transdermal drug delivery system with tween The microscopic pictures of TPM were revealed that the formulations prepared from ethylcellulose and carbopol were observed to be nonuniform in drug distribution. In microscopic pictures of formulations prepared from CAP, surface morphology was good in lower concentrations.
Transdermal patches prepared from Eudragit L and PVP were found to have the uniform surface morphology from lower to higher ratios of the polymer, indicating that the drug was uniformly distributed all over the patch. The prepared formulations with different polymer concentrations were smooth, opaque, flexible and uniform. The thickness of the films varied from 0. From these values, it was observed that the thickness of the polymer depends on the solubility and concentration of the polymer.
As the solubility decreases and concentration increases would increase the thickness of the patch. It infers that usage of the competent polymer is the prerequisite step to prepare a patch of optimum thickness, which can retard the release of drug from the patch. Weight variation of all the formulations varied from 0.
Low SD values in the film ensure uniformity of the patches prepared by solvent casting technique. The formulations prepared with Eudragit L was found to have the highest value of folding endurance and formulations made of CAP, PVP and carbopol respectively were found to have the lowest value of folding endurance. The drug content of all the formulations was in the range of Drug release studies are required for predicting the reproducibility of the rate and duration of drug release.
The importance of polymer dissolution on drug release from matrices has been known for ensuring the sustained release performance. The cumulative percent of drug release in 12 h was noted. The drug release was found to increase with the increasing concentration of hydrophilic polymer in the polymer matrix.
This is due to the fact that dissolution of an aqueous soluble fraction of the polymer matrix leads to the formation of gelataneous pores.
The formulation of such pores leads to decreasing mean diffusion path length of drug molecules to release into the diffusion medium and hence, to cause higher release rate. The in vitro release data of the formulations F5, F12, F14, F15, F18, F19, F21, F23 were best fitted into peppas model having the maximum r 2 values of 0. All the remaining formulations were following the zero order model as the best fit model.
Hence, zero order was found to be the best fit model for TPM release from formulations. From this, we can infer that concentration of the HPMC polymer plays a key role in drug release kinetics with a permeation enhancer.
The results of ex vivo drug permeation studies were compared for optimized formulations with and without permeation enhancers.
Formulation and evaluation of transdermal drug delivery of topiramate.
Formulation and evaluation of transdermal drug delivery of topiramate
Transdermal patch of Repaglinide was prepared to sustain the release and improve bioavailability of drug and patient compliance. In vitro release data were fitted to various models to ascertain kinetic of drug release. Regression analysis and analysis of variance were performed for dependent variables. The results of the F2 statistics between factorial design batches and theoretical profile were used to select optimized batch. Transdermal drug delivery system TDDS has been an increased interest in the drug administration via the skin for both local therapeutic effects on diseased skin topical delivery as well as for systemic delivery of drugs. The skin as a site of drug delivery has a number of significant advantages over many other routes of drug administration, including the ability to avoid problems of gastric irritation, pH and emptying rate effects, avoid hepatic first-pass metabolism thereby increasing the bioavailability of drug, reduce the risk of systemic side effects by minimizing plasma concentrations compared to oral therapy, provide a sustained release of drug at the site of application; rapid termination of therapy by removal of the device or formulation, the reduction of fluctuations in plasma levels of drugs, and avoid pain associated with injections.
Formulation and Evaluation of Transdermal Patch of Repaglinide
Matrix type transdermal drug delivery system TDDS of Pregabalin was prepared by the solvent evaporation technique. Propylene glycol was used as plasticizer and DMSO was incorporated as a permeation enhancer. Formulated transdermal patches were charachterised for their physicochemical parameters like thickness, weight variation, flatness, tensile strength, folding endurance, moisture content, moisture uptake and drug content uniformity. Patches were evaluated for their in-vitro drug release profile and ex-vivo skin permeation studies. Patches were also subjected to stability studies and skin irritation studies to determine their compatibility with skin.