INTRODUCTION:

Generally oral route is the most common route of drug delivery method and it may have good patient compliance except few drawbacks of oral route drug administration such as drug degradation, first pass metabolism, gastrointestinal tract irritation, and pH-dependent drug release etc., Hence, the current research aimed to develop a novel transdermal product to overcome these drawbacks. Initially, the NDDS was created by China in 1992, Banker in 1990, and Guy in 1996 as a solution to these issues.

For that, Transdermal drug delivery systems (TDDS), or transdermal patches, were used. Medicated adhesive patches are created in this system, and when applied to the skin, they distribute a therapeutically effective dosage of medication. They were available in various sizes and contain multiple ingredients. After application to intact skin, they may cross the skin barriers to release the active ingredients into the bloodstream^1-2.

TDDS are self-consisted dosage forms, the drug release happened in a controlled manner for over period of time when applied to skin. Major attribute through transdermal delivery of products was designing of dosage design to minimize drug retention and metabolism while simultaneously optimizing the amount of drug that is absorbed through the intact skin and into the systemic circulation. Because it avoids first pass metabolism and increases patient compliance, TDDS offers a significant advantage over injectables and oral routes. Among these, TDDS is the most appealing due to its low rate of rejection, exceptional ease of administration, and exceptional patient convenience and persistence^3-4. Administration of doxazocin with alcohol, it may lower blood pressure, breathing problems, fainting. To avoid these drawbacks, the current research aims to develop a transdermal product.

Doxazosin is a quinazoline-based alpha 1-adrenoceptor antagonist are used to treat benign prostatic hyperplasia and hypertension. medications that, because of their established dose and toxicity profiles, have already received approval for new indications, cutting down on the time and expense needed to develop new medications⁵. Doxazosin appears to be beneficial in treating posttraumatic stress disorder (PTSD), according to available data. Prazosin's "me-too" counterpart is doxazosin. Because doxazosin has a better absorption profile, the possibility of unintentional negative hypotensive effects is probably reduced⁶.

Various types of TDDS^5-7:

Single-layer Drug-in-Adhesive System:

The medication is contained in the system were adhesive layer. There is a backing and a temporary liner all around the adhesive layer.

Reservoir System:

The drug reservoir in this system is maintained between a rate-controlling membrane and a backing layer. The drug may be distributed throughout the reservoir compartment in a solid polymer matrix or as a gel, suspension, or solution.

Matrix System:

The system includes two types

Drug-in-Adhesive System:

In the drug-in-adhesive system, the drug is dissolved in an adhesive polymer and then the medicated polymer adhesive is spread onto an impermeable backing layer either by solvent casting or, in the case of hot-melt adhesives, by melting the adhesive.

Matrix-Dispersion System:

Polymer matrix disperses the drug uniformly in the matrix-dispersion system. The application of adhesive layer on the drug reservoir's face to create an adhesive rim strip, this system distributes the adhesive around the circumference.

Micro-Reservoir System:

This system combines matrix and reservoir types. This involves suspending the drug in an aqueous solution of a water-soluble polymer. Out of all of these varieties, the matrix transdermal system was chosen for the current study, and the formulation was completed appropriately⁸. Among these types, matrix type of transdermal system was selected for present research and formulation has done accordingly. Types of patches in diagrammatic representation is shown in Figure 1.

Figure 1: Types of various TDDS approaches

The current research work proposes to develop a transdermal patch of doxozocin mesylate which is not existed in the current market. We have considered the literature established on the same category of another drug and formulated and evaluated the prepared patches.

MATERIALS AND METHODS:

Materials:

The HPMC K100 and PVP K30 was purchased from Sigmaldrich, India. Methanol was purchased from Sai chemicals, Hyderabad. Starch and Glycerine were purchased from Asha chemical lab, Hyderabad.

Preparation of transdermal patch using solvent casting technique:

Solvent casting technique was used for the preparation of transdermal patches with a petri dish area of 42.98 cm² respectively. The selected polymers were weighed as per required weight and dissolved in solvent in which two patches were prepared with methanol and water (1:1) and three patches were added with methanol. The prepared ratios were kept aside until to form clear solution. This solution was used to mix with drug and then continuous stirring is required to form a clear solution. The prepared solution was poured on to the petri dish and a funnel is placed in inverted position to prevent fast evaporation of the solvent. The dried patches were taken out after 24h for further evaluation^9-10. The various compositions of patches are shown in Table 1.

Table 1: Formulation composition of different patches

Drug/Excipients	PF1	PF2	PF3	PF4	PF5	PF6
Doxazosin mesylate	2.6 mg	2.6 mg	2.6 mg	2.6 mg	2.6 mg	2.6 mg
HPMC K100	-	-	-	0.3mg	0.5mg	0.7mg
PVP K30	0.3mg	0.5mg	0.7 mg	-	-	-
Methanol	10ml	5ml	-	-	-	10ml
Ethanol	-	-	5ml	10ml	10ml	-
Water	-	5ml	5ml	-	-	-
Glycerin	1ml	-	-	1ml	1ml	1ml
Starch	-	0.5mg	0.5mg	-	0.5mg	-

Figure 2: Schematic representation of patch formation

Pre formulation studies:

For the present research work we performed solubility studies to know highest maxima of solubility for obtaining uniform drug distribution for patch and UV Absorption maxima to know maxima drug spectrum.

Solubility:

Doxazocin mesylate molecule was test for solubility in different solvents like dimethyl sulfoxide (DMSO), methanol, water and acetic acid respectively.

UV Absorption maxima:

The UV spectrophotometer was used to identify the drug absorption maxima, for the doxazocin mesylate, spectra λ_max was observed at 280 nm. The observed spectral data was used for the preparation of calibration curve of doxazosin mesylate¹¹.

Calibration Curve:

The calibration curve was performed using pH 6.8 phosphate buffer and 2, 4, 6, 8, 10 and 12 µg/ml concentrations were prepared to record the standard graph respectively. The samples were measured in UV spectrophotometer at a λ_max of 280 nm. The calibration curve of doxazosin mesylate yield a value of 0.984 for square of correlation at linearity.

Dose calculation for transdermal drug delivery:

Till now there is no transdermal product of Doxazosin mesylate in the market. The aim of current research is to develop a dermal patch to reduce the side effects encountered through oral route. Based on the other investigations based on the same pharmacological activity of drug molecule, we have developed transdermal dose for Doxazosin mesylate as follows^8,12. The equation shown in Eq 1.

Oral dose x bioavailability

Transdermal dose = ------------------------------------- Eq 1

100

4Mg X 65

T. D = -------------------

100

260

T.D =------------- = 2.6mg/day

100

Methods for evaluation of patches:

Among various methods of patch evaluation, we have performed few parameters based on the laboratory facility in our institution.

Thickness of patches:

The thickness of patch was determined at ten various points on patch using screw gauge. The same procedure was repeated for each formulation and average thickness for all patches were measured¹³. The formula shown in equation 2

Thickness = Main scale + (Circular scale + Least count)

Eq 2

Folding endurance:

The specific area (2cm∗2cm) of patch was cut with square shape and repeatedly folded at the same place until it gets break. Counted the number of times of folds at the same place and reported for folding endurance⁶.

Drug content:

The required area (2 cm∗2 cm) of patch was dissolved in 100 ml of methanol and shaken continuously until patch gets dissolved completely. Then the solution was sonicated up to 15 min and then filtered the solution to remove unwanted material. Finally, the sample was estimated spectrophotometrically at 280 nm respectively.

Percentage Moisture Content:

The patches were weighed and placed in a desiccator containing fused calcium chloride and stored at room temperature of 24 h. After the specific time period, the films were reweighed and conducted the percentage moisture content analysis using following equation 3⁷:

Initial weight – Final weight

% Moisture content = ---------------------------------

Final weight

Eq 3

Drug release studies through paddle over disk apparatus:

Generally, the paddle over disk apparatus is used for transdermal patches. But in our institution, it is not available. Hence, we fabricated a model to perform the drug release studies. The paddle dimensions and vessel configuration remain constant. The dosage form is placed over the small watch glass which is covered with wire mesh screen, which was used to release the drug slowly. The watch glass is then placed at the bottom of the apparatus which was placed at a height of 2.5 cm above the watch glass, and basket filled with pH 6.8 phosphate buffer up to 900 ml. The complete system was maintained at 32±0.5^oC respectively^13-15. The drug release test scheme was shown in figure 3.

Figure 3: Illustration of dissolution studies of patch

Kinetics of drug release studies:

The kinetic models were used to justify the pattern and mechanism of drug release for the prepared formulations. Pharmaceutical formulations were used mathematical expressions for kinetics respectively. The kinetic parameters effected by the type of drug, drug dose, types of excipients, preparation method, environmental conditions respectively. The zero-order and the first order model describe that the release pattern of drug whether the release was independent of concentration or dependent of concentration. Whereas Higuchi and Korsmeyer-Peppas model describe the mechanism of drug release i.e., diffusion mechanism of drug release by erosion, non-Fickian diffusion, Fickian diffusion and super case transport respectively^16-17.

FTIR studies:

Drug-excipient interactions are important for the formulation to know compatibility among drug and excipients. The IR spectra of samples were recorded in the range of 400 to 4000cm^-1 using Bruker FTIR spectrophotometer (Thermo Scientific, Model: NicoLET 6700) equipped with Opus software^18-19.

RESULTS:

The transdermal patches of doxazosin mesylate were prepared and evaluated for various parameters. The results were mentioned below for all the evaluated parameters. The thickness of various patches were evaluated and the results are shown in Figure 4. The major difference between all the prepared formulations were not observed may be due to uniform distribution of the drug and pouring solution in one direction.

Figure 4: Bar diagram for thickness of patches

Folding endurance was studied to know the fragile or rigid nature of the prepared patches. The required measured patch was taken to hand and folded according to method specified in literature. The PF4 formulation shown rigid up to six folds and the remaining prepared patches were flexible to obtain only four folds. From table 2, the % MCA is very less from PF4 as compared to other developed formulations. The results are tabulated in Table 2.

Table 2: Results of percentage moisture content

S. No.	Formulation	Initial weight (mg)	Final weight after 24h (mg)	% Moisture content absorption (MCA)
1	PF1	0.99	0.89	10.2±0.2
2	PF2	0.73	0.63	15.7±0.1
3	PF3	0.80	0.71	12.6±0.2
4	PF4	1.05	1.01	4.6±0.4
5	PF5	0.95	0.91	5.0±0.6
6	PF6	0.81	0.56	14.3±0.1

*The % MC values are mentioned as mean ± s. d

From the drug content results, we have observed that use of PVPK30 (PF1- PF3), the % DC values are less as compared with HPMCK100 containing formulations (PF4-PF6) all the prepared patches were shown very similar results and the results are shown in table 3.

Table 3: Percentage drug content values of prepared patches

Formulation	Area of the patch (cm²)	Drug content (% yield)
PF1	40.69	72.1±0.1
PF2	42.98	70.8±0.2
PF3	40.69	60.1±0.6
PF4	42.69	85.8±0.4
PF5	40.72	74.1±0.1
PF6	42.69	79.6±0.8

*The % DC values are mentioned as mean ± s.d

Drug release studies:

The drug release studies of all the prepared patches were performed using paddle over disc method apparatus. From the results, we have observed that HPMCK100 containing patch shown maximum drug release (85.2%) and also noticed that lower range of polymer HPMCK100 shown maximum release as compared to intermediate (PF5) and higher concentration (PF6) respectively. Whereas for polymer PVP K30 also found in the same manner, i.e., retardation of drug release was observed with increasing concentration. The drug release pattern of all patches are shown in Figure 5.

Figure 5: Cumulative drug release profiles of prepared patches

It was observed that all the prepared patches for drug release up to 12h followed first order release kinetics, because the correlation coefficients for first order were more than the corresponding value for the zero order in almost all the cases. It was found that all the prepared patches followed diffusion mechanism. Plots of first order release of doxazocin mesylate released for all the patches were found to be linear. The mechanism of drug release was followed diffusion, it can be denoted with its highest correlation coefficient ‘r’ values of the Higuchi equation. The first order rate constant values of all patches were found to be in the range of 0.027 to 0.044 and correlation coefficient values (PF1 to PF6) up to 12 h were found to be in the range of 0.8960 to 0.9962. All the patch formulations followed Fickian diffusion, as indicated by the ‘n’ values of their Peppas plots respectively. The results are shown in table 4 and the optimized batch PF4 kinetic plots are shown in Figure 6.

Table 4: Correlation coefficient (r) values for drug release kinetics of doxazocin mesylate up to 12 h of drug release

Batch Codes	Zero order (M/s or M/min or M/hr)		First order (s^-1 or min^-1 or hr^-1)		Higuchi	Korsmeyer-Peppas
Batch Codes	K_O	R	K₁	r	r	R	n
PF1	3.78	0.8655	0.027	0.8960	0.9792	0.9602	0.259
PF2	5.34	0.9584	0.043	0.9863	0.9880	0.9793	0.341
PF3	4.84	0. 9175	0.044	0.9378	0.9800	0.9723	0.266
PF4	5.74	0.9466	0.051	0.9962	0.9835	0.9613	0.326
PF5	5.31	0.9502	0.045	0.9614	0.9955	0.9820	0.325
PF6	4.84	0.9481	0.038	0.9540	0.9817	0.9681	0.314

Figure 6: Release Kinetics of PF4

DISCUSSION:

Transdermal patches of doxazocin mesylate were prepared using solvent casting technique and evaluated for various parameters. The thickness observed was more for PF1, it may be due to low solubility of polymer in selected solvent. The folding endurance has been checked to know the brittleness. This has been proven by observing the result that, patches prepared using HPMCK100 were flexible not brittle. The % MCA is very less for PF4, it indicated that at intermediate stage of polymer may absorb very low quantity of moisture and it helps them to remain stable and fully dried. The percentage drug content observed as maximum for PF4 may be due to the uniformity with drug and excipients used together and also the maximum solubility of HPMCK100 with solvent system. The drug release from PF4 was found as more may be due to uniform distribution of all excipients in patch and the release mechanism followed slow diffusion controlled because of low viscosity of HPMC K100 polymer. All the prepared patches followed first order drug release, indicated that concentration dependent drug release over period of the time. Whereas mechanism of drug release was found to be fickian based on the ‘n’ value obtained through peppas kinetics. FTIR results concluded that there will be no deviation or extra spectrum formation was observed and it make a sense that formulation components used in the study was fully compatible with each other.

CONCLUSION:

Transdermal patch of doxazosin mesylate was prepared successfully and performed evaluation. All formulations showed desirable physiochemical properties like thickness, folding endurance, moisture content, in vitro drug release respectively, among these the PF4 formulation shown maximum drug release in 12 h. However, by the use of HPMCK100, maximum drug release was obtained as compared with PVPK30. Based up on the physicochemical evaluation and in vitro drug release and FTIR studies, it was concluded with the prepared patch thoroughly suitable to transdermal use with good potential application in the therapeutic and effective in producing controlled drug delivery by reducing dosage frequency. The current research future plan is to be extend the work to get a clear information of effectiveness of the dosage form through in vivo studies and bioavailability studies.

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Received on 30.07.2024 Revised on 18.12.2024

Accepted on 22.04.2025 Published on 01.07.2025

Available online from July 05, 2025

Research J. Pharmacy and Technology. 2025;18(7):3307-3313.

DOI: 10.52711/0974-360X.2025.00478

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