Lipid Formulations: Key Absorption-Enhancing Technologies in New Drug Development

According to reports, nearly 90% of poorly soluble drugs are found in newly discovered compound entities, while only 40% of the top 200 drugs in the U.S. market are poorly soluble. It is evident that a large number of candidate compounds are discontinued in development due to the lack of appropriate solubilization methods. In the early stages of innovative drug development, compounds are synthesized on a small scale with high synthetic costs. To save costs, formulation technologies often intervene in the CMC (Chemistry, Manufacturing, and Controls) phase. However, early involvement of formulations not only increases the success rate of drug development but also reduces the risk of screening out some highly active candidate compounds due to poor physicochemical properties. Additionally, it helps in achieving effective alignment between preclinical PK (Pharmacokinetics) and toxicology study formulations and clinical formulations, making PK and toxicology data more representative. Therefore, the involvement of formulation technologies throughout the lifecycle of drug development can reduce the screening cost of active ingredients and avoid the repetition of critical preclinical research data, thus accelerating development efficiency.

Fig. 1. Pathways to PWSD absorption from oral lipid-based formulations (Adv Drug Deliv Rev. 2016, 101: 167-194).

Lipid formulations, after over half a century of research, have relatively matured technology. The preclinical prescription screening process of this formulation type has a short cycle, requires less compound usage, and offers significant cost control advantages, making it one of the best early-stage intervention options in preclinical drug development.

Advantages of Lipid Formulations

Lipid formulations offer unique advantages for poorly soluble compounds in terms of solubility and permeability:

Enhancing drug dissolution and release

Lipid formulations improve drug dissolution and release to enhance drug absorption. This technology dates back to the 1970s and is now applied in several clinical drugs such as cyclosporine soft capsules, fenofibrate soft capsules, and olaparib capsules.

Maintaining drug solubilization stability

Lipid formulations, under the action of gastrointestinal digestive enzymes and bile salts, are digested and transformed into a series of microstructures like vesicles and mixed micelles. These microstructures stabilize the dissolution state of drugs throughout the digestion process, ensuring prolonged drug absorption and increased bioavailability.

Increasing intestinal permeability

Medium-chain fatty acids (C8-C10) and some surfactants have the ability to promote paracellular absorption and transcellular transport across intestinal epithelial cells, thereby enhancing drug intestinal permeability.

Reducing hepatic metabolism

By using unsaturated long-chain fatty acid esters (such as C16-C18) as solubilizing excipients, lipid formulations form chylomicron particles during absorption across intestinal epithelial cells, binding drugs with lipoproteins to facilitate lymphatic absorption and reduce hepatic first-pass metabolism.

Minimizing food effects

By designing the composition of lipid formulations, it is possible to minimize the impact of high-fat diets on absorption. For example, the second-generation self-emulsifying formulation of cyclosporine (Neoral) significantly reduces individual absorption differences caused by food compared to the first-generation oil solution formulation of cyclosporine.

Composition and Types of Lipid Formulations

The selection of components in lipid formulations needs to consider the physicochemical properties of drugs, the affinity between drugs and lipid excipients, pharmacokinetic requirements, and the future dosage form of the drug (oral emulsion/liquid soft capsules/hard capsules). The formulation typically includes oils, and/or surfactants, and/or small molecular solvents or co-solvents. Lipid formulations are usually categorized into four classes:

• Class I: Composed of a pure oil phase, the dispersion process of this type of formulation in the gastrointestinal tract does not significantly affect drug solubilization, but the digestion process typically has a considerable impact on drug solubilization.
• Class II: Composed of oil and water-insoluble surfactants, the dispersion process of this formulation in the gastrointestinal tract does not significantly affect drug solubilization, but the digestion process may influence drug solubilization.
• Class III: Composed of oil, water-soluble surfactants, and solvents, this formulation type has self-emulsifying capabilities, typically forming small and uniformly distributed nanoparticles that can be directly absorbed by intestinal epithelial cells. The dispersion and digestion processes in the gastrointestinal tract may affect drug solubilization and absorption.
• Class IV: Composed of water-soluble surfactants and solvents (without oils), this formulation type does not contain oils, and the dispersion process may significantly impact drug solubilization, with digestion having a relatively minor effect.

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Applications of Lipid Formulations

Preferred delivery technology for poorly water-soluble compounds

Lipid-based formulation design is a preferred delivery route for poorly soluble drugs in the gastrointestinal tract, or for low-absorption drugs with pH-dependent solubility. Listed drugs, such as cyclosporine soft capsules, Olaparib capsules, enzalutamide soft capsules, etc., have adopted lipid solubilization technology.

Ideal delivery techniques for liquid lipophilic or volatile drugs

Soft capsules of pharmaceutical oil solutions such as vitamin E and fish oil are no longer unfamiliar. Lipid formulations have become the ideal delivery form for liquid fat-soluble compounds. In addition, delivery in the form of well-sealed soft capsules is also an ideal choice for volatile drugs. For example, the oil solution of butylphthalide, a new drug, is delivered in the form of soft capsules, which not only has the effect of masking bad odors, but also avoids the volatilization of active ingredients, ensuring the stable quality of the drug.

Optimal delivery techniques for extremely low-dose poorly soluble compounds

The oil solution after the drug is dissolved is a homogeneous dispersion system. For products with smaller dosage specifications, technical problems such as poor drug content uniformity can be avoided (a common technical problem in extremely small-sized solid preparations). For example, drugs such as alphacalcidol or calcitriol that are already on the market have a specification of only 0.25 ug. Through the design of lipid dosage forms, they have been industrialized and are still on sale.

Design Principles of Lipid Formulations

• Initial stage: The initial application of lipid preparations was inspired by the "diet-induced increase in the absorption of some drugs." At this stage, lipid excipients were only used to improve the apparent solubility of poorly soluble drugs.
• Development stage: With the research on the absorption-promoting mechanism of lipid preparations, scientists have discovered that the in vivo digestion process of lipid preparations has an impact on absorption. By controlling the particle size, the digestion rate of lipid preparations can be improved, thereby affecting the dissolution and absorption of drugs. Therefore, oral emulsions or self-emulsifying dosage forms with small particle sizes and uniform dispersion have been developed.
• The latest stage: In the past ten years, the absorption-promoting mechanism of lipid preparations has been studied in depth. Scientists have discovered that during the dispersion and digestion process of lipid preparations in the body, the "solvent" effect disappears and the "supersaturation" effect occurs, and the stability of the supersaturated state greatly determines the absorption time and body exposure of the drug.

Fig. 2. Schematic diagram of supersaturation effect of lipid formulation (Adv Drug Deliv Rev. 2016, 101: 167-194).

Therefore, the design concept of lipid dosage forms has evolved from "how lipid excipients can improve the apparent solubility or dispersion stability of drugs" to "how to design and realize a formula with a stable supersaturated state during the digestion process."

Formulation Screening Process for Lipid Formulations

The formulation screening process for lipid formulations involves evaluating the solubilization and stability properties of single or mixed lipid formulations, followed by in vivo absorption assessments to determine the optimal formulation.

Key In Vitro Evaluation Techniques for Lipid Formulations

• Particle size has been a focal point in studies related to the in vitro and in vivo correlation of lipid formulations. However, research has shown that the particle size of lipid formulations designed for poorly soluble drugs like probucol, danazol, and lopinavir did not directly correlate with in vivo absorption. Nonetheless, formulations with smaller particle sizes, such as self-emulsifying formulations, exhibit relatively less individual variability in absorption compared to oil solutions.
• In vitro ester hydrolysis models simulate the dispersion, digestion, and absorption processes of lipid formulations in the body and are currently the best in vitro evaluation model for lipid formulations. These models assess the digestion rate, stability during the digestion process, and the solubilization capacity of post-digestion systems, guiding the formulation screening of lipid formulations. While these models have limitations in their applicability to all poorly soluble drugs due to the complexity of in vivo absorption of lipid formulations, ongoing optimization efforts aim to enhance their suitability for a wider range of drugs.

However, any model has certain limitations in its scope of adaptation. Due to the complexity of in vivo absorption of lipid formulations, current models are not suitable for performance assessment of all poorly soluble drugs. In order to further improve the applicability of the model to more drugs, scientists continue to optimize the model, which has evolved from the solubilization performance evaluation of the digestion end point to the current supersaturated solubilization stability evaluation of the entire digestion process, and is still continuously improving and optimizing.

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Reference

1. Feeney, O.M. et al. 50 years of oral lipid-based formulations: Provenance, progress and future perspectives. Adv Drug Deliv Rev. 2016, 101: 167-194.