Developing Lipid-Based Formulations

Lipid-based formulations (LBFs) may improve oral bioavailability by exploiting the body’s lipid digestion and absorption pathways, offering a proven means of addressing the physicochemical and biological challenges of poorly soluble APIs. LBFs can be complex systems, so their development requires a multifaceted approach, and experience in how to approach their development provides significant benefits. With the availability of robust delivery systems, such as the softgel dosage form, LBFs can offer formulators potential benefits, provided that the most appropriate excipients are selected.

Pharmaceutical Technology spoke with Karunakar Sukuru, vice-president of Product Development, Pharmaceutical Softgel, and Vincent Plassat, lead scientist, Softgel Product Development, both from Catalent, about the importance of excipient selection and stability testing in the development of LBFs. 

Challenges to LBF development

PharmTech: Can you discuss the challenges in the development of LBFs and the key considerations when working with these systems? 

Sukuru and Plassat (Catalent): LBFs provide a versatile platform to formulate APIs with a wide range of physicochemical properties. The excipients that can be used within these formulations have a wide range of properties themselves, accommodating lipophilic compounds to be solubilized in oil as well as hydrophilic compounds that can be solubilized in high hydrophilic–lipophilic balanced (HLB) surfactants or hydrophilic solvents. The development of successful formulations requires specialized formulation expertise to perform preformulation screening and assessments due to the great versatility and dynamic nature of LBFs in vivo.

The first hurdle is choosing appropriate formulation excipients that not only have adequate solvent capacity to solubilize the entire dose, but which also ensure that the formulation maintains its solvent properties in the intestine after dilution and digestion. The balance between these two requirements is currently poorly understood, and there is a considerable risk of precipitation of drug during the various intermediate stages of drug transfer, for example, from the solution state to the micellar state. The extent of this precipitation is dependent upon the formulation-it is, therefore, crucial to conduct various in-vitro studies to challenge the formulation and help predict the likelihood of precipitation and/or guide the appropriate excipient selection. 

Some of the important parameters to consider in LBFs include: screening for solubility in excipients, biorelevant media and lipid-digestion products, excipient compatibility, and finally, the risk of precipitation upon dispersion and digestion.

Another key consideration in oral formulation design is the safety and regulatory status of proposed lipid excipients. Not all lipid excipients are generally recognized as safe (GRAS), hence, specific attention to their maximum daily intake should be considered as soon as possible in the development of a LBF. This is a critical factor for new molecular entities because high doses of excipients could be required during dose escalation studies. 

Stability assurance

PharmTech: How do you ensure the formulation is stable? And how do you test for stability?

Sukuru and Plassat (Catalent): The physicochemical stability of LBFs is just as crucial as with any other formulation. Chemical stability is handled the same as it would be with other dosage forms, with appropriate excipient selection based on a compatibility study with a mixture of API and a single or blend of excipient(s), along with analysis of the impurities formed (if any) during storage at various temperature and humidity conditions. Once the formulation is established, a formal stability study is performed on the dosage form in the proposed packaging at International Council for Harmonization (ICH) conditions to establish the shelf life. For LBFs, the differences come in testing for physical stability. For example, when LBFs are made with excipients that could be semisolid or that have different hydrophilicity or lipophilicity characteristics, these excipients can settle over time, especially during storage at 40 °C. It is, therefore, necessary to conduct stress studies to challenge the robustness of the formulation. Cycling studies are commonly used with cycles of high and low temperature to stress the formulation. Additional tests to challenge the LBF’s robustness to ensure the API does not precipitate out in in-vivo or in-vitro conditions can also be performed.

PharmTech: Can you outline the different excipients used in LBFs and the role they play?

Sukuru and Plassat (Catalent): There are a wide range of excipients that can be used in LBFs. They can be classified under five different categories:

• Triglycerides are vegetable oils composed of triglyceride esters of fatty acids. They are a component of many foods and do not present safety issues. Triglycerides are foundational excipients for LBFs. Their solvent power is usually limited, but after digestion, the fatty acids released form mixed micelles with bile salts that can dissolve a portion of the API and thus become carriers for the now suspended API. Examples include corn oil and sesame oil.

• Mixed glycerides and polar oils are partially hydrolyzed triglycerides that are generally much better solvents than triglycerides. These excipients help to form self-emulsifying systems but can still be sensitive to digestion. Other esters such as propylene glycol or sorbitan esters of fatty acid are currently available and may be valuable additives in cases of chemical incompatibility. An example is glycerol monocaprylocaprate.

• Water-insoluble surfactants include non-ionic polyethoxylated or polyglycerylated esters of fatty acid that are not hydrophilic enough to be soluble in water but form a good oil/water interface. They are considered dispersible in water and are therefore commonly used to create selfemulsifying systems. Examples include linoleoyl polyoxylglycerides.

• Water-soluble surfactants are the most commonly used excipients for formulation of self-emulsifying drug delivery systems (SEDDS) or selfmicro-emulsifying drug delivery systems (SMEDDS). Above their critical micelle concentration, these excipients spontaneously form micellar solutions that help to solubilize the API. Examples includes polysorbate 20 and 80.

• Co-solvents are water-soluble solvents such as ethanol, propylene glycol, and polyethylene glycol. They have multiple roles in LBFs. They increase the solvent capacity of the formulation for drugs and aid the dispersion of systems containing a high proportion of water-soluble surfactants. However, because they lose solvent power during dilution in gastrointestinal fluids, their use is limited. Because lipids are prone to lipid peroxidation, which generates free radicals that can adversely affect API stability, liposoluble antioxidants such as tocopherols and butylated hydroxytoluene/hydroxyanisole are sometimes also needed as additives in LBFs.  

Excipients effects

PharmTech: Can you tell us about the variability of lipid excipients and how it can affect the formulation? What must formulators do to address this issue?

Sukuru and Plassat (Catalent): Due to their natural origin, some excipients can have a variable composition. Subsequent chemical modifications on excipients that are inherently variable, such as hydrolysis and esterification, can lead to even greater variability and challenges. The formulator must have a good understanding of the exact excipient specifications to select the one most suitable for the formulation. The formulator must also understand and accept that there will be small variations between batches of the same product. The formulation must, therefore, be robust enough not to be sensitive to these small variations in the composition of the excipients. If the LBF cannot withstand small variations, a strategy to mitigate the impact from such variations should be put in place.

Article Details

Pharmaceutical Technology
Vol. 42, No. 10
October 2018
Pages: 26–29

Citation

When referring to this article, please cite it as A. Siew, “Developing Lipid-Based Formulations,” Pharmaceutical Technology 42 (10) 2018.

About the author

Adeline Siew was previously editor for Pharmaceutical Technology and Pharmaceutical Technology Europe.