Optimizing Bioavailability and Antihypertensive Activity of Carvedilol Cubosomes using D-Optimal Design: Comparative Analysis of Cremophor RH 40 and Polyvinyl Alcohol as Secondary Stabilizers


Carvedilol (CARV) -a nonselective β-receptor antagonist indicated in treatment of hypertension- suffers from poor oral bioavailability due to its poor solubility and hepatic first-pass metabolism. This study aimed to optimize CARV-loaded cubosomes to enhance oral CARV bioavailability and prolong its action in the treatment of hypertension. D-optimal design was used to optimize CARV CUBs based on either Polyvinyl alcohol (PVA) or Cremophor RH 40 (RH 40) as secondary stabilizers. Furthermore, the effect of Poloxamer P407 percentage and secondary stabilizer concentration was studied. Comparing PVA-based to the RH 40-based CUBs, CARV-CUBs-RH40 showed lower particle size (PS), higher polydispersity index (PDI), lower zeta potential (ZP) and slightly lower CARV content. Optimized PVA-based and RH 40-based CUBs showed PS of 141 ± 1 nm and 105 ± 0 nm, PDI of 0.166 ± 0.00 and 0.247 ± 0.01, ZP of 4.9 ± 0.3 mV and 6.3 ± 0.3 and CARV content of 105.0 ± 1.4 % and 93.6 ± 0.9 %, respectively. TEM imaging confirmed the characteristic cubic morphology of the prepared CUBs. Moreover, the prepared CARV-CUBs exhibited an in vitro sustained release behavior and comparable in vivo antihypertensive performance.


Carvedilol (CARV) is a nonselective β-receptor antagonist, which is indicated in the treatment of several cardiovascular diseases (hypertension, heart failure and coronary artery diseases) [1]. The biopharmaceutical classification system (BCS) is a framework for categorizing drug molecules based on solubility and permeability. CARV belongs to class II of BCS, which has low solubility and high permeability. CARV is a weakly basic drug with a pKa value of 7.8 and is practically insoluble in water (4.4 μg/mL) [2]. In addition, CARV is a highly lipophilic drug with poor oral bioavailability (25 % – 35 %) due to hepatic first pass metabolism [3] and low solubility [4]. Several techniques have been explored to improve CARV solubility, as discussed by Fernandes et al [5].

Nanotechnology-based drug delivery systems are thought to be an effective technique for improving the therapeutic efficacy of lipophilic medicines [6]. Recently, lipid-based liquid crystalline nanoparticles (LCN) have gained increasing interest in pharmaceutical research owing to their ability to enhance the bioavailability of lipophilic drugs. Using amphiphilic lipids offers many benefits, including the potential to incorporate either hydrophilic or lipophilic drugs, protecting the entrapped drug from enzymatic decomposition and controlling the drug release [7]. Nanoparticles (NPs) are among the most promising particulate drug delivery strategies for increasing CARV oral bioavailability. NPs are easy to administer and easily permeate capillary and epithelial membranes, allowing for the effective delivery of lipophilic medicines.

Cubosomes (CUBs) are liquid crystalline nanoparticles made of amphiphilic polar lipids. When these lipids are dispersed in water at a high enough concentration (higher than their critical micelle concentration), they form a micellar structure that is compelled to take on a cubic shape with a honeycomb-like pattern. CUBs typically range from 100 to 500 nanometers [8], [9], [10], [11] and heating is substantial to form them [12]. The hydrocarbon chains of the amphiphilic lipid melt at a lower temperature while the polar heads stay robust and join together with strong hydrogen bonds [13], [14]. The conformation of the carbon-carbon bonds is changed from all-trans to gauche in the liquid crystalline state [15]. The amalgamation between the disordered melted atoms and the highly ordered planar layers is the main characteristic of the cubosomal structure. CUBs have a three-dimensional structure with two continuous but non-intersecting water channels separated by a curved and non-intersecting lipid bilayer [16].

Glyceryl monooleate (GMO) is the most commonly used amphiphilic lipid in CUBs preparation. It is a synthetic mixture of glycerides ester of Oleic acid and other fatty acids, primarily monooleate, that can self-assemble into bicontinuous cubic structures [17]. Because of its amphiphilic character, it is employed to formulate a variety of lyotropic liquid crystals [18], such as lamellar, reversed bicontinuous cubic and reversed hexagonal structures [19]. GMO is biocompatible and biodegradable material due to ester hydrolysis. It is safe, non-toxic, and mostly used as an emulsifier in the food industry. Lipophilic, hydrophilic, or amphiphilic drugs can be incorporated within its polar or non-polar domains. Because of its floating and bioadhesive properties, GMO has also been used as a gastroretentive drug delivery system [20].

GMO alone cannot form a stable aqueous dispersion. Using stabilizing agents is a must in CUBs preparation to prevent re-coalescence. Poloxamer 407 (P407) is the most commonly used primary stabilizer. Polyvinyl alcohol (PVA) [21] (a polyol-efficient stabilizer and size-controlling polymer), Tween 80 [22] and Brij® 58 [23] are the most commonly used secondary stabilizers.

P407 is a non-ionic tri-block copolymer formed of polypropylene oxide (PPO) units bonded to polyethylene oxide (PEO) units from each side, with the molecular formula (PEO)99-(PPO)67-(PEO)99. PPO and PEO units are responsible for hydrophobic and hydrophilic properties, respectively [24]. It dramatically stabilizes the cubosomal dispersions through steric stabilization by PPO incorporation in the bilayer or adsorption on the surface of CUBs. At the same time, the PEO chains are being solubilized in the aqueous phase. This configuration provides stability to the vesicles and protects them from coalescence into large particles [25]. The golden standard cubosomal dispersions are usually formulated with GMO, P407 and PVA.

This study investigated the suitability of Cremophor RH 40 (RH 40) to produce stable CUBs dispersions compared to the PVA, the most commonly used secondary stabilizer. The specific choice for RH 40 surfactant was based on its ability to inhibit liver metabolizing enzymes [26], which may protect CARV from first-pass metabolism. Furthermore, RH 40 has an HLB value between 14 and 16. Accordingly, it has the optimum balance between polar and non-polar parts, which is necessary for the CUBs stabilization. RH 40 has the polar moiety (PEO) and the non-polar moiety (monooleate). RH 40 proved its ability to stabilize LCN at a very low concentration of 0.5% w/w of the oily phase [27]. Therefore, this study aimed to enhance the oral CARV efficacy, prolong its action in the treatment of hypertension through CUBs preparation, and investigate the suitability of using RH 40 as a secondary stabilizer in CUBs preparation.

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Carvedilol (CARV) was kindly supplied by SAGA pharmaceutical Co. (6th October Governorate, Egypt). Glyceryl monooleate (GMO) was received as a kind gift from Gattefosse Co. (Lyon, France). Poloxamer 407 (P407) was purchased from BASF Co. (Ludwigshafen, Germany). Analytical grade Methanol was purchased from El-Nasr Pharmaceutical Co. (Cairo, Egypt). Polyvinyl alcohol (PVA) (molecular weight 13,000 – 23,000 D) was purchased from Acros organics (Geel, Belgium).

Esraa M. Salem, Hamdy M. Dawaba, Marawan Abd Elbaset, Shadeed Gad, Tamer H. Hassan, Optimizing Bioavailability and Antihypertensive Activity of Carvedilol Cubosomes using D-Optimal Design: Comparative Analysis of Cremophor RH 40 and Polyvinyl Alcohol as Secondary Stabilizers, Journal of Drug Delivery Science and Technology, 2024, 105817, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2024.105817.

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