Design, Characterization, and Evaluation of Solid-Self-Nano-Emulsifying Drug Delivery of Benidipine with Telmisartan: Quality by Design Approach

Abstract

The main purpose of this study was to design and develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS) for the oral administration of benidipine (BD) and telmisartan (TEL) using the adsorption method with eucalyptus oil, Transcutol P, and Kolliphor EL via the Box–Behnken design approach. The prepared SNEDDS formulations were characterized using FTIR, DSC, SEM, and PXRD techniques and evaluated for zeta potential, refractive index, drug concentration, resistance to dilution, viscosity, and thermodynamic stability. Additionally, in vitro and stability studies were conducted. The results revealed that all prepared formulations (BT1–BT15) exhibited favorable zeta potential (17.2–28.39 mV) and polydispersity index (PDI) values (0.226–0.354). Among them, formulation BT11 demonstrated a desirable droplet size of 175.12 ± 2.70 nm, a PDI of 0.226, a zeta potential of −24.98 ± 0.18 mV, a self-emulsification time of 53.00 ± 2.10 s, a transmittance percentage of 99.6 ± 0.3%, and a drug release of 92.65 ± 1.70% within 15 min. BT11 exhibited significantly faster drug release compared to the commercially available product benidipine T (4 mg/40 mg) and the pure drugs BD and TEL, releasing more than 96% of both drugs in 0.1 N HCl within 60 min. Furthermore, BT11 demonstrated stability throughout the product’s stability testing. These findings suggest that the oral S-SNEDDS formulation of BD and TEL can enhance the drugs’ water solubility, potentially improving therapeutic outcomes and increasing patient compliance.

Introduction

Delivery of drugs through the oral route is frequently encouraged for a number of reasons, including patient adherence, simplicity of self-medication, and cost-effectiveness. The Biopharmaceutical Classification System (BCS) identifies classes II and IV as the most significant issues in oral delivery due to their limited water solubility, resulting in decreased and inconsistent bioavailability. (1) Due to the increasing popularity of computer-aided drug design, almost 70% of newly developed drugs face this challenge. The decreased oral bioavailability has been linked to several factors, including fast first-pass metabolism, P-gp efflux, and presystemic elimination. To address these challenges, researchers use several formulation strategies to improve the absorption of medications. Solubilization, the process of achieving a uniform and stable distribution of compounds in a certain solvent, plays a major role in drug delivery. (2)

Optimizing solubility is critical to increasing oral bioavailability. Researchers have employed several common methods, including solid dispersions, nanoparticles, crystallization, supersaturable systems, micronization, and complexation, to enhance oral bioavailability and address the issue of low solubility. (3−5) Nanostructured lipid-based drug delivery technologies enhance the solubility of medications and bypass first-pass metabolism, thereby increasing their bioavailability when administered orally. In these cases, self-nanoemulsifying drug delivery systems (SNEDDS) receive attention. In gastrointestinal fluids, SNEDDS are isotropic composites that form fine oil-in-water nanoemulsions. (6)

They swiftly disperse throughout the gastrointestinal tract, forming nano droplet-sized emulsions that the lymphatic system absorbs, thereby enhancing drug absorption. The stability and adaptability of SNEDDS make them suitable for production on a large scale. The increase in both the percentage and maintenance of drug absorption results in accurate blood concentration profiles. (7) SNEDDS development identifies a drug with a small dose, a significant logarithmic P value, and a low melting point. (8)

SNEDDS may be efficiently and systematically generated by combining components, making them suitable for commercial use because they can be manufactured in large quantities without requiring specialized equipment. (9) Inherently, the manufacturing process does not require high energy-consuming procedures, which may prove extremely useful for biopharmaceuticals. Concerns have been raised about the chemical and physical stability of liquid self-nanoemulsifying drug delivery systems (SNEDDS). Different solidification methods can turn liquid SNEDDS into powders that can flow freely. Furthermore, these powders can be transformed into several solid dosage forms, including tablets, capsules, or pellets. (10)

Benidipine, a dihydropyridine calcium channel-blocking agent, is used to treat angina and hypertension. The substance’s hepatic breakdown and high lipophilicity (log P of 4.28) restrict its absorption, classifying it as a BCS class II agent. (11,12) Similarly, TEL, a class II angiotensin II receptor antagonist used to treat hypertension, faces challenges in terms of its oral bioavailability. (13,14) Frequently, it is administered in combination with other antihypertensive medications, particularly calcium channel blockers, to control hypertension associated with renal failure. (15,16) The literature has reported an extensive range of approaches to enhance the solubility of benidipine and telmisartan (TEL). These approaches include solid dispersion and complexation, among others. (17,18)

The primary aim of this study was to formulate and assess solid-state nanoemulsion drug delivery systems (S-SNEDDS) for benidipine and TEL using a quality by design (QBD) methodology. A review of the literature indicates that no techniques have been reported for improving the solubility of benidipine with TEL using S-SNEDDS, emphasizing the ″novelty of our study.″ The Box–Behnken design (BBD) was used to evaluate the influence of formulation factors on the efficacy of the developed S-SNEDDS, including Neusilin US2, Aerosil 200, and Aeroperl 300. This study is crucial in optimizing oral delivery of benidipine and TEL by enhancing solubility, improving lymphatic transport, bypass first-pass metabolism, and ensuring complete release of the drug. The developed formulation strategies offer a scientifically robust approach to improve bioavailability and therapeutic efficacy. (19−21)

Download the full article as PDF here Design, Characterization, and Evaluation of Solid-Self-Nano-Emulsifying Drug Delivery of Benidipine with Telmisartan

or read it here

Materials

Nikishan Pharmaceuticals and Torrent Research Center, respectively, have provided specimens of benidipine and TEL. Cremophor RH 40, Solutol HS 15, Labrafil M 2125 CS, and Transcutol P were originally supplied by BASF and Gattefossé (Mumbai, India). The following chemicals were bought from SD. Fine Chem: Span 80 (sorbitan monooleate), Span 20 (sorbitan monolaurate), Tween 80 (polyoxyethylene sorbitan monooleate), Tween 20 (polyoxyethylene sorbitan monolaurate), propylene glycol (PG), polyethylene glycol (PEG) 200, PEG-400, sodium lauryl sulfate, peanut oil, olive oil, eucalyptus oil, oleic acid, sunflower oil, sesame oil, castor oil, cottonseed oil, and oleic acid. Water, which underwent repeated distillation, served as the solvent throughout the experiment. All of the other substances used during this experiment remained of research quality. Hard gelatin empty capsules were acquired from the Torrent Research Center.

Sheetal S. Buddhadev, Kevinkumar C. Garala, Mohamed Rahamathulla, Ali H. Alamri, Umme Hani, M. Yasmin Begum, Saurabh Singh Baghel, Mohammed Muqtader Ahmed, and Ismail Pasha, Design, Characterization, and Evaluation of Solid-Self-Nano-Emulsifying Drug Delivery of Benidipine with Telmisartan: Quality by Design Approach, ACS Omega Article ASAP, DOI: 10.1021/acsomega.4c10838