Assessment of a Nano emulsion-Based Drug Delivery System for Improving the Solubility of Imatinib Mesylate: In Vitro Evaluation.

Shiva KM, Mohd I, Kavita S, Kajal R and Ranveer S

Published on: 2023-12-12

Abstract

The objective of the present study was to develop a Self-Nano emulsifying Drug Delivery System (SNEDDS) as a means of enhancing the bioavailability, release rate, and solubility of imatinib mesylate, classified as a BCS class II drug for oral administration. The SNEDDS formulation, comprising an isotropic and thermodynamically stable mixture of oil, surfactant, co-solvent/surfactant, and the medication, demonstrated spontaneous emulsification upon application to an aqueous phase with mild agitation. Various combinations of oil, surfactant, and co-surfactant were systematically screened using a ternary phase diagram to identify a more homogeneous mixture.

The SNEDDS formulations underwent evaluation for appearance, mean droplet size, phase separation, in vitro drug release, and oral bioavailability. The screening process identified Labrafil M 2125 CS as the oil, Tween 80 as the surfactant, and Transcutol®P as the co-surfactant, demonstrating the most favourable solubilizing qualities. The optimized SNEDDS exhibited a notable 98.39% drug release, with dissolution behaviour attributed to the oil/surfactant ratios and surfactant phase properties. Moreover, the optimized SNEDDS displayed a threefold increase in the Area under the Curve (AUC) compared to conventional imatinib mesylate.

The study highlights several factors contributing to the effectiveness of SNEDDS over other drug delivery forms, including a larger droplet surface area, enhanced drug solubilisation facilitated by Labrafil M 2125 CS, and the surfactant's impact on mucosal permeability. The findings suggest that SNEDDS could serve as a promising alternative strategy to enhance the solubility and accessibility of orally administered poorly soluble drugs.

Keywords

Imatinib mesylate Self-nano-emulsifying Drug delivery System

Introduction

Nano emulsions, characterized by their extremely fine droplets ranging from 20 to 200 nanometers in diameter and stabilized by surfactants, have emerged as a versatile colloidal dispersion. Their unique properties make them highly advantageous in pharmaceuticals, food, cosmetics, and biotechnology [1]. Nano emulsions play a pivotal role in enhancing the solubility, stability, and bioavailability of various substances, addressing challenges associated with poorly soluble drugs and enabling more effective therapeutic outcomes.

The kinetically stable nature of Nano emulsions prevents phase separation or coalescence over time, ensuring the efficacy and shelf-life of formulations with sensitive or active ingredients. Their small droplet size facilitates improved absorption and permeation through biological barriers, enhancing drug delivery [2]. The formulation process involves the meticulous selection of oils, surfactants, and co-surfactants tailored to the specific application and characteristics of the active substance, allowing for customization to meet unique requirements.

Nano emulsions find applications across diverse industries. In pharmaceuticals, they offer a strategic approach to formulating and administering poorly water-soluble drugs, potentially revolutionizing treatment options. In the food industry, Nano emulsions enhance the stability and bioavailability of nutraceuticals, flavours, and essential oils. Moreover, Nano emulsions show promise in cosmetics, improving the delivery of active ingredients for skincare and beauty products [3].

This overview only scratches the surface of the vast potential and applications of Nano emulsions. Ongoing research into their formulation, characterization, and utilization promises boundless innovation and improvement across industries. The future holds the potential for Nano emulsions to play a pivotal role in advancing drug delivery, food technology, cosmetics, and beyond [4].
As for Nano emulsifying Drug Delivery Systems (NEDDS), they are designed to enhance the solubility and bioavailability of poorly water-soluble drugs. This involves formulating drug-containing oil droplets at the Nano scale using emulsifying agents, typically between 20-200 nanometres in diameter. The small droplet size contributes to improved drug absorption and distribution in the body. Notably, SNEDDS (Self-Nanoemulsifying Drug Delivery Systems) exhibit stability without vitrification during a three-month storage period.

Advantages of Nano emulsifying Drug Delivery Systems

Enhanced Solubility And Bioavailability

Nano emulsions increase the surface area available for drug absorption, particularly benefiting poorly water-soluble drugs, thereby improving their solubility and bioavailability [5].

Improved Stability

Nano emulsions exhibit kinetic stability, minimizing the risk of phase separation or droplet coalescence over time. This characteristic enhances the overall shelf-life of the formulation.

Versatile Formulations

The flexibility of Nano emulsions allows for the formulation of diverse combinations of oils, surfactants, and co-surfactants. This versatility enables customization to match the specific properties of the drug and the desired route of administration [6].

Targeted Delivery

Nano emulsions can be tailored to target specific tissues or cells, potentially reducing side effects and enhancing the therapeutic efficacy of the delivered drug [7].

Enhanced Permeation and Absorption

The small droplet size of Nano emulsions facilitates efficient absorption through biological barriers, such as the gastrointestinal tract or skin, leading to enhanced drug delivery.

Potential for Various Routes of Administration

Nano emulsifying drug delivery systems are adaptable for intravenous, oral, topical, and parenteral administration, providing versatility for different therapeutic applications.

Reduced Dosing Frequency

By improving drug bioavailability, Nano emulsions have the potential to reduce the required dosage and dosing frequency, thereby enhancing patient compliance.

Suitable For Both Lipophilic And Hydrophilic Drugs

Nano emulsions are applicable to a broad spectrum of drugs, including both lipophilic and hydrophilic compounds, making them versatile for diverse pharmaceutical formulations [8].

Applications of Nano emulsifying Drug Delivery Systems

Nano emulsifying drug delivery systems have been explored in various fields, including pharmaceuticals, nutraceuticals, and cosmetics.
It's important to note that the design and development of a Nano emulsifying drug delivery system involve careful consideration of factors like the choice of oils, surfactants, co-surfactants, and manufacturing methods. Additionally, appropriate characterization techniques are crucial for evaluating the physicochemical properties of the Nano emulsion.
Overall, NEDDS represent a promising avenue for improving the delivery and therapeutic efficacy of poorly water-soluble drugs.

Classification

Nano emulsions can be classified based on different criteria, including their composition, preparation methods, and application areas. Here are some common classifications [8, 9].

Based on Composition

Oil-in-Water (O/W) Nano emulsions

In O/W Nano emulsions, oil droplets are dispersed within a continuous water phase. These are the most common type of Nano emulsions.

Water-in-Oil (W/O) Nano emulsions

In W/O Nano emulsions, water droplets are dispersed within a continuous oil phase. These are less common but can be useful for certain applications.

Based on Preparation Methods

High-Energy Methods

These methods involve using high-energy input to break down the larger oil droplets into smaller droplets. Examples include high-pressure homogenization, micro fluidization, and ultrasound-assisted emulsification.

Low-Energy Methods

These methods rely on the spontaneous formation of Nano emulsions without the need for high-energy input. Examples include phase inversion temperature (PIT) method and phase inversion composition (PIC) method.

Based on Application Areas

Pharmaceutical Nano emulsions: These are designed to enhance the solubility, stability, and bioavailability of drugs. They are used for various routes of administration, including oral, topical, and parenteral.
Food and Beverage Nano emulsions: Nano emulsions are used to improve the stability and bioavailability of food ingredients, such as flavors, colours, nutraceuticals, and essential oils. They are used in products like dressings, sauces, and beverages.
Cosmetic and Personal Care Nano emulsions: Nano emulsions are used in skincare, hair care, and cosmetic products to improve the delivery of active ingredients, enhance stability, and provide desirable sensory attributes [10].
Agricultural Nano emulsions: These are used for delivering agrochemicals, such as pesticides and herbicides, to improve their efficacy and reduce environmental impact.
Biomedical Nano emulsions: These are used for various biomedical applications, including drug delivery, medical imaging, and diagnostics.

Based on Stability:

Kinetic Stability: Kinetically stable Nano emulsions remain stable over time due to the presence of surfactants or emulsifying agents. They do not undergo phase separation or droplet coalescence.
Thermodynamic Stability: Thermodynamically stable Nano emulsions are stable under specific conditions, such as temperature and pressure. They may require additional stabilizers or methods to maintain stability.

Material And Method

Material

imatinib mesylate API was kindly donated by jigs chemical Pvt. Ltd, Ahmadabad. Labrafil M 2125 CS, Labrafil 1944, Labrafac, Peceol, Labrasol, Transcutol®P, Lauroglycol, Caproyl 90, and Caproyl P, Capmul, Captex, and Caproyl PGE were kindly gifted from Abitec, USA. All other chemicals and reagents were of analytical grade.

Methods

Solubility studies: The solubility of imatinib mesylate in various oils, surfactants, and cosurfactants was ascertained by introducing an excess of imatinib mesylate to a 2-mL microtube (Tarson-500020) containing a 1-mL vehicle. The mixture was vortexed and kept at 25°C in a shaking water bath for 24 hours to facilitate solubilization. The samples were spun for 15 minutes at 4000 rpm in an Allegra 64 R centrifuge (Beckman Coulter, USA). Next, the supernatant was taken off. The amount of drug dissolved was determined at 248 nm using a UV-visible spectrophotometer.

Fig 1: Solubility of imatinib mesylate in various oils.

Fig2: Solubility of imatinib mesylate in various surfactants and co-surfactants.

Construction of Ternary Phase Diagram: Pseudo-ternary phase diagrams were developed to determine the component concentration range and the effective self-emulsifying region for the present SNEDDS boundary (23). The ternary phase diagram was plotted using the PCP-Disso tool. Oil, surfactant, and co-surfactant concentrations were varied from 10 to 80% (v/v). These substances were diluted drop by drop with double-distilled water to form an emulsion that was gently stirred [11, 12].

Preparation of SNEDDS: 150 mg of imatinib mesylate were dissolved in 1 mL of oil, surfactant, and co-surfactant mixture. Before being vortexed, all materials were mixed together on a magnetic stirrer at 50°C. Additional screening was performed on these batches based on phase separation, droplet size, and imatinib mesylate solubility (Table 1).

Table 1: Preparation of Various SNEDDS Batches.

Batch code	Composition of SNEDDS
Batch code	Labrafil 2125 (%)	Tween 80 (%)	Transcutol (%)
F 1	30	40	30
F 2	30	42.5	27.5
F 3	30	45	25
F 4	30	47.5	22.5
F 5	30	50	20
F 6	35	45	20
F 7	35	40	25

Table 2: Pharmacokinetic Parameters of Neat imatinib mesylate and SNEDDS.

Sample	t_max (h)	C_max (μg/mL)	AUC_(0→last) (μg/h/mL)
neat imatinib mesylate	5±0	20.427±2.065	272.15±13.865
SNEDDS	5±0	62.557±1.990	717.23±10.578

Each value represents the mean±SD (n=3) AUC area under curve

Fig 3: Droplet size distribution of all batches.

Fig 4: Mean droplet size of batch 3.

Droplet Size Analysis

The particle sizes of each SNEDDS batch were determined using a particle size analyzer (Mastersizer 2000 SM, Malvern Instruments, UK) based on the laser light scattering phenomena after each batch (1 mL) had been diluted in 250 mL of distilled water.

Phase Separation Study

With every batch of SNEDDS, a phase separation analysis was performed. For the phase separation research, three different media were used: 1% sodium lauryl sulphate (SLS), 0.1 N HCl, and distilled water. Determining if oils are compatible with surfactants and co-surfactants was the aim of the study. After SNEDDS was introduced to each 5-mL medium, phase separation was monitored for a maximum of 24 hours [13].

Diluted Formulations (99% or 100 Times’ Dilution)

One good way to estimate the drug's likely fate during dispersion or dilution with water is to look at the drug's solubility in the formulation that is the most diluted. It's feasible to calculate the maximum amount of TAL that be added at the recommended dosage to the anhydrous mixture in order to be diluted in the normal quantity of gastric secretions. 99 percent. The diluent employed to make the diluted formulations was water. The drug-free anhydrous formulation weighed one milliliter. Mixed with 100 times-diluted 99 milliliter of water and vortexed to ensure a well-mixed final product. Additionally, studies for the solubility of TAL were performed in water micellar solutions and phospholipid/bile salt solutions. To create the samples, an excess of TAL was added to the diluted formulations, the mixture was periodically shaken, and the mixture was kept in a dry heat incubator at 37°C for seven days. This was done in order to calculate the amount of TAL that was still present in the solution following a 100-fold dilution. Using the same methods as the anhydrous formulations above, the solubility of TAL was evaluated after seven days in the 99% diluted and aqueous formulations [14, 15].

In Vitro Dissolution Study

The in vitro dissolution study set out to determine the rate of dissolution of neat imatinib mesylate and SNEDDS. Size 2 hard gelatine capsules containing 150 mg of imatinib mesylate and SNEDDS were manually packed prior to undergoing a dissolving analysis. The dissolving test was carried out in a USP Type II (Paddle) apparatus (Electro lab, Mumbai, India) at a speed of 50 rpm using 900 mL of 1% SLS solution. The medium was maintained at a temperature of 37±0.5°C throughout the experiment. A 5-mL aliquot was removed and filtered through 0.45-μm filters at predetermined intervals of 5, 10, 20, 30, 45, 60, 90, 120, 180, and 240 minutes. Five milliliters of fresh medium were added in order to maintain a constant volume of the dissolving medium. Spectrophotometry was used to determine the imatinib mesylate content at 248 nm. The data was assessed using PCP-Disso software (India).

Result And Discussion

Solubility Study

The goal of solubility studies was to determine the optimal combinations of oil, surfactant, and co-surfactant that would best dissolve imatinib mesylate. The solubility of the imatinib mesylate in various oils, surfactants, and co-surfactants is displayed in Figures 1 and 2. Of the used oils, the Labrafil M 2125 CS had the highest imatinib mesylate solubility. Moreover, Tween 80 and Transcutol®P were used as co- and surfactants, respectively. The emulsification time increases and droplet size decreases upon addition of a specific amount of surfactant. These discoveries led to the selection of the ideal surfactant concentration, which decreased the droplet size and emulsification time.

Stability studies

The chemical and physical stability of the improved formulation was studied. The stability studies were carried out under refrigeration (5±3°C) and at room temperature (25±3°C) for a period of three months. At the end of each month, samples are evaluated for appearance, color, and imatinib mesylate concentration.

Construction of Ternary Phase Diagram

Oil, surfactant, and co-surfactant selection criteria were established based on their ability to form emulsions, hydrophilic-lipophilic balance (HLB), and medication solubility (25). Figure 3 shows the blue area of steady Nano- emulsion in the presence of imatinib mesylate. The improved SNEDDS compositions with the lowest mean droplet size and drug solubilization are listed in Table II. The systems containing approximately 30–50% (v/v) oil, 30–50% (v/v) surfactant, and 20–40% (v/v) co-surfactant exhibit translucent, clear oil droplets that do not clump, precipitate, phase separate, or break. The emulsification process worked better when the oil content exceeded 50% v/v of the SNEDDS formulation. The ternary phase diagram was used to identify certain emulsification areas, and within that range, several batches for further study were produced by adjusting the ratios of Labrafil M 2125 CS (30–35%), Tween 80 (40–50%), and Transcutol®P (20–30%).

Droplet Size Analysis

The size of the droplets in the emulsion is the main factor affecting the degree and rate of drug absorption as well as release. Smaller emulsion droplets may lead to a quicker rate of drug absorption (26). Table III and Fig. 4 show the mean particle size and homogeneity of the SNEDDS formulation. For batch L3, the particle size and emulsification time are acceptable (Fig. 5).

Fig 5: Dissolution profiles of optimized SNEDDS and imatinib mesylate.

Phase Separation Studies

For the phase separation investigation, three different media were employed: 1% SLS, 0.1 N HCl, and pure water (Table IV). An analysis of phase separation revealed that all batches were stable and that there was no phase separation between the drug and the excipient. Batch L3, which exhibited no phase separation and was very transparent among all the manufactured batches, was selected for further investigation.

In Vitro Dissolution Study

When the emulsion contains imatinib mesylate. Table II lists the ideal SNEDDS formulations considering the lowest mean droplet size and drug solubilization. With around 30–50% (v/v) oil, 30–50% (v/v) surfactant, and 20–40% (v/v) co-surfactant, the oil droplets in these systems are transparent, clear, and do not precipitate, phase separate, break, or agglomerate. When the oil content was higher than 50% v/v of the SNEDDS recipe, the oil was emulsified more successfully. Based on the ternary phase diagram, the ratios of Labrafil M 2125 CS (30–35%), Tween 80 (40–50%), and Transcutol®P (20–30%) were adjusted to create distinct batches for additional study inside the chosen emulsification zones. Oil/surfactant ratios and the characteristics of the surfactant phase were identified as the causes of the SNEDDS dissolving behavior. The more oil a mixture included, the longer the emulsification process took. However, as the oil droplets are bigger, this could result in subpar self-Nano-emulsifying systems (27). Labrafil M 2125 CS is a linoleoyl macrogol glyceride with a modest chain length. Medium-chain triglyceride oils are simpler to Nano-emulsify than long-chain triglycerides. The SNEDDS formulation frequently uses Transcutol®P, or amphiphilic solubilizers, to enhance drug loading and reduce the amount of time needed for self-Nano-emulsification (28). Furthermore, the use of Tween 80 as a co-surfactant lowers interfacial tension, enhances interface fluidity, and contributes to the formation of a flexible interracial film (29).

Table 3: Dissolution Profile of Neat imatinib mesylate and SNEDDS.

Time interval (min)	% drug release	SNEDDS
Time interval (min)	Neat imatinib mesylate	SNEDDS
0	0±0	0±0
5	4.80±1.82	14.48±1.75
10	10.45±2.01	27.33±1.92
15	22.35±2.07	38.23±1.92
30	35.56±2.04	59.42±1.97
45	43.60±1.85	77.08±1.93
60	48.31±1.92	90.19±1.98
90	53.71±1.98	97.51±2.01
120	51.66±2.09	98.39±1.97
180	54.79±2.01	98.67±1.77
240	51.82±1.81	98.26±1.79
Each value represents the mean±SD (n=3) SNEDDS self-Nano-emulsifying drug delivery system, imatinib mesylate efavirenz

Conclusion

The development of an imatinib mesylate stable SNEDDS formulation was accomplished. Drug release both in vivo and in vitro was greatly enhanced by SNEDDS that included imatinib mesylate. The solubility, emulsifying potential, and dissolving behaviour of the imatinib mesylate are significantly influenced by the chemical composition and concentration of the oil, co-surfactant, and a surfactant. Outstanding physicochemical properties were exhibited by SNEDDS due to the unique combination of Tween 80, Transcutol®P, and Labrafil M 2125 CS. It helps to increase the stability, solubility, bioavailability, and dissolving behaviour of imatinib mesylate. Based on the information at hand, SNEDDS offers a chance to create a drug delivery system that could improve the oral bioavailability, stability, rate of dissolution, and solubility of a number of BCS class II candidates.

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