Abstract
Solidification of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) is commonly used to avoid formulation leakage during storage. However, traditional solidification using the adsorption method has limitations, including the trapping of drugs within adsorbent pores and the high total dosage required. Pluronic F-68, a triblock copolymer, was utilized to prepare a polymeric SNEDDS with an in situ liquefying property (IL-SNEDDS) using candesartan cilexetil as a model drug. Drug solubility was examined to choose the optimum L-SNEDDS formulation. Afterward, S-SNEDDS and IL-SNEDDS were prepared and subjected to physicochemical characterization. In vitro dissolution was conducted to explore the influence of the formulation type on the dissolution profile of candesartan cilexetil (CC). The selected optimum L-SNEDDS formulation consisted of Tween-80:Imwitor-308:propylene glycol (2:1:1). The IL-SNEDDS formulation containing 7.5% w/w Pluronic-F-68 was selected as the optimum formulation with a liquefying temperature (34 °C) and liquefying time (75 s). Furthermore, physicochemical characterization revealed that candesartan cilexetil was present in the amorphous state within the prepared S-SNEDDS and IL-SNEDDS formulations, with no indication of a chemical interaction. In contrast to S-SNEDDS, IL-SNEDDS was able to enhance the dissolution of candesartan cilexetil with no sign of drug trapping. The present study presents a new approach that can overcome the limitations of traditional solid SNEDDS and enhance the application of SNEDDS as a pharmaceutical dosage form.
Introduction
Oral administration has garnered substantial interest in pharmaceutical research due to its reported advantages, including low production costs, patient self-administration, reduced risk of infection, and improved patient compliance. (1,2) These benefits underscore the importance of oral drug delivery system development in the pharmaceutical field. (3) However, most therapeutic drug molecules have limited solubility and permeability, which negatively impacts on drug bioavailability. (4) Therefore, various types of pharmaceutical formulations have been developed to address these limitations. (5) They include solid dispersion, (6) nanostructural lipid carriers, (7) liposomes, (8) solid lipid nanoparticles, (9) polymeric nanoparticles, (10) and self-nanoemulsifying drug delivery systems (SNEDDS). (11)
SNEDDS formulation has been widely utilized in the literature due to its reported advantages. It is easily prepared by blending ingredients, making it suitable for large-scale manufacturing. (12) Additionally, its anhydrous nature improves stability during storage and is only converted to a nanoemulsion within the gastrointestinal lumen once exposed to peristaltic movement. (13) Furthermore, its anhydrous feature has led to a pronounced improvement in drug-loading capacity for lipophilic drugs. (14) This has resulted in the development of various pharmaceutical formulations available as commercial drug products, such as cyclosporine (Sandimmune and Neoral), saquinavir (Fortavase), and ritonavir (Norvir). (15,16)
The liquid dosage form of SNEDDS (L-SNEDDS) suffers from the possibility of leakage, drug precipitation, and incompatibility between the formulation and the capsule. (17) Therefore, several technologies have been employed to convert L-SNEDDS into S-SNEDDS. These include adsorption onto porous materials, lyophilization, spray drying, and hot melt extrusion technologies. (18) However, most of these technologies have several limitations, including high cost, time consumption, and compromised product yield.
In response to the demand for an alternative strategy, an adsorption approach was developed to overcome these issues owing to its simple preparation method. (19) However, the adsorption of L-SNEDDS on porous carriers suffered from high drug dosing and drug trapping within solid adsorbents. (20,21) This aligns with our previous study, in which an S-SNEDDS loaded with a triple combination therapy for metabolic syndrome was prepared in a single dosage using Syloid as an adsorbent. Results showed that the candesartan cilexetil (CC) drug was trapped within the formulation, and less than 20% of the drug was released at the end of the in vitro dissolution study. (22) Therefore, an innovative strategy is required to overcome the aforementioned limitation of the traditional solid SNEDDS formulation.
Herein, an innovative polymeric formulation was developed to prepare the next generation of solid SNEDDS. This was achieved by incorporating polymers, such as Pluronic, into the L-SNEDDS formulation. This new generation of SNEDDS exists in the solid state at room temperature and converts into L-SNEDDS upon exposure to body temperature. Consequently, CC was used as a model drug based on our previous findings to address this issue.
CC is a potent antihypertensive agent and exerts its therapeutic activity by blocking the angiotensin II receptor.(23) This reduces blood pressure following the termination of the vasoconstriction effect produced by angiotensin II. (24) Along with its antihypertensive activity, CC exhibits cardioprotective effects produced by angiotensin II. (25) However, CC belongs to BCS class II drugs (low solubility and high permeability) with reported low bioavailability following oral administration (15%). This is attributed to its inherent lipophilic characteristic and low solubility, which significantly hinder drug dissolution. (26) Therefore, SNEDDS formulation provides a promising solution to overcome the reported low bioavailability of CC. (27,28)
This study’s innovation lies in the development of a next-generation SNEDDS formulation that overcomes the two major limitations reported for the traditional solidification method. The invented polymeric approach maintains the formulation in a solid state at room temperature while allowing complete liquefaction at body temperature. This avoids drug trapping within the porous adsorbent and reduces dosage volume by eliminating the usage of low-density porous materials. To achieve this goal, we systematically evaluated the CC solubility in various oils and SNEDDS formulations to identify optimal SNEDDS components. The traditional SNEDDS formulations (liquid and solid) were prepared as a comparative reference against the in situ liquefying formulation (IL-SNEDDS). The prepared formulations were characterized using FTIR, PXRD, and dissolution study.
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Materials
Candesartan cilexetil (analytical purity >98%) was provided through a generous donation from Riyadh Pharma (Riyadh, Saudi Arabia). Various surfactant components were sourced as follows: Tween-80, Tween-85, Tween-20, Kolliphor EL, and Labrasol (LB) were acquired from Techno Pharma Chem Haryana (Bahadurgarh, India), Merck-Schuchardt OHG (Germany), BDH (England), BASF (Ludwigshafen, Germany), and Gattefossé (Saint-Priest, France), respectively. Cosurfactant components Kollisolv PEG 400 and propylene glycol were procured from BASF (Ludwigshafen, Germany) and Winlab Laboratory (Leicestershire, UK), respectively. The free fatty acid (oleic acid) was sourced from Avonchem (Cheshire, UK). Captex-355, Peceol, soybean oil, and Imwitor-308 were obtained from Abitec Corporation (Janesville, USA), Gattefossé (Saint-Priest, France), John L. Seaton & Co., Ltd., and Croda International Plc. (East Yorkshire, UK), and Sasol Germany GmbH (Germany), respectively. The adsorbent material Syloid was procured from Grace Gmbh and Co. KG (Worms, Germany).
Pluronic F-68 Triblock Copolymer Architecture for a Next-Generation Self-Nanoemulsifying System: Overcoming Drug Trapping and Dosage Challenges of Candesartan Cilexetil, Abdelrahman Y. Sherif and Mohamed Abbas Ibrahim, ACS Omega Article ASAP, DOI: 10.1021/acsomega.5c06315
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