Lipid-Based Formulations for Early-Stage Clinical Trials

One of the main challenges faced by the small molecule industry today is the increasing number of poorly water-soluble molecules in the drug development pipeline. We estimate that more than 80% of the drug candidates currently under development are poorly water-soluble and experience bioavailability challenges, which leads to difficulties in formulating drug products. Indeed, the use of conventional dosage forms to deliver these molecules is not always sufficient to achieve the expected drug exposure.

A simultaneous issue is the urgent need for accelerated development, which is more critical than ever. This is especially true for small and emerging biopharmaceutical companies, which often depend on rapidly developing a small number of candidate molecules toward clinical development. An additional factor driving increased focus on accelerated development timeliness are the specialized meds and regulatory pathways being utilized today, including orphan drugs, breakthrough and fast-track designations, as well as NDA 505(b)2 programs.

Several technologies have extensive track records in enhancing oral bioavailability, including particle size reduction and nano-milling, salt formation, amorphous solid dispersions and lipid-based drug delivery systems. The choice between enabling technologies is dependent upon physicochemical and biologic parameters, as well as the target product profile of the candidate drug. Among these methods, lipid-based formulations (LBFs) may be the most appropriate, but only under certain circumstances.

To successfully employ LBFs for bioavailability enhancement and shorter timelines to clinical trials, biopharma decision-makers will benefit from using a rational approach that evaluates the drug’s properties against the qualities of LBF. A rational approach can include digital tools to select lipidic excipient candidates in silico, which avoids a lengthier trial-and-error approach. Soft-gel capsule and liquid-filled hard capsule (LFHCs) dosage forms can also help shorten LBF development timelines due to their manufacturing simplicity versus other dosage forms.

How Different Types of Lipid-Based Formulations Aid in Drug Development

Lipid-based formulations are widely used in drug development to improve the oral absorption of Biopharmaceutical Classification System (BCS) Class II or IV molecules, which have a high/low permeability and a low aqueous solubility, respectively. Drugs that are well-suited for LBFs for oral absorption enhancement include those widely described as “grease ball”-type drugs. These drugs typically exhibit solvation-limited absorption and are thus often sensitive to changes in the local solubilization environment in the gastrointestinal tract. The use of LBFs can overcome the inherent slow dissolution and poor oral absorption of these drugs, by retaining them in a solubilized state during gastrointestinal transit.

In addition to improving drug solubilization, LBFs can also increase drug absorption for “grease ball”-type compounds by circumventing the drug dissolution step, recruiting endogenous solubilizers to effectively shuttle the drug to the absorption site and by promoting the uptake of certain drugs into the lymphatic system. Moreover, lipid- and liquid-based formulations are highly versatile (see Figure 1) and can provide acceptable content uniformity of high-potency/lowdose drugs, achieve a fast onset of action, prevent interaction with food, reduce inter-/intrahuman variability, produce modifi ed/targeted release profiles or use a combination of these qualities to meet market and patient needs.

The Lipid Formulation Classification System (LFCS), introduced in 2000 and depicted in Figure 2, classifies LBFs into four main types based on the relative proportions of included lipids, surfactants and co-solvents:

• Type I formulations are the simplest and are comprised of drugs dissolved in triglycerides alone or in mixed glycerides.
• Type II formulations combine glycerides and lipophilic surfactants, with hydrophilic-lipophilic balance (HLB) less than 12.
• Type III formulations refer to those containing a mixture of glycerides, lipids and more hydrophilic surfactants (HLB>12). Type III formulations are further stratified into Type IIIA, which contain larger proportions of lipids and lower proportions of surfactant and co-solvent, and Type IIIB formulations, containing relatively limited amounts of glyceride lipids (<20%) and larger quantities of hydrophilic excipients.
• A classification of Type IV “lipid-based” formulations was introduced later in response to the increasing use of formulations that contain no traditional lipids. Type IV LBFs only contain a combination of surfactants and co-solvents.

Type I formulations, due to their rich content of lipids, require digestion to allow for dispersion into intestinal fluids, whereas Type II-IV contain sufficient surfactants to promote spontaneous dispersion. Increasing quantities of surfactants and co-solvents in Type IIIB and IV usually increase the potential for drug loading since, with the exception of the most lipophilic drugs, the majority of poorly water-soluble drugs are more soluble in surfactants and co-solvents than in glyceride lipids.

An analysis of the physicochemical and biological parameters and the available in vitro/in vivo data generated from 20 New Chemical Entities (NCEs) over a decade confirmed that Type IV LBFs typically display attributes that can significantly increase the oral bioavailability of NCEs, including a molecular weight of 400-750 g/mol, a cLog P of 3 or higher, a high permeability and a polar surface area, in almost all cases, of less than 100 Ų.

Using a Rational Approach to Accelerate LBF Development

Since LBFs span a wide range of potential compositions, the development of a robust LBF that aids in shortening development timelines to clinical testing involves an in-depth analysis of the physicochemical and biopharmaceutical drug properties. Effective analysis will include the Target Product Profile (TPP), which refers to the desired characteristics of the drug being developed. A rational LBF design approach for each new drug in development can help drug makers maximize the success rate of LBFs in early-stage clinical trials.

Developing a bespoke LBF for each new drug relies in part on skilled experts in the field, access to up-to-date experimental techniques and, increasingly, the use of digital tools, databases and in silico analysis to identify initial LBF candidates more quickly and understand the underlying drug-LBF structure at the molecular scale. Also, extensive knowledge of lipidic excipients and their behavior in the gastrointestinal tract is required to select suitable lipidic excipients for the initial step of development. Other aspects like manufacturing, compatibility, stability and regulatory acceptance also need to be considered at the early stage of development.

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The first step to robust LBF development is drug selection, which includes collating and evaluating all relevant properties of the drug molecule in relation to its stability, physicochemical and biopharmaceutical properties (Figure 3). From this assessment, and in guidance with the TPP, the initial framework of the LBF design approach can be established. Successful LBF design then moves to the selection of appropriate excipients from a wide range of oils, surfactants, cosurfactants and co-solvents, based on their structures and properties, regulatory acceptance for oral delivery and commercial availability. The most effective lipid excipients may be those showing the highest affinity and solubility for the drug product.

From the results of this screening phase, the development will progress into the testing of a series of LBF compositions. A software platform for library management and data-processing tool for lipids, may be used to speed the transition from excipient screening into the development phase, and then to avoid the trial-and-error approach of screening dozens of different formulation compositions. This digital tool contains hundreds of phase diagrams for one-, two- or three-excipient LBFs and, based on a series of drug-specific inputs, can rapidly identify candidate LBFs that meet initial set criteria. These criteria include the target LBF dispersibility (i.e., microemulsion), the ability to solubilize the target dose and/ or percentage of excipients known to inhibit intestinal efflux transporters. The subsequent LBF experimental testing phase will consist of evaluating the pre-selected LBF compositions, namely formulation performance, stability and processability.

The primary goal of these tests during early LBF development is not to closely predict LBF behavior in vivo, but rather to determine its respective performance, and then to identify the formulation compositions that match it most closely. With respect to performance, the goal is to evaluate the properties of the LBF and the fate of the drug following oral administration. This may be achieved through a combination of in vitro dispersion tests (in conditions simulating the fasted/fed stomach) and digestion tests (in conditions simulating the upper small intestine).

Soft Gelatin and Liquid-Filled Hard Capsules Can Further Accelerate LBF Testing in Clinical Trials

Physically, LBFs are often liquids but may also be solid or semi-solid at room temperature when high melting point lipids are employed. Depending on the formulation compositions, soft or hard gelatin capsules can potentially cut down process steps and lead to simpler scale-up than other conventional dosage forms. Due to their manufacturing simplicity versus other dosage forms, soft gelatin capsules and liquid-filled hard capsules (LFHC) can be considered a the “fast-into-human” technology of choice and a tool for accelerated development and scale-up timelines.

Beyond increasing speed to clinic, these capsules can easily be scaled-up to aid with larger Phase II and additional studies, which is a helpful quality if development speed is also important beyond Phase I trials. Another benefit is that soft-gel and LFHC capsules can support a wide range of dose strengths, ensuring content uniformity even at a low dose, and they tend to be better than powder forms at limiting variation in physical or polymorphic makeup of the drug product.

Looking Ahead: What’s Next for LBFs?

For pharmaceutical decision-makers dealing with an increasing proportion of low-solubility molecules and a rising need for speed to clinic, lipid-based formulations can be used for the rapid development of certain bioavailability-challenged molecules. A rational approach to technology selection between major enabling technologies – e.g., particle size reduction, solid dispersions, and lipid-based formulations – is critical. LBF technology advancements and formulation guidance tools such as Lipidex® can shorten timelines and increase the success rate in reaching the Target Product Profile (TPP) in early development. Due to their manufacturing simplicity versus other dosage forms, soft gelatin capsules and LFHC formats are readily scalable and can further speed development timelines of lipid-based formulation products.

As the rising proportion of bioavailability-challenged molecules and highly potent/low-dose applications continues to be major formulation challenges for new molecules, lipid-based formulations will remain an important part of drug makers’ formulation toolkits. For biopharma companies that have limited internal expertise and/or resources for drug development and manufacturing, specialized external partners with deep capabilities in LBFs and other key enabling technologies can help them meet their target product profiles and development timelines.

References

1. Lonza webinar titled “Lipid-based formulations for early stage clinical trials” – November 2019
2. H.D. Williams, N.L. Trevaskis, S.A. Charman, R.M. Shanker, W.N. Charman, C.W. Pouton, C.J. Porter, Strategies to address low drug solubility in discovery and development, Pharmacological Reviews, 65 (2013) 315-499.
3. R. Holm, Bridging the gaps between academic research and industrial product developments of lipid-based formulations, Advanced Drug Delivery Reviews, 142 (2019) 118-127.
4. O.M. Feeney, M.F. Crum, C.L. McEvoy, N.L. Trevaskis, H.D. Williams, C.W. Pouton, W.N. Charman, C.A. Bergström, C.J. Porter, 50 years of oral lipid-based formulations: provenance, progress and future perspectives, Advanced Drug Delivery Reviews, 101 (2016) 167-194.
5. D.J. Hauss, Oral lipid-based formulations, Advanced Drug Delivery Reviews, 59 (2007) 667-676.
6. J. LaFountaine, P. Gao, R.O. Williams III, Lipid-Based Formulations, in: R.O. Williams III, A.B. Watts, D.A. Miller (Eds.) Formulating poorly water-soluble drugs, Springer 2012, pp. 295-382.
7. H. Williams, M. Morgen, E. Jule, J. Vertommen, H. Benameur, D. Friesen, D. Vodak, Science-Based Technology Selection And Formulation Development For Oral Bioavailability Enhancement.
8. E.T. Cole, D. Cadé, H. Benameur, Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into capsules for oral administration, Advanced Drug Delivery Reviews, 60 (2008) 747-756.
9. R.G. Strickley, R. Oliyai, Solubilizing vehicles for oral formulation development, Solvent systems and their selection in pharmaceutics and biopharmaceutics, Springer2007, pp. 257-308.
10. A. Igonin, J. Vertommen, H. Benameur, Physical and biological parameters of poorly bioavailable compounds that infl uence the development of lipid-Based Oral Drug Delivery Systems, Annual Academy of Pharmaceutical Scientists Annual Chicago, 2012.
11. C.W. Pouton, C.J. Porter, Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies, Advanced drug delivery reviews, 60 (2008) 625-637.
12. E. Jule, Accelerating Lipid-Based Drug Formulation Through Application of an Expert System, Capsugel White Paper, 2013.
13. H.D. Williams, E. Jule, A. Igonin, H. Benameur, Drug permeability and metabolism for in silico formulation of lipid-based systems, Annual Academy of Pharmaceutical Scientists Annual Meeting San Antonio, 2015.
14. H.D. Williams, P. Sassene, K. Kleberg, M. Calderone, A. Igonin, E. Jule, J. Vertommen, R. Blundell, H. Benameur, A. Müllertz, C.J. Porter, C.W. Pouton, Toward the Establishment of Standardized In Vitro Tests for Lipid‐Based Formulations, Part 15: Proposing a New Lipid Formulation Performance Classifi cation System, Journal of Pharmaceutical Sciences, 103 (2014) 2441-2455.