Formulation Development and Evaluation of Solid Self Microemulsifying Drug Delivery System of Azelnidipine

This study aimed to develop a self-micro emulsifying drug delivery system (SMEDDS) for poorly soluble azelnidipine using Capryol 90 as the oil, Tween 80 as the surfactant, and transcutol-HP as the co-surfactant. A factorial design was used to optimize the formulation, and Neusilin UFL2 was used as an adsorbent to convert the liquid SMEDDS to solid SMEDDS. The optimized formulation had a particle size of 80.5nm, a transmittance of 98.2%, a zeta potential of -3.1 mV, and a polydispersibility index of 0.226. The solid SMEDDS tablet exhibited improved drug release (99.4% in 60 minutes) compared to the marketed tablet (67.09.75%) and pure drug (26.17%). This study demonstrates the potential of the SMEDDS approach to enhance the solubility and in-vitro drug release of poorly soluble drugs such as azelnidipine.

Introduction

Pharmaceutical for the chronic treatment of human diseases, the oral route has been the primary route of drug delivery. However, oral administration of 50% of the drug compound has drawbacks because of the high lipophilicity.[1] These days, a growing number of medications are classified as class- II medications by biopharmaceutical classification systems (BCS) due to their poor water solubility and high lipophilicity.[2-5] Poor oral bioavailability, high intra- and inter-subject variability, and a lack of dose proportionality are common side effects of class-II medications. Therefore, it is crucial to create appropriate formulations to increase such drugs’ solubility and bioavailability.[6-8] The most prevalent antihypertensive medication is a calcium channel antagonist, which is also used to treat hypertension, the most common chronic disease. In the past 30 years, there has been an increase from 650 million to 1.28 billion adults aged 30 to 79 who have hypertension, according to a WHO report. There are more than 700 million undiagnosed cases of hypertension worldwide.[9-12] 57% of stroke deaths and 24% of deaths from coronary heart disease in India are attributed to hypertension. In India, about 33% of urban Indians and 25% of rural Indians suffer from hypertension.[13-15] Azelnidipine is a third-generation and long-acting dihydropyridine calcium channel antagonist I. A series of research has demonstrated that azelnidipine produced an effective antihypertensive effect in patients with essential hypertension.[16-18]

The main mechanism by which azelnidipine reduces blood pressure is by inhibiting transmembrane Ca2+ influx through the vascular smooth muscle’s voltagedependent channels. Azelnidipine favors L-type Ca2+ channels specifically. Strong lipophilicity and affinity for vascular smooth muscle cell membranes are properties of azelnidipine.[19] The most common approach for delivering drugs is to incorporate them into inert lipid carriers, such as oils, surfactant dispersions, liposomes, microemulsions, and nanoemulsions. The emphasis is on self-emulsifying drug delivery systems (SEDDS), which are stirred to form small droplets ranging in size from 10–100 nm. Due to their ability to increase the interfacial surface area, small droplets improve drug absorption. The drug dissolves in this system’s oil, solvent, or surfactant, enhancing its bioavailability and efficacy. SEDDS has been demonstrated to improve the oral bioavailability of poorly water-soluble drugs, making them a promising option for drug delivery.

Overall, the use of SEDDS is an effective method for improving the solubility and absorption of drugs. [20] Formulating drugs with low water solubility, especially those in BCS class II or IV, is complex. Self-emulsifying drug deliver y systems (SMEDDS) have become a favored solution in recent years, particularly with the rise of lipid-based oral pharmaceuticals. This study is centered on creating solid SMEDDS for azelnidipine, an antihypertensive medication classified as BCS class II because of its poor solubility. SMEDDS have been shown to improve drug solubility, absorption, and bioavailability, making them a promising alternative for poorly soluble drugs. Developing solid SMEDDS for azelnidipine could potentially enhance its therapeutic efficacy and reduce side effects. A phase diagram is a graphical representation that displays the relationship between the phase behavior of a mixture and its composition. In the case of a ternary phase diagram, it shows the phase behavior of a micro-emulsion system that consists of oil, surfactant, and co-surfactant.

Each corner of the diagram represents 100% of that particular component. Predetermined amounts of oil, surfactant, and co-surfactant were used to construct pseudo-ternary phase diagrams. The mixtures of surfactant and co-surfactant were formulated in different ratios, such as 3:1, 2:1, and 1:1. The ratio of oil to Smix (Surfactant: co-surfactant) was also varied from 9:1 to 1:9. water was gradually added drop by drop to a predetermined amount of oily mixture under constant magnetic stirring. These mixtures were left to equilibrate overnight, and micro-emulsions were identified through visual observation and polarized light microscopy. L-SMEDDS can be solidified into S-SMEDDS using different techniques, such as capsule filling and adsorption onto solid carriers.

Capsule filling is a simple and common method that offers high drug-loading potential and suitability for low-dose potent drugs. Adsorption onto solid carriers involves mixing L-SMEDDS with suitable carriers to form free-flowing powders that can be filled into capsules. The adsorption technique offers content uniformity and can accommodate high levels of L-SMEDDS (up to 70% w/w) onto the carriers. These solidification techniques can improve the bioavailability and stability of poorly soluble drugs, such as azelnidipine. [21] Our research aims to develop a self-micro emulsifying drug delivery system (SMEDDS) for azelnidipine, as no existing formulation exists for this drug. This innovative approach is intended to improve Azelnidipine oral bioavailability, thus increasing its effectiveness as a treatment. To support this aim, we will review and analyze previously published manuscripts related to SMEDDS formulations and their impact on drug delivery and bioavailability, providing a solid foundation for our research. Ultimately, our goal is to contribute to the development of more effective drug delivery systems and improve patient outcomes.

Materials and Methods

Material

Azelnidipine API was gifted from Pure Chem Ltd., Ankleswar. Capryol-90 and Transcutol- HP were generous gift from Gattefose for research. Kolisolv GTA, Kolisolv MCT, Koliphor RH-40 were given as gift samples by BASF, Mumbai. Acrysol EL 135 and Acrysol K-140 were given as gift samples by Corel Pharma, Ahmedabad. Tween 80, Tween 20, propylene glycol, PEG-400, Fujicalin, Neusilin, aerosil were obtained from S.D. Fine Chem, Mumbai. Captex-355 was gift from Abitech Corporation, Mumbai.

Table 2: Solubility study in various vehicles

S. No.	Solvent	Solubility (mg/mL)
1	Capryol-90	223 ± 1.76
2	Kolisolv GTA	31.1 ± 0.26
3	Captex-355	128 ± 2.19
4	Kolisolv MCT	20.7 ± 1.32
5	Koliphor RH-40	22.47 ± 1.2
6	Tween 80	130 ± 3.22
7	Tween 20	35 ± 1.32
8	Acrysol EL-135	52.1 ± 1.78
9	Acrysol K-140	38 ± 1.64
10	PEG 400	9.39 ± 0.94
11	Propylene Glycol	13.6 ± 1.1
12	Transcutol-HP	270 ± 0.27

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Prajapati, A. P., P. S. Patel, N. S. Vadgama, S. Narkhede, S. Luhar, and S. J. Gandhi. “Formulation Development and Evaluation of Solid Self Microemulsifying Drug Delivery System of Azelnidipine”. International Journal of Pharmaceutical Sciences and Drug Research, Vol. 15, no. 3, May 2023, pp. 237-49,
doi:10.25004/IJPSDR.2023.150303.