Design, Formulation and Evaluation of a Pediatric-Friendly Bilayer Fast Dissolving Oral Film of Paracetamol and Ibuprofen Using Hybrid (Synthetic+ Natural) Excipients for Synergistic Analgesic and Antipyretic Therapy

Difference between Fast Dissolving Oral Films and Oral Dispersible Tablets for Pediatric Use [11]

Table 1. Difference between Fast Dissolving Oral Films and Oral Dispersible Tablets for Pediatric Use

Table 2. Drug profile of Paracetamol

         Drug Profile of Ibuprofen  [7][8]

Table 3. Drug profile of Ibuprofen

Advantages of Bilayer Oral Films

Better Patient Compliance

Bilayer fast dissolving oral films provide improved patient compliance, especially in pediatric, geriatric, and dysphagic patients who experience difficulty in swallowing conventional tablets and capsules. The films dissolve rapidly in the oral cavity without the need for chewing or swallowing large dosage forms.[10]dr

Dual Drug Release

Bilayer oral films contain two separate layers that allow delivery of two drugs in a single dosage form. This system can provide immediate release as well as sustained or modified release of drugs, thereby improving therapeutic effectiveness and reducing dosing frequency. [11]

Rapid Onset of Action

The films rapidly disintegrate and dissolve in saliva after administration. Due to the large surface area and absorption through oral mucosa, the drug is released quickly, resulting in faster onset of therapeutic action.[12]

No Water Requirement

Bilayer oral films can be administered without water, making them highly convenient for pediatric patients, bedridden patients, and during traveling or emergency conditions. [13]

Easy Administration

The films are thin, flexible, and easy to handle. They can be placed directly on the tongue or oral cavity without difficulty, improving ease of administration and patient acceptability. [14]

Improved Bioavailability

Absorption of drug through oral mucosa may partially bypass hepatic first-pass metabolism, leading to enhanced bioavailability and improved therapeutic efficacy. [16]

Accurate Dose Delivery

Each oral film contains a precise amount of drug uniformly distributed throughout the film matrix, ensuring accurate and reproducible dosing. [17]

Improved Mouth Feel and Palatability

Use of sweetening agents and flavoring agents improves taste masking and mouth feel, which is highly beneficial for pediatric patients. [18]

Reduced Risk of Choking

Unlike conventional tablets, oral films possess very low risk of choking due to their thin and rapidly dissolving nature. [19]

Strong Interlayer Separation Control

Bilayer films allow physical separation of incompatible drugs into different layers, thereby preventing drug-drug interaction and improving formulation stability. [20]

AIM

To design, formulate, and evaluate a novel pediatric-friendly bilayer fast dissolving oral film of Paracetamol and Ibuprofen using hybrid (synthetic + natural) excipients for enhanced synergistic analgesic and antipyretic therapy with improved palatability, rapid disintegration, and better patient compliance.

OBJECTIVES

Primary Objectives

•      To formulate a bilayer fast dissolving oral film containing Paracetamol and Ibuprofen for pediatric use.

•      To develop an oral film using the solvent casting method.

•      To utilize Hydroxypropyl Methylcellulose (HPMC) as the film-forming polymer for obtaining suitable mechanical strength and rapid disintegration.

•      To incorporate Propylene Glycol as a plasticizer for improving flexibility and elasticity of the film.

•      To use Sodium Lauryl Sulphate (SLS) as a surfactant for enhancing solubility and drug release.

Secondary Objectives

•      To improve the palatability of the formulation using Saccharin as sweetening agents.

•      To incorporate Peppermint oil as a natural flavoring agent for better taste masking and patient acceptability.

•      To use Beet Juice as a natural coloring agent to provide an attractive appearance and reduce synthetic color usage.

•      To prepare bilayer films using water as the solvent during solvent casting.

•      To achieve rapid disintegration and faster onset of analgesic and antipyretic action.

•      To study the compatibility of drugs and excipients using suitable analytical techniques.

Evaluation Objectives

To evaluate the prepared films for:

•           Physical appearance

•           Thickness

•           Weight variation

•           Folding endurance

•           Surface pH

•           Moisture content

•           Disintegration time 

         Materials ,Chemicals and Equipment-

In the present study the following raw materials, Active pharmaceutical ingredients and excipients were used for the design, formulation and evaluation of a novel bilayer fast dissolving oral film of Paracetamol and Ibuprofen by hybrid (synthetic + natural) excipients for synergistic analgesic and antipyretic therapy in pediatric use. All chemicals and excipients were of pharmaceutical grade and were used without further purification:

Materials and Chemicals

Hydroxypropyl Methylcellulose (HPMC) - Polymer:

Hydroxypropyl Methylcellulose (HPMC) is a semi-synthetic, non-ionic cellulose ether used commonly as a film-forming polymer in the design of oral thin films. HPMC provides a good film-forming ability, transparency, flexibility and mechanical strength and it ensures a uniform dispersion of the drug as well as rapid hydration and quick disintegration of oral thin film in saliva. It is also non-toxic and biocompatible which makes it the desired polymer in case of the oral drug delivery system and pediatric use.[1]

Propylene Glycol- Plasticizer:

Propylene glycol is widely used as an inexpensive, low toxicity, readily available pharmaceutical plasticizer which increases flexibility and elasticity of the polymer films. This would increase the smooth feel of oral film and make it suitable for handling by oral administration. The solubility of many drugs is also increased in the presence of this excipient. It will not also irritate the oral mucosa and will make the oral film suitable for pediatric administration.[1]

Sodium Lauryl Sulphate (SLS)- Surfactant:

Sodium lauryl sulphate, anionic surfactant, was included to enhance the wetting, solubility, and disintegration time of less soluble drug (ibuprofen). This increases the wettability which leads to the fast penetration of saliva into the film and thereby enhancing dissolution and absorption. It is also used in oral films to promote their fast disintegration and thereby improving the bio-availability of Active Pharmaceutical ingredients.[1]

Saccharin - Sweetening agent:

Saccharin, an artificial, high-intensity sweetener is used in small amounts to provide additional sweetening capacity in formulations of oral drugs, and particularly for masking a bitter or unpleasant taste. It is about 300-500 times sweeter than sucrose. It will make the dosage form tasty so it would make the oral film acceptable to children and increase the patient compliance in fast dissolving oral film dosage form.[4]

Peppermint oil - Flavoring agent:

Peppermint oil is a natural flavoring agent that provides a pleasant cooling sensation along with a refreshing mint aroma and taste. It is used in the formulated oral films to improve palatability, especially for pediatric patients, and to effectively mask the bitter taste of the drugs. Peppermint oil also enhances patient acceptability and complements the “hybrid excipient” approach used in the formulation.[4]

Beet juice - Coloring agent:

 Beet juice is the aqueous extract from the root of the beetroot, this natural coloring agent is used to produce pink to reddish color which would be highly acceptable to the children in pediatric dose form. This ensures that it is harmless when ingested by children in recommended dose, making it an alternative to synthetic dyes and hence acceptable for oral drug delivery and pediatric use.[4]

Water - Solvent:

Water is used as a solvent in the preparation of oral films by the solvent casting method. It helps in the preparation of a homogeneous mixture of all the constituents of the oral film, ensuring uniform distribution of the drugs within the film matrix. Water also aids in proper film formation and evaporates during the drying process. [1]

Paracetamol - Active pharmaceutical ingredient (Analgesic & Antipyretic):

Paracetamol is widely used for its analgesic and antipyretic property. Paracetamol is effective for pain and fever in dose range suitable for children of all age group with mild to moderate pain. Prostaglandins inhibitors acting as analgesic and antipyretic are preferred in such kind of drug formulation.[1]

Ibuprofen - Active pharmaceutical ingredient (NSAID):

Table 5 : Formulation Components and Their Functions in Bilayer Oral Film Preparation

Apparatus and glassware

The following apparatus and glassware were used for the design, formulation and evaluation of a novel bilayer fast dissolving oral film of Paracetamol and Ibuprofen by hybrid (synthetic + natural) excipients for synergistic analgesic and antipyretic therapy in pediatric use.

Analytical balance: - Analytical balance was used for precise weighing of active pharmaceutical ingredients (Paracetamol and Ibuprofen) as well as polymers, plasticizers, surfactants and sweetening agents so that optimum concentration of each formulation component can be added for making oral films with desired quality characteristics.

Magnetic stirrer:- Magnetic stirrer was used for uniform dissolution of all polymers and active pharmaceutical ingredients in solvent and to enhance the mixing process by rotating magnetic bar with consistent speed for increasing the solubility.

Beakers (50 ml, 100 ml, 250 ml, 500 ml): - Beakers of different capacity were used for mixing, preparing solutions of the polymers and drug dispersions. Heating of the mixture was also carried out by placing it over a hot plate.

Measuring cylinders: -Measuring cylinders were used for the accurate measurement of volume of solvent (water), plasticizer (propylene glycol), flavor (Peppermint oil) and coloring agent (beet juice).

Glass rod: -Glass rod was used for stirring of solutions when the mixture was not placed on magnetic stirrer and it was also used for spreading of liquid film onto casting plate.

Petri dish: Petri dish were used for preparing the films by casting the polymer solution on them using the solvent evaporation technique.

Digital Vernier Caliper: It was used to measure the thickness and diameter of the oral films which should be almost uniform.

Disintegration apparatus: The disintegration time was determined using the disintegration apparatus which provides an acceptable end point (film disappeared completely).

Hot air oven -It was used for drying of formulated films at appropriate temperature to eliminate any volatile solvent.

Weighing boats and Spatulas: -Weighing boats and spatula were used for handling and transfer of drugs and other solid excipients.

Film Cutter / Scissors: -Films were cut with the help of a film cutter or sharp scissors to obtain the dosage units of definite dimension.

Stopwatch: -Stopwatch was used for measurement of disintegration time.[1][2][3][4][5]

Preformulation Studies [7]

Table 6. Preformulation Studies

         Experimental work-

Procedure for Preparation of Bilayer Oral Films (Three Batches: F1, F2, and F3) ,Batch Composition:

Table7: Composition of Different Bilayer Oral Film Formulations (F1–F3)

Method of Preparation

STEP 1: Weighing of Materials [1][2][3][4]

•      Three batches of bilayer oral films (F1, F2, and F3) were prepared using different concentrations of drugs and excipients.

•      All solid ingredients including paracetamol, ibuprofen, HPMC, SLS, Saccharin were accurately weighed using a calibrated digital balance.

•      Liquid ingredients including propylene glycol, Peppermint oil, beet juice, and water were measured using a graduated measuring cylinder or pipette.

•      Accurate weighing ensured dose uniformity and reproducibility among all batches.                                                                                           

Fig 2 Weighing of material

Preparation of Film A (Paracetamol Layer) [2][3][5][6]

STEP 2: Polymer Dispersion

•      Required quantity of HPMC for each batch was slowly dispersed in a portion of water with continuous stirring at 200–500 RPM using a magnetic stirrer.

•      The polymer solution was allowed to hydrate completely to obtain a clear viscous solution.

HPMC Quantity Used

•      F1 = 225 mg

•      F2 = 250 mg

•      F3 = 275 mgSTEP 3: Drug Solubilization

•      Paracetamol was separately dissolved in a small quantity of water and added slowly into the hydrated polymeric solution under continuous stirring.

Paracetamol Quantity Used

•      F1 = 125 mg

•      F2 = 150 mg

•      F3 = 175 mg

STEP 4: Addition of Excipients [2][3][5][6]

•      Propylene glycol was added dropwise as plasticizer.

•      SLS was incorporated to improve wetting and dissolution.

•      Saccharin were added for taste masking.

•      Peppermint oil and beet juice were added as flavoring and coloring agents.

Excipients Quantity

Table 8 Excipients Quantity

STEP 5: Mixing

•      Continuous stirring was maintained until a homogeneous, clear, and bubble-free solution was obtained.

•      The prepared solution was allowed to stabilize before casting.

STEP 6: Casting and Semisolid Drying of Film A[2][3][5][6]

•      The prepared Film A solution of each batch was poured into a leveled Petri dish or glass casting plate.

•      The solution was spread uniformly to obtain consistent film thickness.

•      The cast films were dried in a hot air oven at 40–45°C until a semisolid tacky stage was achieved.

Purpose of Semisolid Drying

•      To ensure strong interlayer adhesion

•      To prevent delamination                                                                               

Fig 3 Drying of film A

•           To provide stable base for bilayer formation

Preparation of Film B (Ibuprofen Layer) [2][3][5][6]

STEP 7: Polymer Preparation

•      Required quantity of HPMC for each batch was dispersed in water with continuous stirring to prepare the polymeric base.

STEP 8: Drug Solubilization

•      Ibuprofen was dissolved separately in water and slowly incorporated into the polymeric solution under stirring.

Ibuprofen Quantity Used

•      F1 = 100 mg

•      F2 = 150 mg

•      F3 = 200 mg

STEP 9: Addition of Excipients

•      Propylene glycol, SLS, sweeteners, Peppermint oil, and beet juice were added similarly as used in Film A preparation.

STEP 10: Final Mixing

•      Stirring was continued until a clear and homogeneous bubble-free solution was obtained.

STEP 11: Formation of Bilayer Film

•      The prepared Film B solution was carefully poured over the semisolid Film A layer of respective batches.

•      Gentle spreading and leveling were performed to maintain uniformity and avoid mixing of layers.

Mechanism of Bilayer Formation

•      Partial dryness of Film A allowed interpenetration of polymer chains, producing strong adhesion between both layers.

Fig 4 Formation of Bilayer Film         Fig 5 Formation of Bilayer Film

STEP 12: Final Drying

•      The bilayer films of all batches were dried in a hot air oven at 40–45°C for 10–12 hours.

•      Controlled drying ensured complete solvent evaporation and smooth film formation.  

Fig 6 final drying of film A,B,C

STEP 13: Removal and Stabilization

•      Dried films were carefully peeled from the casting surface.

•      Films were examined for:

o     Uniformity

o     Integrity

o     Absence of cracks and air bubbles

•      The films were stored in a desiccator to minimize residual moisture and improve stability.

STEP 14: Cutting of Films

•      The prepared bilayer films were cut into uniform strips of size 2 × 2 cm.

STEP 15: Packaging and Storage [1]

•      The film strips of all batches were individually packed in aluminum foil sachets or airtight containers.

Purpose of Packaging

•      Protection from moisture and humidity

•      Prevention of mechanical damage

•      Maintenance of drug stability

•      Improvement of shelf life

Evaluation Tests for Bilayer Oral Films [7][2][3][5][6]

         Introduction

Evaluation tests are performed to determine the quality, stability, strength, appearance, and performance of the prepared bilayer oral films containing Paracetamol and Ibuprofen. These tests help in confirming whether the prepared films are suitable for oral administration and provide satisfactory drug delivery performance.

1. Physical Appearance [21]

Introduction

Physical appearance evaluation is performed to examine the visual quality and surface characteristics of the prepared oral films. This test helps in determining patient acceptability and uniformity of formulation.

Observation

The prepared films were visually inspected for:

•      Color

•      Transparency

•      Smoothness

•      Presence of cracks

•      Presence of air bubbles

Result

The prepared bilayer oral films were pink and white in color and transparent in appearance. The films showed smooth surface texture without formation of cracks or air bubbles. The films were found to be flexible and uniform.

Fig 7 Physical Appearance

2. Thickness Test[21]

Introduction

Thickness measurement is performed to ensure uniformity of the film. Uniform thickness helps in maintaining accurate drug distribution and consistent drug release.

Observation

The thickness of films was measured at different positions using a vernier caliper

Result

The prepared films showed uniform thickness throughout the surface. The average thickness of the films was found to be 0.1 mm.

3. Weight Variation Test [21]                                                                               

Table 9 weight variation table

Introduction

Weight variation test is performed to determine uniformity in weight

among different film strips. Uniform weight indicates proper distribution

 of drug and excipients within the formulation.

Observation

Individual films were weighed separately and compared with the average weight

Result

Number of films-        10

Mean weight- 335 mg

Minimum weight-       328 mg

Maximum weight-      343 mg

4. Folding Endurance [22]

Introduction

Folding endurance test is used to evaluate the mechanical strength and flexibility of oral films. It determines the ability of the film to withstand repeated folding during handling and packaging.

Observation

The film was repeatedly folded at the same place until breakage occurred.

Result

The prepared films withstood more than 100 folds without breaking, indicating good flexibility and satisfactory mechanical strength.

5. Surface pH [23]

Introduction

Surface pH evaluation is performed to determine the compatibility of the oral film with oral mucosa. Films with neutral pH minimize the chances of irritation inside the oral cavity.

Observation

The film surface was moistened with distilled water and the pH was measured using pH paper or pH meter.

Result

The surface pH of the prepared films was found to be 7, indicating neutrality and compatibility with oral mucosal tissues.

Fig 8 PH of film

6. Disintegration Time [2][3][5][6]

Introduction

Disintegration time is an important evaluation parameter for fast dissolving oral films as it determines the time required for the film to break down after administration in the oral cavity. Rapid disintegration ensures faster drug release, quick onset of action, and improved patient compliance, especially in pediatric patients. In the present study, artificial saliva solution was prepared to simulate the conditions of the oral cavity during the disintegration study.

Preparation of Artificial Saliva Solution (500 mL)

Table 10 Composition of Artificial Saliva

Procedure for Preparation of Artificial Saliva [24]

•      Accurately weighed quantities of sodium chloride, potassium chloride, calcium chloride dihydrate, sodium dihydrogen phosphate, sodium sulfide, and urea were taken.

•      All ingredients were dissolved in a small quantity of distilled water with continuous stirring.

•      The final volume was adjusted to 500 mL using distilled water.

•      The prepared artificial saliva solution was mixed thoroughly until a clear solution was obtained                                                   

Fig 9 : Preparation of Artificial Saliva

Procedure for Disintegration Study

Observation

•      The prepared artificial saliva solution was maintained at 37°C ± 0.5°C to simulate oral cavity conditions.

•      The bilayer oral film was placed in the artificial saliva solution.

•      The time required for complete disintegration of the film was recorded visually.

Result

The prepared bilayer oral films containing Paracetamol and Ibuprofen showed rapid disintegration in artificial saliva with an average disintegration time of 58 seconds, indicating suitability for fast dissolving pediatric oral drug delivery.

Fig 10: Disintegration study

7. Layer Separation Test [25][26]

Introduction

Layer separation test is specifically performed for bilayer films to evaluate the adhesion between both layers and to ensure stability during handling and administration.

Observation

The films were examined during folding, handling, and evaluation for any separation between the layers.

Result

No layer separation was observed in the prepared bilayer oral films, indicating strong adhesion and proper bonding between both layers.

8. Dissolution Study

The dissolution study of the prepared bilayer oral films was performed using USP Dissolution Apparatus Type II (Paddle method). The study was carried out in 900 mL phosphate buffer pH 6.8 maintained at 37 ± 0.5°C with a paddle rotation speed of 50 rpm.A film strip of size 2 cm × 2 cm was placed in the dissolution medium. Samples of 5 mL were withdrawn at predetermined time intervals and replaced with an equal volume of fresh phosphate buffer to maintain sink conditions. From the withdrawn sample, 1 mL was diluted to 10 mL with phosphate buffer before UV spectrophotometric analysis.

Fig 11 Dissolution study

Table 11. Dissolution Profile of Paracetamol and Ibuprofen

Interpretation of Dissolution Study

The dissolution study demonstrated rapid and efficient release of both Paracetamol and Ibuprofen from the bilayer oral films. The percentage drug release increased progressively with time for both drugs.

Paracetamol exhibited 95% drug release within 30 minutes, while Ibuprofen showed 94% release during the same period. The gradual increase in absorbance values with time confirmed continuous drug dissolution into the phosphate buffer medium.

The results indicate satisfactory dissolution characteristics of the prepared bilayer oral films and suggest that the formulation is suitable for fast drug release and oral delivery applications.

Result

The dissolution study of the prepared bilayer oral films containing Paracetamol and Ibuprofen demonstrated satisfactory drug release characteristics in phosphate buffer pH 6.8 using USP Dissolution Apparatus Type II (Paddle method).The dissolution profile revealed a gradual and continuous increase in drug release with increasing time intervals. Paracetamol showed 15% drug release at the initial stage and reached 95% release within 30 minutes. Similarly, Ibuprofen exhibited 18% initial release and achieved 94% drug release at the end of 30 minutes.

The absorbance values obtained during UV spectrophotometric analysis increased proportionally with drug release, confirming the accuracy of the calibration curves and uniform dissolution behavior of the films.The rapid dissolution behavior observed for both drugs indicates efficient hydration and disintegration of the bilayer oral films in the dissolution medium. The results further suggest uniform distribution of active pharmaceutical ingredients within the film matrix and satisfactory formulation performance.

 “Evaluation Parameters and Results of Prepared Bilayer Oral Films”[27]

Table 12 Evaluation Parameters and Results of Prepared Bilayer Oral Films

Storage Conditions of Bilayer Oral Films

To evaluate the stability of the prepared bilayer oral films containing Paracetamol and Ibuprofen, the films were stored under different storage conditions for a period of 2–3 weeks. The films were periodically observed for any changes in physical appearance, texture, flexibility, and stability.

1. Butter Paper Storage[27]

One set of bilayer oral films was wrapped in butter paper and stored at room temperature. The films remained stable during the storage period without any visible changes in color, texture, or flexibility. No cracking, brittleness, or stickiness was observed. Butter paper provided suitable protection from dust and moderate environmental exposure while maintaining film integrity.

Observation

•      No change in color

•      Films remained smooth and flexible

•      No cracking or deformation observed

Result

The oral films were found to be stable in butter paper packaging.

2. Aluminum Foil Storage[28]

Another set of films was packed in aluminum foil and stored at room temperature. The films remained highly stable throughout the study period. Aluminum foil protected the films from moisture, air, and light exposure, thereby preserving their physical characteristics and stability.

Observation

•      Films remained intact and flexible

•      No moisture absorption observed

•      No changes in appearance or texture

Result

The bilayer oral films showed maximum stability when stored in aluminum foil packaging.

3. Refrigerator Storage (2–8°C)[29]

A portion of the bilayer oral films was stored in a refrigerator at 2–8°C. After storage, the films became hard and less flexible in nature. The low temperature affected the physical properties of the films and reduced their elasticity. Although no major degradation was observed, the films lost their smooth flexible texture.

Observation

•      Films became hard and rigid

•      Flexibility decreased

•      Slight brittleness observed

Result

The bilayer oral films were found to be unstable under refrigerated conditions due to hardening and loss of flexibility.

Table 13. Storage Conditions of Bilayer Oral Film