Repaglinide has the half life of 1 hour, and bioavailability in the body is 56% due to first-pass metabolism. The total daily dose of Repaglinide is 16 mg (e.g., 4 mg four times daily depending on meal patterns); hence, it required frequent dosing. Transdermal patch of Repaglinide was prepared to sustain the release and improve bioavailability of drug and patient compliance. Different formulations were prepared by varying the grades of HPMC and concentration of PVP K30 by solvent casting method. The prepared formulations were evaluated for various parameters like thickness, tensile strength, folding endurance,% elongation,% moisture content,% moisture uptake,% drug content, in vitro drug release, in vitro permeation, and drug excipient compatibility.
On the application of Transdermal patches, the delivery of the drug across dermis gives the systemic effect. Paracetamol is widely used as Antipyretics as well as mildly Analgesics. In this study Transdermal patches were prepared by Mercury Substrate Method using ethyl cellulose polymer and Poly Vinyl Pyrrolidone (PVP) was used as a plasticizer. International Scholarly Research Notices is a peer-reviewed. Formulation and Evaluation of Transdermal Patch of Repaglinide. Preparation of Transdermal Patch. 44 Transdermal patch for severe painA transdermal analgesic or painrelief patch is a medicatedadhesive patch used to relieveminor to severe pain. There aretwo primary types of analgesicpatches: patches containingcounterirritants, which are usedto treat mild to moderate pain,and patches containing fentanyl,a narcotic used to relievemoderate to severe pain inopioid-tolerant patients.
A 3 2 full factorial design was applied to check the effect of varying the grades of HPMC ( X 1) and PVP concentration ( X 2) on the responses, that is, tensile strength, percentage drug released in 1 hr ( Q 1), 9 hr ( Q 9), and diffusion coefficient as a dependent variables. 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. Batch F6 was considered optimum batch which contained HPMC K100 and PVP (1.5%), showed release 92.343% up to 12 hr, and was more similar to the theoretical predicted dissolution profile ( f 2 = 69.187).
IntroductionTransdermal 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. MaterialsRepaglinide was received as a gift sample from Torrent Pharmaceutical Ltd., Gujarat, India. HPMC K4M, HPMC K100, and HPMC E15 LV were purchased from Yarrow Chem, Mumbai, India. PVP K30 was obtained from SD fine—Chem. Polyethylene glycol 400 and propylene glycol were obtained from Merck Specialities Private Ltd. (Mumbai) and Chemdyes Corporation (Ahmedabad, Gujarat) respectively.
Cellulose acetate membrane was obtained from Sartorius Biotech GmbH (Germany). All other materials and chemicals used were of either pharmaceutical or analytical grade. Preparation of Transdermal PatchDrug-loaded matrix-type transdermal patches of Repaglinide were prepared by using solvent casting method. A petri dish with a total area of 44.15 cm 2 was used. Polymers were accurately weighed and dissolved in 10 mL of water, methanol (1: 1) solution and kept aside to form clear solution. Drug was dissolved in the above solution and mixed until clear solution was obtained. Polyethylene glycol 400 (30% w/w of total polymer) was used as plasticizer and propylene glycol (15% w/w of total polymer) was used as permeation enhancer.
The resulted uniform solution was cast on the petri dish, which was lubricated with glycerin and dried at room temperature for 24 h. An inverted funnel was placed over the petri dish to prevent fast evaporation of the solvent.
After 24 h, the dried patches were taken out and stored in a desiccator for further studies. Optimization of Variables Using Full Factorial DesignA 3 2-randomized full factorial design was used in the present study. In this design, 2 independent factors were evaluated, each at 3 levels, and experimental trials were performed for all 9 possible combinations. The different grades of HPMC ( X 1) and concentration of PVP K30% ( X 2) were chosen as independent variables in 3 2 full factorial designs. Tensile strength, cumulative% drug release at 1 h ( Q 1), cumulative% drug release at 9 h ( Q 9), and diffusion coefficient ( n) were taken as dependent variables.
The formulation layout for the factorial design batches (F1 to F9) are shown in. Batch codeX1 (HPMC grade)X2 (% PVP K30 concentration)Y1 (tensile strength kg/cm 2)Y2 ( Q 1)(%)Y3 ( Q 9)(%)Y4 (diffusion coefficient)F1HPMC E15 LV0.50.38.915821.043F2HPMC E15 LV10.46.599491.001F3HPMC E15 LV1.50.63.265310.983F4HPMC K10.3020.665F5HPMC K.9170.746F6HPMC K10.9610.641F7HPMC K4M0.50.58.520410.959F8HPMC K4M10.87.984690.656F9HPMC K4M1.50.97.704080.853. In Vitro Drug Release Studies —In Vitro drug release studies were performed by using a Franz diffusion cell with a receptor compartment capacity of 60 mL. The cellulose acetate membrane was used for the determination of drug from the prepared transdermal matrix-type patches. The cellulose acetate membrane having a pore size 0.45 μ was mounted between the donor and receptor compartment of the diffusion cell. The prepared transdermal film was placed on the cellulose acetate membrane and covered with aluminum foil.
The receptor compartment of the diffusion cell was filled with phosphate buffer pH 7.4. The whole assembly was fixed on a hot plate magnetic stirrer, and the solution in the receptor compartment was constantly and continuously stirred using magnetic beads, and the temperature was maintained at 32 ± 0.5°C, because the normal skin temperature of human is 32°C. The samples were withdrawn at different time intervals and analyzed for drug content spectrophotometrically. The receptor phase was replenished with an equal volume of phosphate buffer at each sample withdrawal. In Vitro Permeation Study —An in vitro permeation study was carried out by using Franz diffusion cell. Full thickness abdominal skin of male Wistar rat weighing 200 to 250 g was used.
Hair from the abdominal region was removed carefully by using an electric clipper; the dermal side of the skin was thoroughly cleaned with distilled water to remove any adhering tissues or blood vessels, equilibrate for an hour in phosphate buffer pH 7.4 before starting the experiment, and was placed on a magnetic stirrer with a small magnetic needle for uniform distribution of the diffusant. The temperature of the cell was maintained at 32 ± 0.5°C using a thermostatically controlled heater. The isolated rat skin piece was mounted between the compartments of the diffusion cell, with the epidermis facing upward into the donor compartment. Sample volume of 5 mL was removed from the receptor compartment at regular intervals, and an equal volume of fresh medium was replaced. Samples were filtered through watman filter and were analyzed using Shimadzu UV 1800 double-beam spectrophotometer (Shimadzu, Kyoto, Japan).
Flux was determined directly as the slope of the curve between the steady-state values of the amount of drug permeated (mg.cm 2) versus time in hours and permeability coefficient was deduced by dividing the flux by the initial drug load (mg.cm 2). Preliminary StudyAll the batches of transdermal patch showed thickness variation range from 0.12 to 0.20 mm as shown in. High thickness of batch P4 and P5 was found, it may be due to low solubility of ethyl cellulose in solvent render uneven distribution of polymer layer. All the batches of transdermal patch showed tensile strength and% elongation in uniform range from 16 to 22 and 17.5 to 22.5, respectively, except batches P4 and P5 may be due to poor solubility of ethyl cellulose and weak bond formation. Hence batches P4 and P5 were eliminated for further study. Batch P1 containing PVA: PVP shows fast release of drug (101.26% at 8 h) from patch due to burst effect of PVP and also more solubility in water.
Edith Cowan University
So batch P1 was also eliminated. Folding Endurance, Tensile Strength,% Elongation and ThicknessThe results of folding endurance, tensile strength,% elongation and thickness of factorial design batches are shown in. The folding endurance values of all the factorial design patches were found satisfactory which indicates that the patches prepared using PEG 400 in a concentration of 30% w/w of polymer were having optimum flexibility and were not brittle. The tensile strength of the patches prepared with HPMC E15 and PVP were found in between 0.38 ± 0.015 kg/cm 2 to 0.63 ± 0.015 kg/cm 2, which were 0.45 ± 0.014 kg/cm 2 to 0.92 ± 0.017 kg/cm 2 for the patches composed of HPMC K100 and were 0.53 ± 0.011 kg/cm 2 to 0.95 ± 0.015 kg/cm 2 for the patches composed of HPMC K4M. It was observed that with the increase of PVP concentrations and HPMC grade, the tensile strength of the patches gradually increased. The% elongation was found to be in the range of 28.95 ± 0.015% to 41.2 ± 0.015%. The formulation F8 showed minimum% elongation among the other entire factorial design batches 28.95 ± 0.015%.
It indicates inverse relation between tensile strength and% elongation. The thickness ranges were 0.12 ± 0.025 to 0.25 ± 0.022 mm. The results showed that the patches were uniform, as it was evidenced by SD value, which were less than 0.01 for all the factorial design batches. No.Batch codeFolding enduranceTensile strength (kg/cm 2) (mean ± S.D.)% Elongation(Mean ± S.D.)Thickness (mm) (mean ± S.D.)% Drug content (mean ± S.D.)f 2 value1F12000.63 ± 0.01537.1 ± 0.0120.25 ± 0.444F42000.45 ± 0.01440.2 ± 0.0130.22 ± 0.1.385F52000.58 ± 0.01539.6 ± 0.0170.15 ± 0.4.756F62000.92 ± 0.01735.8 ± 0.0120.17 ± 0.9.187F72000.53 ± 0.01139.2 ± 0.0130.16 ± 0.6.138F82000.84 ± 0.01728.9 ± 0.0150.13 ± 0.3.099F92000.95 ± 0.01530.1 ± 0.0150.23 ± 0.4.03. Moisture Content, Moisture Uptake, and Drug Content StudiesThe moisture content in the patches ranged from 3.24 ± 0.017 to 4.12 ± 0.015%. The moisture content in the formulations was found to be increased by increase in the concentration of PVP K30 and also with increasing the grade of HPMC. The moisture uptake in the patches ranged from 5.27 ± 0.012 to 7.89 ± 0.019%.
The moisture uptake was found to be higher in batches F7, F8, and F9, which might be due to HPMC K4M. The lower moisture content in the formulations helps them to remain stable and become a completely dried and brittle film. Again, low moisture uptake protects the material from microbial contamination and bulkiness. The drug content ranged from 74.282 to 78.98%. All formulations were acceptable with regard to Repaglinide content. In Vitro Drug Release StudyThe drug release characteristics of the formulation were studied in in vitro conditions by using artificial semipermeable membrane. The formulation F1–F3 has shown release of about 96.83%, 101.057% at 10 h and 98.26% at 9 h, respectively.
This is may be due to low viscosity of HPMC E15 LV polymer which is rapidly soluble than HPMC K4M and HPMC K100. The formulation F4–F9 has shown release of about 70.02%, 88.49%, 92.343%, 68.01%, 69.014%, and 84.804% at 12th hour, respectively. HPMC K4M shows slow release of drug from patch due to matrix formation and also its high viscosity which affect the release while HPMC K100 shows predicted release.
The order of drug release was found to be F2F3F1F6F5F9F4F8F7. The in vitro release data of F1 to F7 formulations fitted well into the Zero order equation, correlation coefficient values were between 0.9869 and 0.9986 while F8 and F9 follows first-order release. Hixon crowell law and Highuchi model was applied to test the release mechanism. R 2 values are higher for Highuchi model than Hixon crowell for all formulations, hence, drug release from all batches follow diffusion rate-controlled mechanism. According to Korsmeyer-Peppas model, a value of slope for F1, F2, F3, F7, and F9 was 0.85, so it indicates that the release mechanism follows zero order while for F4, F5, F6, and F8 was between 0.5 to 0.85 which indicates the release mechanism was non-Fickian diffusion. In Vitro Permeation StudyThe formulation F6 exhibited 87.4% of drug permeated in 12 h with a flux of 8.65 μg/cm 2/h (with a permeation coefficient of 3.967 cm/h). Plotting the cumulative amounts of drug permeated per square centimeter of the patches through the rat abdominal skin against time showed that the permeation profiles of drug might follow zero-order kinetics as it was evident by correlation coefficients 0.992, better fit than first order ( R 2 = 0.982) and Higuchi model ( R 2 = 0.987).
According to korsmeyer-Peppas model, a value of slope for F6 was between 0.5 and 0.85 (0.678) which indicates that the release mechanism was non-Fickian diffusion. The results of drug permeation from transdermal patches of Repaglinide through the rat abdominal skin confirmed that Repaglinide was released from the formulation and permeated through the rat skin and, hence, could possibly permeate through the human skin. (5)where Y is the dependent variable, b 0 is the arithmetic mean response of the 9 runs, and b i is the estimated coefficient for the factor Xi. The main effects ( X 1 and X 2) represent the average result of changing 1 factor at a time from its low to high values. The two way interaction terms ( X 12) show how the response changes when two factors are simultaneously changed.
Dushyant A Shah
Polynomial terms ( X 11 and X 22) are included to investigate nonlinearity. The in vitro release profile for 9 batches showed a variation (i.e., tensile strength,% cumulative drug release at 1 h ( Q 1),% cumulative drug release at 9 h ( Q 9), and diffusion coefficient). The data indicate that the release profile of the drug is strongly dependent on the selected independent variables. The fitted equations (full and reduced) relating the responses, tensile strength, Q 1, Q 9, and diffusion coefficient to the transformed factor are shown in. The polynomial equations can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (i.e., negative or positive). Shows the results of analysis of variance (ANOVA), which was performed to identify insignificant factors. Data were analyzed using Microsoft Excel.
Tensile strengthResponseb 0b 1b 2b 12b 1 2b 2 2(tensile strength)FM0.63670.190.0425−0.067RM0.63670.19–––Q1 hrResponse ( Q1)b 0b 1b 2b 12b 1 2b 2 2FM15.05272−1.251.734694−0.038−5.504RM15.39286–––−5.53572–Q9 hrResponse ( Q9)b 0b 1b 2b 12b 1 2b 2 2FM60.3996.649658−0.04.517858RM68.469––––Diffusion coefficientResponseb 0b 1b 2b 12b 1 2b 2 2(diffusion coefficient)FM0.64641−0.09322−0.03172−0.01.056385RM––––––.
Just use the 'High' setting.Here is the source. Some people have the same problem, but here is the solution.First, if you have more than 1 GPU, it's normal: Thief does not support (as of March 2014) multi-GPU. Thief 64 bit crack file. Maybe there was an update since then.Of course, you have to check if you're using the latest drivers, and also if you uninstalled the previous one, to be sure they're not conflicting.A user on a Steam community thread also said this:Mantle seems to be incompatible with the setting 'Depth of Field' set on 'normal'.
FORMULATION AND EVALUATION OF TRANSDERMAL PATCH OF PREGABALIN HTML Full TextFORMULATION AND EVALUATION OF TRANSDERMAL PATCH OF PREGABALINChakshu Bhatia., Monika Sachdeva and Meenakshi BajpaiDepartment of Pharmacy, Raj Kumar Goel Institute of Technology, Ghaziabad, Uttar Pradesh, IndiaABSTRACT:The objective of present study is to determine the permeation of Pregabalin from transdermal patch into microcirculation of skin. Matrix type transdermal drug delivery system (TDDS) of Pregabalin was prepared by the solvent evaporation technique.
Several batches were prepared by using combination of HPMC and PVP; PVA and PVP; Eudragit RL-100 and Eudragit RS-100; HPMC and EC in different ratios. 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. Formulation P 1 containing HPMC and PVP in the ratio of 3:1 and propylene glycol, 5%w/v and DMSO, 6%w/v was found to be the most optimum formulation. P 1 was also found to exhibit maximum in -vitro%drug release of about 81.70%. Result of evaluation studies revealed that Pregabalin can be administered as a controlled drug delivery system to reduce frequency of drug administration. But this hypothesis requires further confirmation via in-vivo pharmacodynamic and pharmacokinetic studies in animal and human models.Keywords:Pregabalin,transdermal,HPMC,PVP,PVA,EC,Eudragit,Propylene glycolINTRODUCTION:Pregabalin (PGB) is an anticonvulsant and analgesic drug 1, which is required to be administered three to four times per day for its therapeutic effect by oral route of drug delivery in the treatment of partial seizures.
It also finds its use in peripheral diabetic neuropathy, fibromyalgia and post-therapeutic neuralgia.So, the objective of present work is to develop a controlled release dosage form of Pregabalin other than oral route and injectables. Hence, a non-invasive system in the form of transdermal patch of Pregabalin was thought to be developed and evaluated with the aim of achieving controlled release of Pregabalin over a prolong time period so that frequency of drug administration will be minimised.Transdermal drug delivery has certain advantages over other systems of drug administration which in turn leads to increase patient compliance. Its non-invasive nature, ease of application and removal, predetermined rate of drug permeation, increased bioavailability of drug and decreased hepatic metabolism; all these factors make this system most suitable for systemic delivery of drug over long time periods of 24hrs.Therefore, market of transdermal patches has made tremendous growth in recent years 2, 3.MATERIALS: Pregabalin was obtained as gift sample from Torrent Pharmaceuticals, Ahmedabad.
Polymers such as HPMC, PVP, PVA, Eudragit RL-100, Eudragit RS-100 and EC was provided by the institute and other chemicals such as propylene glycol and DMSO and methanol used in the study were of analytical grade.METHOD:Technology Employed: Transdermal patch of Pregabalin was prepared by solvent evaporation technology. In this technology, mixture of polymer and drug solution was spread as a film on a suitable support (glass, mercury, aluminium foil etc.) and solvent was allowed to evaporate by keeping the petri dish containing solution for appropriate time period generally at room temperature. After evaporation of solvent, dried residue is the required patch containing drug trapped in the matrix of polymer 4, 5. The patch thus obtained was then evaluated for various parameters like physicochemical parameters, drug content, drug release profile and for skin irritation studies.Preparation of different Placebo Polymeric Films: Different placebo patches are prepared by employing hit and trial method on various combinations of different hydrophilic and hydrophobic polymers 6, 7. From these various placebo patches, the combination having desired properties to support a transdermal drug delivery system is selected for incorporation of drug. Different combinations of polymers are as follows:. HPMC and PVP.
HPMC and EC. Eudragit RL-100 and Eudragit RS-100.
Anand K Bhandari
PVA and PVPTable 1 below shows the composition and characterization of placebo patches prepared by using different polymers in different ratios. From the table 1, it was concluded that most appropriate combination of polymer was that of HPMC and PVP. Different ratios of HPMC and PVP were tried in order to obtain most optimum placebo patch.