INTRODUCTION:

Hypertension is one of the most significant modifiable risk factors for cardiovascular disorders. The global prevalence of hypertension is steadily increasing, with India accounting for a significant portion of this burden. According to the global burden of disease report, systolic blood pressure causes the most deaths and disability adjusted life years of all risk factors, accounting for 10.2 million deaths and 208 million disability adjusted life years (DALYs)^1,2,3.

Transdermal administration has been identified as a possible route for local and systemic delivery of hypertensive drugs, delivering a predetermined amount of medication to intact skin at a pre-programmed pace.⁴

Every pharmaceutical researcher and industry wants to create a safe and effective drug delivery system. Drug delivery via the transdermal route may have both local and systemic therapeutic effects. Transdermal drug delivery is an appealing alternative to oral drug administration since it avoids first-pass metabolism and gastrointestinal side effects and it can also resolve poor patient compliance involved in other routes of drug delivery^5,6,7,8.

The drug is typically inserted into a liquid, gel, rigid matrix, or pressure-sensitive adhesive carrier in transdermal patches. A drug is often dispersed in a pressure-sensitive adhesive matrix nowadays. The backing membrane, the adhesive, excipients, drug, and a release liner are all basic elements of a drug in an adhesive system. A pressure-sensitive adhesive (PSA) layer is included in all transdermal delivery systems to secure the patches in place on the skin. The drugs are specifically used in the adhesive in monolithic drug in adhesive (DIA) patches. These systems have the benefits of being relatively simple to manufacture and having limited thickness and surface area^9,10,11. Polyisobutenes (PIB) are a chemically inert pressure sensitive adhesive used in transdermal therapeutic systems. They also show good resistance to ageing, weathering, heat, and chemicals. Polyisobutene is used in monolithic medication in adhesive (DIA) patches since it is relatively simple to manufacture and has limited thickness and surface area. The viscosities of PIB adhesives with different molecular weight distributions will affect drug recrystallization. Furthermore, the drug diffusion coefficients are affected by the matrix's molecular weight. As a result, drug release can differ depending on the molecular weight distribution of PIB matrices^12,13.

Atenolol is a low-lipid-soluble beta 1 selective adrenoreceptor antagonist. It has been used to treat hypertension and stable angina. It is a BCS class 3 drug with low permeability and having a maximum dose of 100mg. In humans, oral absorption is around 50% due to incomplete intestinal absorption. It has been reported that when Atenolol is taken orally, it can induce diarrhea, nausea, mesenteric arterial thrombosis, ischemic colitis, and dry mouth. Atenolol undergoes extensive first-pass hepatic metabolism and has a biological half-life of 6-7 hours^14,15,16. Polyisobutene may exhibit a sustained release without any burst effect in the case of Atenolol.According to the literature review, there hasn't been much research done on polyisobutene as a blend in terms of release pattern and other properties¹⁷.

Literature review showed, silicone,polyisobutene and acrylate matrices containing lidocaine at its saturation solubility were used to investigate the effect of the pressure-sensitive adhesive (PSA) matrix on the permeation, release, and physical characteristics of transdermal delivery system, which concluded that the drug release and permeation profiles were influenced by the PSA used.⁹In another study 4-benzylpiperidine drug-in-adhesive matrix type transdermal patch was formulated wherein, drug in silicone adhesive patch and Polyisobutylene adhesive based patch were developed and evaluated for its in-vitro transdermal permeation profile. Polyisobutylene adhesive-based patches with higher drug concentrations showed superior transdermal permeation among the patches developed.¹⁷Some other approaches used to minimize the adverse effects and increase the utilization of drug were,attaining sustained release of atenolol by using a crosslinked graft co-polymer of natural gum, Gum dammar (Gd), acrylamide, Gd-cl-poly(AAm) and its organo-inorganic hydrogel composite with zirconium (i.e. ZHC)¹⁸. Development of proniosomes as a transdermal drug delivery system for Atenolol¹⁹.

The current aim of the study was to formulate different matrix patches of Atenolol using two different molecular weight polyisobutenes varying the proportion in combination with ethyl cellulose as thickening agent and its evaluation for effective transdermal delivery of drug.

MATERIALS AND METHODS:

Materials:

Atenolol was obtained as a gift sample from ZydusCadila, Goa. Polyisobutene polymers (PV 10 & PV 200) were procured from M.R. Silicone Industries, Dahisar-Mumbai. Ethyl cellulose was procured from Hi Media. Polyethylene glycol 400 was obtained from Merck, Mumbai. Propylene glycol was obtained from Ranbaxy, New Delhi. Chloroform and acetic acid were obtained from SD Fine Chemicals Pvt. Ltd.

Method:

Formulation of Atenolol transdermal patches:

Solvent evaporation was used to prepare transdermal placebo patches. High molecular weight and low molecular weight polyisobutenes, as well as ethyl cellulose as a thickening agent, were used to formulate atenolol patches (Table 1).The required quantity of polyisobutenes was accurately weighed and dispersed in chloroform using a magnetic stirrer until it was completely dissolved in the solution. Then, to the above solution, ethyl cellulose was added and stirred until a clear solution was obtained. Simultaneously, a precisely weighed necessary quantity of drug was taken and dissolved in acetic acid in another beaker.To achieve a homogeneous mixture, the resultant solution was progressively applied to the polymeric solution. To the above homogeneous solution, plasticizers and penetration enhancers were applied. The solution was poured into a petridish and left overnight to dry. A backing membrane made of aluminium foil was used. Patches were cut to the appropriate sizes and placed in a desiccator for storage^20,21.

Evaluation of transdermal patches:

Physical appearance and surface texture:

The appearance, texture, and clarity of the prepared formulations were examined visually.

Thickness:

Thickness was measuredat three different places using verniercaliper²².

Weight uniformity:

The total weight was determined after weighing three different films from different batches²³.

Percent moisture content:

The films were weighed individually and stored at room temperature for three days in a desiccator containing fused calcium chloride. Individual films were weighted once more. The procedure was repeated until the weight remained unchanged.The percent moisture contentwas calculated using forumula²⁴.

Initial weight

Percent moidture content = ---------------------------- × 100

Final wieght

Percent moisture uptake:

Films were weighed and stored in dessicator for three days at normal room temperature.They were exposed to 75 percent relative humidity (200ml of saturated sodium chloride solution) before a steady weight for the film was achieved. Percent moisture uptake was calculated using the formula²⁵:

Final weight – Initial weight

Percent moisture uptake = ----------------------------------- ×100

Initial weight

Flatness:

The length of each strip was determined, and the difference in length was calculated using the percent constriction method. 100% flatness was perceived to be the same as zero percent constriction²⁶.

Folding endurance

The patch's folding endurance was calculated manually by folding the patch at the same point before noticeable cracks or breaks appeared. The value of folding endurance was determined by the number of times the patch could be folded in the same position without splitting²⁶.

Surface pH:

pH meter was calibrated using buffer solutions pH 4 and pH 7. Surface of the patches was kept in contact with distilled water. After bringing the electrode of the pH metre in contact with the surface of the formulation for 1 minute to allow for equilibrium, the pH was reported. For each formulation, the average of three determinations was taken²⁷.

Tensile strength:

The applied load at rupture was divided by the strip's cross-sectional area to determine tensile strength, as shown in the equation below:

Load (kgs) ×100

Tensile strength (g/cm2) = ----------------------------------- ×100

Strip thickness X strip width

A film strip measuring 2 X 2 cm² was clamped between two clamps that were spaced 3 cm apart. To keep the film from being cut by the clamp's grooves, a double-sided tape was used to stick a cardboard to the clamp's surface. The strips were pulled at the bottom clamp by adding weights to the pan until the film broke and the load was measured during the measurement²⁸.

Percentage elongation (%):

When a film sample is stressed, it stretches, which is referred to as strain. Strain is defined as the deformation of the film separated by the sample's original dimensions.Percentage elongation was calculated using formula²⁸:

Length of patch at break when

stress is applied – Original length

Percent elongation at beak = -------------------------------------------×100

Original length

Drug content:

Using phosphate buffer pH 7.4, a standard calibration curve for Atenolol was obtained. The absorption maxima of 273nm was obtained and used in subsequent calculations. By dissolving a correctly measured portion of the patch in 10ml of methanol in a 100ml volumetric flask, the drug content was determined. The solution was stirred until the substance was fully dissolved. Phosphatebuffer was used to increase the volume to 100 mL. The solution was filtered. 1mL from the above solution was pipetted into a 50mL volumetric flask, which was then made up to mark with pH 7.4 phosphate buffer. The drug content of each formulation was measured using the normal calibration curve after calculating the absorbance at 273nm²⁹.

In-vitro skin permeation study:

A Franz diffusion cell with a receptor compartment capacity of 35ml was used to conduct an in-vitro permeation analysis. The receptor compartment was filled with phosphate buffer pH 7.4. Between the donor and receptor compartments, a dialysis membrane was mounted.The formulated film of 1×1cm was cut and placed over the dialysis membrane. With the aid of rubber bandages, the donor compartment was then placed and secured over it. The entire assembly was mounted on a magnetic stirrer, which continuously stirred the solution in the receptor compartment. The temperature was held at 37±2ºC. Samples of 1 ml were withdrawn at time intervals of 1, 2, 3, 4, 5, 6, 24, 25, 26, 27, 28, 29, 30 hours and were analyzed at 273nm spectrophotometrically for drug content against blank. Every time the sample was removed, the receptor phase was replenished with an equal volume of phosphate buffer. The permeation percentage of the drug was measured and plotted against time³⁰.

Ex-vivo permeation study:

Ex-vivo permeation studies were carried out in a similar manner to in-vitropermeation studies, but in this case the dialysis membrane was replaced with that of rat skin³⁰.

Stability study:

Stability study of the formulated patches was carried out at normal condition (25°C±2°C/60% RH ±5% RH) and accelerated condition (40°C±2°C/75% RH ±5% RH) for a period of 30 days and 60 days.Each film was wrapped in an aluminium foil and was kept in stability chamber. The films were evaluated for drug content, tensile strength and in vitro drug permeation rate for a period of 30 and 60 days³¹.

RESULTS AND DISCUSSION:

Preparation of transdermal patches:

A mixture of low molecular weight PIB polymers and high molecular weight polymers was used to make placebo patches. With chloroform as the solvent (the concentration used was 15% w/w) patches were very sticky and difficult to remove.When the PIB concentration was changed, it was discovered that the patches were too sticky or that the film formation was not uniform, so thickening agents such as PVP, ethyl cellulose, CMC, sodium alginate, gelatin, carbopol, xanthan gum, HPMC, and others were tried in combination with PIB to improve the film forming capability of the PIB. Finally, ethyl cellulose was chosen because, when combined with PIB polymer, it produced a transparent and uniform patch. In a 1:2 ratio, chloroform and acetic acid were chosen as solvents. Polyethylene glycol 400 was used as a plasticizer, along with propylene glycol as a penetration enhancer. Except for propylene glycol, all other solvents (DMSO, dibutyl phthalate, isopropyl myristate) exhibited turbidity and took on an oily consistency as a result of the formation of oil globules, as shown in (Fig. 3).

Fig. 3: Transdermal patches. (a) Patch prepared using dibutyl phthalate (b) Patch prepared using tween 80 (c) patch prepared using PVP using chloroform as solvent (d) Different PIB formulations from F1 to F5

Physicochemical evaluation of transdermal patches:

All of the patches had a smooth surface, were clear and elegant in appearance, and were uniformly thick between 0.29mm and 0.33mm. It was discovered that as the concentration of polymers increased, the weight of the films increased gradually from 251 mg to 273 mg. As the concentration of low molecular weight PIB in the solution increased, so did folding endurance and tensile strength as shown in table no.3. The percentage elongation ranged from 15% to 65%, indicating that the prepared films were pliable. Since the moisture content was low, it meant that microbial growth was unlikely.

Using phosphate buffer pH 7.4, the standard calibration curve of atenolol was found to be in the range of 2-10 g/ml at a λ max of 273 nm with a straight line equation (y= 0.019x + 0.001) and an R2 value of 0. (0.999). The uniformity of drug content in all formulations was found to be sufficient, ranging from 93.13 percent to 98.36 percent.

In vitro permeation studies:

A phosphate buffer pH 7.4 was used in an in-vitro permeation analysis. In vitro permeation tests were performed on Formulations F1 to F5. Formulation F1 had the highest percent cumulative drug permeation rate (85.54%), while Formulation F5 had the lowest percent CDP (74.93%).

This may be due to a variation in the concentration of low molecular weight polyisorbutene. At the end of the 30th hour, the formulation with the lowest concentration of low molecular weight PIB had the highest drug permeation rate. The percent cumulative drug permeation rate was F1>F2>F3>F4>F5 in sequence as shown in (Fig. 4). Optimized formulation F1 was subjected to in-vitropermeation studies without the use of a penetration enhancer. Results of drug permeation showed that using a penetration enhancer increased permeation rates by about 7 times as compared to using a formulation without penetration enhanceras shown in (Fig. 5).

Fig. 4: In vitro permeation profile of formulation F1 to F5

Fig. 5: In vitro drug permeation profile of formulation without penetration enhancer in comparison with In vitro drug permeation profile of optimized formulation

Optimization:

Three parameters were included in the optimization process: tensile strength, folding endurance, and drug release, and data was compared as seen in Table 6.Based on tensile strength (1.92 kg/mm2), folding durability (220), and in-vitro drug permeation rate (85.54), the F1 formulation was determined to be the optimum. Rat skin was also used in an ex-vivo permeation analysis. At the end of the 30th hour, F1 showed a %cumulative drug permeation rate of 67.09 percent.

Ex-vivo permeation study:

Ex-vivo permeation study was carried out using rat skin for the optimum formualtion F1. F1 reported a % cumulative drug permeation (CDP) rate of 67.09% at the end of 30th hour as seen in (Table 5). It showed a sustained release till 30^th hour.

Table 5: Ex vivo drug permeation studies

Time	%CDP
0	0
1	1.50±0.5
2	2.80±0.8
3	5.48±1.1
4	7.55±1.2
5	13.46±0.8
6	17.43±1.6
24	43.36±2.2
25	46.90±1.6
26	53.03±2.3
27	56.36±2.8
28	60.58±3.1
29	64.72±2.5
30	67.09±3.4

Kinetic modeling of drug release:

The zero order, first order, Higuchi kinetic model, and Korsmeyerpeppas models were used to match the data from the drug permeation analysis. Formulation F1 followed peppas kinetics in its release profile. Higuchi kinetics was followed in case of other formulations.Except for optimized formulation F1 (r²= 0.997), all other formulations were governed by diffusion mechanism.

Stability studies:

After 30 and 60 days of storage under various conditions, physical properties, medication content, tensile strength, and in vitro permeation rate did not show any significant changes, and patches were found to be mechanically and chemically stable.

CONCLUSION:

In the current study formulation and Characterization of Atenolol transdermal patches was carefully and successfully carried out. Polymers and drugs were found to be compatible using IR spectra and DSC analysis (results not shown).Since PIB adhesive polymers alone were ineffective for the fabrication of Atenolol patches, an attempt was made to combine the properties of both PIB and ethyl cellulose using the solvent casting process to achieve the desired properties.Patches were formulated and analyzed based on various of parameters.Polyethylene glycol 400 was used as plasticizer and it increased flexibility, tear resistance and permeability of the adhesive composition to the drug.Permeation findings demonstrated that patches with penetration enhancer had a 7-fold improvement in permeation rate as compared to patches without penetration enhancer. Based on in vitro permeation rate, folding endurance, and tensile strength, the F1 formulation was found to be the optimum formulation.As a result, an optimal mix of adhesives for the fabrication of Atenolol patches will be the best choice for a sustained effect of Atenolol with enhanced permeation characteristics and robustness.

ACKNOWLEDGEMENT:

We gratefully acknowledge the KLE Academy of Higher Education and Research Belagavi, Department of Pharmaceutics, KLE College of Pharmacy, Belagavi, Karnataka for providing research facilities.

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Received on 04.05.2021 Modified on 13.03.2022

Research J. Pharm. and Tech 2023; 16(5):2085-2090.

DOI: 10.52711/0974-360X.2023.00342

Ingredients	F1	F2	F3	F4	F5
Atenolol	566.7 mg	566.7mg	566.7mg	566.7mg	566.7mg
Polyisobutene (MW 30000): Polyisobutene (MW 950)	3:1	3:1.5	3:2	3:2.5	3:3
Ethyl Cellulose	200mg	200mg	200mg	200mg	200mg
Chloroform	10mL	10mL	10mL	10mL	10mL
Acetic Acid	5 mL	5 mL	5 mL	5 mL	5 mL
Polyethylene Glycol 400(Plasticizer)	1.5 mL (10%v/v)	1.5 mL	1.5 mL	1.5 mL	1.5 mL
Propylene Glycol(Penetration Enhancer)	2.25mL(15%v/v)	2.25mL	2.25mL	2.25mL	2.25mL

Formulations	Folding Endurance^*	Tensile Strength^* (%)	Percentage Elongation* (%)	Percentage Moisture *Content^(%)**	Percentage Moisture *Uptake^(%)**	Drug Content^* (%)
F1	220±4.50	1.92±0.01	15±0.12	2.38±0.628	0.65±0.23	92.06±1.86
F2	245±3.60	2.82±0.02	25±0.11	1.93±0.385	1.16±0.39	96.66±0.44
F3	353±5.40	2.95±0.03	35±0.12	1.143±0.385	1.52±0.385	94.13±0.97
F4	365±2.50	3.05±0.06	42.5±0.15	0.73±0.365	1.85±0.37	91.46±0.46
F5	393±3.20	3.48±0.04	65±0.11	0.48±0.207	2.19±0.365	94.81±0.16