Solid lipid nanoparticle-loaded oral dispersible films of eletriptan hydrobromide for enhanced bioavailability and sustained migraine relief

1. INTRODUCTION

Migraine are very painful recurrent episodes of the nervous system. Approximately 15% of people worldwide suffer from this persistent neurological condition [1]. Patients with migraine suffer from excruciating and incapacitating health conditions. It shows recurrent, unilateral, throbbing headache episodes that range in intensity from moderate to severe [2]. Headache is the second most prevalent cause of migraines, and other common symptoms include nausea, vomiting, photophobia, and/ or phonophobia [3]. The symptoms could progressively get worse. After 2–12 hours, migraine discomfort peaked and then gradually subsided. But it comes into attack if it lasts for 4–72 hours [4]. Although the exact pathogenesis of migraine is unknown, it is generally accepted that migraine is caused by activation and sensitization of trigeminal nerve fibers brought about by neurogenic inflammation [5]. Trigeminal neurons contain one axon, which is divided into central and peripheral stimuli, with both capable of sensitizing and activating these neurons [6]. There are different types of migraine triggers, such as physiologic, dietary, and environmental factors that cause activation of the trigeminal nerve fiber, which may turn into migraine attacks [7]. Neurogenic inflammation in the cerebral dura mater is the first cause of migraine headache. The physiological circumstances surrounding trigemino-vascular activation provide opportunities for new antimigraine medications and enable in vivo research into the molecular causes of cephalic discomfort [8]. Therefore, medications with a rapid pharmacological action are frequently selected to restore the patient’s functioning capacities as quickly as possible. Ibuprofen and acetaminophen are good nonsteroidal anti-inflammatory medications, but triptans such as eletriptan, sumatriptan, zolmitriptan, naratriptan, almotriptan, frovatriptan, and rizatriptan are necessary for severe and chronic migraines [9,10]. Eletriptan hydrobromide is a selective serotonin 5-HT1B/1D receptor agonist of an orally fast-acting triptan class anti-migraine drug. They act by inhibiting the stimulation of the trigeminal nerve, calcitonin gene-related peptides, and SP release substance. They also act by inhibiting nociceptive transmission, avoiding the activation of second-order sensory neurons in the brainstem, and decreasing the c-fos expression in the trigeminal nucleus caudalis [11]. The absorption of the drug was very rapid, but the absolute oral bioavailability is low, about 40–50%, due to first-pass metabolism. The conventional dosage form (tablets) has the slowest onset of effect. Therefore, it is necessary to create dosage forms that provide immediate headache relief while also reducing the first-pass effect to increase bioavailability [12]. The aforementioned factors clearly suggest the need for a better pharmaceutical dosage form that would attenuate the issues while using conventional dosage forms. Somewhat new, “innovative, useful and patient-driven progress directed towards is oral dispersible film (ODF) [13]. Oral dispersible films are flexible, ultra-thin film that contains an active pharmaceutical ingredient that dissolves or disintegrates in the salivary fluid within a second without using any solvent or chewing. The fast release action of the thin film is due to the larger surface area and lesser thickness of the film as compared to a tablet. They are typically composed of plasticized hydrocolloids, which can be manufactured by hot-melt extrusion or the solvent casting method [14]. Transmucosal administration provides a better pathway for systemic availability of the drug since the drug is absorbed directly into the bloodstream, which prevents the degradation of the drug in the GI tract and avoids the hepatic first pass metabolism [15]. Better patient acceptability is also anticipated because this approach is advantageous for patients with dysphagia or swallowing difficulties, because it does not need to be ingested like traditional dosage forms [16]. Furthermore, the thin non-keratinized sublingual mucosa has a high blood supply and low enzymatic activity, enable extraordinarily good drug absorption to achieve high plasma drug concentration, which results in a prompt migraine response. However, some of the problems associated with transmucosal administration are the washout effect of saliva, involuntary swallowing, and mucoadhesion of the film. As per the literature survey, oral dispersible film must have mucoadhesive qualities to prevent the dosage form from being removed by the flushing action of saliva and to guarantee a prolonged retention of the dosage form with the sublingual mucosa surface. For this context, various types of mucoadhesive polymer, such as carbopol, chitosan, hydroxypropyl methylcellulose (HPMC), other cellulose derivatives, and so on, have been utilized for sublingual administration to enhance mucoadhesion. In the present research work, pullulan was used as a mucoadhesive polymer for film preparation [17]. To prolong the retention time of the dosage form, were employed in an oral dispersible film. They are made up of a solid lipid core that is stabilized by one or more surfactants [18]. They can be delivered by oral dispersible films and redispersed from the film matrix without losing their nanoparticulate features. Additionally, the lipid particles could be stabilized to a significant degree in the metastable polymorphism state. When lipid nanosuspensions are embedded in a film-forming polymer to generate orodispersible, they can be dried at more moderate temperatures [19]. Oral dispersible films based on solid lipid nanoparticles (SLN) exhibit a variety of characteristics, including controlled release, mucus penetration, mucoadhesion, and deformation ease [20,21]. Overcome the use of penetration enhancers, which irritate the mucosa [22,23]. A few research studies focused mainly on the loading of SLN in oral film formulations. Didanosine SLN were effectively produced by researchers Jones et al. [24] and administered by buccal route to prevent rapid breakdown of the Active Pharmaceutical Ingredient in the gastrointestinal system. To facilitate buccal medication distribution, the film matrix was composed of HPMC, triethyl citrate, and eudragit^® RS 100 [24]. Another study manufactured SLN of coumarin loaded in hydroxypropyl methyl cellulose film to examine the quality and mucoadhesive properties of film formulations [25]. SLN have been described as a taste-masking approach, and loading in oral dispersible films allows longer residence time on the mucosal surface area [26]. The discernible benefits of employing SLN over more widely used polymeric nanoparticles are their excellent biocompatibility, particularly when phospholipids are used [27]. The aim of the present research work was to establish the foundation for the enlargement of a solid lipid nanoparticle-loaded oral dispersible film of eletriptan hydrobromide for migraine. SLNs comprise a solid lipid (glyceryl monostearate) and a surfactant (poloxamer-188) and were prepared by the high-pressure homogenization process. Special attention was on the SLN, that how the presence of lipid-based system affected the films’ mechanical characteristics, mucin interaction, and uniformity.

2. MATERIALS AND METHODS

3. RESULTS AND DISCUSSION

3.1. Preliminary trial batches

On the basis of trial batches, glyceryl monostearate was selected as a solid lipid, and poloxamer 188 was selected as a surfactant. Based on the trial batches, poloxamer 188 showed a low particle size (275.48 ± 1.82nm) and the highest entrapment efficiency (62.37% ± 0.72%) as compared to other surfactants. Therefore, poloxamer 188 was taken as a better surfactant for further analysis. Glyceryl monostearate (1% w/v), poloxamer 188 (1% w/v), and a homogenization speed of 5,000 rpm for 15 minutes were selected for the preparation of SLN. From the trial batches, the levels selected for further study were 0.5%–1.5% w/v, 1%–2% w/v, and 5,000–10,000 rpm for concentration of surfactant, concentration of solid lipid, and homogenization speed, respectively.

3.2. Optimization of factors affecting SLN by Box–Behnken experimental design

Dependent variable responses for 15 batches by Box–Behnken statistical software are shown in Table 2. When various values of independent variables were combined, particle size, polydispersity index, and entrapment efficiency ranged from 119 nm to 589.5 nm, 0.214% to 0.473%, and 52.9% to 74.12%, respectively. The best-fitted models were selected for each value based on the correlation coefficient (R²), projected R², adjusted R², and standard deviation (S.D.). A quadratic model was selected as best best-fitted model for particle size, PDI, and % entrapment efficiency. Quadratic model for particle size (R² = 0.9,983), PDI (R² = 0.9,748), and % entrapment efficiency (R² = 0.9,608), respectively. The regression equation was created using the analysis of variance, which is tabulated in Table 3. The regression equation shows that the results of the dependent variables were caused by all independent variables.

Table 3. Regression analysis results for SLN.

Responses	Model	R2	R2 Predicted	R2 Adjusted	Std Dev	Polynomial equation
Particle size	Quadratic model	0.9983	0.9,754	0.9,951	10.79	Y1= +142.17 + 60.76A –39.83B –160.81C + 6.37AB –10AC+17.48BC+ 95.89A2 +38.67B2 +118.99 C2
PDI	Quadratic model	0.9,748	0.7,848	0.9,294	0.0,217	Y2= +0.2513 + 0.0335A – 0.0299B – 0.0834C – 0.0100 AB + 0.0030 AC + 0.0137 BC + 0.0510 A2 + 0.0332 B2 + 0.0452 C2
Entrapment efficiency	Quadratic model	0.9,608	0.9,248	0.9,501	1.35	Y3= +64.14 + 4.12A – 3.45B – 5.72 C

3.2.2. Effect on particle size

The particle size of SLN was affected by varying the speed of the homogenizer from low to high and the concentration of surfactant and lipid. At a very low speed of the homogenizer 5,000 rpm, a very large particle size resulted. It may be due to the aggregation of particles at low speed. When the speed of the homogenizer increases from 5,000 rpm to 10,000 rpm, the particle size decreases. However, it is also noticed that the amount of surfactant and lipid added during the preparation of SLN also affects the particle size. Additionally, SLN were greater at extremely low surfactant concentrations (0.5% w/v) because the emulsified globules were comparatively larger at low surfactant concentrations. As a result, the surfactant was further optimized using the optimal range. In the same way, a very high concentration (2% w/v) of lipid led to a larger particle size. The 1.5% w/v of lipid was found to be the optimum concentration for the preparation of SLN. Optimization of particle size is important while manufacturing SLN because it affects the nanoparticles’ biocompatibility and bioactivity. Furthermore, it demonstrates the formulation’s stability. The optimized batch of SLN had an average particle size of 149.189 ± 0.87 nm (Fig. 1). The surface response plot shown in Figure 2 and the polynomial equation suggest that factors interact with each other and affect the particle size of SLN.

Figure 1. Zeta sizer of final optimized SLN formulation. [Click here to view]

Figure 2. Surface response plot displays the following dependent variables of SLN: (A) particle size; (B) PDI; (C) entrapment efficiency; and (D) overlay plot. [Click here to view]

3.2.3. Effect on PDI

Table 2 showed that at very low homogenizer speeds (5,000 rpm), the PDI resulted, a larger size of particles, signifying a less uniform distribution. However, an increase in the PDI may be due to the fact that at lower speeds, the lipid dispersion may not be sufficiently broken down. Higher lipid concentration (2% w/v) also increases PDI. However, surfactant concentration had a non-significant effect on the polydispersity index of the formulation. The PDI of 0.274 was found to be optimum as it showed a narrow and uniform particle size distribution that stabilized the formulation.

3.2.4. Effect on entrapment efficiency

As per the data mentioned in Table 2, the result was that a high concentration of surfactant (1.5% w/v) showed low entrapment efficiency. Increasing surfactant concentrations might result in increased drug partitioning from the internal to the exterior phase, thus solubilizing the drug and lowering the amount accessible for encapsulation. Moreover, a more densely packed polymer layer caused by high surfactant concentrations may impede drug entrapment and penetration into the nanoparticles. High homogenization speed (10,000 rpm) might result in low entrapment efficiency. Because of things like increased shear stress and heat generation, which could harm the encapsulated substance. The structure and characteristics of the lipid matrix may also be impacted by high homogenization speeds, which may result in the development of unstable solid lipid nanoparticles (SLNs) or modifications to the drug’s solubility in the lipid matrix. From the result, it was observed that 1% w/v of surfactant concentration, 1.5% w/v of lipid amount, and 7,500 rpm homogenizer speed were found to be optimum since they have a desired particle size of 149.2 nm, a narrow PDI range of 0.274, and maximum drug entrapment efficiency of 65.51%. From the overlay plot, lipid concentration 1.58,883% w/v, surfactant 0.883% w/v, and 7,795 rpm homogenization speed were selected as the optimum formulation. Based on results obtained from the preliminary trial batches, which were further optimized by design of experiments, formulation F12 was selected as optimum for the preparation of SLN.

3.2.5. Morphology

Transmission electron microscopy was performed to physically check the prepared solid lipid nanoparticles (SLNs). The SLN that were located as almost spherical in shape were also found to be smooth, in the nano range, and devoid of any debris (Fig. 3). The SLN were found to be in the 150–200 nm range.

Figure 3. TEM images of SLN at magnification of 500 nm. [Click here to view]

3.3. Evaluation of solid lipid nanoparticle-loaded oral dispersible film

3.3.1. Weight variation

The weight variation analysed the uniform distribution of the drug and other excipients of the film. The individual films were weighed accurately, and the mean value was calculated. The weight variation of the optimized formulation was 567.5 ± 2.11 mg. A low value of standard deviation indicates uniformity in the weight of the film.

3.3.2. Surface pH

The pH of oral film administered to the oral mucosa must be near 7.0 to prevent any damage to the oral mucosa. The pH value of the solid lipid nanoparticle-loaded film was 6.7, which is close to that salivary. Result of the study suggests that the films would be easy to administer and would not irritate the oral mucosa. In the present work, only physicochemical evaluation, including pH measurement, was performed as a preliminary safety indicator. No cytotoxicity or mucosal irritation studies were performed.

3.3.3. Thickness

Thickness is one of the main physical attributes of oral dispersible film that demonstrates its consistency in film casting. The thickness of the oral dispersible film depends on the concentration of the film-former polymer. The coating should not be so thick that it takes a longer time to dissolve, or so thin that it cannot be removed without causing damage. Furthermore, the film thickness also affects how accurately the dose is distributed. However, the ideal thickness value of oral film should be between 50 and 1,000 μm. The thickness of the optimum batch was found to be 387.41 μm ± 0.024 m. The consistency of the film was evidenced by the minimal standard deviation.

3.3.4. Disintegration time

The optimized formulation’s disintegration time was 54 ± 0.32 seconds, which is less than a minute and suggests a rapid onset of action of the film. Results showed that pullulan film former polymer alone gives faster disintegration without the addition of any super-disintegrant. The hydrophilic nature of pullulan polymer exhibits hydration on the surface of the film and gives rapid disintegration.

3.3.5. Folding endurance

Folding endurance determines the brittleness or flexibility of oral dispersible film. Folding endurance increases as we increase the concentration of polymer and plasticizer. The optimized formulation gives no sign of breaking until 82 folds. But after 90 folds, a thin line was seen on the surface of the film. The test was performed in triplicate, and the optimum value of folding endurance was found to be 106 ± 1.43 folds. The result of the study showed that pullulan film-forming polymer gives excellent strength to film, and plasticizer propylene glycol provides flexibility to the oral dispersible film.

3.3.6. Tensile strength

Tensile strength is also one of the main mechanical characteristics of oral dispersible film that indicates the toughness of the film. It analysed the force or stress that is endured by the film during manufacturing, packaging, and transport. Tensile strength of the film should be optimum, as too-thick film gives a bad or uncomfortable feel in the mouth. Tensile strength of formulated oral dispersible film was found to be 153 ± 0.18 g/cm², which revealed that the film has better strength to bear force during processing and handling of the film.

3.3.7. Morphology study by transmission electron microscopy

TEM images of SLN loaded oral dispersible film demonstrated that the SLN were uniformly dispersed in the film matrix (Fig. 4). The SLN had an almost spherical in shape and a very smooth surface.

Figure 4. TEM image of SLN-loaded oral dispersible film. [Click here to view]

3.3.8. X-Ray Diffraction

X-ray diffraction study was performed to determine the diffraction pattern of eletriptan hydrobromide in pure form, physical mixture, solid lipid nanoparticle, and for oral dispersible film loaded with nanoparticle. X-ray study of pure drug eletriptan hydrobromide was detected at 2 theta angle, which showed many sharp peaks at 10°, 11.5°,13.2°, 15.1°, 16.5°, 18.2°, 20.2°, 22.5°. These sharp peaks indicate drug exists in pure crystalline form. All these peaks shift to some extent, but also appear in a physical mixture to some lesser extent. However, distinct sharp peaks disappear in the solid lipid nanoparticle and the solid lipid nanoparticle-loaded film. This type of halo pattern of characteristics peaks of SLN and SLN-loaded oral dispersible film showed a change of the crystalline nature of the drug into an amorphous form. The type of polymer, surfactant, and lipid was responsible for the loss of crystalline nature of the drug. They get absorbed on the surface of SLN and inhibit the recrystallization of the drug, which stabilizes the amorphous form of the formulation. An amorphous form of oral dispersible film incorporated with SLN suggests a higher rate of dissolution of the formulation. X-ray diffractograms of eletriptan hydrobromide, physical mixture, SLN, and SLN-loaded oral dispersible film are shown in Figure 5.

Figure 5. Comparison of x-ray diffractograms of: A) Eletriptan hydrobromide; B) Physical mixture; C) SLN; D) SLN -loaded oral dispersible film. [Click here to view]

3.3.9. Differential scanning calorimeter

The DSC thermogram of eletriptan hydrobromide showed a melting peak at 165°C. The individual melting peaks of glyceryl monostearate and poloxamer 188 were revealed at 65°C and 54°C, respectively. The physical combination thermogram likewise showed these independent melting peaks at about the same value. However, melting peaks in solid lipid nanoparticle (SLN) and solid lipid nanoparticle-loaded oral dispersible film formulations (SLN-ODF) were almost absent. The absence of the melting peak of eletiptan hydrobromide in SLN and SLN-ODF suggests that the drug exists in amorphous form or disperses molecularly in the lipid matrix (Fig. 6).

Figure 6. DSC profile of SLN-loaded oral dispersible film: A) Eletriptan hydrobromide; B) glyceryl monostearate; C) poloxamer 188; D) Physical mixture; E) SLN; F) SLN -loaded oral dispersible film. [Click here to view]

3.4. In vitro drug release

In vitro drug release of oral dispersible film containing SLN of eletriptan hydrobromide (Test film) was compared with oral dispersible film containing free drug (Reference film) in phosphate buffer pH 6.8. Figure 7 resulted, 74.67% drug release from ODF containing free drug with a period of 4 hours. The solid lipid nanoparticle-loaded oral dispersible film illustrates that 26.51% of the drug is released from the film in half an hour. Initially, film exhibits burst release, which can be due to the presence of an unentrapped amount of drug in the matrix of the oral dispersible film. The quick release of the drug within the first half hour may be due to the presence of a hydrophilic film-forming polymer, pullulan. However, after a resulting burst release in half an hour, the oral dispersible film containing SLN of eletriptan hydrobromide showed a slower drug release rate than the oral dispersible film containing free drug, which can be due to the presence of entrapped drug in SLN. Since glyceryl monostearate is well known for its ability to provide sustained drug release through its matrix. The drug is embedded in a matrix created by glyceryal monostearate, which reduces the drug’s mobility inside the matrix and causes a slower release. Moreover, the surfactant poloxamer 188 stabilizes the nanoparticles and may have an impact on release rates by influencing the drug’s position within the SLN loaded in ODF. The cumulative percent drug release of 87.02% was measured within 24 hours. A controlled and prolonged release results from the lipid’s solid state at body temperature, which limits the movement of the drug. Drug release pattern of oral dispersible films was analysed by applying zero order, first order, Korsmeyer–Peppas, and Higuchi models. The R² value of the Higuchi model was 0.9,386 for SLN-ODF and 0.9,335 for ODF-free drug, which indicates that the release of the drug is primarily followed by Higuchi’s model.

Figure 7. % Cumulative drug release of ODF-free drug and SLN-ODF. [Click here to view]

4. CONCLUSION

In the present research study, the oral dispersible film containing SLN of eletriptan hydrobromide was manufactured successfully by using pullulan as a film-forming polymer and propylene glycol as a plasticizer. The incorporated SLN were manufactured by glyceryl monostearate as a solid lipid and poloxamer-188 as a surfactant. All the parameters of optimized formulations depended on the types and concentration of excipients used for the preparation of oral dispersible film. The oral dispersible film showed sufficient mechanical strength. Studies using DSC, XRD, and TEM further validate the development of the film. X-ray diffraction study demonstrated that the crystallinity of the drug changed into an amorphous form after incorporating into the oral dispersible film. The in vitro drug release data clearly show that a solid lipid nanoparticle-loaded oral dispersible film of eletriptan hydrobromide provides controlled and sustained drug release as compared to free drug-loaded oral dispersible film. However, unentrapped drug present on the surface of the film provide fast action of drug, which is needed in migraine situation. The SLN-ODF illustrated sustained drug release up to 24 hours. Stability study data showed that the film was stable at 25°C/60% RH for 3 months. From the study, it was concluded that oral dispersible films do not require water during dose administration, avoid first-pass metabolism, show potential to enhance bioavailability, and improve patient compliance. Bioavailability studies and clinical validation are required to confirm these findings. Mucoadhesion and transmucosal absorption were discussed as potential advantages based on the properties of the polymer and lipid carriers. However, experimental mucoadhesion and tissue permeation studies are necessary to validate the assumptions of mucoadhesion strength and transmucosal permeation across sublingual tissue. In vitro cytotoxicity assays and mucosal histological analysis will be essential in future studies to fully establish safety for sublingual administration.

5. ACKNOWLEDGMENT

We would like to express our heartfelt gratitude to Department of Pharmacy, M.M. College of Pharmacy, Maharishi Markandeshwar, Mullana, Ambala for providing adequate labs for Scientific Research and guidance for their invaluable support and contributions to our work.

6. AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work. All the authors are eligible to be an author as per the International Committee of Medical Journal Editors (ICMJE) requirements/guidelines.

7. FINANCIAL SUPPORT

There is no funding to report.

8. CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.

9. ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

10. DATA AVAILABILITY

All the data is available with the authors and shall be provided upon request.

11. PUBLISHER’S NOTE

All claims expressed in this article are solely those of the authors and do not necessarily represent those of the publisher, the editors and the reviewers. This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

12. USE OF ARTIFICIAL INTELLIGENCE (AI)-ASSISTED TECHNOLOGY

The authors declares that they have not used artificial intelligence (AI)-tools for writing and editing of the manuscript, and no images were manipulated using AI.

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