Nanostructured Lipid Carriers to Enhance the Bioavailability and Solubility of Ranolazine: Statistical Optimization and Pharmacological Evaluations

Chronic stable angina pectoris is the primary indication for ranolazine (RZ), an anti-anginal drug. The drug has an anti-ischemic action that is unaffected by either blood pressure or heart rate. Due to the first-pass effect, the drug has a reduced bioavailability of 35 to 50%. The study emphasized developing a novel transdermal drug delivery system of nanostructured lipid carriers (NLCs) for delivering RZ. Many pharmaceutical companies employ lipid nanoparticles as biocompatible carriers for medicinal, cosmetic, and biochemical uses. These carriers are appropriate for many applications, such as topical, transdermal, parenteral, pulmonary, and oral administration, because of the large variety of lipids and surfactants that are readily available for manufacturing. RZ NLCs were made using high-pressure homogenization. Statistical analysis was utilized to find the best formula by varying the concentrations of Precirol ATO 5 (X1), oleic acid (X2), and Tween 80 (X3).

Variables such as entrapment effectiveness (EE) (Y1), particle size (Y2), polydispersity index (PDI) (Y3), and zeta potential (Y4) were tested. A variety of tests were performed on the new formulation to ascertain how well it would be absorbed in the body. These tests included in vivo absorption studies, skin permeability assessments, in vitro drug release assessments, and physicochemical analyses. The particle size of RZ-NLCs was shown to be very small (118.4 ± 5.94 nm), with improved EE (88.39 ± 3.1%) and low ZP and PDI (−41.91 ± 0.38 and 0.118 ± 0.028). SEM and TEM analysis confirmed the structure of the NLCs and showed a smooth, spherical surface. Improved RZ-NLCs were used to create NLC gel, which was then tested for elasticity both physically and rheologically.

The formulation’s elasticity was investigated. Optimized RZ-NLCs and NLCG were found to have transdermal fluxes of 48.369 g/cm²/h and 38.383 g/cm²/h, respectively. These results showed that the transdermal delivery of RZ distribution through NLC’s transdermal gel had more significant potential. According to in vivo experiments, the drug’s bioavailability in Wistar rats increased when it was delivered through NLCs. The findings demonstrated that NLCs loaded with RZ successfully transported the RZ to the designated site with no interruptions and that a quadratic connection existed between the independent and dependent variables.

1. Introduction

A drug condition known as angina pectoris develops when the heart obtains less oxygenated blood [1]. Potassium channel openers remain an important therapeutic class for angina pectoris and hypertension [2]. Angina pectoris is a chronic illness that affects many people and is linked with significant morbidity and mortality. It often results from heart muscle ischemia brought on by coronary artery spasm or occlusion [3]. Nitrates, calcium channel blockers, beta-blockers, and other anti-anginal drugs treating angina pectoris relieve symptoms and control heart rate [4,5].

Ranolazine (RZ), a piperazine acetamide derivative, acts as an anti-anginal drug. It works by partially inhibiting fatty acid oxidase, which boosts the myocardium’s ability to produce adenosine triphosphate from glucose. As a result, it has anti-ischemic effects that are not dependent on hemodynamic factors like blood pressure or heart rate. The issues above and other co-morbidities will not substantially impact its efficacy. This benefit makes it sound like an efficient anti-ischemic or anti-anginal drug for treating myocardial infarction, cardiac arrhythmias, and unstable chronic angina pectoris [6,7].

The Food and Drug Administration (FDA) approved RZ for angina pectoris therapy in 2006. It is a unique anti-anginal drug with anti-ischemic and metabolic actions. Biopharmaceutical classification places RZ as a class II agent. The first-pass effect on RZ is enormous and erratic. Half-lives of RZ range from 1.4 to 1.9 h, and doses of 500 to 1000 mg twice a day are efficacious [8,9], but the t1/2 of the extended-release (ER) formulation is 7 h. First-pass metabolism, gastrointestinal (GI) side effects, poor absorption, insufficient bioavailability, and the need for a large dosage are all problems with orally administered RZ. Transdermal drug delivery is excellent for treating angina pectoris because of its reduced drug dose, avoidance of the first-pass impact, higher bioavailability, controlled drug administration, and 100% patient compliance. To make RZ more easily administered topically, a nanovesicular drug delivery system composed of nanostructured lipid carriers (NLCs) was created [10].

Many drugs cannot be absorbed via the skin because of the barrier function of the stratum corneum (SC) [11]. Several strategies have been explored to improve transdermal permeability across the SC barrier. The sustained impact that may be achieved with these methods gives them hope for the treatment of chronic illnesses like hypertension [12,13]. The transdermal administration of anti-hypertensive drugs has been extensively researched and developed to overcome the shortcomings of conventional drug delivery methods [14].

Some of the ways that anti-anginal drugs are delivered are through liposomes [15], biodegradable particles [16], micelles [17], dendrimers [18], nanoparticles [19], and nanogels [20]. Lipid-based delivery methods are more biocompatible with skin lipids, making them an attractive carrier for transdermal administration [21]. To create NLCs, solid lipid, liquid lipid, and an aqueous emulsifier solution are combined. Adding liquid lipids to NLCs gives them a crystalline shape comparable to solid lipids, expanding the NLCs’ space for drug storage [22]. Their low cytotoxicity and systemic toxicity come from the physiological and biodegradable lipids they contain, making them ideal for systemic distribution over the skin [23]. A higher surface area is available for skin absorption of the drug in the nano-size range, improving therapeutic effectiveness [24]. A reduction in transepidermal water loss results from the skin sticking to it, forming a thin layer, and exerting an occlusive effect. H₂O may help expand the SC’s inter-corneocyte spaces, improving drug penetration into deeper layers.

Statistical experimental designs have been popular in recent years for their ability to speed up the creation of novel formulations with fewer trials and better quantify the influence of factors [25]. Response surface methods (RSM) [26] include the central composite design (CCD), the D-optimal design (D-optimal), and the Box-Behnken design (BBD), all of which can help improve different formulations. The three variables used in the experimental design of BBD are located in the central region, the periphery, and the extremes of the process space, respectively. Since there are no hidden areas to explore, doing BBD trials that could involve a significant outlier is a breeze to avoid. In addition, fewer runs are required for BBD than for other models based on the three-level response surface design approach. As a result, BBD has been touted as a tool for improving a wide variety of nanocarriers.

In this study, we used design expert software to create a nanosized lipid carrier that could transport RZ. Different aspects of the optimized NLC formulation were analyzed, including its %EE, particle size (PS), shape, in-vitro release, in-vivo absorption, and skin contact.

3. Materials and Methods

Dr. Reddy’s Laboratories in Hyderabad, Telangana, generously provided a sample of RZ. We ordered the methanol and HPLC-grade liquid from Merck in Mumbai, India. From “Gattefosse India Pvt. Ltd. (Mumbai, India)”, we ordered Glyceryl monostearate (GMS), “Labrafil M 2125, Peceol” (oil), and Labrafil M 1944. Every other chemical and solvent used were of analytical purity and purchased only from reliable sources. SD Good Compounds (Mumbai, India) supplied Tween-80 and Carbopol 940.

Excipients mentioned in the study: Dynasan 118, Geleol, Compritol 888 ATO, Olive oil, Tween 20, Tween 80, Kolliphor Rh 40, Kolliphor P188, Precirol ATO 5

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Unnisa, A.; Chettupalli, A.K.; Alazragi, R.S.; Alelwani, W.; Bannunah, A.M.; Barnawi, J.; Amarachinta, P.R.; Jandrajupalli, S.B.; Elamine, B.A.; Mohamed, O.A.; et al. Nanostructured Lipid Carriers to Enhance the Bioavailability and Solubility of Ranolazine: Statistical Optimization and Pharmacological Evaluations. Pharmaceuticals 2023, 16, 1151.
https://doi.org/10.3390/ph16081151

excipients formulation