Development and Characterization of Orodispersible Tablets Containing Sumatriptan Succinate and Feverfew for the Treatment of Migraine

 Introduction

Conventional dosage forms, are widely embraced due to their compactness, simplicity in manufacturing, and precise dosing capabilities.¹ The orodispersible tablets (ODT), as defined by the USFDA (U.S Food and Drug Administration), represent a solid dosage form that swiftly disintegrates upon contact with the tongue.² They are also referred to as mouth-dissolving tablets, fast-dissolving tablets, melt-in-mouth tablets, porous tablets, quick-dissolving tablets and rapimelts. These formulations have a distinctive capacity to quickly disintegrate and release the medication upon contact with saliva, removing the necessity for water during use. This property transforms them into a soft paste ensuring ease in swallowing and mitigating the choking risk. Superdisintegrants are incorporated into this formulation to expedite tablet disintegration, thereby providing a rapid onset of action.^1,3

Migraine, marked by repeated episodes of moderate to severe headaches and reversible neurological and systemic symptoms, poses a considerable challenge to health. In adults, the length of a migraine headache can vary from 4 to 72 hours, while in children, it can range from 2 to 48 hours.⁴ Internationally, migraine ranks as the third most common medical condition and the second most disabling neurological disorder according to the World Health Organization. Clinical studies affirm the efficacy and tolerability of sumatriptan, administered intravenously, subcutaneously, or orally, as a reliable treatment for migraines.⁵

The medication selected for this study is sumatriptan succinate, which is approved by the FDA for the abortive treatment of migraine attacks in adults, with or without aura.⁵ By acting as a specific and selective agonist of 5-HT1 receptors in cranial blood vessels, sumatriptan prompts vasoconstriction, selectively decreasing flow in the dural and cranial vessels and internal carotid arteries. Its bioavailability is notable, with 96% when administered subcutaneously and orally it is 14% with a plasma half-life of two hours. Sumatriptan possesses a bitter taste, which can be effectively masked using ion exchange resins.^6,7

Feverfew (Tanacetum parthenium), a member of the Asteraceae family, is a medicinal plant historically used to address a range of ailments. Traditionally, it has been employed for treating migraines, fever, stomach aches, toothaches, menstrual issues, etc. Additionally, it has been applied for conditions such as allergies, asthma, psoriasis, tinnitus, nausea, dizziness and vomiting. The therapeutic effects of feverfew are attributed to its active compounds, primarily sesquiterpene lactones like parthenolide.⁸

The combination of Sumatriptan succinate and Feverfew is based on their therapeutic effects in treating migraines. Sumatriptan targets the underlying neuro-logical pathways by activating serotonin receptors, leading to vasoconstriction and pain relief. Feverfew, a well-known herbal remedy, has anti-inflammatory properties and helps prevent migraine onset. The synergy between these two agents enhances the overall therapeutic efficacy and provides a more comprehensive approach to migraine management.^7,8

Given the expanding ODT market driven by enhanced patient compliance, this study endeavours to formulate and optimize ODTs incorporating a combination of Sumatriptan succinate and Tanacetum parthenium.³ The ODT formulations dissolve rapidly in the mouth without the need for water, providing faster onset of action, which is crucial in treating acute migraine episodes. Taste masking is essential for enhancing patient compliance, especially in ODT formulations, where the drug comes in direct contact with the taste buds. Sumatriptan and other active ingredients may have a bitter or unpleasant taste that can be off-putting for patients. Effective taste masking ensures a better patient experience and increases the likelihood of consistent usage. An ion-exchange resin, such as Kyron T114, is used to overcome the bitter taste of Sumatriptan succinate, ultimately enhancing patient adherence.

Marketed formulations, while effective in relieving symptoms, often require improved bioavailability and patient compliance. Previous studies have explored Sumatriptan succinate in various formulations, but combining it with Feverfew in orodispersible tablets offers a novel approach, enhancing patient comfort and therapeutic outcomes.

Materials and Methods

Materials

Sumatriptan succinate was received from Porus labs, Andhra Pradesh as a gift sample and Tanacetum parthenium was purchased from Kshipra Biotech Pvt Ltd, Indore. KyronT114 was a gift sample from Corel Pharma Chem, Gujarat, while croscarmellose sodium, crospovidone, microcrystalline cellulose and stevia were obtained from Empree Medicaments, Karnataka as a gift sample and sodium starch glycollate, mannitol, magnesium stearate and sodium lauryl sulphate were procured from Burgoyne Burbidges Ltd, Mumbai. All other materials employed were of analytical grade quality.

Methods

Preformulation Studies

Pre-formulation investigations such as Differential Scanning Calorimetry (DSC) and Fourier Transform Infrared (FTIR) spectroscopy were conducted to ascertain the physical and chemical characteristics of the active pharmaceutical ingredient (API) and excipients. These studies aimed to identify factors that could impact the formulation design, manufacturing process, and pharmaceutical properties of the end product.^9-11

Differential Scanning Calorimetry (DSC)

The thermal behavior of Sumatriptan succinate, both alone and in physical mixtures with tablet excipients, was analyzed using DSC. Samples weighing 3-5 mg were sealed in aluminum pans and heated at a constant rate of 10°C/min over a temperature range of 25°C to 250°C. Thermograms of the samples were obtained using DSC (Mettler Toledo DSC). Thermal analysis data were recorded using a system with Mettler Toledo software programs. Nitrogen was used as the purging gas and the rate was fixed at 30 mL/min.

Fourier Transform Infrared (FTIR) spectroscopy

Drug-excipient interaction is one of the key compatibility studies. FTIR study was used for this purpose on samples of pure Sumatriptan succinate, and physical mixture of Croscarmellose Sodium, Crospovidone, Sodium starch glycolate, Camphor, Thymol and Menthol. As per the KBr (Potassium bromide) disk method, Agilent was used to obtain spectra. About 2-3 mg of samples were mixed with dried IR grade potassium bromide powder and the spectra were in between the wave number range of 4000-400 cm^-1.

Sumatriptan Kyron T114 Preparation Method

To mask the taste, ion exchange resin Kyron T114 was utilized due to its property of releasing the drug at salivary pH. Three varying concentrations of Kyron T114 combined with Sumatriptan succinate (in ratios of 1:1, 1:2 and 1:3) were formulated. The procedure involved adding Kyron T114 to 25 mL of water in a beaker, stirring the mixture for 30 minutes, then adding Sumatriptan succinate and stirring the mixture for two hours at 1000 rpm. Afterward, the complex was filtered using Whatman filter paper, dried in a tray dryer at 60℃, and sifted through a #60 mesh. The drying process was continued until the desired loss on drying (LOD) was achieved, with a limit not exceeding 2%. For LOD, a clean, dry petri dish with a lid was weighed. Then 1 gm of the sample was accurately weighed and placed in the dish. This dish with the sample was placed into a preheated drying oven. The sample was repeatedly dried until a constant weight was achieved. The LOD% was calculated using the formula: Initial Weight Final Weight/ Initial Weight x 100. The resulting dried granules were utilized for subsequent processing.¹²

Formulation of ODTs

The ODTs were fabricated through the direct compression method, incorporating 25 mg of sumatriptan succinate and 50 mg of feverfew in each tablet. Superdisintegrants such as crospovidone, croscarmellose sodium, and sodium starch glycolate were employed to enhance tablet disintegration. Sodium lauryl sulfate served as the surfactant, while mannitol and microcrystalline cellulose functioned as diluents. Stevia was included as the sweetening agent, magnesium stearate as the lubricant, and talc as the glidant. To ensure precision, the drug and all components were accurately weighed and sieved through a #60 sieve before mixing. Subsequently, the ingredients were meticulously transferred to a mortar in a geometric manner and thoroughly mixed for 15 minutes. The resultant mixture was compressed using a single-punch compression machine equipped with a 10 mm flat punch.^13-15

The identification of the optimum formulation was based on disintegration time (DT) and drug release profile, which was subsequently chosen for sublimation studies. Sublimating agents, namely camphor, thymol, and menthol, were used for tablet preparation using the sublimation technique. To facilitate sublimation, the tablets were vacuum-dried at 60℃ for 24 hours. Detailed formulation information is provided in Tables 1 and 2. All prepared formulations were appropriately packaged and stored for subsequent evaluations.

Determination of Pre-Compression and Post Compression Parameters

The tablets thus prepared underwent evaluation for various pre-compression and post-compression properties including bulk density, tapped density, angle of repose, Carr’s index (compressibility index), Hausner’s ratio, weight variation, friability, hardness, thickness, in vitro DT, wetting time, wetting ratio, assay (using UV spectrophotometric method and HPLC technique), in vitro dissolution, and short-term stability study.

Bulk density

It is defined as the ratio of total mass of powder to the bulk volume of the powder. Bulk density (Pb) was determined by pouring the blend into a graduated cylinder. The bulk volume (Vb) and mass of the powder (M) was determined. Bulk density was calculated by using the below formula, Pb=M/VB.

Tapped density

The measuring cylinder containing a known mass of blend (M) was tapped for a fixed time (100 tapings). The minimum volume (Vt) occupied in the cylinder was determined, along with the weight of the blend. The tapped density (Pt) was then computed using the formula, Pt= M/VT.

Angle of repose

The angle of repose was measured using the funnel method. The powder blend was poured through a vertically adjustable funnel until it formed a heap with a maximum cone height (h). The radius (r) of the heap was then measured, and the angle of repose (θ) was calculated using the formula: θ = tan-1 h / r

Carr’s index (Compressibility index)

The easiest method for measuring the free flow of powder is compressibility, an indication of the ease with which material can be induced to flow and is given by compressibility index (I) which is calculated as: I={ (Pt– Pb) / Pt }*100

Hausner’s ratio

This is an indirect index of ease of powder flow. It is calculated by the following formula, Η= Pt / Pb.

Weight variation

The uniformity of weight was assessed following the procedure outlined in the Indian Pharmacopoeia (IP). Twenty tablets were individually weighed using a digital balance, and their collective weight was recorded. The average weight of a single tablet was calculated by dividing the total weight of the batch by the number of tablets.

Friability

The weight of 20 tablets was determined. They were placed in the friabilator and allowed to make 100 revolutions. The tablets were then de-dusted and reweighed. The percentage weight loss was calculated. Percentage friability was calculated as follows: Percentage Friability = (W1 - W2) x 100/W1; Where, W1 = Initial weight of the 20 tablets, W2 = Final weight of the 20 tablets after testing.

Hardness

A Monsanto hardness tester was utilized to assess the hardness of the formulated ODTs. Five tablets were selected from each batch for testing, and their mean hardness was calculated. The breaking strength (in kg) of each tablet was determined using the tester. After resetting the dial on the tester to zero, a tablet was positioned between the two jaws, and the force was gradually increased until the tablet broke radially into two halves. The breaking strength represents the applied force required to achieve this.

Thickness

The thickness of the tablets was measured using digital Vernier calipers. Five tablets were randomly selected, and their thickness was individually measured. Each tablet was placed between the anvils of the calipers, and the sliding knob was adjusted until the tablet was securely positioned for an accurate reading. The thickness reading was then recorded from the digital scale.

Wetting Time

The first step in the disintegration of ODT involves water uptake and wetting of the tablet; hence determination of wetting time is also important. Wetting time of dosage form is related to the contact angle. It provides an insight into the disintegration properties of the tablets. Lower the wetting time, faster is the disintegration of the tablet. This method also aids in analyzing the impact of different excipients on the disintegration process. A petri dish containing 6 mL of distilled water was taken and a tissue paper folded twice was placed in it. Time taken for the tablet’s upper surface to become fully wet was noted.

Water absorption ratio

The water absorption ratio, R can be the determined according to the following equation.

R = 100 (Wa-Wb) / Wb

The weight of the tablet before placing in the petri dish was noted and the wetted tablet from the petri dish was taken and reweighed.

Assay

a) UV spectrophotometric method: Assay was calculated using the below formula.

Assay =

Absorbance * Dilution factor * Average weight x 100

Absorptivity * Weight of tablet * Label claim

b) HPLC:

i. Buffer solution A: 2.93 g/L of monobasic sodium phosphate, 1.3 mL/L of dibutylamine, and 0.4 mL/L of phosphoric acid in water. Adjust with 10 N sodium hydroxide to pH of 6.5

ii. Buffer solution B: 3.9 g/L of monobasic sodium phosphate. Adjust with 10 N sodium hydroxide to a pH of 6.5 before dilution.

iii. Mobile phase: Acetonitrile and Buffer A (1:3)

iv. Diluent: Acetonitrile and Buffer B (1:3)

v. Standard solution: Equivalent to 0.1 mg/mL of Sumatriptan from USP Sumatriptan Succinate RS in Diluent.

vi. Sample solution: Nominally 0.1 mg/mL of Sumatriptan in diluent

vii. Chromatographic conditions: Detector: UV 282 nm Column: 4.6-mm x 25-cm; 5-mm packing L1 Flow rate: 1.5 mL/min; Injection size: 10 mL; Run time: 10 min.

In Vitro disintegration test

The disintegration time (DT) was evaluated using a modified disintegration method. A Petri dish was filled with 10 mL of water maintained at a temperature of 37°C ± 0.5°C. The tablet was gently placed in the centre of the petri dish, and the time taken for the tablet to completely disintegrate into fine particles was recorded.^10,11

In Vitro dissolution studies

The in vitro dissolution studies were conducted using a USP apparatus type II rotating basket operating at 50 rpm. The dissolution medium utilized was 6.8 phosphate buffer (900 ml), maintained at a temperature of 37±0.5°C. At various intervals, aliquots of the dissolution media were withdrawn, and the drug content was determined using a UV/Visible spectrophotometer at a wavelength of 227 nm. The cumulative percentage of drug release was calculated.^12-14

Statistical optimization

The quality of the model fit was assessed using analysis of variance (ANOVA). By comparing various statistical parameters, such as the coefficient of determination (R2), sum of squares (SS), adjusted R2, mean square (MS), F-value ratio, Fischer's degrees of freedom (DF), and probability (p), the best-fit model was determined. The design of experiments (DOE) program provided these statistical parameters. Response surface plots, including contour and 3-D surface plots, were utilized to illustrate the relationship between dependent and independent variables. These plots were instrumental in investigating the impact of various factors on the reaction at specific time points. Furthermore, numerical optimization techniques such as the desirability approach and graphical optimization techniques (overlay plots) were employed to identify the optimal formulation. These approaches facilitated finding the best combination of variables to achieve desired outcomes.^16,17

Stability study

The stability study of the optimized orodispersible Sumatriptan succinate and Tanacetum parthenium tablet formulation was carried out in accordance with ICH guidelines (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) for 1, 2, and 3 months. The tablets were packed and sealed in double polybags within a tightly sealed container under normal room temperature conditions. At intervals of 1, 2, and 3 months, various evaluation parameters including weight variation, hardness, thickness, friability, DT, assay, and dissolution test were performed to monitor the stability of the product. These assessments were conducted to ensure that the formulation maintained its quality and characteristics over the specified duration of the stability study.^18-20

Results

DSC Studies

The thermograms of pure drug Sumatriptan succinate was obtained using DSC instrument Mettler Toledo. DSC thermogram of sumatriptan succinate revealed a sharp endothermic peak at 176°C. In drug excipient blend, the peak of Sumatriptan succinate was slightly shifted from 176°C to 166.32°C with retained characteristic peak of excipient.

FTIR Spectroscopy

FTIR spectrum of pure sumatriptan succinate was compared with excipient spectrum. Compatibility of Sumatriptan succinate with the individual excipient and a physical mixture of formulation were established by FTIR. There was no significant change in the peaks obtained.

Sumatriptan Succinate and Kyron T114 Complex

The complex of Sumatriptan succinate and Kyron T114 at different concentrations (1:1-D1, 1:2-D2 and 1:3-D3) were prepared to mask the bitter taste. They were evaluated for appearance and LOD. All formulations D1, D2, D3 were white in colour. The LOD of D1, D2 and D3 was 2.5, 2 and 1.6, respectively. The formulation with concentration ratio of 1:3 (D3) was found to be within the limit, and was taken for further processing.

Formulation of ODTs

The ODT formulation of Sumatriptan succinate was developed using the direct compression method. Superdisintegrants, including croscarmellose sodium, crospovidone, and sodium starch glycolate, were incorporated at varying concentrations. The evaluation of pre- and post-compression parameters confirmed favorable flow properties across all formulations. Particularly F1 and F8 showed excellent flow property. Further, the formulation containing 6% crospovidone exhibited the lowest mean DT at 34 seconds, surpassing other concentrations as shown in Table 3. Hence this formulation with 6% crospovidone underwent further refinement through the sublimation method to achieve additional reductions in DT.

Sublimating agents, namely camphor, thymol, and menthol, were introduced at three different concentrations (1%, 2%, and 3%) to assess their impact on DT. The comprehensive evaluation of pre and post compression parameters showed good and excellent flow properties. The formulation incorporating 2% menthol exhibited the most favourable results, with a minimal DT of 14 seconds while meeting other essential criteria as shown in Table 4. An intriguing observation surfaced with increase in the concentration of the sublimating agent resulting in a linear decrease in DT.

To ascertain the significance of these findings, Formulation F17, containing 2% menthol, was selected for statistical comparison with the formulation containing superdisintegrants (6% w/w crospovidone). This comparative analysis aimed to provide valuable insights into the enhanced disintegration properties achieved through sublimation and optimize the ODT formulation for Sumatriptan succinate.

Wetting Time Study

Wetting time was performed to determine the disintegration properties of the tablet. Lower wetting time indicates a faster disintegration of the tablet. All of the ODTs in this investigation showed complete wetting with low wetting time.

Disintegration Time

The disintegration times (DT) for all batches were within the prescribed range, meeting the official requirements for ODTs, which mandate a DT of less than three minutes. Among the formulations tested, the variant with 6% crospovidone demonstrated the most efficient disintegration, achieving a remarkably low mean DT of 34 seconds. In comparison, formulations with croscarmellose sodium and sodium starch glycolate exhibited longer DTs of 49 seconds and 69 seconds, respectively.

Driven by the superior disintegration performance of the 6% crospovidone formulation (F-6), a refinement was undertaken using the sublimation method. In this process, sublimating agents, including camphor, thymol, and menthol, were assessed across three concentrations (1%, 2%, and 3%), with subsequent measurement of DT. It was observed that an increase in the concentration of the sublimating agent corresponded to a consistent linear decrease in DT. Further evaluation of the formulations revealed that the variant containing 3% menthol (F18) exhibited the minimum DT of 11 seconds. However, it did not meet the friability test criterion (1.4% w/w). Therefore, the formulation with 2% menthol (F17) was judiciously selected. This formulation not only demonstrated a favourable DT of 14 seconds, but also met all essential criteria, making it the optimal choice for further development.

In-vitro Dissolution Characteristics of ODTS of Optimised Batch

In vitro dissolution studies were conducted utilizing the USP apparatus type I rotating basket, operating at 50 rpm. The dissolution medium consisted of pH 6.8 buffer at a volume of 900 mL, maintained at a precise temperature of 37±0.5℃. In the quest to unravel the mechanism underlying drug release from the dosage form, mathematical modeling played a pivotal role. The matrix tablets, formulated with Sumatriptan succinate and Feverfew, were engineered to exhibit a rapid drug release profile. Upon conducting a comparative analysis of first and second-order kinetic models, it was determined that the drug release mechanism was best described by the first-order kinetic model. Graphical representation of the data, plotting log cumulative percentage of drug remaining versus time, resulted in a straight line with a slope. This linear relationship characterizes the drug dissolution kinetic of the ODT formulation contained within a porous matrix.

Assay

The assay was performed using the HPLC technique. The data obtained showed % drug content (Sumatriptan) as follows: F16: 95.26±2.41, F17: 94.13±3.54, F18: 94.73±2.71.

Stability Study Results

The stability studies conducted on the optimized formulation of ODTs demonstrated no significant changes in the weight variation, hardness, DT, friability, assay and dissolution when stored under accelerated conditions (40°C/75% RH) for a duration of three months. The results remained within the specified limits, providing confidence that the product will maintain its quality and remain within its specification limits throughout its shelf life.

Discussion

This study aimed to develop orally disintegrating tablets (ODTs) of Sumatriptan succinate that disintegrate within seconds. Preliminary investigations were conducted to optimize the concentrations of superdisintegrants, subliming agents, and other excipients in the formulation.In the DSC thermogram, the slight shift in the peak of Sumatriptan succinate from 176°C to 166.32°C can be attributed to mannitol. As mannitol was the major excipient used which served as a bulking agent, with a melting point of 165℃, the drug could have dissolved in mannitol, demonstrating a peak at 166.32℃. Hence it can be said that no drug-excipient incompatibility was noticed.¹⁰

All the formulations exhibited good flow properties. The ODTs were prepared by sublimation method employing Kyron T114 as taste masking agent to mask the unpleasant taste, croscarmellose sodium, crospovidone, or sodium starch glycolate as superdisintegrants and camphor, thymol, or menthol as subliming agents.

The complex of Sumatriptan succinate and Kyron T114 was assessed for LOD. The formulation with concentration ratio of 1:3 (D3) was found to be within the limit, and this was taken for further processing.

The results of post-compression parameter analysis indicated that all formulated tablets exhibited uniform weight with acceptable weight variation and thickness. The hardness of the tablets ranged from 2 to 3.2 kg/cm², and friability loss remained within acceptable limits. Hardness and friability studies demonstrated that the tablets had good mechanical resistance. The inclusion of the sublimating agent slightly increased the friability, likely due to enhanced porosity.²¹

The disintegration time (DT) is the most critical parameter requiring optimization in the development of mouth-dissolving tablets and for selecting the optimized formulation. An increase in the concentration of the superdisintegrant resulted in a reduced DT. At low concentrations, the DT was higher, likely due to inadequate swelling of the tablets. However, at higher concentrations, the DT significantly decreased, as the tablets exhibited optimal swelling necessary for efficient disintegration and the wicking action of the superdisintegrant. Among the formulations, F6 emerged as the most promising, with the lowest DT of 14 seconds.²²

The tablets, formulated with Sumatriptan succinate and Feverfew, were designed to exhibit a rapid drug release profile of > 90% within five minutes. Upon a comparative analysis of first and second-order kinetic models, the drug release mechanism was best fitted for First-order kinetic model (r²=0.9646). Expanding the analysis to include the Higuchi, Korsmeyer-Peppas, and Hixon-Crowell models, the drug release mechanism exhibited compatibility with both Higuchi (r²=0.9421) and Peppas (r²=0.9411) models. This intriguing revelation signifies a matrix system formulation where the initial concentration within the matrix significantly exceeds drug solubility. In this scenario, drug diffusion occurs unidirectionally, with both diffusion and dissolution contributing synergistically to the overall drug release from the ODT formulation. This understanding of dissolution kinetic elucidates the intricate interplay between matrix composition and drug release behaviour, providing valuable insights for the optimization of ODT formulations. The HPLC analysis showed a good % purity between 94 and 95%.

A stability study was conducted on the optimized formulation F17 following ICH guidelines. The evaluated parameters included color, odor, hardness, friability, disintegration time, drug release percentage, and drug content. The results indicated that the optimized formulation remained stable throughout the evaluation period.

Conclusion

In conclusion, this study encompassed the formulation of nine batches of ODTs incorporating Sumatriptan succinate with Tanacetum parthenium. Through comprehensive analysis of counter plot graphs, 3D response surface plots, and overlay plots, it was concluded that the taste-masked ODT formulation containing 6% crospovidone as the disintegrant and 2% menthol as the sublimating agent, denoted as the F17 formulation, emerged as the optimal formulation. This formulation exhibited a DT of 14 seconds, coupled with an elevated drug release profile, indicative of enhanced bioavailability and improved efficacy.

The pronounced benefits associated with the F17 formulation, including rapid disintegration and efficient drug release, contributed significantly to mitigating the challenge of swallowing, thereby augmenting patient compliance. The judicious selection of disintegrant and sublimating agent concentrations not only influenced taste masking, but also laid the foundation for an ODT with superior characteristics. As a result, the F17 formulation stands out as the most promising candidate for further development, showcasing its potential to address therapeutic challenges associated with Sumatriptan succinate administration and enhancing overall patient experience.

Conflict of Interest

The authors declare that there are no conflicts of interest.

 Acknowledgements 

The authors express their gratitude to Empree Medicament Pvt Ltd and Rani Chennamma College of Pharmacy, both located in Belagavi, Karnataka, for providing laboratory facilities to conduct the research work.