Transformative solidification techniques for self-emulsifying drug delivery and its foresight in modern-day drug delivery
Abstract
Self-emulsifying drug delivery systems (SEDDSs) represent a significant breakthrough in addressing bioavailability
challenges by enhancing the solubilization of poorly water-soluble drugs, ensuring consistent formulation properties,
and facilitating easy industrial scale-up. Despite their liquid form posing some limitations, these challenges can
be effectively addressed by solidifying SEDDSs, offering numerous advantages. The solidification of SEDDS has
opened avenues for overcoming limitations associated with liquid formulations. Different approaches to solidification
of SEDDS have been investigated to overcome the practical limitations of liquid formulations. Each method offers
a plethora of benefits such as improved physiochemical stability, extended gastric residence time, controlled release
of the drug, enhanced bioavailability, ease of handling, dose accuracy, and so on. While limitations persist, ongoing
research is paving the path for the commercialization of solid SEDDS formulations with enhanced therapeutic
effects. In light of previous publications, the current review paper makes an effort to give a comprehensive account
of the most recent advancements in solid SEDDSs technology, with a focus on the formulation aspects of various
types of novel solid self-emulsifying dosage forms for oral and nonoral drug delivery.
Introduction
The importance of advancing drug delivery systems lies in their potential to address existing challenges related to current drug formulations. The challenges arise from the inherent physical and chemical properties of drug molecules and the natural barriers present within the human body. These limitations manifest as poor drug solubility and permeability. A considerable number of pharmaceutical compounds (up to 70%) encounter difficulties due to limited water solubility, potentially influencing their absorption within the gastrointestinal system, emphasizing the importance of overcoming them for successful drug development [1]. Several approaches have been developed thus far, among which, lipid-based drug delivery systems have emerged as a fundamental formulation method aimed at
overcoming challenges related to poor bioavailability. Self-emulsifying drug delivery systems (SEDDSs) are lipid-based drug delivery systems made up of oil, surfactant, and co-surfactant. SEDDS possess the ability to self emulsify spontaneously within the gastrointestinal tract (GIT), resulting in the formation of an oil-in-water emulsion that improves the absorption of drugs [2]. Although SEDDS is not considered novel, there has been an increasing interest in developing it for therapeutic applications in recent years. The potential of SEDDS to enhance the dissolution rate of Biopharmaceutics classification system (BCS) II and IV drugs has prompted the growing interest in their development. The lipid component of SEDDS stimulates chylomicron/lipoprotein, resulting in micellar solubilization in the duodenum, and the drug becomes entrapped in colloidal micelles, as a result, the drug becomes more soluble, and its absorption is also improved [3]. The small globule size of the emulsion formed upon dilution of SEDDS offers a large surface area for interaction with the GIT, Improving absorption and reducing drug absorption variability [4].
SEDDS are generally classified into two types based on the emulsion formed upon dilution: self-nanoemulsifying drug delivery systems (SNEDDSs) and self-microemulsifying drug delivery systems (SMEDDSs). The characteristic of SMEDDS is the formation of an optically clear to slightly translucent microemulsion when exposed to the aqueous medium. Microemulsion offers small droplet sizes that range from 100 to 400 nm. SMEDDS requires low interfacial tension for the formation of emulsion which offers a wide surface area for absorption. SNEDDS forms an oil-in-water nanoemulsion with droplet sizes less than 100 nm. SNEDDS are kinetically stabilized, whereas SMEDDS is thermodynamically stable [5,6].
Commercially available formulations of SEDDS are liquids, encapsulated in hard or soft gelatin capsules. Table 1 shows various marketed formulations of SEDDS. The limited number of marketed products is primarily a result of their high cost of manufacturing, stability, and portability challenges, the risk of drug precipitation upon dilution, the absence of accurate in-vitro prediction tools, and the complexity of manufacturing equipment. The prevalent approach for overcoming these challenges is the solidification of liquid SEDDS. The primary objective is to improve both its physicochemical stability and reduce the overall manufacturing costs [15]. In addition, solidification has several advantages such as extended gastric residence time [16], controlled release of drug [17], improved solubility and bioavailability [18], ease of handling, dose accuracy, targeting drugs to a specific absorption region in the GIT, protecting the drugs from the harsh gut environment, spontaneous emulsification, [19] and so on. Solidification of liquid SEDDS can reduce the surfactant amount and enhance the oxidative stability of lipids by protecting them from degradation [20]. Achieving effective oral delivery of liquid SEDDS of macromolecules such as proteins and peptides is challenging due to the precipitation and conformational changes. Solid SEDDS (S-SEDDS) demonstrate the ability to stabilize peptides and proteins [21]. This review aims to build on earlier review articles in the field by highlighting current developments and challenges associated with the solidification of SEDDS. The focus of the article is to review various applications of S-SEDDS found in existing works of literature.
Building Blocks of S-SEDDS
The building blocks of S-SEDDS are lipid, surfactant, cosurfactant, and solid carrier. These components synergistically contribute to the formulation and performance of S-SEDDS. Types of oil and surfactant, along with their concentrations, are important for designing a highly effective self-emulsifying system. Adequate solubility drugs in lipids, surfactants, and co-surfactants and the self-emulsification efficiency of surfactants and cosurfactants are to be considered before formulation [22]. The performance, stability, and release profile of S-SEDDS are impacted by the types of solid carriers. It is crucial to choose a solid carrier that guarantees the best drug solubility, dispersion, and bioavailability after administration in addition to offering a stable matrix for the formulation. The compatibility of solid carriers with other components is a critical factor in achieving the intended therapeutic effect [23].
Lipids
Lipids play a vital role in the functionality of SEDDS. The solubility of the drug in the oil phase is the key consideration in the selection of oils. The drug solubility in the oil phase has a significant impact on the efficiency of nanoemulsion in maintaining the drug in a solubilized state; this is particularly significant when it comes to oral formulations [15]. The oil phase improves drug bioavailability by enhancing solubility and facilitating lymphatic transport. However, having high solubility does not ensure optimal in vivo efficiency [24]. A variety of long- and medium-chain triglyceride oils that are distinguished by their saturation levels, are used for the development of SEDDS. Natural oils and fats are composed of triglyceride combinations that comprise fatty acids with varying chain lengths and levels of unsaturation. The melting point of a particular oil increases as the chain lengths of its fatty acids lengthen and drop as the degree of unsaturation increases. Furthermore, increased unsaturation makes the oil more susceptible to oxidation [25]. Unmodified vegetable oils, especially those with medium-chain triglycerides (Examples: Palm kernel oil and coconut oil), are considered favorable due to their natural origin. However, limited drug loading and inefficient self-emulsification, reduce their usage in SEDDS formulation [15]. Long-chain lipids (Examples: Oleic acid and castor oil) were found to be able to maintain drug concentrations at significant levels, avoiding precipitation, in contrast to medium-chain triglycerides [20]. The use of modified vegetable oils (Campul MCM, Acconon CC-6) has become prevalent recently due to their high emulsification capabilities when combined with suitable surfactants [26]. Table 2 represents commonly used natural, semi synthetic, and synthetic oils for the formulation of SEDDS.
Table 2. Various oils used for the formulation of SEDDS
| Types | Examples |
|---|---|
| Natural oils | Coconut oil, palm oil, castor oil, sesame oil, clove oil, soyabean oil |
| Semi synthetic | Campul MCM, Imwitor®, Peceol™ |
| synthetic oils | Labrafil® M1944CS, Labrafil® M2125CS, Gelucire® 44/14 |
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Induja Govindan, Annamalai Rama, Anjana A. Kailas, Srinivas Hebbar, Anup Naha, Transformative solidification techniques for self-emulsifying drug delivery and its foresight in modern-day drug delivery, Journal of Applied Pharmaceutical Science Vol. 14(07), pp 001-013, July, 2024, Available online at http://www.japsonline.com, ISSN 2231-3354, DOI: 10.7324/JAPS.2024.184385
Read also our introduction article on Pharmaceutical Oils here:
