Formulation, Optimization and In vivo Evaluation of Freeze-Dried Nanocapsules for Enhancing the Oral Delivery of Valsartan

Abstract

This study aims to develop the freeze-dried core–shell nanoparticles (nanocapsules; NCs) as an effective dosage form for improving the therapeutic activity of valsartan (VAL). NCs were created employing the nanoprecipitation process and optimized using a 3² full factorial design to estimate the effect of the oily core and the polymeric shell concentrations on the particle size (PS), entrapment efficiency (EE), and % release efficiency after 4 h (RE_4h). The optimized NCs exhibited a PS of 50.37 ± 6.39 nm, a PDI of 0.120 ± 0.016, a ZP of -63.7 ± 1.7 mV, an EE of 89.83 ± 1.49%, and a RE_4h of 48.32 ± 2.35%, while displaying a spherical morphology with a transparent coating membrane under TEM. Furthermore, lyophilization with 5% w/v mannitol developed a porous powder that exhibited the ideal required features (EE of 88.49 ± 1.75%, PS of 104.8 ± 4.38 nm, PDI < 0.25). FT-IR analysis revealed the compatibility of valsartan with the used excipients, while DSC and XRD demonstrated the drug’s transformation to an amorphous state upon dispersion in the nanocapsular matrix. Additionally, the lyophilized formulation substantially improved VAL’s dissolution rate and showed superior stability at different storage temperatures. In vivo studies demonstrated a rapid antihypertensive effect of the lyophilized VAL-loaded NCs within 15 min and a 2.71-fold increase in oral bioavailability compared to the pure valsartan suspension, emphasizing the potential of these generated carriers for the efficient oral delivery of VAL and the control of hypertension.

Introduction

The oral route is the most convenient method for medication delivery and consistently improves patient compliance. However, most novel chemical entities (NCEs) have restricted oral bioavailability because of their poor aqueous solubility and inadequate dissolution within the gastrointestinal (GI) tract. Also, the majority of them undergo an extensive first-pass metabolism after being taken orally [1, 2].

Lipid nanoparticles (LNPs) are biocompatible, biodegradable, and lipid-cored nanocarriers that are effectively utilized as unique drug delivery systems due to their physicochemical diversity and known safety profile. Additionally, they can successfully encapsulate an extensive variety of medications and enhance the therapeutic efficacy of poorly soluble active pharmaceutical ingredients [3, 4]. LNPs comprise a variety of nanosystems, including liposomes, niosomes, nano-emulsions, self-emulsifying drug delivery systems, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and nanocapsules (NCs) [5].

Nanocapsules (NCs) are nano-vesicular systems that contain the therapeutic agent in a reservoir or within a cavity comprised of an internal fluid center enclosed by an ultrathin polymeric film [6, 7]. NCs are superior to other delivery systems due to their high drug loading capacity, achieved by optimizing the medication dissolving in the nanocapsules’ center, and a lower amount of the polymer relative to nanospheres. Additionally, the polymeric coat can protect the enclosed drug from degrading elements like pH and light and also decreases tissue irritation [8]. Compared to liposomes and emulsions, nanocapsules are more efficient for drug-targeting delivery by the lymphatic system [9]. Nanocapsules can increase the drug’s oral bioavailability by enhancing the dissolution rate and maximizing the intestinal permeability. Their subcellular size improves bio-distribution, allows higher intracellular uptake, and overcomes oral physiological barriers [10,11,12].

Because of the Brownian motion of the colloidal nanocapsular dispersions, these systems are believed to be stable; however, polymer degradation, drug migration from the nanocapsule center, and microbial growth in the liquid medium may all negatively impact their stability [13, 14]. For improving the nanocapsule’s shelf-life stability and simplifying manipulation at storage, the lyophilization approach has been heavily utilized for such polymeric NPs [15].

Lyophilization, or freeze-drying, is a drying process that involves the sublimation of ice at low pressure to remove the water from the formulation and turn it into a solid dosage form [16, 17]. Before lyophilization, cryoprotectant excipients are typically introduced to the sample to shield the nanoparticles from freezing and drying stressors, maintain their structural integrity, inhibit particle aggregation, and prevent the therapeutic substance from escaping through the dehydration technique [18, 19]. It was reported the activity of the oily-core nanocapsules following lyophilization for improving the oral delivery of Olmesartan Medoxomil, a restricted water-soluble antihypertensive medication [20].

Valsartan (VAL), is the oral antihypertensive medication, that lowers blood pressure by inhibiting the renin–angiotensin–aldosterone system (RAAS). It is a selective antagonist to the type 1 angiotensin II receptor, which also utilized for diabetic nephropathy and heart failure [21, 22]. Despite being used to treat a variety of cardiovascular diseases, valsartan has a low bioavailability of 25% and inconsistent bioequivalence due to its poor aqueous solubility and substantial first-pass effect. These reduce VAL’s potency in the traditional oral strategies; hence, innovative delivery methods are required [23, 24]. Proliposomes and self-emulsifying drug delivery systems are examples of lipid-based formulations that previously employed for boosting the oral bioavailability of valsartan [2, 25].

In light of the aforementioned, a lyophilized formulation of valsartan nanocapsules (VAL-NCs) was created to boost the drug’s solubility and lymphatic absorption, which will lead to greater oral therapeutic efficacy as well as extend its shelf life stability. For preparing VAL-loaded nanocapsules, the nanoprecipitation method was used, generating colloidal spheres comprising an oil core and a polymeric coat. The impacts of the liquid lipid and the polymer concentrations on the nanocapsules’ size, entrapment efficiency and % release efficiency after 4 h were studied via a 32 full factorial design. The selected VAL-NCs were lyophilized after adding mannitol as a cryoprotectant and subjected to in vitro assessments before in vivo studies against pure drug suspension.

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Materials

Valsartan was donated from the Arab Company for Pharmaceutical and Medicinal Plants (MEPACO), El Sharqiya, Egypt. Castor oil, Eudragit S100, Span 80 (sorbitan oleate), mannitol, and Spectra/Por® dialysis membrane (molecular weight cutoff 12,000–14,000 Da) were bought from Sigma Aldrich Chemical Co., USA. Acetone, methanol, hydrochloric acid (37%), and sodium dodecyl sulfate (SDS) were acquired from El-Nasr Pharmaceutical Chemicals Co., Cairo. Every material used was of analytical quality.

Abdelhameed, A.H., Farghaly, U., Fathalla, Z.M. et al. Formulation, Optimization and In vivo Evaluation of Freeze-Dried Nanocapsules for Enhancing the Oral Delivery of Valsartan. AAPS PharmSciTech 27, 211 (2026). https://doi.org/10.1208/s12249-026-03443-1