FORMULATION FORUM - Self-Emulsifying Drug Delivery Systems for Improving Oral Bioavailability of Drugs

KEYWORDS: Emulsions, Microemulsions, Nanoemulsions, Self-Emulsifying Systems, Liquid SEDDS/SNEDDS, Solid SEDDS, Absorption, Oral Solubility, Oral Bioavailability, Lipid Classification System, Liquid Capsule

INTRODUCTION

Self-emulsifying/nanoemulsiying drug delivery systems (SEDDS/SNEDDS) have been a subject of continued interest in enhancing solubility and oral bioavailability of drugs as more new chemical entities (NCEs) are being discovered. This enabling technology represents an opportunity for treatment of life-threatening diseases because of lower cost, convenience, and wide acceptance by patient population. Therefore, drug manufacturers are taking a holistic approach for bringing in the innovative molecules to clinics faster. Drug shortages stemming from finding the appropriate excipients and technologies as well efficacies and long-term stability, have also generated opportunities for drug and excipient manufacturers to expedite the development to close the gaps for bringing innovative medicines across all modalities. SEDDS has drawn attention lately because of its simplicity in scale up and manufacturing, cost effectiveness, and its abilities to overcome the absorption via gastrointestinal mucus barrier.¹ It is generally believed that smaller droplet size and surface area, and ability to shape deformation, could help penetrate the mucus layer to enhance the oral bioavailability.²

SEDSS/SNEDDS, a homogenized pre-concentrate isotropic mixture composed of drug solubilized and encapsulated in oils, surfactants, and cosurfactant assemblies, are used an alternative to solid oral tablets for immediate release of drugs.³ Once dispersed in GI fluids, the preconcentrate simultaneously rapidly self-emulsified to smaller particles or oil droplets ranging 10-500 nm o/w emulsions, as shown in Figure 1.^4,5

This step is important for SEDDS containing higher percentages of solubilizers and/or surfactants (Type III of lipid formulation classification system (LFCS).⁶ Furthermore, faster dispersibility of molecules helps improve their absorption and oral bioavailability.⁷ In spite of lower drug solubility and loading challenges compounded with long-term stability for sensitive molecules and those requiring medium to higher doses, with few exceptions, SEDDS/SNEDDS are still used in development of drugs to mitigate or minimize the food effect. This is due, in part, to increase of bile salts, phospholipids, and hydrolysis of digestive triglycerides and their breakdowns in complex lipid aggregates post postprandial in intestine facilitate the solubilization and dissolution of drugs in mixed micelles and uni- and multilamellar vesicles.^8,9 There are, however, challenges due to impediment in release of poorly soluble and lipophilic drugs dissolved in tiny oil droplets, while the soluble and hydrophilic drugs might release more instantaneously.¹⁰ Thus, SEDDS have been applicable for a wide range of molecules with a range of excipients for both lipophilic and hydrophilic molecules. Both solubility and dissolution rate play an important role in improving oral bioavailability by SEDDS administration.

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LIPID FORMULATION CLASSIFICATION SYSTEM (LFCS)

Type I lipid formulation comprised of oils without surfactants inhibits the emulsification of drugs in biological systems, leading to poor drugs absorption due to precipitation in gastrointestinal (GI) tract. However, the presence of pancreatic lipases and slower lipolysis could lead to increase in bioavailability with this formulation. Type 2 lipid formulation comprised of oil and surfactant is the next level wherein the drug is solubilized in surfactants with HLB <12 and self-emulsified as much as possible to facilitate the dispersions in the GI aqueous environment. This could also lead to partial or inadequate solubilization leading to lower oral bioavailability of lipophilic drugs. Type III formulations comprised of high surfactants and co-surfactants with higher HLB values >12, are readily dispersed in aqueous systems by spontaneous self-emulsification process, leading to formation of tiny oil droplets or o/w micro/nanoemulsions and significantly higher oral absorptions than Type I and Type II formulations.¹²

SEDDS FORMULATIONS

Barreiro et al (2024) examined a range of delivery systems for poorly soluble drugs. Of them include the SEDDS/SNEDDS and cited a number of drugs marketed in lipid assemblies. Table 3 lists the approved drugs and their formulation compositions.¹³

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To design a better and smarter SEDDS/SNEDDS formulation with smaller particle size and low polydispersity index, a range of solubilizers, surfactants, and oils have been used. Clauss et al (2023) used hydrophobic ion pair with a solubilizer to emulsify insulin glargine complex in a range of excipients composed of Maisine CC as a mixture of mono-, di-, and tri-glycerides of linoleic acid and oleic acid and compared with other solubilizers, including polysorbate 80, Kolliphor® HS15, Labrasol ALF, oleyl alcohol, Plurol oleique CC 497, among others, for immediate emulsification and stability. Long-chain triglycerides help facilitate drug absorption and transport via lymphatic system.^14,15 One formulation was composed of 20% Labrasol ALF, 30% Polysorbate 80, 10% Croduret 50, 20% oleic acid, and 20% Maisine CC; whereas, a second formulation, composed of 30% Labrasol ALF, 20% polysorbate, 30% Kolliphor® HS15, and 20% Plurol oleique CC497, were compared for droplet size, polydispersity index, and zeta potential on post self-emulsification in simulated intestinal fluid at pH 6.8. Both formulations were stable over 4 hours, and the PSD, PDI, and zeta potential of both formulations were within the range of each other, though the second formulation showed a slightly higher droplet size compared with the first formulation. In a similar study, Menzel et al (2018) evaluated in vivo the self-emulsified formulation of exenatide ion paired with sodium docusate composed of 35% polyoxyl 35 castor oil, 25% Labrafil 1944, 30% Capmul PG 8, and 10% propylene glycol. The release data suggests that blood sugar was controlled in male Sprague Dawley rats.¹⁶

Gao et al (2021) evaluated the encapsulation of cepharanthine (CEP) in SEDDS composed of 30% oil and emulsifier/co-emulsifier ratio of 5 and achieved the drug loading of >36 mg/ml (3.6%) with droplet size of 38 nm, and the oral bioavailability was >203% compared to free drug. The SEDDS formulations were stable over stable over 6 months as evident from no obvious change on particle size, PDI, and drug loading.¹⁷

Malkawi et al (2020) evaluated a highly water soluble captopril (CTL), a anionic drug (log P of 0.34) complexed with a cationic polymer in SEDDS composed of 40% Kolliphor® RH40, 20% Kolliphor® EL, and 40% castor oil, and found that droplet size was 100 nm with PDI of <0.5, and showed a sustained release over 3 hours with CTL0: polymer ratios of 1:2 and 1:4. It was also found that only 4%-11% of cationic polymer was incorporated in SEDDS that helped stabilized the drug for sustained release from the oily droplets.¹⁸

Elnaggar et al (2011) evaluated sildenafil citrate in SNEDDS and nanoemulsions in oral and topical delivery composed of 16% Maisin® 35-1, 32% Kolliphor® RH40, 33% Caproyl 90, and 16% propylene glycol. Sildenafil nanoemulsions with 0.1% drug loading were prepared by adding the drug in placebo SNEDDS diluted in 1:50 mixture with carbonate buffer at pH 10.3.³ The particle size was <200 nm and on dilutions to 50-fold, 100-fold, and 1000-fold, while for nanoemulsions, the droplet size from preconcentrate was about 70 nm (not shown). In vitro release confirmed that SNEDDS formulation showed a similar release as nanoemulsions, upon dialysis of 7.5 mg each sample) with cellulosic membrane (MWCO 12-14K), with faster release in citrate buffer at pH 5 as compared to phosphate buffer at pH 7.4 and carbonate buffer at pH 10.3. In spite of higher in vitro drug release by dialysis, transdermal permeability of sildenafil was limited in stratum corneum due to lower water content (20%) by lack of spontaneous self-emulsification in higher concentrations of Kolliphor® RH40 and oils.³

Kim et al (2021) evaluated sildenafil in liquid and solid SEDDS for enhancing the oral bioavailability of drugs. Liquid SNEDDS composed of Labrasol:Transcutol HP:Captex 300 in ratio of 70:15:15 with 1% drug loading, was evaluated against the solid-SNEDDS derived from the same composition as liquid SNEDDS and was adsorbed on a solid porous matrix carrier HDK N20. In comparison with amorphous sildenafil derived from spray dried powder of PVP, Labrasol in ethanol, solid SNEDDS showed significantly higher bioavailability in rats compared to amorphous spray dried powder (AUC 1508 h.ng/ml vs. 1339 h.ng/ml) in spite of similar dissolution behavior.¹⁹

SOLID SEDDS (S-SEDDS)

Yet, in many of the examples previously cited relate to liquid SEDDS and the approved drugs in liquid soft gel capsules, there have been equal interests to develop an s-SEDDS on solid matrix. Therefore, the research continues to improve the stability of liquid SEDDS as some of the drug may not be stable over their shelf lives.²⁰ There are several challenges that could unravel; first, identifying the right excipients and solubilizers compatible to drugs, second, should be able to self-emulsify leading to give rise to small droplets, third increase drug loading, and fourth is the stability of drugs in SEDDS. The latter is critical and can be addressed by identifying the appropriate excipients and polymers. The key criteria for matrix are porosity, hydrophilicity, surface area, and good flowability. Table 4 lists a number of solid matrices as carriers for delivery of drugs in s-SEDDS.

CHARACTERIZATION OF SEDDS & S-SEDDS

Several physical techniques are used to characterize the SEDDS formulations in liquids and solids. Though a technique used might be specific for liquid SEDDS, the same technique might be applied to s-SEDDS. For instance, the particle size distribution of SEDDS derived from lipid droplets can be measured by dynamic light scattering and laser diffraction methods. Self-emulsifying efficiency resulting from liquid cocktail and/or solid SEDDS can be measured by rate of droplet formation from each lipid assembly upon contact with aqueous GI fluid that could provide insight into emulsification quality and potential for drug absorption. Other physical characteristics such as cloud point also help determine the stability of formulation at varying temperatures, while the lipolysis and dissolution characteristics provide the in vitro release from liquid cocktail and s-SEDDS formulations. These characterizations are important to ensure SEDDS retain the desirable properties to yield faster dispersibility with smaller particles by self-emulsifying process.²⁹

s-SEDDS require additional techniques to fully characterize them. For example, powder x-ray diffraction (PXRD) and differential scanning calorimetry (DSC) are used to evaluate the solid state of drug, while infrared (IR) and Raman are typically used to evaluate drug-polymer interactions at molecular levels. SEM and TEM are used to understand the morphology of the drug in the solid matrix. In addition, the powder flowability, compressibility, and Hausner ratio and Carr’s index are all contribute to basic understanding of robust s-SEDDS formulations in solid matrices.

FUTURE PERSPECTIVES & SUMMARY

As more NCEs continue to be discovered with less options to find the appropriate excipients and solubilizers for Class II and IV drugs, the pharma industry has begun to evaluate liquid SEDDS for expediting drugs to market. With the understanding of easier to scale up and manufacture than oral solid tablets and capsules, liquid capsules containing SEDDS have gained more traction for early development of NCEs in the recent past. SEDDS is applicable to molecules across all modalities and therapeutic areas, especially those requiring stable formulations and targeted delivery.

With the new paradigm shift in personalized medicines, we also observed that SEDDS can be 3D printed into individual dosages, thus highlighting its broader applicability in producing multi component formulations with customized release kinetics. On the other hand, delivery of oral peptides and proteins with the appropriate permeation enhancers in SEDDS are equally important because it offers a promising platform for enhancing stability and permeability across epithelial membrane in GI tract. SEDDS encapsulating peptides and proteins, and for biologics for unmet medical needs, can minimize enzymatic degradation and improve permeability across intestinal membrane.³⁰ Supersaturable SEDDS (Su-SEDDS) created by incorporating hydrophilic polymers/ solubilizers, such as poloxamers, may help precipitate drugs, thus allowing drug to maintain its supersaturated state upon dilution in GI fluids. It is applicable to those drugs having a narrow therapeutic window.³¹

Ascendia’s EmulSol® technology can be used for a range of challenging molecules. Designed by selection of appropriate lipids, solubilizers, and surfactants, EmulSol® offers the solutions for enhancing solubility and bioavailability of molecules and biologics across all modalities. Ascendia’s GMP manufacturing capabilities equipped with the state of art liquid capsule filling and banding equipment for formulation development and scale up, offer choices for bringing the new therapy modalities from preclinical to the clinic studies at a faster speed.

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Shauket Ali, PhD
Sr. Director, Scientific Affairs & Technical Marketing
Ascendia Pharmaceutical Solutions
sali@ascendicdmo.com
www.ascendiacdmo.com

Dr. Shaukat Ali joins Ascendia Pharmaceutical Solutions as Senior Director of Scientific Affairs and Technical Marketing after having worked in the pharma industry for many years. His areas of expertise include lipid chemistry, liposomes, lipid nanoparticles, surfactant-based drug delivery systems, SEDDS/SMEDDS, oral and parenteral, topical and transdermal drug delivery, immediate- and controlled-release formulations. He earned his PhD in Organic Chemistry from the City University of New York and carried out his post-doctoral research in Physical Biochemistry at the University of Minnesota and Cornell University. He has published extensively in scientific journals and is inventor/co-inventor of several US and European patents.

Jim Huang, PhD
Founder & CEO
Ascendia Pharmaceutical Solutions
jhuang@ascendiacdmo.com
www.ascendiacdmo.com

Dr. Jim Huang is the Founder and CEO of Ascendia Pharmaceutical Solutions. He earned his PhD in Pharmaceutics from the University of the Sciences in Philadelphia (formerly Philadelphia College of Pharmacy and Sciences) under Joseph B. Schwartz. He has more than 20 years of pharmaceutical experience in preclinical and clinical formulation development, manufacturing, and commercialization of oral and parenteral dosage forms. His research interests are centered on solubility/bioavailability improvement and controlled delivery of poorly water-soluble drugs through nano-based technologies.