Development of Patient-Friendly Oral Thin Film of Flunarizine for Migraine Management

Abstract

The development of patient-friendly dosage forms, such as oral thin films (OTFs), represents a viable alternative to improving drug compliance and delivering quick therapeutic benefits (1,3). Flunarizine, a calcium channel blocker used in migraine prevention, has low water solubility and limited bioavailability, necessitating formulation improvements (3,10). Flunarizine OTFs were studied in three studies employing the solvent casting process with HPMC (E15 or K15) and PVA or PEG 400 plasticisers (1,2,3). Optimised films exhibited uniform drug distribution, a smooth texture, high mechanical strength, and quick disintegration (25-45 seconds) (1,17). In-vitro dissolution experiments showed that over 95% of the medication was released within 5 minutes, significantly surpassing traditional tablets (1,25). Stability experiments validated the formulation's robustness, with no significant modifications occurring over 30 days (24,26). Overall, the Flunarizine OTFs improved dissolution, absorption, and patient convenience, making them a viable fast-acting method for migraine therapy (1,2,9).

Keywords

Introduction

Migraine is a recurring neurological illness characterised by severe headaches, nausea, and sensitivity to light and sound. It generally requires long-term treatment ^(9,10). Traditional oral dosage forms including tablets and capsules, while commonly used, exhibit delayed onset, inconsistent absorption, and poor compliance-particularly during nausea or vomiting episodes ^(9,11). Flunarizine dihydrochloride, which is a calcium channel blocker utilised in migraine prevention, has poor solubility and first-pass metabolism, resulting in a poor bioavailability (40-50%) ^(1,2,3).

Fig no: - 01

The tongue without a need for water, allowing for immediate absorption through the oral mucosa while bypassing hepatic metabolism ^(4,5,6). This enables a speedier onset, higher bioavailability, and increased patient convenience ^(11,15). OTFs are made with hydrophilic polymers such as HPMC, PVA, or PVP, as well as plasticisers such as PEG 400 or glycerol, and are commonly made using the solvent casting process to produce homogeneous and flexible films ^(3,14,19).

The review experiments sought to create instant release Flunarizine OTFs with faster disintegration, improved solubility, and uniform drug content ^(13,15). These findings highlight OTFs as an effective, patient-friendly strategy to overcoming the solubility and compliance difficulties of traditional Flunarizine formulations, resulting in quicker and more consistent migraine relief ^(28,30).

Fig: Flow chart for the development of oral solid dosage forms

Fig no: - 02

Table no: - 01

Parameter	Information
Drug Name	Flunarizine
Brand Name	Sibelium, Stugeron Forte (varies by region)
Structure
Weight	404.50 g/mol
Chemical formula	C??H??F?N
IUPAC Name	1-[Bis(4-fluoropheyl) methyl]-4-[(2E)-3-phenylprop-2-en-1-yl] piperazine
BCS Class	Class II (low solubility, high permeability)
Half life	~18–19 days (very long, explains once-daily dosing)
Pka 1	~2.7 (basic piperazine group)
Pka 2	~9.2(second nitrogen of the piperazine ring)
Log P	~5.0 (lipophilic, crosses BBB easily)
Particle size	Not less than 90% below 50 μm (for solid dosage forms, varies by manufacturer)
Hygroscopicity	Slightly hygroscopic in nature.
Polymorphic form	Form I (most stable and widely used), Form I (less stable).
Solid state Stability	Stable, Crystalline, Photosensitive
Melting Point	~115–117 °C (10,11)
T max	2-4 hours
Solubility	Practically insoluble in water; soluble in chloroform, methanol, ethanol, acetone (9,11)

4. Formulation Approaches for Flunarizine Films:

The Flunarizine oral thin films (OTFs) are designed to provide a fast-dissolving, patient-friendly dose form that provides quick antihistaminic effect and increased absorption. The methodologies employed to develop these films build upon the formulation procedures used for Flunarizine oral thin films, as mentioned in earlier pharmaceutical studies ^(1,3,5).

Active Pharmaceutical Ingredient (API)

• Drug: Flunarizine Hydrochloride
• Dose: Typically, 5–10 mg per film (suitable for thin-film technology) ^(1,14).
• Properties: Moderately water-soluble, bitter-tasting, lipophilic, stable.
• Function in Film: Flunarizine is a calcium channel blocker and antihistamine, used for the treatment of vertigo, migraine prevention, and motion sickness.

Challenges:

• Taste masking is essential due to the drug's bitter profile.
• Uniformity medication distribution in the film matrix is critical for uniform release and bioavailability.
• Solubility enhancement may be necessary due to the moderate water solubility of Flunarizine.

Selection of Film-Forming Polymers

The strength, dissolving, and flexibility of the film are all dependent on the polymer used. Based on the Flunarizine formulations, the most favoured polymer is Hydroxypropyl Methylcellulose (HPMC) due to its superior film-forming capabilities and biocompatibility.

• Commonly used grades: HPMC E-15, HPMC K4M, and HPMC K15M ^(3,14,18).
• Polymer concentration: 200-900 mg per batch maintains film consistency.
• Alternative polymers: Polyvinyl alcohol (PVA) and Pullulan can be added to improve transparency and strength ^(19,20).
• Key role: Provides rapid hydration, flexibility, and uniform drug dispersion

Plasticizers and Humectants

Plasticisers increase the elasticity and folding durability of films, preventing them from breaking or becoming brittle during storage.

• Plasticizers used: Propylene glycol and Polyethylene glycol (PEG-400) ^(3,14,25).
• Recommended range: 5–20% w/w of polymer weight
• Function: Enhances flexibility, reduces brittleness, and ensures smooth texture
• Humectants like glycerol Maintain moisture balance to keep films supple and avoid drying.

Sweeteners and Saliva-Stimulating Agents

Taste masking and mouthfeel are vital for patient acceptability Flunarizine has a slightly bitter taste, so the inclusion of sweeteners and saliva stimulants helps improve palatability.

• Sweeteners used: Mannitol and Aspartame ^(21,22).
• Saliva stimulants: Citric acid (3–6% w/w) enhances saliva secretion and accelerates disintegration
• Additional benefits: Improves mouthfeel and taste, ensuring patient comfort and adherence

Solvent and Casting Medium                                                                                    

The solvent casting process is still the most extensively used and reproducible method for producing oral films, as seen in all three Flunarizine film experiments.

• Solvent system: Ethanol–water mixture for dissolving both polymer and drug ^(3,14,19).
• Procedure:
  • Polymer is soaked in solvent for 30 minutes to swell
  • Drug and excipients are added with continuous stirring
  • The homogenous, bubble-free solution is poured onto a glass plate
  • Films are dried at 40–45°C for 24 hours
• Result: Clear, smooth, and uniform thin films ready for cutting into accurate dose units

Optimization of Film Composition

The polymer and plasticiser quantities must be optimised to provide a balance of strength, disintegration time, and medication release.

• Ideal combination: For best results, combine a moderate polymer concentration (HPMC 400-500 mg) with 0.15 mL propylene glycol.
• Outcome: The result is flexible, transparent films with few drying flaws.
• Performance: Rapid breakdown (15-30 sec) and medication release of over 95% within 10 minutes ^(1,3,17).
• Goal: Provide immediate antihistaminic relief for acute allergies.

Evaluation Parameters

Each film should go through a systematic physicochemical examination to assure quality, repeatability, and effectiveness. These tests are comparable to those used for Flunarizine OTFs ^(27,29).

• Thickness: 0.11–0.20 mm for uniform dosing
• Weight variation: ±10 mg tolerance limit
• Folding endurance: Should withstand 150–250 folds without breaking
• Surface pH: 6.5–6.8, compatible with oral mucosa
• Disintegration time: Within 15–45 seconds for fast action
• Drug content uniformity: 95–105% to ensure accurate dosing
• In vitro drug release: >90% within 10 minutes, reflecting immediate availability

Mechanism of Drug Release

The drug release behaviour from the film depends on polymer matrix swelling and diffusion dynamics.

• Observed kinetic model: Korsmeyer–Peppas model (non-Fickian diffusion) ⁽¹¹⁾.
• Mechanism: Combined effect of polymer relaxation and drug diffusion
• Implication: Predictable, controlled drug release ensuring therapeutic efficiency

Fig No:- 03

Stability Considerations

To maintain efficacy and physical integrity, stability testing is essential under controlled conditions.

• Storage conditions: 40°C ±2°C and 75% ±5% RH for 3 months
• Results from similar films: No major change in drug content, appearance, or disintegration time
• Packaging recommendation: Aluminum foil pouches or laminated sachets for moisture protection
• Shelf-life expectation: Stable for at least 3 months under accelerated conditions ^(24,26).

5. MATERIALS AND METHODS

Materials

The study used flunarizine dihydrochloride as the active pharmaceutical ingredient (API). Several hydrophilic polymers, such as HPMC E15, HPMC K15, PVA, and PVP, were used ^(3,14). to produce films. Plasticizers like PEG 400 and glycerol were employed to increase flexibility and mechanical strength. Other excipients included sweeteners (sucralose, aspartame) and flavorings agents (peppermint, orange) ⁽²¹⁾ to improve palatability and patient acceptance. All reagents were analytical grade.

Formulation Design

To optimise film thickness, mechanical strength, and disintegration time, many formulations were created by altering polymer concentration (2-10% w/v), plasticiser percentage (0.5-2% w/v), and solvent volume. Flunarizine loading was kept at 5-10 mg per film, based on the intended therapeutic dosage ^(26,27).

Preparation Method: Solvent Casting ^(1,3,14)

1. Polymer dissolved in distilled water or hydroalcoholic mixture.
2. Plasticizer added gradually.
3. Flunarizine dispersed into the polymer-plasticizer solution.
4. Degassing to remove air bubbles.
5. Casting into leveled petri dishes or trays.
6. Drying at room temperature (25–30°C) or in a hot air oven at 40°C.
7. Cutting into uniform sizes (2×2 cm²) and storing in airtight containers.

6. Evaluation Parameters

Oral thin films are evaluated using various critical characteristics to verify their quality, performance, and patient acceptance. Thickness and weight variations are assessed to ensure medication content homogeneity and mechanical consistency. Folding endurance, tensile strength, and elongation all influence the film's flexibility, durability, and handling properties ^(1,24). The surface pH is kept near neutral to avoid mucosal irritation, and the disintegration time measures how rapidly the film dissolves-ideally within 30 seconds for fast drug administration. To guarantee consistent dosage, drug content uniformity is tested using analytical techniques such as UV spectroscopy or HPLC. In vitro dissolution experiments measure the rate and amount of drug release in simulated saliva, providing information on bioavailability. In conclusion, taste evaluation—whether using human panels or electronic sensors-ensures good taste masking, which is critical for patient compliance ⁽²⁵⁾

7. Applcations and Benefits in Migraine Treatment

Flunarizine oral thin films (OTFs) provide a quick and easy solution for migraine treatment. These films dissolve quickly in the mouth and allow for buccal absorption, bypassing first-pass metabolism and resulting in quicker onset and higher bioavailability ^(1,2,9). The dose form is suitable for people who experience nausea or vomiting during migraine attacks since it reduces swallowing issues ^(11,13). According to studies, optimised Flunarizine OTFs dissolve in 15-30 seconds and reach over 95% drug release in 10 minutes, giving rapid therapeutic relief. Furthermore, their portable, unit-dose form improves convenience and compliance, making them appropriate for acute and prophylactic migraine treatment ^(1,3,15).

8. Challenges and Limitations

Although Flunarizine OTFs have great potential, significant formulation and processing problems remain. Flunarizine's limited water solubility complicates medication dispersion and influences dissolution rate ^(1,3). To make the bitter taste more acceptable to patients, effective masking agents are required ^(21,22). Another challenge is maintaining mechanical strength and flexibility, since an imbalance of polymer and plasticiser can result in brittle or sticky films. Additionally, moisture sensitivity and scale-up restrictions during solvent casting provide challenges for commercial manufacture ^(19,24,25).

9. Future Perspectives

Future study might concentrate on increasing solubility and stability by nanoparticle inclusion, solid dispersions, or lipid-based coatings. The introduction of innovative biopolymers and sophisticated production processes like 3D printing and electrospinning may enable accurate dosage control and combination treatment ^(15,18). Furthermore, in-vivo investigations and long-term stability testing are required to establish the therapeutic efficacy of Flunarizine OTFs for routine clinical usage. With further modification, these films might become a standard fast-acting dose form for migraine prevention and acute care ^(16,19,20).

CONCLUSION

The development of oral thin films (OTFs) or following research might concentrate on increasing solubility and stability by nanoparticle inclusion, solid dispersions, or lipid-based coatings ^(1,3). The introduction of innovative biopolymers and sophisticated production processes like 3D printing and electrospinning may enable accurate dosage control and combination treatment ⁽⁹⁾. Furthermore, in-vivo investigations and long-term stability testing are required to establish the therapeutic efficacy of Flunarizine OTFs for routine clinical usage. With further modification, these films might become a standard fast-acting dose form for migraine prevention and acute care by using HPMC-based polymers, PEG-400 or propylene glycol as plasticisers, and taste-masking chemicals such mannitol and citric acid, the optimised films disintegrate in seconds and release more than 90% of the medicine in a few minutes ^(1,15,25). These properties enable immediate relief from migraine symptoms, increased bioavailability via buccal absorption, and higher adherence among paediatric, geriatric, and dysphagic patients who struggle with traditional pills or capsules ^(2,9,11).

Although challenges such as low solubility, taste masking, and large-scale production persist, ongoing advances in polymer engineering, nanotechnology, and sophisticated manufacturing techniques such as 3D printing are likely to improve formulation quality and therapeutic effectiveness ^(18,19,26).

Overall, Flunarizine oral thin films are a patient-friendly, fast-acting, and unique drug delivery technology with enormous promise for effective, safe, and easy migraine control in contemporary pharmaceutical therapy.

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