Transdermal Patch-Based Delivery of Rizatriptan Benzoate: A Novel Strategy for Migraine Treatment

Migraine is a prevalent neurological disorder characterized by recurrent headache episodes often accompanied by nausea, vomiting, photophobia, and phonophobia. It significantly affects the quality of life and work productivity of patients worldwide [1]. Among various therapeutic options, triptans remain the first-line drugs for acute migraine management due to their high efficacy in relieving headache and associated symptoms [2]. Rizatriptan, a selective serotonin 5-HT1B/1D receptor agonist, is one of the most effective antimigraine drugs with a rapid onset of action [3]. However, oral rizatriptan therapy is limited by its low bioavailability (~45%), short elimination half-life (2–3 h), and extensive first-pass metabolism, leading to the recurrence of migraine and reduced patient compliance [4].

Transdermal drug delivery systems (TDDS) provide an innovative approach to overcome these drawbacks. TDDS allows the drug to directly penetrate through the skin into systemic circulation, bypassing the gastrointestinal tract and hepatic first-pass metabolism [5]. This mode of delivery offers several advantages, including sustained and controlled release, improved bioavailability, ease of administration, and enhanced patient compliance [6]. Moreover, the ability to terminate drug action simply by removing the patch provides an additional safety advantage [7]. An ideal candidate for TDDS should possess a low molecular weight (<500 Da), sufficient lipophilicity, and high potency at low doses [8]. Rizatriptan, with a molecular weight of 269 Da, low plasma protein binding (~14%), and efficacy at doses of 5–10 mg, fulfills these requirements, making it a suitable candidate for transdermal patch formulation [3,4]. Therefore, the present study aims to formulate and evaluate rizatriptan benzoate transdermal patches using hydroxypropyl methylcellulose (HPMC) as the polymer, along with suitable permeation enhancers and plasticizers. The patches were subjected to physicochemical characterization, in-vitro drug release, permeation, and stability studies to establish their potential as a sustained-release, patient-friendly alternative for migraine therapy.

MATERIALS AND METHODS

Materials

The drug Rizatriptan benzoate was obtained as a gift sample for the present study. Hydroxypropyl methylcellulose (HPMC K100), ethanol and isopropyl alcohol were procured from Loba Chemie Pvt. Ltd., Mumbai, while polyvinyl alcohol (PVA) was purchased from S.D. Fine Chemicals, Mumbai. Glycerol was obtained from Merck Specialties Pvt. Ltd., Mumbai. All the chemicals and reagents employed were of analytical grade.

Methods

Preformulation Study

 Organoleptic characters

Organoleptic character like colour, odour were observed and recorder using descriptive terminology [9].

Determination of solubility

Rizatripta solubility has been evaluated by dissolving excess quantities of the drugs in the solvent [10].

Melting point determination

Melting point apparatus was used to determine the drug sample's melting point using the capillary method. Small quantity of drug was taken in capillary tube (fused at one end) and placed in melting point apparatus, and the melting temperature was recorded [11].

Calibration curve of rizatriptan

Preparation of standard curve for rizatriptan benzoate

Standard drug solution of rizatriptan benzoate was prepared by dissolving 10mg rizatriptan benzoate in distilled water and made to 10ml with distilled water to obtain stock solution of 1 mg/ml or 1000µg/ml concentration. From the stock solutions, 1.0ml of Rizatriptan Benzoate was transferred to 100ml volumetric flask and the volume was adjusted to the mark with distilled water to obtain strength of 10µg/ml. The solution was scanned in the UV range 200-400 nm.First, second, third, fourth order derivative UV spectra for the solutions of Rizatriptan Benzoate were recorded in a 10mm cell over the range 200-400nm using distilled water in the reference cell. Each spectrum was recorded in triplicate. The zero-crossing point (ZCP) for Rizatriptan Benzoate were recorded. Characteristic wavelengths (ZCPs) for Rizatriptan Benzoate were confirmed by varying the concentration of the drug. For each replicate measurement, the cell was refilled with fresh solution.Average of 5 sets of values were taken and summarised in (Table 1 and Figure 19) and the standard curve was plotted [12].

Compatibility studies

The incompatibility between the drug and excipients are studied by FTIR spectroscopy. .

Fourier Transform Infrared (FTIR)

The FTIR spectra of Rizatriptan benzoate, HPMC, ethanol, isopropyl alcohol, and the optimized formulation (P1) were recorded using a Bruker FTIR spectrophotometer to study drug–excipient interactions. Samples were prepared by mixing 2 mg of drug or formulation with 200 mg of dry KBr, compressed into pellets, and scanned over 400–4000 cm?¹ at a resolution of 4 cm?¹. The spectra were compared to detect any shifts or changes in characteristic peaks [13].

Dose Calculation of Drugs

Transdermal dose                            = Oral dose × Bioavailability fraction [14]

Oral dose = 10 mg

Bioavailability fraction = the fraction of drug that reaches systemic circulation orally (as a decimal, e.g., 45% = 0.45)

Transdermal dose of Rizatriptan = 10 × 0.45                                                            = 4.5 mg

Formulation of Rizatriptan benzoate patch

The Rizatriptan benzoate transdermal patch was prepared using the solvent casting method. Accurately weighed amounts of hydroxypropyl methylcellulose (HPMC) were dissolved in ethanol and stirred until completely solubilized. Rizatriptan benzoate was separately dissolved in a mixture of ethanol and isopropyl alcohol and then added to the polymer solution. The combined solution was mixed thoroughly to ensure complete solubilization of the drug. Glycerol was added dropwise to the polymer–drug solution to improve flexibility and prevent brittleness, followed by continuous stirring to achieve uniform distribution of all components. The final solution was poured onto a levelled petri dish or glass plate to form an even film of uniform thickness. The solvent was allowed to evaporate at room temperature under controlled conditions, and the film was completely dried to obtain the transdermal patch. After drying, the patch was carefully peeled from the surface and stored in a sealed container to prevent moisture absorption. The prepared patch was visually inspected for homogeneity, clarity, and color, and its melting point was measured at room temperature before storage in a cool, dry place. As shown in table 1[15].

Table 1 : Formulation of Rizatriptan benzoate patch

POST EVALUATION STUDIES OF TRANSDERMAL PATCHES

Physical appearance

Visual evaluations for colour, clarity, flexibility, and smoothness were made for each prepared patch[11].

Film thickness

At three different points on the drug-loaded patches, the thickness of the patches was measured using a screw gauge micrometre. For each drug-loaded patch, the average and standard deviation of the three measures were calculated [15].

Weight variation

Weight variations of the transdermal patches were done by cutting the patches into 1cm² from 3 different points of the patches and weight of each patch was determined by using the digital balance. The average weight and its standard deviations was calculated [16].

Folding endurance

The evaluation of folding endurance of the transdermal patches was done to determine the folding capacity of the film subjected to frequent extreme condition of folding. A strip of specific area 2.5 cm² was cut evenly and repeatedly folded at the same place till it breaks. The number of times the patches folded at same place without breaking was noted as its folding endurance value [11].

Drug content uniformity

The patch of 2.5 cm² transferred into a glass stopper flask-containing methanol. The flasks were closed and shaken till the patch was completely dissolved. This solution was filtered and the volume was made upto 100 ml by using buffer of pH 7.4, from this 1 ml of  solution was pipette out and was diluted upto 10 ml and the absorbance was measured by UV spectrophotometer at 227 nm [12].

Tensile strength

The tensile strength of the patch had been evaluated by using the tensiometer. It consists of two load cell grips of which the lower one was fixed and upper one was movable. Film strips with the dimensions of 2 × 2 cm were fixed between these cell grips, and force should be gradually applied until the film get broke [15].

Percentage moisture content

The formed films must be weighed individually and kept at room temperature in a desiccator together with fused calcium chloride for 24 hours. The films must be reweighed after 24 hours in order to calculate the percentage moisture content using the formula below [16].

       % Moisture Content = (Final weight - Initial weight) / Initial weight ×100

In-Vitro Permeation study

The in vitro drug release from the rizatriptan transdermal patch was studied using a Franz diffusion cell with a dialysis membrane (or specified synthetic membrane) as the diffusion barrier. The receptor compartment was filled with phosphate buffer (pH 7.4) and maintained at 37 ± 0.5 °C with continuous stirring. A known area of the patch was placed in contact with the membrane, with the drug-loaded side facing the receptor medium. At predetermined time intervals, 1 mL of the receptor medium was withdrawn and replaced with fresh buffer to maintain sink conditions. The samples were analyzed using a UV–Visible spectrophotometer at 227 nm

Stability study

The stability study was carried out for the most satisfactory formulation as per ICH guidelines. The selected formulation was subjected to stability testing for a period of 3 months under accelerated conditions at 40 °C ± 2 °C / 75% RH ± 5% RH. The formulation was periodically analyzed for changes in appearance, pH, percentage drug content, and in-vitro diffusion profile [14].

RESULT AND DISCUSSION

PREFORMULATION STUDIES

Organoleptic characters

The organoleptic evaluation of rizatriptan benzoate confirmed its authenticity and purity. The drug was observed to be a white to off-white, odourless, crystalline powder with a bitter taste, which complied with the standard reference data. These findings confirm its suitability for pharmaceutical applications, as presented in Table 2.

Table 2: Test for pure rizatriptan benzoate drug

Determination of solubility

The solubility study of the drug in various solvents revealed significant differences. As shown in Table 8, the drug exhibited good solubility in water (42 mg/ml), methanol (8 mg/ml), ethanol (1 mg/ml), and chloroform (15 g/ml). Among these solvents, the highest solubility was observed in water, followed by methanol, chloroform, and ethanol. This indicates that water is the most suitable solvent for the drug, while ethanol shows the least solubility.

Melting point determination:

The melting point of Rizatriptan benzoate was determined by placing a small quantity of the drug in a capillary tube and subjecting it to analysis using a melting point apparatus. The observed melting point was found to be 179 °C, which is in agreement with the reported range, thereby indicating the purity of the drug sample.

Determination of λmax

The UV absorption spectrum of Rizatriptan benzoate was recorded using a UV–Visible spectrophotometer. The drug exhibited a maximum absorption at 227 nm, which was selected as the analytical wavelength (λmax) for further quantitative studies. The obtained UV spectrum is shown in Figure 1.

Calibration curve of Rizatriptan   benzoate

A calibration curve for Rizatriptan benzoate was constructed by measuring the absorbance of standard drug solutions of different concentrations at 227 nm using a UV–Vis spectrophotometer. The absorbance values were plotted against concentration to obtain the calibration plot. The high correlation value (R² = 0.998). The high correlation value indicates excellent linearity, confirming adherence indicates excellent linearity, confirming adherence to Beer-Lambert’s law. The results are presented in Table 3 and Figure 2   

Figure 1: λmax curve of  Rizatriptan       Figure 2 : Calibration curve of Rizatriptan

Table 3: Standard curve of rizatriptan benzoate

Compatibility studies:

The incompatibility between the drug and excipients was studied by FTIR spectroscopy. The results indicate that there was no chemical incompatibility between drug and excipients used in the formulation.

FTIR Study:

The FTIR spectrum of Rizatriptan benzoate is shown in Figure 22, while the spectrum of the Rizatriptan benzoate transdermal patch (P1) is presented in Figure 23. The comparison of characteristic peaks of the pure drug and the formulation showed no significant shifts or disappearance of major functional group peaks, indicating the absence of chemical interaction between Rizatriptan benzoate and the selected excipients (HPMC, ethanol, and isopropyl alcohol). This confirms that the excipients did not alter the physicochemical properties, stability, or efficacy of the drug in the best transdermal patch (P1).

Figure 3: FTIR Spectrum of pure drug of Rizatriptan

Figure 4: FTIR Spectrum of Formulated Rizatriptan benzoate transdermal patch (P1)

Formulation of Rizatriptan transdermal patch

The prepared Rizatriptan patch was successfully formulated using a polymeric base composed of HPMC K100, which provided the required viscosity and consistency. The incorporation of the drug solution into the polymer matrix was facilitated by continuous stirring, ensuring a homogeneous dispersion of active ingredients.

Figure 5: Formulation of Rizatriptan Transdermal Patch

Post Evaluation Studies of Transdermal Patches

The prepared transdermal patches (P1, P2, and P3) were evaluated for various physicochemical parameters, and the results are summarized in Table 4.

Physical appearance

All three formulations (P1, P2, and P3) of the transdermal films were observed to be whitish-yellow in color, smooth, and flexible. The uniform appearance across all formulations indicates proper dispersion of the drug and excipients and suggests good film-forming properties.

Film thickness

The film thickness for P1, P2, and P3 was found to be 0.132 ± 0.01 mm, 0.153 ± 0.03 mm, and 0.169 ± 0.04 mm, respectively. An increase in thickness was observed with the increasing polymer concentration from P1 to P3. Uniform thickness is crucial for consistent drug release, and the measured values show acceptable uniformity (n = 3).

Weight variation

The weight of the films varied slightly across formulations: 0.430 ± 0.02 g (P1), 0.562 ± 0.04 g (P2), and 0.567 ± 0.02 g (P3). The slight increase in weight with thicker films correlates with the polymer concentration. Minimal weight variation indicates reproducibility of the film casting process.

Folding endurance

The folding endurance of the transdermal films, which reflects their mechanical strength and flexibility, was found to be 83 ± 0.15, 79 ± 0.07, and 74 ± 0.09 for P1, P2, and P3, respectively. A gradual decrease in folding endurance was observed with increasing polymer concentration or film thickness, indicating slightly reduced flexibility in thicker films. Despite this, all formulations exhibited adequate mechanical strength to withstand handling and application, with P1 showing the highest flexibility and P3 demonstrating comparatively greater stiffness.

Drug content uniformity

The drug content uniformity for P1, P2, and P3 was 86.2 ± 0.59%, 80.3 ± 0.045%, and 78.3 ± 0.032%, respectively. A slight decrease in drug content with increasing polymer concentration was observed, possibly due to increased polymer matrix density affecting drug dispersion.

Tensile strength

The tensile strength of the transdermal films was 2.90 ± 0.23, 2.73 ± 0.27, and 1.91 ± 0.21 kg/cm² for P1, P2, and P3, respectively. P1 showed the highest strength, indicating it is the most resistant to breaking, while P3 was the weakest. All films had enough strength to handle and use without breaking, with P1 being the strongest and most durable.

Percentage moisture content

The percentage moisture content of the films was 2.97 ± 0.40% (P1), 3.35 ± 0.33% (P2), and 3.45 ± 0.51% (P3). Lower moisture content, as seen in P1, is generally preferable because it ensures better stability of the drug and prevents microbial growth, while still maintaining adequate flexibility. Therefore, P1 is the best in terms of moisture content.

Table 4: Post Evaluation Studies of Transdermal Patches

n±3

IN VITRO DRUG RELEASE STUDY

The in-vitro drug release from the rizatriptan transdermal patches showed that P1 released the highest amount of drug (95.45 ± 0.22% at 360 min), followed by P2 (83.43 ± 0.26%) and P3 (76.23 ± 0.32%)as shown in Table 5 and Figure 6 . P1 exhibited the fastest and most complete release because it has the lowest polymer concentration and thinnest film thickness, which reduces the diffusion barrier and allows the drug to permeate more easily through the membrane. In contrast, P2 and P3 have thicker and denser polymer matrices, which slow drug diffusion and result in more sustained release. Therefore, P1 is considered the best formulation for achieving rapid and effective drug delivery.

Table 5: In-vitro permeation studies data of rizatriptan transdermal patch P1to P3

n±3

Figure 6: In-vitro permeation studies data of rizatriptan

Stability Study

The P1 transdermal patch exhibited excellent stability when stored for 3 months under accelerated conditions (40?°C ± 2?°C / 75% RH ± 5% RH). The patch remained transparent throughout the study, indicating no physical changes such as cracking, peeling, or discoloration. The in vitro drug release remained high at 93.63 ± 0.2%, and the drug content stayed well within acceptable limits at 84.01 ± 0.21%.These results demonstrate that P1 maintains its physical integrity, drug release performance, and chemical stability even under harsh conditions, highlighting the effectiveness of the optimized polymer matrix and low moisture content. Therefore, P1 is a robust and reliable formulation suitable for long-term storage and use. The results of the stability study are presented in Table 6.

Table 6: Stability studies of the Rizatriptan Transdermal Patch Formulation P1

n±3