INTRODUCTION:

The transdermal drug delivery system (TDDS) is a commonly used method of drug administration, and transdermal patches are used to treat a variety of ailments. A transdermal patch, also known as a flesh patch, is a therapeutic sticky pad (a thin mass of soft substance utilized for safety, filling, and convenience) put on the skin to administer a particular quantity of drugs into the blood circulation via the skin^1,2,3,4,5.

The patch offers a managed discharge of drug into the patient, typically through a permeable membrane designed to cover a reservoir of drug or through body temperature melting a thin coating of medication incorporated in the sticky tape, which is a benefit of TDDS over other types of delivery of drug. They are designed to avoid hepatic first-pass metabolism and also gastrointestinal issues related to drugs and low absorption^6,7,8,9,10. Because most drug molecules permeate through the skin via the intercellular microchannel, the role of permeation enhancers in TDDS is critical because they reversibly diminish the Horny Layer's barrier resistance without harming living cells^11,12,13. Losartan potassium is an orally potent angiotensin II receptor (AT1 Type) antagonist that is heavily metabolized by cytochrome P450 enzymes in the first pass. Losartan potassium has a terminal biological half-life of roughly 2hours. The medication is used either once or twice a day as a 25mg tablet, with total daily dosages ranging from 25mg to 100mg. It's a crystalline powder that's white and has great flow qualities¹⁴. Losartan potassium is a commonly prescribed medication for the treatment of high blood pressure. Because it is an antagonist of the Angiotensin II receptor (AT1), it has a hypotensive effect¹⁵. Additionally, Losartan potassium combined with its active carboxylic acid metabolite summatively accounts for the antagonistic effect on the Angiotensin II receptor^16,17. Losartan potassium is freely soluble in water as it belongs to Biopharmaceutics Classification System (BCS) Class III medication. It is somewhat soluble in typical organic solvents and soluble in alcohols. And it has a bioavailability of about 33%^18,19. For the reasons stated above, this study will seek to improve the therapeutic impact of Losartan Potassium by forming it into Transdermal Patches.

Figure 1. Structure of losartan potassium.

Calibration curve of Losartan Potassium:

Using ultraviolet (UV)-visible spectroscopy, the maximum wavelength of Losartan Potassium was discovered to be 205nm. Losartan potassium standard stock solution was made by properly weighing 100mg of medication and transferring it to a 100mL volumetric flask. To reach a concentration of 1000µg/mL, the medication was dissolved in saline phosphate buffer 7.4pH and the final volume was prepared with saline phosphate buffer¹². To obtain standard drug concentrations between 1-5µg/mL, aliquots of varied quantities were taken from working dilution into 10mL volumetric flasks and was make up with Saline phosphate buffer (pH 7.4). The absorbance of these Losartan potassium dilutions was calculated to be 205 nm in each case.

Formulation of Trial Batches:

Different trial batches were taken where T1 batch had polymer combination of PVPk15-ERS100 but it failed as lump formation was observed of PVP in methanol. T2 batch contained combination of PVPK15-EC but again negative results were obtained due to lump formation and water as a solvent. T3 Batch had combination of ERS100-HPMCE50 but the patch observed was found to be sticky and rough. T4 batch had combination of HPMCE50-EC which showed positive result with methanol as a solvent. By Trial batches it was found that T4 batch was found to give positive results among all the four trial batches.

Losartan potassıum loaded HPMC E50 – Ethyl cellulose transdermal patches by 3² full factorıal design:

Polymeric solution was prepared by blending HPMC E50 and Ethyl cellulose in 10ml of methanol till a clear solution occurs. After clear solution is achieved specified amount of losartan potassium is taken and added in 5ml of dimethyl sulphoxide and clear solution should be achieved. Later both the solution should be mixed and 5ml of polyethylene glycol 400 should be added in it. 5 ml of the casting solution was poured down into a glycerin-lubricated glass mould; entrapped air bubbles were evacuated, and the mould was allowed to dry at room temperature for 24hours to allow the solvent to evaporate. By inverting a glass funnel over the petriplate, the rate of solvent evaporation may be regulated. After 24hours, the patches were peeled off and cut into a circle with a radius of 2.1cm and a surface area of 13.85 cm². These patches were dried for two days in a desiccator.

Optimization Data Analysis:

For the influence of each variable on the designated response, STAT-EASE 360 trial version was employed. For the statistical significance of each response coefficient, surface plots were created. The full factorial design was utilized. In the current investigation, using design expert software Stat-Ease 360, the influence of these variables on moisture uptake, cumulative amount of medication released in 2hours, and %CDR at 12hours were explored. 3²factorial design was used for preparation of 9 formulation. 2 factors were taken which are observed as independent variables such as HPMC E50 (X1) and Ethyl cellulose (X2). Three responses (Dependent variables) were considered Y1 as %CDR at 2 hours, Y2 as %CDR at 12 hours and Y3 as % Moisture uptake. Three levels were considered as low, medium and high and all possible combinations of all formulations was shown in Table 1.

Table 1. Experimental design as per 3² Full factorial Design

Formulation code	CODED VALUES
	X1	mg	X2	mg
F1	1	800	1	600
F2	1	800	0	500
F3	1	800	-1	400
F4	0	700	1	600
F5	0	700	0	500
F6	0	700	-1	400
F7	-1	600	1	600
F8	-1	600	0	500
F9	-1	600	-1	400

Here low level indicates -1, Medium level indicates 0, High level indicates 1.

MATERIALS AND METHODS:

Materials:

Losartan potassium was procured as a gift specimen from Sozin flora pharma LLP. HPMC E50, Ethyl cellulose was obtained from Research-lab fine chem industries where as methanol, DMSO and PEG 400 was procured by Hexon laboratories pvt. Ltd. Instrument- For analytical estimates, a Shimadzu double beam UV-visible spectrophotometer with matched pair of 1 cm quartz cells was utilized, Franz diffusion cell of orchid was used , vernier caliper of mitutoyo was utilized.

RESULT:

Preformulation studies:

The drug was characterized for the organoleptic properties and the observed properties was correlated with the reported standards where the observed characteristic of patches complies to that of reported standards.

Melting point determination:

The observed melting point of the LP was found to be within the range of reported standard of LP (182- 185˚C). The melting point determination was done by Thile’s tube method.

FTIR Studies:

[a]

[b]

Figure 2. [a] FTIR of Losartan Potassium. [b] FTIR of Losartan drug and Physical mixture.

The Functional group Test absorption of Losartan potassium were found to be within the limits of characteristic absorption. By interpreting FTIR of physical mixture it was concluded that there is no interaction between the polymers and the drugs as discussed in Figure 2.

Dıfferentıal scannıng calorımetry:

[a]

[b]

Figure 3. [a] DSC of Losartan potassium. [b] DSC of Physical mixture.

The DSC curve of losartan potassium shows a endothermic peak between 170.84–177.68^ÕC corresponding to its melting, which confirms the purity of the drug. The drug do not undergoes decomposition following its melting. The drug do not undergoes decomposition following its melting.

Evaluations:^{20,21,22,23,24,25}

Physical Appearance

The physical appearance of all 9 batches of transdermal patches were found to be flexible, smooth, clear and transparent as well as non-sticky.

Thickness:

Each film's thickness was determined to be consistent across all formulations. The thickness of the material ranged from 0.104mm to 0.354mm as shown in Table 2.

Folding Endurance:

The findings of the test showed that the patches did not shatter even after being folded 250 times, indicating that they had strong elasticity and could withstand ordinary skin folding. The folding endurance of a patch is a measurement of its capacity to endure a rupture as shown in Table 2.

Drug Content:

The drug content was found between 97.79-98.9% as depicted in Table 2.

Table 2. Physical characteristics

Sr.no	Formulation code	Thickness (mm)	Folding endurance	Drug content (%)	Surface pH
1)	F1	0.200 ±0.88	278 ±4.72	97.9 ±1.24	5.99
2)	F2	0.216 ±0.72	259 ±2.51	98.00 ±1.41	6.23
3)	F3	0.310 ±0.55	265 ±3.46	98.00 ±1.73	6
4)	F4	0.190 ±0.99	270 ±3.18	98.21 ±1.87	6.14
5)	F5	0.169 ±0.39	290 ±4.72	98.31 ±1.15	6.50
6)	F6	0.232 ±0.92	242 ±3.05	97.72 ±1.45	6.59
7)	F7	0.198 ±0.67	256 ±3.13	98.10 ±1.51	6.01
8)	F8	0.321 ±0.25	280 ±4.16	97.96 ±1.42	5.88
9)	F9	0.334 ±0.18	278 ±4.32	98.23 ±1.36	5.01

% Moisture Absorption:

The percentage moisture uptake for HPMC-EC was found to be in the range of 1.2 % to 4.8 %, which might be attributable to the polymer's hydrophilic and hydrophobic properties as shown in Table 3.

% Moisture Loss:

The patches remained stable and became a totally free from becoming completely dry and brittle due to the decreased moisture content in the formulations as represented in Table 3.

Swellability:

The percentage of Losartan Potassium loaded HPMC E50 and EC patches that swelled was about 35%, indicating significant swelling as depicted in Table 3. The swelling was significant because the hydrophilic polymer improved the surface wettability and, as a result, Moisture permeation into the matrix.

Table 3. Physicochemical characteristics of transdermal patches

Sr. No.	Formulation code	Swellability (%)	Moisture uptake (%)	Moisture loss (%)
1)	F1	25.52 ±1.9	2.72 ±0.67	1.93 ±0.54
2)	F2	26.14 ±1.03	3.09 ±0.76	2.31 ±0.97
3)	F3	29.98 ±0.98	3.66 ±0.73	2.23 ±0.91
4)	F4	43.46 ±1.16	2.58 ±1.65	3.68 ±1.06
5)	F5	23.30 ±0.86	2.51 ±0.98	2.16 ±0.80
6)	F6	36.60 ±0.99	2.69 ±0.70	3.00 ±0.99
7)	F7	36.83 ±1.10	2.96 ±0.96	3.13 ±1.20
8)	F8	31.60 ±1.16	2.83 ±1.19	2.68 ±0.79
9)	F9	26.10 ±0.98	2.33 ±1.20	2.99 ±1.01

In-Vitro Drug Release Study:

For a low dose of Losartan potassium, % CDR was higher in the case of F5 batch, which released 11.50 mg/cm²/12hrs, egg shell membrane was used as membrane for the test. The hydrophobic nature of the Ethyl cellulose polymer could explain the controlled release. The cumulative % drug release for all formulation ranges from 38.97±1.10 to 45.98±2.12 in 12hrs as shown in Table 4.

Table 4. Cumulative percentage amount of drug released of losartan potassium loaded Transdermal patches [F1-F9].

Time (Hours)	F1 (%)	F2 (%)	F3 (%)	F4 (%)	F5 (%)	F6 (%)	F7 (%)	F8 (%)	F9 (%)
1	0.22 ±0.87	0.94 ±0.44	1.24 ±0.27	1.01 ±0.19	0.82 ±0.13	0.62 ±0.67	0.54 ±0.23	1.51 ±0.05	0.43 ±0.13
2	3.37 ±1.26	4.09 ±1.33	4.99 ±1.33	5 ±1.8	2 ±1.4	3.03 ±1.0	3.79 ±0.87	4 ±0.76	2.73 ±0.20
3	8.01 ±1.33	8.23 ±1.45	8.01 ±1.45	9.23 ±1.22	4.69 ±2.4	7.87 ±1.05	8.54 ±1.0	9.54 ±1	6.35 ±0.76
4	12 ± 1.89	11.98 ± 1.72	12.23 ± 1.72	13.95 ±1.38	9.3 ± 1.49	13.76 ±1.23	13.2 ± 0.83	14.53 ±0.79	11.31 ±0.99
5	17.1 ±2.0	15.76 ±1.63	16 ±1.63	17.66 ±1.59	15.01 ± 2.48	18.06 ± 2.4	17.42 ±1.02	19.99 ±1.01	15 ±1.0
6	22.13 ±2.3	20.98 ±1.82	22.1 ±1.82	21.74 ±1.66	21.9 ±2.02	23.43 ±1.29	22 ±2.03	24.01 ±1.23	19.8 ±1.07
7	28.9 ±1.67	26.77 ±1.25	25.97 ±1.25	25.23 ±1.91	27.63 ±1.30	28.01 ±2.30	26.76 ±1.99	28.88 ±0.45	23.05 ±1.15
8	34.02 ±1.31	31.23 ±1.19	29.76 ±1.19	29.45 ±1.83	33.86 ±2.10	33 ±2.54	31.32 ±1.65	35 ±0.99	27.76 ±1.11
9	37.67 ±1.63	35.88 ±1.31	34.39 ±1.32	34.34 ±1.77	39.15 ±2.56	36.09 ±2.0	36.17 ±1.90	37.23 ±1.45	30.09 ±0.54
10	40.03 ±1.26	41 ±1.67	38.74 ±1.83	38 ±1.45	42.02 ±1.99	41.99 ±1,14	39 ±2.0	39 ±2.05	34.98 ±1.45
11	41.89 ±2.3	42.42 ±1.33	39 ±1.95	39.11 ±1.21	45.29 ±2.54	42.01 ±2.6	40.9 ±1.52	40.12 ±2.12	37.8 ±1.47
12	43 ±1.72	40 ±1.72	39.85 ±1.18	40.24 ±1.07	45.98 ±2.12	42.50 ±2.03	41.01 ±1.34	43.99 ±2.03	38.97 ±1.10

Optımızatıon Data Analysis:

In this design, 3²factorial design was used following the linear model. 2 factors were taken which are observed as independent variables such as HPMC E50 and Ethyl cellulose. And as dependent variables 3 responses were taken such as % Drug released after 2hours, %Drug released after 12hours and % Moisture uptake.

ANOVA for Linear Model:

Table 5. Response 1- DRUG RELEASE at 2 HOURS (%)

Source	Sum of Squares	df	Mean Square	F-value	p-value
Model	6.68	2	3.34	14.26	0.0052	Signifi-can’t
A-HPMC	6.68	1	6.68	28.50	0.0018
B-EC	0.0048	1	0.0048	0.0206	0.8907
Residual	1.41	6	0.2343
Cor Total	8.09	8

The model's F-value of 14.26 suggests that it is significant.

[a]

[b]

[c]

Figure 4. [a] 3D surface of Response 1. [b] Contour graph of Response 1. [c] Perturbation graph of Response 1.

[a] indicates 3d surface graph of all 9 formulation where it can be concluded that as concentration of polymers increases drug release decreases. [b] indicates Contour graph which is a 2D version of 3d surface plot. [c] indicates perturbation graph of response 1 where it has been confirmed that HPMC (A) and Ethyl cellulose (B) have an equal effect on drug release at 2 hour.

Table 6. Response 2- DRUG RELEASE 12 HOUR (%)

Source	Sum of Squares	df	Mean Square	F-value	p-value
Model	16.34	2	8.17	6.16	0.0351	Signific-ant
A-HPMC	14.54	1	14.54	10.97	0.0162
B-EC	1.80	1	1.80	1.36	0.2877
Residual	7.95	6	1.33
Cor Total	24.30	8

The F-value of 6.16 for the model indicates that it is significant.

Figure 5. [a] 3D surface of Response 2 [b] Contour graph of drug release at 12 hour [c] Perturbation graph of Response 2

[a] indicates 3d surface graph of all 9 formulations where it can be concluded that drug release decreases as the quantity of both the polymers increases. [c] indicates perturbation graph of response 2 where it has been confirmed that HPMC (A) and Ethyl cellulose (B) have an equal effect on drug release at 12 hour.

Table 7. Response 3 - % Moisture uptake

Source	Sum of Squares	df	Mean Square	F-value	p-value
Model	0.4483	2	0.2241	22.17	0.0017	significant
A-HPMC	0.4483	1	0.4483	44.33	0.0006
B-EC	0.0000	1	0.0000	0.0016	0.9689
Residual	0.0607	6	0.0101
Cor Total	0.5090	8

The significance of the model is indicated by the Model F-value of 22.17.

Figure 6. [a] 3D surface of Response 3 [b] Contour graph of Response 3 [c] Perturbation graph of Response 3

[a] indicates % Moisture uptake where 3 formulations above surface are in green colour indicating less uptake. [c] indicates perturbation graph of response 2 where it has been confirmed that HPMC (A) and Ethyl cellulose (B) have an equal effect on % Moisture uptake.

[a]

[b]

Figure 7. [a] Desirability graph [b] Overlay plot

Desirability is indicated in [a] showing the value of 1 of the formulations. Overlay plot [b] indicates the optimized quantity of X1 and X2.

The confirmation analysis of design expert software confirmed that F5 batch was found to be the best batch among the 9 formulation batches.

2.5. Kınetıcs study:

The optimum formulation, Losartan Potassium loaded HPMC E50-Ethyl cellulose, was discovered to follow zero order kinetics and korsmeyer-peppas model (non-fickian diffusion) as described in Table 8.

Table 8. Release kinetic modelling of drug release

Formulation code	Zero order (R²)	Korsemeyer peppas (R²)	n value
F1	0.978	0.897	0.805
F2	0.975	0.963	1.106
F3	0.980	0.967	1.212
F4	0.979	0.414	1.168
F5	0.993	0.998	0.578
F6	0.988	0.956	0.990
F7	0.983	0.951	0.578
F8	0.986	0.978	1.227
F9	0.993	0.946	0.944

[a]

[b]

Figure 8. [a] Zero order model (F1-F9) [b] Korsmeyer peppas model (F1-F9)

Table 8 and Figure 8 explains that the formulation follows zero order kinetic model and korsmeyer peppas model.

2.6 IN-VITRO flux calculatıon

F5 (Optimized batch) showed flux of 64.37±1.06µg cm^-2 h ^-1.

2.7 Stability studies:

Stability study of optimized f5 batch was conducted at 40°C±2°C/75±5% RH for 2 months and the results obtained concluded that the formulation was found to be stable with minimum changes in parameters such as drug release at 12 hour and % drug content.

CONCLUSION:

The focus of this research was to develop sustain release transdermal patch of losartan potassium utilizing different polymers such as HPMC E50, PVP, Eudragit RS100, and ethyl cellulose and plasticizers such as PEG-400 and Dibutyl phthalate and DMSO as a penetration enhancer via solvent casting method for a low dose of the drug. Several trial batches were taken for the right combination of polymer. A proper mixture of Hydrophilic polymer and Hydrophobic polymer was done. After many combinations, the right combination was found of HPMC E50 as hydrophilic polymer and Ethyl cellulose as hydrophobic polymer. The weight gain or water absorption of the patches owing to the presence of polymer was assessed, and the transdermal patches demonstrated excellent swelling and maintained the formulation integrity necessary for bio-adhesion. We were able to determine the permeation properties by measuring the amount of moisture transfer through the unit area of a patch. Even in humid settings, a minimum water vapor transfer rate implies a higher stability. The low water loss and absorption percentages keep the patches steady and prevent them from becoming brittle, as well as protecting them from microbial growth. According to in-vitro drug trials, Losartan Potassium loaded with polymers HPMC E50-EC with PEG-400 as a plasticizer was shown to be the optimum formulation, with drug release of 11.50mg/cm²/12hours. The patches Losartan Potassium concentration remained steady for two months, and the patches physicochemical and drug release properties did not alter significantly. Determining the interplay of formulation factors was facilitated through optimization, as evidenced by the fact that increasing both the polymer concentration and the drug quantity reduces drug release, and it was discovered that the quantity of HPMC E50 had an effect on water uptake, i.e. when its quantity was enhanced, water absorption also was enhanced. To examine the medication release kinetics release details was assessed using the zero order model and Korsmeyer-Peppas model. The drug release from TDDS patches formulated followed zero order kinetics. When the release data was evaluated using Peppa's equation, TDDS patches confirmed non-fickian (anomalous) diffusion as the release mechanism. According to the findings of this study, such transdermal patches of Losartan Potassium may give sustained release transdermal distribution for extended durations in the treatment of hypertension, which might be a good strategy to avoid substantial hepatic first-pass biotransformation. The study's findings demonstrated the viability of developing rate-controlled transdermal films of Losartan Potassium for successful hypertension treatment. To establish an appropriate transdermal system for Losartan Potassium, more in-vivo research is needed to match in-vitro permeability experiments.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors wish to acknowledge the help provided by the technical and support staff of GES’s Sir Dr. M. S. Gosavi College of Pharmaceutical Education and Research, Nashik.

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Received on 05.10.2024 Revised on 20.12.2024

Accepted on 15.02.2025 Published on 23.04.2025

Available online from April 26, 2025

Asian J. Pharm. Tech. 2025; 15(2):119-126.

DOI: 10.52711/2231-5713.2025.00020

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.