Exploring novel type of lipid-bases drug delivery systems that contain one lipid and one water-soluble surfactant only
Abstract
None of transitional lipid-based drug delivery systems (LBDDS) includes compositions containing one lipid and one water-soluble surfactant that form stable microemulsions. The conversion of liquid LBDDS to solid LBDDS has been limited by low drug loading. Previously, we have developed drug solid microemulsions containing one lipid and TPGS (a water-soluble surfactant) that achieved high drug loading and remarkably increased oral bioavailability. This study aimed to test if binary lipid systems (BLS), composed of one lipid and one water-soluble surfactant that form stable self-emulsifying microemulsions, is not an exclusive but widely applicable type of LBDDS for other lipids and surfactants and evaluate the influences of chemical structures of lipids and surfactants on microemulsions and solid microemulsions. We systemically identified new BLS by using a library of lipids and surfactants. Propylene glycol diesters and glycerol triesters were favorable for forming stable microemulsions with Tween 80, Cremophor EL, or TPGS. To the best of our knowledge, this is the first report exploring and confirming that the BLS is a new addition to traditional LBDDS, provides a promising option for researchers, and has the potential to increase drug loading to facilitate the development of solid microemulsions.
Introduction
Lipid-based drug delivery systems (LBDDS), discovered in the 1980s, are considered a well-established and very important strategy for developing formulations of water-insoluble compounds (Gupta et al., 2013, Pouton, 2000). LBDDS were broadly classified into four types according to the lipid formulation classification system (LFCS) introduced in 2000 (Savla et al., 2017, Shrestha et al., 2014). LFCS Type I only contains lipids. LFC Type II consists of mixtures of lipids and water-insoluble surfactants (hydrophile/lipophile balance (HLB) < 12), which forms crude and turbid emulsions usually with energy input. LFCS Type III contains lipids, water-soluble surfactants (HLB > 11), co-surfactants, and/or co-solvents. LFCS Type IV is only based on water-soluble surfactants and co-solvents. The LFCS has been a gold standard and framework to identify the appropriate formulas for specific drugs. Drug solubility in the excipients determines the maximum drug loading capacity in a lipid formulation. In many cases, water-insoluble drugs do not have high solubility in lipids. In addition, once excipients are dispersed and digested in the GI tract, the solubilization capacity of LBDDS is likely to decrease, consequently causing extreme drug precipitation. Thus, co-surfactants and co-solvents have been added into formulations to enhance solubility and stability, which discovered LFCS Type III and IV. However, while satisfying solubility, drug loading (the percentage of a drug in the final dosage form) decreases because of using high amounts of co-excipients. Also, the LBDDS becomes very complex so that drug solubility screening in numerous excipients is time and resource intensive. The formulators must empirically develop the LBDDS.
LBDDS are colloidal systems in which excipients are dispersed in an aqueous environment. The colloid state may cause particle instability due to the presence of large interfaces. Thus, instead of using LBDDS as final drug products, they are prepared as liquid preconcentrates and filled into capsules (Gursoy and Benita, 2004, Salawi, 2022). Upon contact with gastrointestinal (GI) fluid, preconcentrates can spontaneously form self-emulsifying particles in the GI tract to deliver oral drugs. However, manufacturing liquid-filled soft capsules is a slow process and requires specialized equipment (Jannin et al., 2008). Moreover, the interaction between liquid formulation and capsule shell may result in either brittleness or softness of the shell (Tan et al., 2013). To address these limitations, efforts have been made to convert liquid preconcentrates to solid dosage forms by spray drying, freeze-drying, and adsorption on carriers (Balakrishnan et al., 2009, Cho et al., 2013, Sha et al., 2021, Tang et al., 2008, Yi et al., 2008). Among these technologies, adsorption on carriers is the easiest process to prepare solid forms. However, the conversion further decreases the drug loading because of the addition of high amounts of solid carriers, which leads to low drug loading in solid forms, e.g. 0.35 % drug in the final tablet (Li et al., 2011). The low drug loading is a significant hurdle to applying LBDDS for solid dosage forms for clinical applications. As a result, although solid LBDDS have great potential and have been studied over two decades, few commercial medications use this strategy.
In our previous studies, we have used a mixture composed of one lipid and TPGS (a water-soluble surfactant with an HLB of 13.2), which produced microemulsions and was different from LFCS Type II, to prepare solid drug granules to increase drug loading, improve stability and enhance oral absorption of water-insoluble drugs such as lopinavir, ritonavir, sorafenib and docetaxel (Guo et al., 2016, Le et al., 2020, Pham et al., 2016). Because of using less amounts of excipients, we were able to achieve high drug loading for these drugs. We have used oleic acid and TPGS to prepare solid granules for ritonavir and a fixed-dose combination of lopinavir/ritonavir with 16 % drug loading. We have also used Miglyol 812 and TPGS to prepare solid granule for docetaxel with 9 % drug loading. All drug granules were stable over 6 months. The benefits of LBDDS for enhancing oral absorption remained in our new drug granules as all drug granules increased oral bioavailability over 3-fold compared to the free drugs (Guo et al., 2016, Le et al., 2020, Pham et al., 2016). Moreover, the solid docetaxel granule remarkably inhibited tumor growth over 24 days (Le et al., 2020). We constructed a ternary phase diagram for Miglyol 812, TPGS, and water. Very interestingly, no phase separation occurred with the increase of %water at the 1:1 ratio of Miglyol 812 to TPGS (w/w) that we used to prepare the solid docetaxel granule, suggesting a stable microemulsion that was different from LFCS Type II emulsions in which the phase separation normally occurred when the water content was increased over 15 % (Charman et al., 1992). Our previous data suggested that one lipid (oleic acid or Miglyol 812) and one water-soluble surfactant (TPGS) could form stable microemulsions. These interesting findings and merits of our previous drug granules motivated us to conduct the current, systematic study to explore a novel LBDD composed of one lipid and one water-soluble surfactant. We named them binary lipid systems (BLS) in this study. We evaluated if the BLS are not particular cases for oleic/TPGS and Miglyol 812/TPGS but an extensively applicable type of LBBDS and if the properties of BLS would change after adsorbing them on solid carriers. We expect the current study to identify and confirms a novel type of LBDD that expands the scope of LBDDS and provides one promising option for the development of LBBDS and solid LBBDS. Moreover, through a systemic study based on a library of lipids and surfactants, we expect to provide guidance to researchers to make formulation screening less empirical, consequently saving development time and resources.
Thus, this study aimed to test if BLS, composed of one lipid and one water-soluble surfactant that forms stable self-emulsifying microemulsion, is not an exclusive but widely applicable type of LBDDS for other lipids and surfactants and evaluate the influence of chemical structures of lipids and surfactants on microemulsions and solid microemulsions. In this study, BLS composed of one lipid and one water-soluble surfactant were prepared by constructing pseudo-ternary phase diagrams and then adsorbed on Aeroperl 300 (solid carrier) to form solid granules. A library of various lipids (HLB 4 ∼ 6) and water-soluble surfactants (HLB > 12) was established in terms of their molecular structures and various compositions of one lipid and one water-soluble surfactant were tested. Particles of BLS and particles of reconstituted solid granules were measured and compared to decipher the influence of chemical structures of lipids and surfactants on microemulsions and solid microemulsions. Based on the current study, we discovered and confirmed a novel type of LBDDS (i.e. BLS) that produces stable self-emulsifying microemulsions by using one lipid and one water-soluble surfactant.
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Materials
Propylene glycol monocaprylate (Capmul PG-8), propylene glycol monolaurate (Capmul PG-12), propylene glycol dilaurate (Capmul PG-2L), propylene glycol dicaprylate/dicaprate (Captex 200P), caprylic triglyceride (Captex 8000), capric triglyceride (Captex 1000) and glycerin monocaprylate (Capmul 808G) were gifts from Abitec (Columbus, OH). Vitamin E TPGS was a gift from Antares (Saint Charles, IL). Tween 80 (Kolliphor PS 80) and Cremophor EL (Kolliphor EL) were gifts from BASF (Florham Park, NJ). Miglyol 812 was a gift of IOI Oleo.
Xiaowei Dong, Ngoc Thao Duyen Nguyen, Exploring novel type of lipid-bases drug delivery systems that contain one lipid and one water-soluble surfactant only, International Journal of Pharmaceutics, Volume 661, 2024, 124447, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124447.
Read the article and see the interesting video on Vitamin E TPGS: