Dual Action Herbo-Modern Orodispersible Delivery System For Migraine Management Through Hormonal And Neurological Modulation

The increasing prevalence of hormonal imbalances and neurological disorders such as migraine demands innovative therapeutic solutions that are accessible to a diverse population. Polycystic ovary syndrome (PCOS) and migraine are common, often comorbid disorders that share metabolic, endocrine and neurochemical deregulations notably insulin resistance, altered steroidogenesis, and disturbances in neuronal excitability and neurotransmitter balance. A therapeutic strategy that simultaneously targets hormonal dysregulation and neuronal hyperexcitability could therefore provide synergistic clinical benefits for patients experiencing both PCOS and migraine.

Migraine is a complex neurological disorder characterized by recurrent episodes of severe headache often accompanied by nausea, photophobia, and phonophobia. Beyond a mere pain condition, migraine is now recognized as a neurovascular and hormonal imbalance disorder, frequently influenced by fluctuations in estrogen and stress-related neurotransmitters such as serotonin. The condition disproportionately affects women, particularly during hormonal transitions like menstruation and menopause, illustrating the intricate crosslink between the endocrine and nervous systems. Effective management, therefore, requires a therapeutic approach that addresses both hormonal and neurological dimensions.

Globally, migraine represents a substantial health burden. According to the Global Burden of Disease (GBD) 2021 data, approximately 1.16 billion people are affected by migraine worldwide, marking a 58% increase in prevalence since 1990. The World Health Organization (WHO, 2024) reports that headache disorders affect about 40% of the global population, or roughly 3.1 billion individuals, making migraine one of the most common neurological illnesses. Recent analyses rank migraine as the third leading cause of disability-adjusted life years (DALYs) among neurology-related diseases, underscoring its significant socioeconomic impact. High-burden countries such as India, China, and the United States report the greatest number of disability-adjusted life years lost due to migraine, reflecting both its global prevalence and its role as a leading cause of neurological disability.

Despite the availability of several pharmacological options—including triptans such as Sumatriptan, ergot derivatives, and CGRP antagonists—limitations such as delayed onset of oral therapy, gastrointestinal disturbances during migraine attacks, recurrence of symptoms, and inadequate long-term relief persist. These issues have spurred interest in integrative pharmacotherapy combining modern drugs with herbal actives that possess adaptogenic, anti-inflammatory, and neuroprotective properties. Herbal formulations such as CXCTS have demonstrated migraine-relieving effects through modulation of neurotransmitters (5-HT and β-endorphin) and vasoactive peptides (CGRP, endothelin-1). Systematic reviews also identify botanicals like feverfew, curcumin, coriander, chamomile, and menthol as promising prophylactic and symptomatic anti-migraine agents.

The present project, titled “Dual Action Herbo-Modern Orodispersible Delivery System for Hormonal and Neurological Balance,” is designed to develop a novel orodispersible strip formulation for migraine therapy. This dual-action concept merges the rapid therapeutic action of modern pharmacological agents with the harmonizing benefits of herbal components that target both hormonal and neurological axes. The use of an orodispersible delivery system ensures faster onset of action, enhanced bioavailability, and improved patient compliance—especially critical for rapid relief during acute migraine episodes.

This integrated Herbo-Modern approach aligns with the current shift toward personalized and holistic medicine, aiming to create a delivery platform that not only alleviates immediate symptoms but also stabilizes underlying hormonal and neural dysregulation. By bridging traditional healing wisdom with modern drug delivery science, this project seeks to offer an innovative, evidence-based solution for sustainable migraine management.

Oral Route

The oral route is one of the most preferred routes of drug administration as it is more convenient, cost effective, and ease of administration lead to high level of patient compliance. The oral route is problematic because of the swallowing difficulty for pediatric and geriatric patients who have fear of choking. Patient convenience and compliance oriented research has resulted in bringing out safer and newer drug delivery systems. Recently, fast dissolving drug delivery systems have started gaining popularity and acceptance as one such example with increased consumer choice, for the reason of rapid disintegration or dissolution, self-administration even without water or chewing.

Oro-dispersible strips

Orodispersible strips, commonly referred to as orodispersible films (ODFs) or orally dissolving films (ODFs), represent an innovative advancement in oral drug delivery systems. These ultra-thin, flexible polymeric films, typically measuring 10-100 micrometers in thickness, are formulated to disintegrate or dissolve rapidly on the tongue or buccal mucosa within 30 seconds without requiring water or chewing. This patient-centric design addresses key challenges in traditional dosage forms like tablets and capsules, particularly for populations such as pediatrics, geriatrics, and those with dysphagia, by eliminating the risk of choking and enhancing compliance.

The concept of ODFs originated from non-medicinal products like breath fresheners, with Pfizer's Listerine Pocket Packs marking an early commercial entry in the late 1990s, followed by therapeutic applications such as Chloraseptic Relief Strips for sore throat relief. Over the past two decades, pharmaceutical companies have leveraged transdermal film technology to develop ODFs for systemic drug delivery, transitioning them from over-the-counter (OTC) products to prescription medications. Today, ODFs are recognized by regulatory bodies like the European Medicines Agency (EMA) as a distinct dosage form, defined by their ability to disintegrate in less than 30 seconds in less than 4 mL of saliva.

Mechanism of Action

When an orodispersible strip is placed on the tongue, the moisture from saliva immediately hydrates the surface of the strip, causing it to adhere to the mucosa. The hydrophilic film-forming polymers such as HPMC, PVA, PVP, or pullulan rapidly absorb saliva, soften, and begin to dissolve. As hydration continues, the polymer matrix undergoes dissolution and erosion, often aided by plasticizers that enhance flexibility and allow quicker penetration of saliva. In some formulations, added superdisintegrants further accelerate film break-up. As the strip dissolves within seconds, the drug is uniformly released into the saliva either in dissolved or dispersed form. From here, a portion of the drug is absorbed directly through the buccal or sublingual mucosa, enabling partial bypass of first-pass metabolism and producing a rapid onset of action. The remaining saliva–drug mixture is swallowed and absorbed through the gastrointestinal tract by conventional mechanisms. Overall, the fast hydration, rapid film dissolution, immediate drug release, and partial mucosal absorption together contribute to the quick therapeutic effect of orodispersible strips.

Furthermore, the incorporation of Sumatriptan into an orodispersible strip system may overcome limitations associated with conventional oral tablets, particularly delayed gastric emptying during migraine attacks. Rapid disintegration and absorption through oral mucosa may provide quicker therapeutic onset, improved bioavailability, and enhanced patient convenience during acute episodes accompanied by nausea or vomiting.

Influence of Modern Lifestyle, Diet, and Environmental Stress

Lifestyle stress, poor diet quality, and environmental toxins are major contributors to hormonal dysregulation and mental imbalance. Sedentary behavior, high glycemic food intake, disrupted sleep cycles, and exposure to endocrine-disrupting chemicals (such as bisphenol A and phthalates) contribute to impaired hormonal synthesis and neurotransmitter imbalance. Chronic stress activates the hypothalamic–pituitary–adrenal (HPA) axis, resulting in elevated cortisol levels that dysregulate sex hormones and serotonin production, thereby linking endocrine instability with neurological manifestations such as migraine, anxiety, or depression. Urban living conditions further amplify these effects through air pollution, light pollution, and reduced physical activity, fostering a psychosomatic environment that predisposes individuals to both hormonal and neural dysfunction.

Limitations of Conventional Therapies

Conventional therapies for hormonal and neurological conditions typically rely on synthetic hormones, antidepressants, anxiolytics, or triptans. While effective for acute management, these therapies often have limitations related to side effects, poor tolerability, dependency potential, and low long-term compliance. For example, synthetic estrogen and progesterone therapies can cause fluid retention, weight gain, or thrombotic events, whereas neurological medications like selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are associated with withdrawal symptoms, sedation, and gastrointestinal distress. Triptans, although effective for migraine, exhibit variable absorption, delayed onset, and contraindications in cardiovascular patients. Consequently, there is a pressing need for holistic, multi-targeted interventions that mitigate hormonal and neurochemical imbalance without provoking systemic toxicity.

Dual-Action Herbo-Modern concept

Integrating herbal and modern pharmacological approaches provides a promising solution for comprehensive management of hormonal and neurological disorders. Herbal adaptogens such as Withania somnifera (Ashwagandha), Bacopa monnieri (Brahmi), and Curcuma longa (Turmeric) have demonstrated capabilities to regulate stress hormones, modulate serotonin and dopamine pathways, and enhance neuroplasticity. Concurrently, modern actives such as Sumatriptan deliver targeted pharmacological relief from acute migraine episodes through selective agonistic action on 5-HT1B/1D serotonin receptors, resulting in cranial vasoconstriction and inhibition of pro-inflammatory neuropeptide release. A dual-action herbo-modern system leverages synergistic interactions between natural bioactives and conventional drugs for potentiated efficacy, reduced dose requirements, and minimized side effects. This approach aligns with the emerging focus on personalized, integrative medicine that treats the mind–body axis rather than isolated symptoms.

Rationale for Orodispersible Delivery System

The choice of an orodispersible delivery system further enhances the therapeutic potential of this dual-action model. Orodispersible strips (ODS) provide rapid onset of action, easy administration without water, and bypass of first-pass hepatic metabolism, ensuring higher bioavailability. This route is ideal for migraine and neurological conditions, where quick relief is essential during acute episodes. The rapid dissolution of the strip may also enhance the onset of action of Sumatriptan by promoting faster pre-gastric absorption and reducing delays associated with gastric stasis commonly observed during migraine attacks. Additionally, ODS formulations improve patient compliance, especially in populations facing difficulty swallowing tablets during nausea or severe headaches—common in migraine patients. The fast-dissolving matrix also enables combination therapy of herbal bioactives and modern antimigraine agents in a single dosage form, contributing to synergistic therapeutic action, rapid symptom relief, and improved patient adherence.

Figer No-1

 

 

Figure no -02 Extraction setup for Ashwagandha roots Extra

 

Figure No-03 Phytochemical Constituents Screening Tests for Ashwagandha root extract

Figure No -04 Phytochemical Constituents Screening Tests for Ashwagandha root extract.

9. METHOD OF PREPARATION

Step 1: Preparation of Polymer Base

• Accurately weigh HPMC E50 and Maltodextrin.
• In a clean beaker, add 20-40 mL of distilled water and start gentle stirring.
• Slowly sprinkle HPMC into the water to avoid lump formation.
• Allow the polymer to hydrate for 10-20 minutes until a clear viscous gel forms.
• Add Maltodextrin and continue stirring for an additional 10 minutes.

Step 2: Addition of Plasticizer

• Add Glycerol to the hydrated polymer base.
• Mix continuously to obtain a smooth and uniform polymer-plasticizer solution.

Step 3: Incorporation of Active Ingredients

• In a separate small beaker, dissolve/suspend the APIs—Myo-inositol, Sumatriptan, and Ashwagandha extract—in a small quantity of water.
• Gently add the API mixture into the polymer base with continuous stirring.
• Continue stirring for 15–20 minutes to ensure uniform dispersion.

Step 4: Addition of Excipients

• Add Crospovidone gradually and mix until uniformly dispersed.
• Add Stevia and mix thoroughly.
• Add Citric acid to enhance saliva stimulation and taste.
• Add Peppermint oil dropwise while stirring to ensure complete aroma dispersion.

Step 5: Final Homogenization

• Adjust the final volume using distilled water depending on required viscosity.
• Homogenize the mixture using a magnetic stirrer for 30 minutes to achieve a smooth casting solution.
• Allow the solution to stand for 15 minutes to remove entrapped air bubbles.

Step 6: Casting the ODS Film

• Pour the prepared solution onto a clean, leveled glass/Petri dish/plastic casting plate.
• Spread uniformly using a film applicator to maintain consistent thickness.
• Dry the film at 40–45°C in a hot-air oven or at room temperature overnight.
• Once dried, carefully peel the film from the surface.

Step 7: Cutting and Packaging

• Cut the dried film into 3 × 5 cm strips using a clean cutter blade.
• Store the finished strips in airtight aluminum pouches to prevent moisture absorption.
• Label and pack the strips for further evaluation and testing.

10. EVALUATION TEST PROCEDURES:

1. Appearance and surface uniformity

To assess the physical appearance, surface characteristics, and uniformity of the prepared orodispersible strips.

Method :

Strips were visually inspected under normal light.

Parameters observed:

• Colour
• Transparency
• Smoothness
• Presence of air bubbles
• Cracks or surface irregularities

Acceptance Criteria:

Strips should be smooth, uniform, flexible, and free from visible defects.

2. Weight Variation

To Assess uniformity of mass of individual strips.

Sample size: 20 strips.

Equipment: Analytical balance (sensitivity ±0.1 mg).

Procedure: Tare weigh boats; weigh each strip individually and record weight (g or mg).Calculate mean weight.

Calculations:Mean weight = ΣWi / 20 % Deviation of each strip = [(Wi − Mean) / Mean] × 100

Acceptance criteria: At least 18 of 20 strips within ±5% of mean; none >±10%.

3. Surface pH

To Ensure neutral/acceptable pH to avoid oral irritation.

Sample size: 3 strips.

Equipment/Reagents: pH meter (calibrated), 5 mL distilled water, glass beakers.

Procedure: Place one strip in 5 mL distilled water; allow to equilibrate for 5 minutes at 25–37 °C.

Measure pH with calibrated pH electrode, record. Repeat for 3 strips.

Acceptance criteria:

Surface pH between 5.5–7.5 (approx. neutral); adjust if too acidic/alkaline (taste or mucosal irritation concerns).

1. Folding Endurance

To Evaluate mechanical flexibility (resistance to breaking when folded).

Sample size: 3 strips.

Procedure: Fix one end of a strip between thumb and forefinger and repeatedly fold at the same point until crack or break occurs. Count number of folds to failure. Repeat for 3 strips and report mean ± SD.

Acceptance criteria: Folding endurance >100 folds (a typical target — confirm acceptable value for your polymer system).

2. Tensile Strength and % Elongation

Measure film strength and extensibility.

Sample size: 5 strips.

Equipment: Texture analyzer or Universal Testing Machine (UTM) with film grips; digital calipers for dimensions.

Procedure: Cut specimens to standard size (e.g., 30 mm length × 10 mm width). Measure thickness (t) and width (w). Record initial gauge length L0 (e.g., 20 mm).

Clamp specimen in grips, apply tensile force at 5 mm/min until break. Record Fmax (N) and extension at break (ΔL, mm). Repeat for 5 specimens.

Calculations:

Cross-sectional area A = width (mm) × thickness (mm).

Acceptance criteria: Tensile strength and elongation within desired ranges for flexibility and handling (e.g., TS 5–40 MPa; % elongation 10–50% depending on polymer).

6. Disintegration Time

To determine the time required for the strip to disintegrate in the oral cavity.

Sample size: 5 strips

Equipment: USP dissolution apparatus (Type II – Paddle),

UV/Visible spectrophotometer or HPLC.

Procedure: Dissolution was performed in 900 mL phosphate buffer pH 6.8 at 37 ± 0.5°C. Paddle speed was maintained at 50 rpm. Samples were withdrawn at 5, 10, and 15 minutes and analyzed.

Acceptance Criteria: ≤ 30–60 seconds for standard ODS. Rapid and complete drug release (>80% within 15 min)

7. Content Uniformity

Sample Size:10 strips

Equipment: UV spectrophotometer / HPLC, Volumetric flasks

Procedure : Each strip was dissolved in a suitable solvent. The solution was filtered and analyzed for: Myo-inositol, Sumatriptan, Withanolides (Ashwagandha marker)

Calculation:

Acceptance Criteria:

85–115% of labelled claim

8. Moisture Content

Sample Size: 3 strips

Equipment: Hot air oven / Karl Fischer titrator, Desiccator

Procedure (LOD Method): Strips were weighed and dried at 105°C until constant weight was obtained.

Calculation:

Acceptance Criteria: Low moisture content (<5%)

11. RESULT:

The Formulated Oro-dispersible strips showed satisfactory physiochemical and mechanical properties. The strips were smooth, flexible, and uniform in appearance with acceptable weight variation and surface pH. Folding endurance and tensile strength indicated good mechanical stability. Rapid disintegration time confirmed suitability for oral fast-dissolving delivery. Content uniformity and moisture content were found within acceptable limits, indicating uniform drug distribution and good stability characteristics.

Table No -05

SR.NO.	EVALUATION PARAMETER	RESULT
1	Appearance and surface uniformity	Smooth, Translucent , flexible strips with uniform surface and no air bubbles
2	Weight variation	102 ± 2 mg
3	Surface pH	6.7 ± 0.2
4	Folding endurance	80 ± 2 folds
5	Tensile strength	2.9 ± 0.3 N/mm2
6	Disintegration time	24 ± 2 sec
7	Content uniformity	98.6 ± 1.4 %
8	Moisture Content	3.1 ± 0.4 %

12. CONCLUSION:

The present research successfully achieved the formulation and development of a dual-action herbo-modern orodispersible drug delivery system intended for hormonal and neurological balance. Sumatriptan and Myoinositol was effectively synthesized and incorporated along with selected herbal constituents into a polymeric orodispersible matrix.

The developed formulation demonstrated acceptable physicochemical properties, adequate mechanical strength, rapid disintegration, and efficient drug release, fulfilling the essential requirements of an orodispersible dosage form. Uniform distribution of active ingredients and satisfactory stability under accelerated and long-term conditions further validated the robustness of the formulation.

The study confirms that orodispersible systems can serve as an effective platform for combining herbal and modern therapeutic agents, offering advantages such as rapid onset of action, improved bioavailability, ease of administration, and enhanced patient compliance.

Thus, the formulated dual-action herbo-modern orodispersible system shows significant potential as a novel and patient-friendly approach for managing hormonal and neurological imbalances and may be further explored through in-vivo studies and clinical evaluation for therapeutic validation.

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