Formulation & Evaluation of Transdermal Patch Containing Bilastine in Combination with Eucalyptol as Penetration Enhancer for Anti-Histaminic Activity

Allergic diseases such as allergic rhinitis, conjunctivitis, and urticaria are among the most common immunological disorders worldwide, with increasing prevalence in both developed and developing countries. These conditions are mediated by histamine release from mast cells, leading to symptoms such as sneezing, itching, nasal congestion, watery eyes, and skin rashes, which significantly impair quality of life. Antihistamines remain the mainstay in the management of these disorders, with second-generation H1-receptor antagonists offering the advantage of high selectivity, minimal sedation, and a favourable safety profile. Bilastine, a novel second-generation, non-sedating oral antihistamine, has been widely used in clinical practice due to its efficacy, rapid onset of action, and low risk of drug–drug interactions [1]. Despite these advantages, oral bilastine therapy is associated with limitations such as variable gastrointestinal absorption, poor aqueous solubility, and first-pass hepatic metabolism, which may reduce systemic bioavailability and necessitate frequent dosing. Transdermal drug delivery systems (TDDS) have emerged as a promising alternative to oral administration, providing controlled and sustained drug release, improved therapeutic efficacy, and enhanced patient compliance. Bypassing the gastrointestinal tract and hepatic first-pass metabolism, TDDS can maintain steady plasma concentrations over an extended period. However, the stratum corneum, the outermost layer of the skin, represents a formidable barrier to drug permeation, limiting the effective delivery of many therapeutic agents. To overcome this, penetration enhancers are often incorporated into transdermal formulations to facilitate drug diffusion through the skin by reversibly altering the lipid structure of the stratum corneum [2].

Among penetration enhancers, natural terpenes have attracted considerable attention due to their effectiveness and safety profile. Eucalyptol (1,8-cineole), a major constituent of eucalyptus oil, is a well-studied monoterpene with proven ability to disrupt the lipid bilayer of the stratum corneum, thereby enhancing the percutaneous absorption of both hydrophilic and lipophilic drugs. In addition to its penetration-enhancing properties, eucalyptol possesses anti-inflammatory and antioxidant activities, which may further contribute to therapeutic benefits in allergic conditions. The incorporation of eucalyptol as a natural enhancer in a bilastine transdermal patch formulation may therefore provide dual advantages: improved drug permeation and supportive pharmacological effects [3]. Formulating bilastine into a transdermal patch with eucalyptol has the potential to offer sustained anti-histaminic activity, improved bioavailability, and reduced dosing frequency compared to conventional oral therapy. This approach may not only enhance therapeutic outcomes but also improve patient adherence, particularly in individuals requiring long-term antihistamine therapy [4]. The present research is focused on the formulation and evaluation of bilastine transdermal patches containing eucalyptol as a penetration enhancer. The study aims to assess the physicochemical characteristics of the patches, their in-vitro drug release and permeation profiles, as well as their potential anti-histaminic activity. This novel drug delivery approach could provide a valuable contribution to the management of allergic disorders by combining the therapeutic efficacy of bilastine with the enhancing capability of eucalyptol in a transdermal platform [5].

1. Experimental Work

2.1 MATERIALS

Bilastine was obtained as gift sample from Alkem laboratories, Eucalyptol was procured from India Mart, HPMC, PEG400, ethanol were procured from Qualikems Fine Chem Pvt. Ltd, SD fine-CHEM and Changshu Hongsheng Fine Chemicals. Sodium Chloride, Disodium Hydrogen Phosphate were procured from MERCK Pvt. Ltd.

2.2 METHODS

2.2.1 Pre-formulation evaluation of Drug

The organoleptic properties of drug, solubility and melting point was determined. [6,7,8].

1. 2. Preparation of Transdermal Patch

The transdermal patches were formulated by solvent evaporation method. Different concentrations of HPMC as polymer were added in suitable volume of solvent. The polymeric dispersion stirred with magnetic stirrer for about 10 min to form clear solution. Drug (Bilastine) was mixed thoroughly by the use of magnetic stirrer. Weighed amount of Eucalyptol as penetration enhancer and Polyethylene Glycol 400 as plasticizer was added to above solution for about 30 minutes. The uniform solution was formed which was allowed to stand for 15 minutes to remove air bubbles and the resulting solution was poured into petri plate and placed inverted funnel which will help to control the evaporation of solvent and will avoid the cracking of patches. This was kept aside for overnight. Dried patches were separated from the plate and stored in desiccator until further use.[9]

2.2.3 Evaluation of Transdermal patches of Bilastine:

2.2.3.1 Weight Variation- The patches were subjected to weight variation by individually weighing selected patches randomly and the average was calculated.[10]

2.2.3.2 Film Thickness: This is measured with a micrometer, electronic Vernier calipers, dial gauge, or screw gauge. Five distinct locations on the film are used to assess thickness, and the average of each formulation were calculated.[11]

2.2.3.3 Folding Endurance: It was discovered by continuously folding a short (2×2 cm) strip of film until it breaks. The folding endurance value is the number of times the film could be folded in the same position without breaking.[12]

2.2.3.4 Surface pH: The pH of the patch was determined by dipping the film in 0.5 ml distilled water, and the pH meter electrode was allowed to touch the surface of film.

2.2.3.5 Flatness: Longitudinal strips were cut out from each film, one from the center and two from either side. The length of each strip was measured and then the variation in the length due to the non-uniformity in flatness was measured. Flatness calculated by measuring % constrictions of strips and a zero percent constriction was considered to be equal to a 100% flatness. % Constriction=(I1-I2)/ I1×100 Where, I1=Initial length of each strip; I2= Final length of each strip.[12]

2.2.3.6 Moisture Loss: The produced films were weighed separately and maintained at room temperature in desiccators with calcium chloride for 24 hours. After a predetermined amount of time, the films were weighed once more until they reach a constant weight. The percent moisture content was calculated using following formula: [10]

% Moisture Content=Initial weight–Final weight/Initial weight×100

2.2.3.7 Moisture Uptake: Weighed individually the films and kept them in desiccator containing calcium chloride at room temperature for at least 24 hrs. Remove the films from desiccators and exposed to 4% relative humidity (RH) using saturated solution of potassium chloride in another desiccator until a constant weight is achieved [10]

% Moisture Uptake=Final weight–Initial weight/Final weight×100

2.2.3.8 Drug Content: Drug content was determined by accurately weighing a patch and was dissolved in 100 ml of phosphate buffered saline pH 7.4 solution. The contents were magnetically stirred for 2 h. The solution was then filtered through the Whatman filter paper and diluted suitably with phosphate buffer saline pH 7.4. The solution was then analyzed for its absorbance at 285 nm using placebo patch as blank. From the absorbance values, the drug content was determined.[13]

2.2.3.9 In-Vitro Drug Permeation Studies: An in vitro release study was done using an egg membrane. The composition of the egg membrane is similar to the composition of the stratum corneum layer of the human skin. The egg membrane was isolated by dipping the egg in an HCl solution. The egg contents were discarded, and the membrane was washed with distilled water. The film under research was kept on the egg membrane, and the membrane was tied around the mouth of a beaker. The beaker was then dipped into another beaker containing buffer pH 7.4 such that the egg membrane came in contact with the buffer of pH 7.4 similar to the blood pH. At an interval of particular time, the buffer solution is collected, and refill with the same volume. The absorbance of the solution is determined using Shimadzu UV–Visible Spectrophotometer at 285 nm.[14]

3. RESULT AND DISCUSSION:

3.1 Preformulation Studies

3.1.1 Organoleptic properties

The organoleptic properties of the bilastine were determined as per the procedure and the results are tabulated here under.

3.2.1 Weight Variation:

Weight variation was determined by weighing the different formulations of transdermal patch individually and the average weight was calculated and taken as a weight of the patch. It was shown that the weights of the various formulations were reliable and exhibited small standard deviations.

Fig.1: Weight Variation of Bilastine patches

It was determined with the help of digital vernier caliper. The results of various formulations were found to be uniform shown in fig. 2 below.

Fig. 2: Thickness of different formulations

The patch should be designed to be applied for a prolonged period by providing strong folding endurance and not breaking after application. Fig 3 below shows the outcomes of several formulations used in the folding endurance study.

Fig. 3: Folding Endurance of different formulations of patch

The percentage moisture loss was determined from the weight differences relative to final weight. The Fig. 4 below shows the percentage moisture loss data for the various formulations. A small amount of moisture keeps the patches from becoming brittle. The % moisture loss in other formulations was found to be low.

Fig. 4: % Moisture loss data of different formulations

After the prepared patches were exposed to potassium chloride, the weight difference with respect to the initial weight was used to compute the percentage moisture uptake. Fig 5 below displays results from studies on the absorption of moisture for various formulations.

Fig. 5: % Moisture Uptake data of different formulations

A smooth surface and the ability to resist constriction over time are two characteristics of a suitable patch's formulation. Studies on flatness were conducted to evaluate the same, as indicated in Fig. 6.

Fig. 6: Flatness of different formulations

3.2.7 Determination of pH of film

Surface pH of the transdermal films was determined with the help of pH meter. Every formulation was found to have a neutral surface pH, ranging between 7.0 and 7.3. It is possible to prevent the risk of skin irritation because the neutral surface pH value has physiological consent.

Fig 7: pH of different formulations

The entrapment and content of drug in HPMC matrix patches was found between 95.8% to 99.9% shown in Fig. 8 below.

Fig. 8: % Drug Content of different formulations

It is well-established that In-Vitro drug release studies are vital for maintaining controlled release performance as well as reliability of drug release rate and duration. Using a Franz diffusion cell, the release study of several formulations was conducted at 34? ± 0.5?, maintained at a magnetic stirrer with a hot plate and the receptor media, phosphate buffer, pH 7.4. During the release studies, phosphate buffer with a pH of 7.4 was provided to maintain the sink condition.

Fig 9: % Cumulative drug release of different formulations