INTRODUCTION:

A migraine is a form of headache that lasts 4–48h and is characterised by pulsating, one-sided pain along with other symptoms like nausea, vomiting, and sensitivity to the environment. Nonsteroidal anti-inflammatory medications such acetaminophen and ibuprofen are helpful treatments; however, triptans are preferable in first-line acute therapy in cases of severe and persistent migraine¹. Their modes of action, which are mediated through the stimulation of 5-HT1B, include antinociceptive modulation, calcitonin gene-related peptide release inhibition, and cerebral vasoconstriction. For the majority of migraineurs, all triptans are thought to be safer and more effective medications². In order to increase the bioavailability of rizatriptan, a literature review documented the use of a variety of drug delivery methods, including buccal film/patches, pulsatile pills thermoreversible nasal gel, microspheres, nanoemulsion, nanoparticles. Additionally, the buccal films are made with excipients that are widely accepted to be safe, making them a potential medication delivery option for children³.

Recently, mucoadhesive carriers such as nanoparticles and micro particles have emerged as an additional effective method for delivering drugs across the mucosa. Additional advantages of colloidal carriers include the ability to alter the properties of drug release and absorption, shielding pharmaceuticals from biological deterioration, increasing drug’s permeability and bioavailability, and providing hydrophobic substances as an aqueous dispersion⁴. Chitosan is a non-toxic, biodegradable, and biocompatible polymer. CNPs have been prepared using a variety of techniques, including emulsion crosslinking, polyelectrolyte complex, inotropic gelation, template polymerization, and precipitation. The ionic interaction between positively charged chitosan amino groups and oppositely charged poly anion groups is the basis of the ionic gelation process. This poly anion is known as a cross linker⁵. One crosslinker that has been employed is sodium tripolyphophate (TPP). After rizatriptan's physicochemical and biopharmaceutical issues taken into account, the decision was made to administer the drug by putting its CNPs into films for buccal distribution. Extended duration of result along with a quick start of action are ideal for the clinical signs of a migraine episode, and buccal films with RCNPs may deliver both of these. So, the aim of this study was to create and assess a thin, mucoadhesive buccal film that was loaded with RCNPs and assess how well it worked as a substitute for migraine medication⁶.

MATERIALS AND METHODS:

Rizatriptan benzoate provided as gift sample by Apotex labs, Bangalore. chitosan and tripolyphosphate (TPP) were obtained from Sigma Aldrich; acetic acid glacial, methanol were obtained from HiMedia Laboratories. POLYOX and guar gum were purchased from Sigma Aldrich.

Preparation of Nanoparticles (RCNPs):

To create NPs with the required particle size, modifications to the ionotropic gelation method were made. To put it briefly, 0.5% v/v glacial acetic acid was added to water to create a 0.2% w/v low molecular weight chitosan solution. Dissolving the precisely weighed amount of drug required by stirring at 900rpm. The resulting solution's pH is adjusted to the necessary amount using 0.1M NaOH solution⁷. Using a syringe pump operating at a flow rate of 0.5mL/min, the drug polymer mixture was progressively combined with 0.2% w/v TPP solution. Almost immediately after TPP was added, drug-loaded nanoparticles were produced. To improve the formulation, many batches of the medication and chitosan solution were made, each with a different pH. Other formulation parameters were held constant for comparison studies⁸. The formulation table of nanoparticles (RCNPs) was shown in (Table 1).

Evaluation of nanoparticles (RCNPs):

Entrapment Efficiency (%EE):

The solution was immediately separated in ultracentrifuge operating at 16000rpm for 60min at 4°C. With the UV spectrophotometer set to 226nm, the amount of drug in the obtained clear supernatant sample was calculated. Based on the value of highest %EE the prepared NPs were selected as optimized and further characterization on them will be continued⁹. These optimized NPs will be incorporated into the prepared BFs for the further studies.

Table 1: Formulation table of nanoparticles (RCNPs)

F Code	Ingredients			Chitosan : TPP ratio	pH of the solution
F Code	Drug (mg)	Chitosan (mg/mL) [Vol. (mL) added]	TPP (mg/mL) [Vol. (mL) added]	Chitosan : TPP ratio	pH of the solution
RCNPs1	150	2 (10 mL)	2 (2.5 mL)	4:1	3.5
RCNPs2	150	2 (10 mL)	2 (2.5 mL)	4:1	4.5
RCNPs3	150	2 (10 mL)	2 (2.5 mL)	4:1	5.5
RCNPs4	150	2 (10 mL)	2 (3.3 mL)	3:1	3.5
RCNPs5	150	2 (10 mL)	2 (3.3 mL)	3:1	4.5
RCNPs6	150	2 (10 mL)	2 (3.3 mL)	3:1	5.5

Table 2: % Entrapment efficiency of nanoparticles (RCNPs)*

F Code	% EE
RCNPs1	90.22±2.32
RCNPs2	94.28±1.26
RCNPs3	89.69±1.54
RCNPs4	88.77±0.96
RCNPs5	82.16±1.33
RCNPs6	85.54±2.11

Particle Size:

The Horiba Scientific SZ-100 with dynamic laser light scattering technology was utilised to measure the polydispersity index (PDI) and mean particle size for the optimized NPs based on their highest % EE. Before the dispersions were tested at a 90° angle, they were diluted 100 times with deionized water¹⁰.

Figure 1: Particle size of RCNPs

Zeta potential:

The Horiba scientific SZ-100 was used to calculate the ZP of optimized NPs based on their highest %EE, using the laser light scattering technique. To suitably dilute the mixture, double distilled water was used. A 90° angle was used to take the measurements¹².

Figure 2: Zeta potential of RCNPs

FTIR Spectroscopy:

Drug, chitosan and optimized RCNPs' FTIR spectra were recorded using Agilent technology FTIR spectrometer. Samples were scanned for differences in the strength of the sample peaks in the 400–4000 cm^-1 wave number range using infrared absorbance scans¹³.

Figure 3A: FTIR Spectra of Rizatritan; Chitosan and RCNPs

In vitro drug release studies:

With a Franz diffusion cell set at 37±0.5°C, the drug release from optimized nanoparticles (NPs) based on their greatest percentage of EE was investigated in-vitro. A dialysis bag containing optimized NPs equivalent to 10mg of drug was tied at both ends in a 100mL of pH 6.8 PBS and was shaken at 50rpm. Samples of 1mL were obtained from the beaker and replaced with an equal volume of pH 6.8 PBS at predetermined intervals (0, 1, 2, 3, 5, 6 h). Each sample that has been removed is then diluted to 10mL. The drug concentration was ascertained using a UV-Visible spectrophotometer¹⁴ that was adjusted to 226nm.

Preparation of Buccal Films (RCNBFs):

An inexpensive solvent casting method used to create 6 different formulations of mucoadhesive buccal films loaded with optimized Rizatriptan-chitosan nanoparticles (RCNBFs)as mentioned in(Table 2). The various concentrations of POLYOX and/or gellan gum were dissolved in 10mL of generated optimized NPs dispersion and swirled for 1h at 400rpm in 60°C is shown in (Table 2). Plasticizer used is glycerol. To allow the solvent to evaporate, the solution was placed in a 35cm² petri dish and baked at 40°C for 48h. The resultant films were sliced with a cutter into 6cm² pieces and kept in a desiccator until used for further research¹⁵.

Table 2: Formulation table of buccal films loaded with optimized nanoparticles (RCNPs2)

F Code	POLYOX (mg)	Gellan gum (mg)	Glycerol (mL)
RCNBFs1	100	0	1.5
RCNBFs2	200	0	1.5
RCNBFs3	100	100	1.5
RCNBFs4	150	150	1.5
RCNBFs5	300	100	1.5
RCNBFs6	400	0	1.5

Evaluation of Buccal Films (RCNBFs):

Physico-chemical evaluation parameters were performed for prepared buccal films. Also the ex vivo permeation studies were performed on the optimized BFs with drug-chitosan NPs and with plain drug.

Thickness:

One crucial factor in assessing the homogeneity of the formulation component distribution is the film's thickness. All six (n=6) of the film's areas should have a maximum difference of less than 5%. To carry out more investigation, the average data were used¹⁶.

Surface pH:

The buccal mucosa was found to be affected by each film using the exterior pH of each formulation¹⁷. Immersing the 1x1 cm films in 1mL of room temperature distilled water lasting for one hour. The electrode of an ELICO pH metre (L1613) was brought into contact with the film's surface in order to measure the pH.

Folding endurance:

To test the film's folding resilience, a thin (2 x 2cm²) strip was folded several times until it broke. A folding endurance number of a film is the number of folds it endures without breaking¹⁸.

Swelling ratio (%):

Following the weight measurement of a 2x2 cm² film (W1), the films' swelling characteristics were assessed by submerging them in pH 6.8 PBS at 37°C. At five-minute intervals, films were removed from the PBS solution, and any remaining PBS was filtered through filter paper until the films started to degrade¹⁹.

Drug content:

Cut from various locations, each buccal film a surface area of 1 cm². It was then submerged in a methanol-water solvent mixture and agitated in a water bath with a thermostat that was set to 37±0.5°C for six hours²⁰. After the medication was removed from the solvent, it was filtered and subjected to spectrophotometric analysis at 226nm.

Figure 4: Swelling Ratio of RCNPS of buccal films

Mucoadhesive strength:

Using goat buccal tissue as the substrate, a texture analyzer was used to assess the films' mucoadhesive strength. Initially, the buccal membrane was fixed onto a stationary stage and a suitable-sized film (1 cm²) was attached to the analyzer's probe²¹. PBS (simulated saliva) was used to wet the tissue at a pH of 6.8. The probe was lowered gradually until it made touch with the mucosal membranes, and then it was left in place for a minute. The mucoadhesive strength that resulted was measured in Newtons.

In vitro drug release:

A study on drug release in vitro was carried out utilising a Franz diffusion cell that was kept at 37±0.5°C. 2mL of pH 6.8 PBS was added to dialysis bags holding 0.6 × 0.6 cm films, each of which contained 0.22mg of the medication. After that, these bags were submerged in 8 mL of the identical PBS solution, which was stirred at 37°C and 100rpm. One millilitre samples were taken out of the medium of dissolution and refilled with an equivalent amount of pH 6.8 PBS at intervals of zero, one, two, three, four, five, and six hours. After that, the samples were examined at the wavelength of 226nm using UV spectroscopy²².

FTIR spectroscopy:

Interactions between the drug and other film formulation components, FTIR spectra of the drug, optimized buccal film without drug (Placebo), and with drug were employed. Each sample was scanned at a resolution between 400 and 4000 cm^–1.

SEM analysis:

SEM images of drug, optimized buccal film without drug (Placebo) and with drug were noted. The SEM was

used to study the BFs external macroscopic structure²³. (Figure-6).

Ex vivo permeation study:

The Franz diffusion cell was used in the ex vivo studies on the goat buccal mucosa, with the temperature set at 37±0.5°C. After being thoroughly cleaned, it was secured to open metal cylinder and put in a 100mL beaker with 50mL of pH 6.8 PBS. Separate cells on the mucosa were used to hold optimised buccal films carrying nanoparticles of drug and buccal films containing plain drug²⁴. The magnetic stirrer is used to position this setup. To maintain sink condition, 5mL of the sample was removed at set times (0, 1, 2, 3, 4, 5, and 6 h) and refilled with brand-new pH 6.8 PBS. At 226 nm, the sample was measured with a UV-Visible spectrophotometer.

Figure 7a and 7b: Zero Order Kinetics and First Order Kinetics

Figure 7c and 7d: Higuchi and Korsmeyer-Peppas Model

DISCUSSIONS:

Evaluation of Nanoparticles:

% EE: By the determination of % EE of all the prepared RCNPs ranges from 82.16 to 94.28% indicating good drug entrapment. Based on these studies, a 4:1 ratio between chitosan and TPP is recommended, due to their higher values than others. The formulation RCNPs2 is found to have highest value of 94.28%. Hence the further studies: Particle size analysis, ZP, FTIR spectra and in vitro drug release were conducted on the optimized NPs (RCNPs2).

Particle size:

Particle size analysis revealed a particle size of 476.6nm (Fig. 1). The size range of the colloidal NPs was 50-1000nm. Particle size increases as a result of the RB being loaded into the chitosan matrix²⁵.

ZP:

Values for ZP typically fall between -30 to +30 mv. The average ZP of optimized RCNPs2, is determined to be +22.6mv (Fig. 2), which indicates the successful loading of drug into the chitosan matrix.

FTIR spectroscopy:

The FTIR study was employed to search for potential drug and chitosan interactions. In the FTIR spectra of drug, the signal at 1603 cm^-1 is ascribed to C=C stretching in aromatic rings. In tertiary amines, the notable absorption peak at 1349 cm^-1is caused by C–N stretching. Carboxylic acid's C–O stretching shows a comparable peak at 1291 cm^-1 (Fig. 3A). In the FTIR spectra of chitosan, N–H bending was the cause of the absorption band at 1576 cm^-1 of primary amine. The absorption bands at 1020 cm^-1 and 3354 cm^-1, respectively, indicate -CO- stretching and -OH bending (Fig. 3B). The FTIR spectrum of optimized RCNPs2 is shown in (Fig. 3C). While there may be a potential interaction between the medication and film components, no new peaks or notable peak changes are identified.

In vitro drug release:

Four mathematical models were employed to analyse in vitro release data in order to investigate the the kinetics of drug from optimised RCNPs2. For zero, first order, Hughchi, and Korsmeyer-Peppas models, the regression coefficients (r2) were computed. The highest 0.9619 r2 value. This suggests a direct correlation between a drug's concentration and rate of release. The drug release rate can be described as either independent or dependent on its concentration using the zero and first order, respectively. The release of pharmaceuticals from a lipophilic matrix can be explained by the Higuchi model. (which is not valid in the present case).

A non-Fickian model is Case II of the drug release mechanism, whereas Case I is categorised as a Fickian model. This is predicated on the coefficient of release (n) value in the power law model, or Korsmeyer-Peppas, for the spherical shape²⁶. Diffusion governs drug release in a Fickian model (Case I) when n = 0.43. When n=0.85, the drug release mechanism is caused by the relaxing or expanding of polymeric chains, according to the non-Fickian (Case II) model. The non-Fickian model is applied when 0.43 < n < 0.85, and the drug delivery mechanisms include swelling and diffusion. The non-Fickian model is applied when n > 0.85, and the drug release mechanisms include stress and polymer breakdown.

Characterization of Buccal Films (RBCNBFs):

Thickness: The precision of drug concentration in distinct sections of every film is directly related to the consistency of thickness and drug content. After repeating all measurements, the film thickness was found to be between 0.168±0.014 and 0.286±0.006 mm (Table 3).

Surface pH:

By measuring the pH of the film's surface, the impact of pH on the buccal mucosa was examined. For every formulation, the surface pH of BFs was determined within the 6.54±0.03 to 6.95±0.05 range (Table 3), which is the pH range of healthy human saliva. Hence they are not supposed to cause the buccal irritation.

Folding endurance:

The mechanical strength and rupturing resistance of BFs were assessed through folding endurance testing. The values are ranging from 270±1.18 to 313±1.26 (Table 3), which showed good flexibility for all formulas.

Swelling index:

Generally, the kind, content, and physicochemical makeup of the film formers determine the degree of film hydration. (Fig. 4) makes it clear that, in contrast to other films, the hydration values in film RCNBFs6 are somewhat greater and comparable. The inclusion of a higher concentration of hydrophilic POLYOX may be the cause of the slight improvement in hydration seen in film RCNBFs6. All of the films had a fast percentage swelling rate, as seen by the sharp curve that appeared in the first hour and kept getting better until the second hour. After then, the percentage of hydration did not change, indicating that there was no further swelling. Fast hydration (20–30%) in 2 hours indicated that the films were ready to expand and offer sufficient mucoadhesion when applied. The swelling index and mucoadhesive strength do, in fact, correlate; mucoadhesion rises with hydration level up to the point at which hydration causes decrease in adhesive strength²⁷.

Drug content:

In order to guarantee medication availability in pharmaceutical products, uniformity of drug content is typically evaluated. Table 3 indicates that the drug content ranges from 93.0±1.23 to 94.6±1.12%, indicating a greater drug concentration of >94% in films RCNBFs6. The constant values across several formulations indicated that the type and composition of the polymer had no effect on the amount of medication.

Mucoadhesive strength:

The values of mucoadhesive strength are ranging from 6.5±0.14 to 7.5±0.22 N (Table 3), signiﬁes higher mucoadhesive strength > 7.5 N in ﬁlms RCNBFs6. The mucoadhesive property exhibited by the polymers is of the order POLYOX > POLYOX + guar gum > guar gum; and could be due to the poly (ethylene oxide) present in POLYOX³⁹. Higher mucoadhesive strength was observed in ﬁlms, prepared with high concentrations of POLYOX than lower concentrations and in combination with guar gum

In vitro drug release:

The kinetic profile of drug release from optimized buccal films RCNBFs6 in pH 6.8 PBS was found to fit the first order model, as evidenced by the highest r² value of 0.9644. This indicates that a drug's rate of release is directly correlated with its concentration.

Based on the value of the exponents of release (n) in the Korsmeyer-Peppas or force law model for the planar / thin films, the drug release mechanism can be categorised into the Non-Fickian models or the Fickian model (Case I). When n = 0.5, drug release in a Fickian model is governed by diffusion. When n = 1.0, the drug release mechanism is caused by the relaxing or expanding of polymeric chains, according to the non-Fickian model. The non-Fickian model is applied when 0.5 < n < 1.0, and drug release happens by swelling and diffusion. The non-Fickian model is applied when n > 1.0, and the drug release mechanisms include stress and polymer breakdown. The non-Fickian Super Case II, with n = 1.3412, is reflected in the optimised RCNBFs6 Table 4. This suggests that drug release is mediated by stress and polymer disintegration.

FTIR spectroscopy:

To search for any possible interactions between drug and the other excipients (chitosan, POLYOX and glycerol) in the BFs, FTIR studies were conducted on drug, optimized film RCNBFs6 without drug (Placebo) and with drug. In the FTIR spectra of drug, the signal at 1603 cm^-1 is ascribed to C=C stretching. In tertiary amines, the notable absorption peak at 1349 cm^-1 is caused by C–N stretching. Carboxylic acid has a similar peak for C–O stretching at 1291 cm^-1(Fig. 6A). In the spectra of placebo the peak observed at 2878 cm^-1 was attributed to C–H stretching vibration in an alkane. The hydroxyl group's C–O stretching is what causes the peaks at 1092 and 1466 cm^-1(Fig. 4B). The FTIR spectra of optimized film RCNBFs6 with drug is shown in (Fig. 4C). While there might be some interaction between the medication and the components of the film, no new peaks or notable alterations to existing peaks are found.

SEM analysis:

SEM was used to study the surface morphology of drug, optimized film RCNBFs6 without drug (Placebo) and with drug. SEM of drug only demonstrates a normal crystal structure (Fig. 7A). The placebo film exhibits small holes and a homogenous structure (Fig. 7B). The optimized film RCNBFs6 with drug, exhibit amorphous nature of drug, increased pore diameters, a uniform surface had an appropriate surface morphology suitable for buccal application (Fig. 7C). Based on the findings, the images of films with and without drug appear to be surface identical.

Ex vivo permeation:

Experiments conducted ex vivo are typically aimed at understanding the absorption dynamics of drugs through biological membranes. The transportation of drugs across any membrane is influenced by both the characteristics of the drug molecules themselves and the physiological properties of the biological barriers. The data from Figure 8 illustrate that optimized buccal films containing drug nanoparticles (RCNBFs6) demonstrate higher drug permeation compared to films containing plain drug (RBFs6). The optimized film RCNBFs6 exhibited significantly higher steady-state flux (83.85± 8.26µg/cm2/h, p < 0.005) compared to RBFs6 (48.88± 6.05µg/cm²/h). Comparing RCNBFs6 (504.12±32.53 µg/cm2) to RBFs6 (320.23±28.15µg/cm2), the total amount of drug delivered into the receiver liquid at 6 hours was similarly significantly greater (p < 0.005).

Additionally, the permeability coefficient was greater for RCNBFs6 (8.38 × 10-3 cm/h) than for RBFs6 (4.88 × 10-3 cm/h). The enhancement in permeation observed in RCNBFs6, approximately 1.7-fold higher than RBFs6, is likely attributed to its increased drug release capabilities, as illustrated in Figure 5.Top of Form

Bottom of Form

SUMMARY AND CONCLUSIONS:

RCNPs are prepared by the ionic gelation process. Based on the highest value of % EE (94.28±1.26 %) the RCNPs2 is selected as optimized ones and further characterized for particle size, ZP, FTIR spectroscopy and in vitro drug release (Franz diffusion cell). The optimized NPs poses the average particle size of 476.6 nm, ZP of +22.6 mv, FTIR reveals the no significant medication interactions between the drug and excipients and they followed first order kinetics (r²= 0.9644) and non-Fickian super case II drug release mechanism (n = 1.3412). The mechanical, mucoadhesive, swelling, and in vitro drug release properties of prepared BFs (RCNBFs1-6) were assessed. Films had the best possible physico-mechanical characteristics, such as mucoadhesive strength, which can increase the duration of buccal residence. The RCNBFs6 with highest mucoadhesive strength (7.5±0.22 N) and the maximum amount of drug released at 6^th hr (95.7±1.32) is considered as optimized one and further screened for FTIR spectroscopy, SEM analysis and ex vivo permeation study with goat mucosa. The optimized BFs (RCNBFs6) followed first order kinetics (r²= 0.9644) and non-Fickian super case II drug release mechanism (n = 1.3412). It exhibited signiﬁcantly higher (p < 0.005) buccal ﬂux (71.94±8.26µg/cm²/h) with a short lag time. The permeation is ~1.7-folds enhanced in optimized BFs with nanoparticles, when compared with the film with plain drug.

ACKNOWLEDGEMENT:

We would like to thank to Department of Pharmaceutical Technology, Sri Padmavahi Mahila Viswavidyalaya (Women’s University), Tirupati-517504, Andhra Pradesh; Department of Pharmaceutics, Seven Hills College of Pharmacy (Autonomous), Tirupati, Andhra Pradesh. Our lab members are also acknowledged for their useful suggestions.

CONFLICT OF INTEREST:

The authors declare that there is no conflict of interest.

ABBREVIATIONS:

NP: Nanoparticle; RCNPs: Rizatriptan Chitosan Nanoparticles; r²: Correlation Coeffecient; n: Diffusion Coeffecient; EE: Entrapment Efficient; FTIR: Fourier Transform Infra-Red Spectroscopy; PBS: Phosphate Buffer Solution; TPP: Tripolyphosphate.

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Received on 14.07.2024 Revised on 13.11.2024

Accepted on 10.01.2025 Published on 27.03.2025

Available online from March 27, 2025

Research J. Pharmacy and Technology. 2025;18(3):1308-1316.

DOI: 10.52711/0974-360X.2025.00190

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

F Code	Thickness (mm)	Surface pH	Folding Endurance	Drug Content (%)	Mucoadhesive Strength (N)
RCNBFs1	0.178 ± 0.01	6.89 ± 0.08	294±1.20	93.4±1.61	6.5±0.14
RCNBFs2	0.284 ± 0.01	6.95 ± 0.05	270±1.18	93.1±2.01	6.8±0.23
RCNBFs3	0.277 ± 0.03	6.54 ± 0.03	305±1.26	93.0±1.23	6.7±0.32
RCNBFs4	0.265 ± 0.04	6.92 ± 0.07	285±1.15	93.1±1.13	6.7±0.13
RCNBFs5	0.168 ± 0.01	6.63 ± 0.06	273±1.18	93.2±1.22	7.2±0.43
RCNBFs6	0.274 ± 0.01	6.75 ± 0.08	313±1.26	94.6±1.12	7.5±0.22

F Code	Zero order	First order	Higuchi	Korsemeyer-Peppas
F Code	r²	r²	r²	r²	n
Optimized nanoparticles (RCNPs2)	0.9296	0.9619	0.9177	0.9517	1.7212
Optimized buccal films with nanoparticles (RCNBFs6)	0.9312	0.9644	0.9261	0.9411	1.3412