Development and Evaluation of Transdermal Patches containing Carvedilol and Effect of Penetration Enhancer on Drug Release

 

Niharika Lal*, Navneet Verma

Department of Pharmaceutics, Pharmacy Academy, IFTM University, Moradabad, 244001, India

 

ABSTRACT:

Adhesiveness, as well as permeation of drug presents a significant challenge for the acceptability of transdermal patches. The current investigation deals with the development of pressure-sensitive based drug in transdermal patches containing Carvedilol with four different grades of acrylic polymer Duro-Tak 87- 4098, Duro-Tak 387-2051, Duro-Tak 387-2052 and Duro-Tak 87-2510 (a pressure-sensitive adhesive). Despite of the functionality or non functionality of these polymers, an attempt has been made to increase their permeability by using three distinct permeation enhancer individually, non ionic surfactant Span 80,oleic acid and a terpene farnesol. Transdermal patches containing Carvedilol were prepared by spreading method by using a fixed concentration of various grades of acrylic polymer; drug and penetration enhancers. The patches were evaluated for different physical parameters with Ex-vivo permeation studies. Skin irritation studies are conducted by using Albino Rats. Ex-vivo permeation across excised rat skin from these formulated carvedilol patches were found to be sustained over 12 h and followed the zero-order model with Fickian diffusion mechanism. The effect of permeation enhancers was in order: Span 80> farnesol >oleic acid. The skin irritation test demonstrated absence of any sign of skin irritation.

 

 

 

INTRODUCTION:

Hypertension is major health problem across the world. It is prevailing factor for cardiovascular disease and influences nearly two-thirds of adults aged 60 years or older. It is also found that in children and adolescents, it is a rising health concern that should be taken seriously and diagnosed early. It is estimated that uncontrolled HTN is responsible for 7.5 million deaths per year worldwide and, in USA alone accounts for over 47 billion dollars spent in health care services, medications and absent workforce. Transdermal route has been investigated as the potential non-invasive drug delivery route for the drug administration for the systemic effects as the systemic drug molecules can be delivered into systemic circulation for prolonged period.

 

The drug delivery through transdermal route has gained importance due to some potential advantages over oral route like avoidance of hepatic first-pass metabolism, predictable and extended duration of drug delivery, reduction in dosing frequency, minimized systemic side-effects, improved bioavailability, avoidance of plasma-drug fluctuations, intra- and inter-patient variations, improved patient compliance, etc. Therefore, the designing of transdermal drug delivery systems is a rational approach. The principal challenge in the transdermal drug delivery is to overcome the inherent barrier of the skin and the low permeability of the drug molecules through the stratum corneum, the outer-most layer of the skin is the limiting factor. To improve the permeability of the drug molecules, numerous studies on the transdermal drug delivery have been reported. Among several approaches, the use of chemical permeation enhancers like terpenes, non ionic surfactants are commonly adopted by the transdermal drug delivery researchers^1-3. Terpenes are proved as effective permeation enhancers in transdermal patches, which are classified as “generally regarded as safe” (GRAS) materials by the USFDA. These are mainly constituents of the volatile oils and can enhance the transdermal permeation of both lipophilic and hydrophilic drugs. Even the use of these permeation enhancers does not experience any long-term irritation and erythema at all. During last decades, terpenes have been also used as permeation enhancers in various transdermal patches. Whereas, use of non ionic surfactant also offers enhanced drug permeation through skin. There are two -possible mechanisms by which the rate of transport is enhanced using nonionic surfactants. The surfactant may penetrate into the intercellular regions of stratum corneum, increase fluidity and eventually solubilize and extract lipid components. And, secondly by penetration of surfactant into the intercellular matrix followed by interaction and binding with keratin filaments may result in a disruption within the corneocyte^4-6. Transdermal patches are flexible, multi-laminated devices of varying sizes and useful to deliver drugs through the skin for systemic effects at the predetermined and controlled rate; comprising of a backing membrane, drug incorporated into matrix, release liner and with or without rate-controlling membrane. In addition, transdermal patches are user friendly and also able to offer multi-day dosing. Generally, today’s transdermal patches are mostly drug-in-adhesive systems, where drugs are dispersed or dissolved in polymeric matrices^7-9. Unfortunately, transdermal patches are experienced fail to adhere for a long time onto the skin and this causes improper dosing of drugs. To overcome this problem, various pressure-sensitive adhesive matrices are currently used in transdermal patches by the drug delivery researchers. In the current work, an attempted has been done to prepare and evaluate transdermal patches containing carvedilol (an antihypertensive agent) using three grades of Duro-Tak 2051, 2052, 4098 and 2510 (a pressure-sensitive adhesive) and to study the effect of skin penetration enhancer like Farnesol , Span 80 and Oleic acid on drug release.

 

Carvedilol is a vasodilating noncardioselective third-generation β-blocker, without the negative hemodynamic and metabolic effects of traditional β-blockers, which can be used as a cardioprotective agent. Compared with conventional β-blockers, carvedilol maintains cardiac output, has a reduced prolonged effect on heart rate, and reduces blood pressure by decreasing vascular resistance. It has a molecular weight of 406.482 g/mol and half-life of 6 h. Carvedilol was chosen for transdermal delivery due to its low molecular weight, high lipid solubility, low dose, high degree of hepatic first-pass metabolism, low oral bioavailability and effects of meal on its absorption^10-11. In the previous literature, transdermal patches releasing carvedilol was reported. However, the development of pressure-sensitive adhesive-based transdermal patches containing carvedilol using different grades of Durotak and effects of Span 80, Oleic acid and Farnesol, and on the skin permeation is unavailable. Therefore, in the present investigation, we made an attempt to develop pressure-sensitive adhesive-based transdermal patches containing carvedilol with different grades of Duro tak (DT). The effects of as skin permeation enhancers on ex-vivo permeation of carvedilol from these newly developed pressure-sensitive adhesive-based transdermal patches were also evaluated and analyzed.

 

MATERIAL AND METHOD:

Carvedilol was procured as a favor from Cipla Pharmaceuticals, Mumbai, India. DuroTak 387- 2051, DuroTak 387-2052 , DuroTak 87- 2510 and DuroTak 87- 4098 were attained by Henkel Adhesive Technologies, USA. Span 80, Oleic acid and Farnesol were procured from Sigma Aldrich. Additional chemical reagents were of higher grade. 3M ScotchpakTM 9723 Backing Polyester Film Laminate and 3M ScotchpakTM 1022 Released Liner Fluoropolymer Coated Polyester Film were purchased from 3M Food Safety Division, Healthcare Business, India. Ethyl actate (Merck Ltd., India) was used. Double-distilled water was used throughout the study. All chemicals, and reagents used were of analytical grade

 

Quantitative Estimation of Carvedilol:

Solutions of Carvedilol ranging between 2 and 10 μg/ml concentration ranges (n = 3) were prepared in phosphate buffer, pH 7.4. The maximum absorption (λmax) of solutions containing Carvedilol was found 239 nm when scanned between 200-400 nm using a UV-VIS spectrophotometer (Shimadzu UV-1800, Japan). The method was validated for linearity, accuracy, and precision. The regression equation for the calibration curve was Y = 0.005 X -0.001; R²=0.9990.

 

Preparation of Transdermal Patches Containing Carvedilol:

Transdermal patches containing carvedilol were prepared by spreading method. Total 12 formulations were formulated using a fixed concentration of acrylic polymer (Durotak), Ethyl acetate and carvedilol with three distinct penetration enhancers. The drug-in-adhesive transdermal patches containing carvedilol were made of flexible backing. The detailed compositions of the transdermal patches containing carvedilol are given in the Table 1.

 

A polymeric solution was prepared by dissolving different grade of Duro-Tak in ethyl acetate in rotary evaporator to obtained desired solution which could be evenly applied on backing membrane. Carvedilol with various penetration enhancers were added previously to ethyl acetate and were homogenously mixed. Specific drug polymeric mixture were casted on backing membrane with final specific thickness of 25µm applying a film applicator (Elcometer 3580). Samples were acknowledged to stand with room temperature for two hours, then dried in oven for thirty minutes at 50ºC to remove residual organic solvents. A film layer of 3M Scotchpak TM 1022 released Liner Fluoropolymer Coated Polyester was laminated upon dried drug in adhesive films. The prepared transdermal patches containing carvedilol were cut into circular shape having surface area of 2 cm². The prepared transdermal patches were stored in air tight container prior use.

 

Table 1: Composition of Pressure-Sensitive Adhesive-Based Transdermal Patches containing Carvedilol

Formulation Number	Pressure Sensitive Adhesives (%w/w)						Penetration Enhancer (%w/w)
	Carvedilol	Ethyl acetate	DT -4098	DT-2051	DT-2052	DT-2510	Span 80	Oleic acid	Farnesol
N1	3	3.5	90	-	-	-	3.5
N2	3	3.5	90	-	-	-		3.5
N3	3	3.5	90	-	-	-			3.5
N4	3	3.5	-	90	-	-	3.5
N5	3	3.5	-	90	-	-		3.5
N6	3	3.5	-	90	-	-			3.5
N7	3	3.5	-	-	90	-	3.5
N8	3	3.5	-	-	90	-		3.5
N9	3	3.5	-	-	90	-			3.5
N10	3	3.5	-	-	-	90	3.5
N11	3	3.5	-	-	-	90		3.5
N12	3	3.5	-	-	-	90			3.5

 

Physico-Chemical Characterization of Transdermal Patches Physical Evaluation Examination of Physical Appearances:

All the transdermal patches were examined visually for their physical appearances like smoothness and transparency.

 

Measurement of Weight:

Average weights of prepared transdermal patches containing Carvedilol were measured by weighing ten patches (2 cm²) of each formulation individually using an electronic analytical balance (Citizen Scale, CY220). The average weights of these patches were taken.

 

Determination of drug contents:

Drug contents in prepared transdermal patches containing carvedilol were determined by dissolving patches (2 cm²) in 100 ml of phosphate buffer, pH 7.4 and shaken vigorously for 24 h at room temperature. These solutions were filtered through Whatman^® filter paper (No. 42). After proper dilution, absorbance was then measured using a UV-VIS spectrophotometer (Shimadzu UV 1800, Japan) at 239 nm against a blank. From the absorbance results, the drug contents in each patch were calculated.

 

Ex-vivo permeation studies Animal:

Skin of Wister rats (150–170 g) were used in ex-vivo permeation studies. The experimental protocol was subjected to the scrutiny of the Institutional Animal Ethical Committee and was cleared before starting. The experimental animals were handled as per guidelines of Committee for the Purpose of Control and Supervision on Experimental Animals (CPCSEA).

Preparation of Skin for ex-vivo Permeation Studies:

Rats were killed using diethyl ether asphyxiation. Hair of the abdominal region was carefully removed and a 5 cm² skin was excised from the abdominal of each killed rat within 1 h. The dermis side was wiped with isopropyl alcohol to remove the residual adhering fat. The skin was dipped and soaked in normal saline solution. Finally, these excised skins were thoroughly rinsed with distilled water, wrapped in aluminum foil and stored in a deep freezer at - 20°C for further use. 1 h prior to the experiments, the samples was thawed.

 

Ex-vivo permeation procedure:

The ex-vivo skin permeation experiment was conducted in a modified Franz diffusion cell using excised rat skins. The donor compartment of the modified Franz diffusion cell was placed in such a position that the surface of the excised rat skin just touches the receptor fluid surface and clamped into position. The transdermal patches were placed over the excised skin. The entire setup was placed over magnetic stirrer. The receptor compartment was filled with 25 ml of phosphate buffer, pH 7.4. The content of the receptor compartment was constantly and continuously stirred using a Teflon coated bead at a constant speed of 50 rpm. The temperature of whole assembly was maintained at 37 ± 0.5°C by circulating hot water inside the water jacket. The withdrawal port was covered with the glass cork. The samples were withdrawn from the withdrawal port at different time intervals up to 24 h and replenished with an equal volume of fresh buffer solution at each time interval. The absorbance of withdrawn samples was measured using a UV-VIS spectrophotometer (Shimadzu UV 1800, Japan) at 239 nm against a blank.

Permeation data analysis Permeation flux:

The amounts of carvedilol from various pressure-sensitive adhesive-based transdermal patches were permeated through excised rat skins (in case of ex-vivo permeation) were plotted against the function of time. The slope and intercept of the linear portion of plots were derived by the regression analysis. Permeation flux was calculated as the slope divided by the skin surface area.

 

J_ss = (dQ/dt)_ss 1/A, where J_ss is the steady-state permeation flux (μg/cm²/h), A is the area of skin tissue (cm²) through which drug permeation takes place, and (dQ/dt)_ss is the amount of drug passing through the skin per unit time at a steady state (μg/h)^12-14.

 

Permeation coefficient (K_p, cm/h) was calculated by dividing J_ss with the concentration of the drug in donor cell (C₀) by using the following equation:

K_p = J_ss / C_o

 

Permeation Kinetics:

The data of ex-vivo carvedilol permeation from various pressure-sensitive adhesive-based transdermal patches through excised rat skins, in case of ex-vivo permeation were evaluated kinetically using various mathematical models.

 

Zero-order model: Q = kt + Q₀;

First-order model: Q = Q₀ e ^{k . t};

Higuchi model: Q = kt^0.5;

Korsmeyer-Peppas model: Q = ktⁿ;

where Q = drug released amount in time t, Q₀ = start value of Q; k = rate constants and n = diffusional exponent.

 

Again, the Korsmeyer-Peppas model was employed in in-vitro and ex-vivo carvedilol permeation behavior analysis of transdermal patches to find out permeation mechanisms: Fickian (non-steady) diffusion (when n ≤ 0.5), non-Fickian or “anomalous” diffusion (when n = within 0.5 and 1) and case-II transport (zero-order) (when n ≥ 1).

 

Skin Irritation Studies:

All animal experiments were carried out in accordance with the guidelines of CPCSEA and the protocol was approved by the Institutional Animal Ethical Committee (IAEC), college of Pharmacy, IFTM, Moradabad. The Skin irritation studies were carried out to investigate the potential for Carvedilol to cause irritation in the hairless rat skin. Each hairless rat (n=3) received one adhesive device containing Carvedilol on the left side of the abdominal skin and an adhesive device containing only adhesive on the right side of the abdominal skin to differentiate irritation caused by the adhesive used or the carvedilol itself^15-17. The devices remained on the hairless rats for 24 hr, and fresh devices were re-applied to the same sites daily for 7 days. The abdominal skin of the hairless rats was evaluated for:

F → flushing of skin (redness)

P → papules and wheals

E → Erythema and oedema

 

Statistical analysis:

All measured data are expressed as mean ± standard deviation (S.D.) and analyzed using MedCalc software, version 11.6.1.0.

 

RESULTS AND DISCUSSION:

Physico-Chemical Characterization of Transdermal Patches:

Twelve formulations were formulated and designated between N1 to N12 respectively. The detailed composition of the patch formulation is shown in Table 1. The formulations were prepared with four different grades of Duro Tak using three different penetration enhancer. The prepared transdermal patches were evaluated for various physicochemical parameters like weight variation, thickness uniformity, and drug content uniformity. The physicochemical characteristics are summarized in Table 2.

 

All the formulations exhibited uniform weight with standard deviation values indicating the uniformity of the patches. The weight of the patch varied between 27.29 ± 0.04 mg to 30.39 ± 0.04. Thickness of transdermal patches was measured by micrometer in which thickness of the patches varies between 0.20 mm to 0.24 mm. Low standard deviation values ensure uniformity of the patch prepared by solvent evaporation technique. The area of the patch was 1 cm².

 

The drug content uniformity was determined for all the twelve formulations by UV-Spectrophotometric method. It was found in all formulations. The result of the drug content varies between 0.276 mg to 0.297mg. It was considered that the drug is dispersed uniformly throughout the patch. The cumulative percent permeated; in ex vivo permeation studies were calculated on the basis of drug content in the respective patch.

 

Figure. 1: Plot of Cumulative Percent of ex vivo Drug Permeated versus Time Across Excised Rat Skin for Carvedilol Transdermal Patches, N1, N4, N7, N10

Table 2: Physical appearances, weight, thickness and drug content of pressure-sensitive adhesive-based transdermal patches containing Carvedilol

^*Mean ± S.D., n = 10

 ^**Mean ± S.D., n = 5

+, ++ and +++ denote poor, satisfactory and good, respectively

 

Ex vivo Permeation Studies:

It is considered that a well-designed TDDS can supply the drug at a rate, to sustain the required therapeutic plasma concentration without much fluctuation that may cause basic manifestation or therapeutic inefficacy. Lag times to reach steady state fluxes are in hours as the transport of most drugs across the skin is very slow. Attainment of a therapeutically effective drug level is therefore difficult, without enhancing skin permeation Since breaking through the barrier of stratum corneum is the most difficult part for transdermal process, several kinds of physical and chemical methods were made use of in TDDS. Chemical enhancers were most widely used because of the ease use, relatively stable in patch and low-cost Different chemical permeation enhancers were added into the patches to investigate their effects^18-20. The permeation of the drug from formulation containing Span 80 as penetration enhancer was very controlled, and gradual enhancement of the drug permeation through the skin was noticed. This may be attributed to the fact that in the first few hours, drug permeation was more dependent on the drug concentration at the skin surface and the initial bursting effect provided the sink condition. However, the drug release from DT-2510 was found to be fast in compare to DT - 4098. From formulation with oleic acid (N2, N5, N8, N11) as penetration enhancer, the drug release was found to very slow. About 62.54% drug was released from N2 at end of 12 hour. While 26 % and 29% drug was released from N5 (DT-2051) and N8 (DT-2052) respectively. However 43% drug was released from N11 (DT-2510). The, permeation rate of carvedilol from matrix PSA with –COOH functional group, (N5 (DT-2051) AND N8 (DT-2052) was too low to provide an adequate permeation rate. Carvedilol has amide (–CON) group^6-8. It was found that –COOH group of PSA gives stronger bond with –CON group of Carvedilol than –OH group because –COO^−δ is a stronger electron-withdrawing group than –O^−δ. Therefore, the positive charge on H^+δ of carboxyl group is greater than hydroxyl group, and it causes stronger hydrogen bonding between H^+δ and –N⁻. Further, addition of oleic acid in acrylic polymer could increase viscosity of solution that could increases the diffusion time of drug. Since Carvedilol is a lipophilic drug, the addition of a lipidic component like OA increased the solubility of the drug in this system and also contributed to drug release reduction from the patch over time. This could be due to the increase in hydrophobicity of the polymeric matrix^21-22.

 

The permeation of the drug from formulation using Farnesol as penetration enhancer showed satisfactory drug release up to 12 hours. About 76.14% drug was released in N3.The release of N6 and N9 was also improved as 60.32% and 69.13 % drug was released at end of 12 hour. Whereas, 84% drug was released from N12 at end of 12 hour. It could be suggested that with addition to the lipophilicity of the drug, the lipophilicity of the terpene also plays an important role in determining the penetration enhancement effect. Most terpenes were applied in the range of 1%~5% in TDDS. For different terpenes, the optimum concentration may be different. The penetration enhancement effect initially increased drastically with the increase in terpene concentration. The skin permeation rate of carvedilol did not increase significantly beyond 3% drug loading. The data obtained from ex-vivo permeation study were shown graphically according to various modes of data treatment (Figure 1 to 3).

 

Drug Release Kinetics:

The data from the ex vivo permeation study was fitted to various kinetic models to determine the kinetics of drug release. The main models are zero order, first order, Higuchi equations to understand the drug release from the transdermal patch. The coefficient of regression and release rate constant values for zero, first and Higuchi models were computed and are listed in Table 3. From the correlation coefficient values, it was found that the permeation followed zero order kinetics. Also, lower variation was obtained for zero order release rate constant as compared with first order release rate constants indicating a zero order release pattern from the formulations. Higuchi equation explains the matrix diffusion mechanism of drug permeation from the transdermal patches^11-12.

 

Figure. 2: Plot of Cumulative Percent of ex vivo Drug Permeated versus Time Across Excised Rat Skin for Carvedilol Transdermal Patches, N2, N5, N8, N11

 

Figure. 3: Plot of Cumulative Percent of ex vivo Drug Permeated versus Time Across Excised Rat Skin for Carvedilol Transdermal Patches, N3, N6, N9, N12

 

The increased partition coefficient value indicates increased lipophilicity and this lipophilic character helps the drug permeations through the barrier by disrupting the layer. The maximum ex-vivo skin permeation of Carvedilol from transdermal patches containing various permeation enhancers was in order: Span 80> Farnesol>Oleic Acid. Span20 enhance absorption by inducing fluidization of the stratum corneum lipids. They are two possible mechanisms by which the rate of transport is enhanced using nonionic surfactants. Initially, the surfactants may penetrate into the intercellular regions of SC, increase fluidity and eventually solubilize and extract lipid components. Secondly, penetration of the surfactant into the intercellular matrix followed by interaction and binding with keratin filaments may results in a disruption within the corneocyte. It is reported that terpenes preferentially distribute into the intercellular spaces of stratum corneum and possibly cause the reversible disruption of lipid domains. The mechanism of terpenes as a skin permeation enhancer may be the permeation of drugs by both the lipid and pore pathways²³. The results of the curve fitting of ex-vivo skin permeation data into various mathematical kinetics models are given in Table 3. When respective correlation coefficients were compared, it was found that ex-vivo permeation of from various pressure-sensitive adhesive-based transdermal patches across excised rat skins followed the zero-order over a period of 12 h as a best-fit amongst all other models investigated. The values of diffusional exponent (n) determined from ex-vivo permeation data ranged between 0.237 and 0.598 (Table 3), indicating Fickian diffusion mechanism. The diffusion mechanism of drug permeation demonstrates a combination of diffusion controlled, delivered a controlled drug permeation²⁴.

Table 3: The results of the curve fitting into various mathematical kinetics models indicate the Ex Vivo permeation of Carvedilol from various transdermal patches across excised rat skin.

 

From ex-vivo permeation results of various pressure-sensitive adhesive-based transdermal patches containing Carvedilol, it was observed that patch N10 exhibited highest steady-state permeation fluxes of 0.286 ± 0.020 µg/cm²/h in ex-vivo permeation studies, respectively. Therefore, transdermal patch N10 (made of 90 % w/w Duro-Tak 2510 as pressure-sensitive adhesive and 3.5 % w/w ethyl acetate with Span 80 respectively as penetration enhancer) was considered as optimized patch among all the formulated patches.

Skin irritation:

The skin irritation test of the Carvedilol transdermal patch N 10 (optimized patch) after application onto the skin of healthy rats was examined up to 24 h for flushing of skin (redness), papules, wheals, erythema and oedema, if any. Any significant development of flushing of skin (redness), papules, wheals, erythema and oedema on the surface of rat skin was not found. The results of the skin irritation study were depicted in Figure 4 and Table 4. These results indicated the safety and acceptability of these transdermal patches without any sign of skin irritation.

 

 

Figure. 4: The skin irritation test of the carvedilol transdermal patch N10 after application onto the skin of healthy albino rat: (a) rat skin before application of the patch, (b) rat skin after removal of the patch.

 

Table 4: Skin Irritation Study Data from optimized formulation

* – ve → no allergic manifestation observed

  F → flushing of skin (redness)

  P → papules and wheals

  E → erythema and oedema

 

CONCLUSION:

Pressure-sensitive adhesive-based transdermal patches containing Carvedilol were developed using various grades of acrylic grades of Durotak and skin permeation enhancers. The patches were evaluated for different parameters such as physical appearances, weight, thickness, drug content, adhesion and ex-vivo permeation studies. The ex-vivo permeation from these formulated transdermal patches containing Carvedilol was found to be sustained over 12 h. The effect of permeation enhancers was in order: Span 80 >farnesol >Oleic acid. The release of drug from DT 2051 and DT 2052 from oleic acid did not show uniform drug release from transdermal patches. The ex-vivo permeation from transdermal patches containing Carvedilol followed the zero-order and Fickian diffusion mechanism controlled by diffusion over a period of 12 h. Transdermal patch N10 exhibited highest steady-state permeation. The skin irritation test of the Carvedilol patch N10 after application onto the skin of healthy male albino rats demonstrated absence of any significant development of flushing of skin (redness), papules, wheals, erythema and oedema on the rat skin surface indicating safety and acceptability of these pressure-sensitive adhesive-based transdermal patches without any sign of skin irritation. Further studies (in vivo pharmacokinetic and pharmacodynamic) are required to monitor the drug level in the blood after the application of these developed pressure-sensitive adhesive-based transdermal patches of Carvedilol on the skin.

 

CONFLICT OF INTEREST:

The authors confirm that this article content has no conflicts of interest.

 

ACKNOWLEDGEMENT:

Authors are grateful to Prof. R. M. Dubey, Vice Chancellor, IFTM University for providing moral support as well as necessary facilities for the completion of this manuscript.

 

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Accepted on 20.11.2017           © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(2):745-752.