Permeation Enhancement of Transdermal Patches Using Penetration Enhancer and Different Concentration of Polymers
by Rohini Rana*, Dharmender Jaglan,
- Published in Journal of Advances and Scholarly Researches in Allied Education, E-ISSN: 2230-7540
Volume 16, Issue No. 5, Apr 2019, Pages 321 - 334 (14)
Published by: Ignited Minds Journals
ABSTRACT
Transdermal drug delivery system is becoming more popular in the field of modern pharmaceutics. In the present work, an attempt has been made to develop a transdermal therapeutic system of drug Fluconazole with different concentration of hydrophilic (HPMC) and hydrophobic (ERS 100) polymeric system by solvent evaporation technique by using 30 ww of Dibutyl phthalate incorporated as plasticizer and DMSO as a penetration enhancer. The physicochemical compatibility of the drug and the polymers was studies by Fourier transform infra-red (FTIR) spectroscopy analysis shows that there is no interaction between drug, HPMC and ERS 100. All the prepared formulations were subjected to physical studies (Weight Variation, Thickness, Folding endurance, Drug content determination, Flexibility or Tensile strength, Flatness, Percentage of moisture uptake, Percentage moisture loss, and Stability studies). Based on the physicochemical and In-vitro dissolution study formulation P2 (ERSHPMC, 28) were the best formulation. The release profile of optimized formulation indicated that the permeation off the drug from the patches was showed diffusion controlled mechanism. Hence, it can be concluded that Fluconazole with the high concentration of hydrophilic polymer showed the better release.
KEYWORD
transdermal drug delivery system, penetration enhancer, polymers, hydrophilic, hydrophobic, solvent evaporation technique, plasticizer, FTIR spectroscopy analysis, physical studies, in-vitro dissolution study
INTRODUCTION
Transdermal systems are a desirable form of drug delivery because of the obvious advantages over other routes of delivery. Transdermal delivery pro-vides convenient and pain-free self-administration for patients.[1] Transdermal delivery provides a leading edge over injectables and oral routes by increasing patient compliance and avoiding first pass metabolism. [2] Fluconazole belongs to a group of medicines called azoles antifungal. The triazole fluconazole inhibits the fungal cytochrome P450 3A enzyme, lanosine 14α-demethylase, which is responsible for converting lanosterol to ergosterol, the main sterol in the fungal cell membrane. Triazoles thus impair the biosynthesis of ergosterol for the cytoplasmic membrane and lead to the cascade of membrane abnormalities in the fungus and accumulation of 14-α methylsterols. The fluconazole is absorbed from the gastrointestinal tract and is excreted largely unchanged by the kidney. It is used prophylatically in a variety of conditions predisposing to systemic Candida infections. There are so many unwanted effects; it may cause gastrointestinal discomfort, abdominal pain, headache, elevation of liver
enzymes and allergic rash. Therefore, the search continues for an effective antifungal with reduced adverse gastrointestinal reaction. Fluconazole possess appropriate physicochemical properties for potential transdermal delivery. It has low molecular weight (306.271 g/mol), low melting point, and low daily therapeutic dose. Moreover, it has been reported that fluconazole formulations exhibits good local tissue tolerability (e.g., dermal, rectal and thus, they appear to be suitable for dermal administration.[3-8] Now days the fungal infection of skin is the common dermatological problems. The physicians have a wide choice for treatment from transdermal and to liquid formulations. So the transdermal drug delivery system is chosen an alternative route to deliver the drug directly to systemic circulation. [9-13]
MATERIALS AND METHOD:
Fluconazole (Symbiosis Pharmaceutical Pvt. Ltd. Kala Aamb (H.P)), Eudragit RS100 (Evonik Roehm Pharma, Mumbai), HPMC (Lobal Chem, Mumbai), Dibutylpthalate (Qualigens, Lobal Chem, Mumbai), DMSO (Lobal Chem, Mumbai), Dichloromethane and Methanol (Merck, Mumbai), Electronic Spectrophotometer (Systronic (2202) Mumbai), FTIR Spectrophotometer (Bruker FTIR spectrophotometer, Mumbai), Magnetic stirrer (Remi Udyog, Mumbai), Hot air oven (Sudheer Scientific, Ambala), pH meter (Systronic (802), Ahemdabad), Dissolution apparatus ( Electro Lab Tablet dissolution Tester USP (TDT 06P), Mumbai).
ANALYSIS OF THE MODEL DRUG
Description: Fluconazole was physically examined for color, clarity, flexibility etc.
Solubility determination: In distilled water and methanol:
An excess amount of drug was taken and dissolved in measured amount of distilled water and methanol in glass beaker to get a saturated solution. The solution was taken intermitentillely to assist the attainment of equilibrium with the undissolved particles. The measured quntitity of the filtered drug solution was withdrawn after 24 hours and successively diluted with distilled water suitably, and the concentration was measured in a UV spectrophotometer.
Melting point determination
Melting point is determined by the capillary tube method. In this method note the temperature at which the drug is melt, by placing the capillary tube which is fused from one side in to melting point apparatus this is its melting point.
Fourier transform infra-red (FTIR) spectroscopy There is always possibility of drug excipients interaction in any formulation due to their intimate contact. The presence of any drug-polymer interaction was recorded in FT-IR spectroscopy. The scanning range was 400– 4000 cm−1. Λmax Scanning Λmax scanning help in identifying the purity of drug. Spectrum of Fluconazole was obtained in methanol solution, observed wavelength maxima was 260 nm. Reagents preparation: Preparation of pH 7.4 phosphate buffer
1.3606gm of KH2PO4 and 0.3128 gm of NaOH were taken and dissolved in 100 ml of distilled water. Then solution was made up to 200ml with distilled water.
was accurately weighed and transferred into a 100 ml volumetric flask. To this, 50 ml of 7.4 pH phosphate buffer solution was added and occasional shaking to disperse and dissolve the contents. The volume was made up to 100 ml with 7.4 pH phosphate buffer solution to give 1000 μg/ml of Fluconazole solution.
Preparation of calibration curve in 7.4 pH phosphate buffer: Calibration curve of Fluconazole was developed in 7.4 pH phosphate buffer at 260 nm wave length. From the stock solution, aliquots of 1 ml were pipette out into a series of 10 ml volumetric flask and volume was made up to 10 ml with 7.4 pH phosphate buffer get a concentration of 10μg/ml. From this dilution further dilutions were made as 2, 4, 6, 8, 10μg/ml. Absorbance of each solution was measured by using UV double beam spectrophotometer at 260 nm using 7.4 pH phosphate buffer as a reference standard. Preparation of working standard solution:
Working standard solution having concentration of 10 to 100 μg/ml were prepared by appropriately diluting the stock solution with 7.4 pH phosphate buffer. The absorbance of each working standard solution was measured at 260nm on UV spectrophotometer using 7.4 pH phosphate buffers as blank. Average of triplicate reading was taken.
Fabrication of Transdermal patches:
Matrix type transdermal patches containing Fluconazole were prepared by solvent evaporation method, using different ratios of polymers ERS 100 and HPMC. The polymers were weighed dissolved in the mixture of solvents i.e. ethanol: acetone. Dibutylpthalate was added as plasticizer (30% w/w of polymers), DMSO as a penetration enhancer (5%v/w of polymers). The drug was added to the polymeric solution, and then they were stirred and poured in to the petridish. The rate of evaporation of solvent was controlled by inverting the funnel over the petridish. After the 24 hrs the dried patch were taken out and stored in a desiccator. The patches with different ratios of Eudragit RS 100: HPMC. The formulation A1 to A4 having different ratio of polymers without penetration enhancer, other formulations from P1 to P4 is having different concentration of polymers with penetration enhancer.
Evaluation of Transdermal Patches
Weight Variation: [4]
Cut 1-3 films from each patch then the patches was weighed directly on the digital balance for the determination of weight variation.
Thickness: [6]
Thickness of each patch at five different locations was done by using digital caliper.
Folding endurance: [7, 8]
Folding endurance was determined by repeatedly folding the patch at the same place until it breaks.
Drug content determination: [9]
For a drug content uniformity, patch was dissolved in a 100ml of isotonic phosphate buffer saline pH 7.4 for 12 hours under occasional stirring. The contents were filtered by whatman filter paper and then filtrate was analysed by U.V spectrophotometer at a specific ג max.
Flexibility or Tensile strength: [11]
The pulley system is used to determine the flexibility and tensile strength. With the help of two small catchers the patch was pulled in opposite direction by gradually increasing the force until the patch was broken. The tensile strength was noted from the scale of pulley in kg/cm2.
Flatness: [12]
The strips were cut out longitudinally from each film i.e. one from center and two from either side. The length of each strip was measured and the variation in the length because of nonuniformity in flatness was measured by determining percent constriction, considering 0% constriction is equivalent to 100% flatness: % Constriction = L1-L2/L2×100 Where L1= initial length of each strip To check the physical stability of film in high humidity condition the film were placed in a desiccator containing a solution of aluminium chloride at room temperature for 24 hrs and exposed to 85% relative humidity until a constant weight of film was obtained. The film was reweighed and the percentage moisture uptake was determined by following formula. Percentage moisture uptake = Final weight – Initial weight/Initial weight×100
Percentage moisture loss: [14]
To check extend of moisture loss the films were weighed accurately and kept in the desiccators containing anhydrous calcium chloride. After 24 hr the film were taken out and reweighed. Percentage of moisture loss = Initial weight – Final weight/Initial weight×100
In-vitro dissolution study: [15]
The in-vitro dissolution test was performed using USP type 2 test apparatus. The patch was tied with paddle of apparatus then drug release study was carried out for 8 hr in 900 ml of pH 7.4 phosphate buffer dissolution media, maintained at 37±0.5°C and agitated at 50 rpm. Periodically 10ml samples were withdrawn and filtered through whatman filter paper and samples were replaced by its equivalent volume of dissolution media. The absorbance of Fluconazole was measured UV/Visible spectrophotometrically at 260 nm. The percentage cumulative drug release was calculated and amount of drug released from patches was determined.
Stability studies: [16]
The patches were exposed to two selected temperatures of 37°C and 45°C in two different hot air ovens. The transdermal patches were kept in the oven for one week. The patches were analysed for the drug content at the end of the day.
Table 2: Organoleptic Properties of Pure Drug: MELTING POINT DETERMINATION: Observed melting point of sample is approx. near to reported data which confirm the authenticity of obtained sample. Table 3: Melting point of Fluconazole: λmax Scanning of pure drug: Fig 1: λmax Scanning plot of Fluconazole The absorption maximum of the drug solutions was found to be 260 nm by using double beam spectrophotometer at pH 7.4 buffer solution in Fig. 1. Hence this test supported the other identification testes, providing the fact that the obtained sample is pure Fluconazole.
SOLUBILITY STUDIES OF PURE DRUG:
The drug is very high soluble in alcohol, DMSO, Slightly soluble in water and sparingly soluble in pH 7.4 phosphate buffer.
COMPATIBILITY STUDIES: FTIR spectral studies: The FTIR spectra of drug and polymers were obtained with FTIR spectrophotometer. The drug was identified and compatibility was confirmed by confirmed by FTIR spectrum from Fig, 2, 3.
Table 5 FTIR spectral data of Fluconazole
The peaks shown in obtained spectra were compare with spectrum reported in the literature to confirm the authenticity of the given sample. The matching of IR spectra proves the identity of pure drug.
Fig 2: FTIR spectra of pure Drug
Fig 3: FTIR spectra of physical mixture (pure Drug + HPMC + ERS100)
Calibration curve of Fluconazole: The calibration curve of Fluconazole was prepared in phosphate buffer having pH 7.4 at 260 nm and the absorbance values at different Concentrations of Fluconazole in pH 7.4 phosphate buffer solution are shown in Table and graphically represented in figure. Table 6 Calibration data of Fluconazole in pH 7.4 phosphate buffer.
Fig 4 Standard curve of Fluconazole in pH 7.4 phosphate buffer (Slope= 0.057, Regression analysis= 0.993)
CHARACTERIZATION AND EVALUATION OF TRANSDERMAL PATCHES:
Description: The prepared patches were clear and smooth.
Table 8 Thickness data of fluconazole transdermal patches Table 9 Folding Endurance data of fluconazole transdermal patches Table 10 Moisture uptake data of fluconazole transdermal patches Table 12 Flatness study data of fluconazole transdermal patches Table 13 Tensile strength data of fluconazole transdermal patches
Table 14 Drug content uniformity study of fluconazole transdermal patches All the films were found to be uniform in their weight, thickness, flatness and folding endurance with low SD values.
Fig. 6.5 Graphical representation of weight variation Fluconazole transdermal patches Fig.6.6 Graphical representation of thickness Fluconazole transdermal patches Fig. 6.7 Graphical representation of % drug content uniformity Fluconazole transdermal patches Fig. 6.8 Graphical representation of % moisture uptake uniformity of Fluconazole transdermal patches
Fig. 6.9 Graphical representation of %moisture loss uniformity of Fluconazole transdermal patches Fig.6.10 Graphical representation of tensile strength of Fluconazole transdermal patches
INVITRO DRUG RELEASE STUDY
Release studies are required for predicting the reproducibility of rate and duration of drug release. The importance of polymer dissolution on drug release from matrices has been known for ensuring the controlled release performance. Table 6.14 In vitro release study of Transdermal patch of fluconazole
Fig. 6.11Graphical representation of % CDR of F1-F4 at different time intervals Fig.6.12 Graphical representation of % CDR of P1-P4 at different time intervals
Formulations P2 (ERS 100 & HPMC in 2:8) exhibited greatest (86.1 %) of drug release value, which are significantly different compared to the lowest value observed with the formulation F1 containing (ERS 100 & HPMC in 1:4) i.e. (51.8 %). In the present study it was observed that as the concentration of hydrophilic polymer (HPMC) increased in the formulations, the drug release rate increased substantially as compared to hydrophobic polymers ERS 100. This is due to the fact that dissolution of aqueous soluble fraction of the polymer matrix leads to the formation of gelaneous pores. The formation of such pores leads to decrease the mean diffusion path length of drugs molecules to release the diffusion medium and hence, to cause higher release rate. Formulations A1-A4 without permeation enhancer showed less release as compared to formulations P1 – P4 with permeation enhancer.
MATHEMATICAL MODELING
In vitro release data of formulations F1 – F4 and formulations P1 – P4: Zero order kinetics
Fig. 6.13 In vitro release data of formulation F1: Zero order kinetic
Fig.6.14 In vitro release data of formulation F2: Zero order kinetic
Fig.6.15 In vitro release data of formulation F3: Zero order kinetic
Fig.6.16 In vitro release data of formulation F4: Zero order kinetic
Fig. 6.17 In vitro release data of formulation P1: Zero order kinetic Fig.6.18 In vitro release data of formulation P2: Zero order kinetic Fig.6.19 In vitro release data of formulation P3: Zero order kinetic
Fig.6.20 In vitro release data of formulation P4: Zero order kinetic 6.3.2 In vitro release data of formulations F1 – F4 and formulations P1 – P4: First order kinetic Fig.6.21 In vitro release data of formulation F1: First order kinetic Fig. 6.22 In vitro release data of formulation F2: First order kinetic Fig.6.23 In vitro release data of formulation F3: First order kinetic Fig. 6.24 In vitro release data of formulation F4: First order kinetic Fig.6.25 In vitro release data of formulation P1: First order kinetic Fig.6.26 In vitro release data of formulation P2: First order kinetic Fig.6.27 In vitro release data of formulation P3: First order kinetic Fig.6.28 In vitro release data of formulation P4: First order kinetic 6.3.3 In vitro release data of formulations F1 – F4 and formulations P1 – P4: Higuchi model Fig.6.29 In vitro release data of formulation F1: Higuchi mode Fig.6.30 In vitro release data of formulation F2: Higuchi model Fig.6.31 In vitro release data of formulation F3: Higuchi model Fig.6.32 In vitro release data of formulation F4: Higuchi model
Fig.6.33 In vitro release data of formulation P1: Higuchi model Fig. 6.34 In vitro release data of formulation P2: Higuchi model Fig. 6.35 In vitro release data of formulation P3: Higuchi model Fig. 6.36 In vitro release data of formulation P4: Higuchi model 6.3.4 In vitro release data of formulations F1 – F4 and formulations P1 – P4: Korsmeyer Peppas model Fig.6.37 In vitro release data of formulation F1: Korsmeyer peppas model Fig.6.38 In vitro release data of formulation F2: Korsmeyer peppas mode Fig.6.39 In vitro release data of formulation F3: Korsmeyer peppas model Fig.6.40 In vitro release data of formulation F4: Korsmeyer peppas model Fig.6.41 In vitro release data of formulation P1: Korsmeyer peppas model Fig.6.42 In vitro release data of formulation P2: Korsmeyer peppas model Fig6.43 In vitro release data of formulation P3: Korsmeyer peppas model Fig.6.44 In vitro release data of formulation P4: Korsmeyer peppas model Table: 6.47 R2 value of model fitting of Fluconazole
The diffusion kinetics of the drug fluconazole was analyzed by graphical method for zero order (Figure 6.10-6.17), First order (Figure 6.18-6.25), Higuchi model (Figure 6.26-6.33) and Peppas kinetics model (Figure 6.34-6.41). After fitting data to these models, value of regression coefficients from all the models were obtained and the value which was closer to 1 was selected as the best fit model for the drug release. The regression value for the formulation P2 (ERS100 and HPMC in the ratio of 2:8) have showed optimum release i.e. R2 = 0.978. It showed the first order kinetic.
appearance, flexibility at a regular interval of days for a week and the drug content observed after one week.
Table: 6.48 Stability study data for Fluconazole patches Fig.6.45 Graphical representation of stability data of Fluconazole transdermal patches
All the patches were stable at 37°C and 45°C with respect to their physical parameters and drug content.
CONCLUSION:
The formulation showed maximum in-vitro drug release (86.1%) having excellent permeability through skin. Formulated Transdermal patches fitted to mathematical kinetic models. From the result of data fitted to various models it was found that the optimized formulation P2 (ERS100: HPMC) by solvent evaporation method had ratio (2: 8) showed first order of drug release i.e. the formulation P2 showed diffusion controlled mechanism.
REFERENCES
1. Dhiman S, Thakur G.S, Rehni A.K. (2011). Transdermal patches: A recent approach to 2. Shingade G.M, Quazi1 A, Sabale P.M, Grampurohit N.D, Gadhave M.V, Jadhav S.L. and Gaikwad D.D. (2012). Review on: Recent trend on transdermal drug delivery system, J. drug delivery Ther. 2012, 2(1), pp. 66-75. 3. Tavallaee M. and Rad M.M. (2009). Fixed drug eruption resulting from fluconazole use: a case report. Journal of medical case report, 3(7368), pp. 1-14. 4. http://www.drugbank.ca/drugs/DB00196 5. https://www.nlm.nih.gov/medlineplus/druginfo/meds/a690002.html 6. http://www.druglib.com/activeingredient/fluconazole/ 7. www.drugs.com/ppa/fluconazole.htm 8. Reddy V.M., Reddy J.V., Y. Ramesh and I. Venkateswarlu (2011). Formulation and evaluation of Fluconazole transdermal patches, Int. J. Ins. Pharm. Life Sci., 2011, 1(1), pp. 18-29. 9. Namdeo A., Garud N. and Guard A. (2012). Development and evaluation of transdermal patches of Quetiapine fumerate for the treatment of psychosis, Int. J. Drug Delivery, 4, pp. 470-476. 10. Verma P., Thakur A.S., Deshmukh K., Dr. Jha A.K. and Verma S. (2010). Route of drug administration, Int. J. Pharm. Stu. Res, 2010, 1, pp. 54-59. 11. Jhawat V.C., Saini V., Kamboj S. and Maggon N. (2013). Transdermal drug delivery system: Approaches and advancement in drug absorption through skin, Int. J. Pharm. Sci. Rev. Res, 20(1), pp. 47-56. 12. Latheeshjlal L., P. Phanitejaswini, Y. Soujanya, U. Swapna, V. Sarika and G. Moulika (2011). Transdermal drug delivery system: An overview, Int. J. Pharm. Res, 3(4), pp. 2140-2148. 13. Kwatra S., Taneja G. and Nasa N. (2012). Alternative routes of drug administration- Transdermal pulmonary and parenteral, 14. Nair R.S., Ling T.N., and Shukkoor M.S.A. (2013). Matrix type transdermal patches of Captopril: Ex vivo permeation studies through excised rat skin, J. Pharm. Res, 2013, 6, pp. 774-779. 15. Nazarkar S., Kondawar M., Prasad V., Khedkar S. and Dayama D. (2014). Formulation of transdermal patches of Miconazole nitrate and assessment for drug release, 6(4), pp. 32-36. 16. Mutalik S. and Udupa N. (2004). Glibenclamide transdermal patches: Physicochemical, pharmacodynamics, and pharmacokinetic evaluation, J. Pharm. Sci, 93, pp. 1577-1594. 17. Kumar S.R., Jain A., Satish N. (2012). Development and evaluation of transdermal patches of Colchicine, Der. Pharm. L, 2012, 4(1), pp. 330-343. 18. Vaja D., Seth A.K., Sailor G.U., Patel J., Patel J., Pandya K., Patel M., Ghelani T.K. and Joshi U. (2011). Formulation and evaluation and evaluation of transdermal patch of Meloxicam, Int. J. Pharm. Sci, 2(4), pp. 89-103. 19. Sarkar G., Saha N. R., Roy I., Bhattacharyya A., Bose M., Mishra R., Rana D., Bhattacharjee A., Chattopadhyay D. (2014). Taro corms mucilage/HPMC based transdermal patch: An efficient device for delivery of diltiazem hydrochloride, Int. J. Biol. Macromol, 66, pp. 158-165. 20. Yadav S.K., M.V. Laxmi and J.V. Krishna (2013). Formulation and evaluation of transdermal patch for anti-rheumatic ayurvedic medicine using different polymer compositions: in vitro, J. Global Trends Pharm. Sci, 4(1), pp. 999-1006. 21. P. Koteswararao, S. Duraivel, K.P. Sampath Kumar and Bhowmik D. (2013). Formulation and evaluation of transdermal patches of anti-hypertensive drug metoprolol succinate, Indian J. Res. Pharm. Biotechnol, 1(5), pp. 629-634. 22. Ganju G., Ganju K. and Pathak A.K. (2011). formulation and evaluation of transdermal patch of Prochlorperazine maleate for hyperemesis gravidarum, Int. J. Res. Pharm. Chem, 1(4), pp. 1115-1118. 23. Oza N.A., Patadiya D.D., Patel P.U. and Patel D.M. (2013). Formulation and 2(1), pp. 151-162. 24. Kumar J.R.K., Murlidharan S. and Dhanaraj S.A. (2012). Formulation and in-vitro evaluation of Terbinafine HCL transdermal patches, J. Pharm. Sci. Res, 4(6), pp. 1840-1843. 25. Nawaz A., Khan G.M., Shah S.U., Shah S.U. and Rehman A., Shah K.U. and Hussain A., Preparation and evaluation of Cotrimazole matrix type patch: Effect of olive oil on drug penetration across rabbit skin, Pak. Acad. Sci, 48(2), pp. 95-100. 26. Jamakandi V.G., Mulla J.S., B.L. Vinay and H.N. Shivakumar (2009). Formulation, characterization, and evaluation of matrix-type transdermal patches of a model antihypertensive drug, Asian J. Pharm, pp. 59-64.
Corresponding Author Rohini Rana*
Keshav College of Pharmacy, Salwan, Karnal ranarohini2804.rr@gmail.com
