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Lipid-based formulations provide a versatile solution to bioavailability issues, but a multi-disciplinary approach is needed to overcome limitations with poorly soluble compounds.
Lipid-based approaches to drug delivery have been extensively researched and have gained importance within the bio/pharma industry for their ability to enhance bioavailability of drug products. This capability to enhance bioavailability is becoming ever more desired in recent times due to the fact that increasing numbers of molecules entering the drug development pipeline are poorly soluble.
“As of late, more than 70% of new chemical entity (NCE) molecules are poorly soluble, with moderate lipophilicity (LogP >2),” says Ravinder Kodipyaka, head, formulation R&D, Custom Pharma Services, Dr Reddy’s. “As a result, industry is witnessing opportunities in novel drug discovery for the formulation of new NCEs in lipid-based drug delivery systems (LBDDS) so that bioavailability is improved.”
“Lipid-based formulations offer a tremendous solution for molecules exhibiting poor solubility and bioavailability,” Kodipyaka continues. “These formulations provide excellent solubilization capacity; improve permeation; overcome transporter, enzyme-based inhibitions; and support lymphatic transport, thereby overcoming major roadblocks for achieving optimum bioavailability.”
Using lipids to enhance oral bioavailability is a popular choice, adds Michiel Van Speybroeck, head of formulation, Ardena. “When an API is dissolved in a lipid formulation and subsequently administered, the API is presented to the gastrointestinal (GI) fluids in a predissolved form, which avoids slow dissolution from the crystalline form,” he notes. “The great advantage that lipids and lipophilic excipients offer over water-miscible solvents is that they are less likely to lose solvent capacity on dilution with the GI fluids. On contact with water, lipophilic excipients phase-separate and form a coarse or finely dispersed emulsion in which the API is sequestered. This protects the API from precipitation in the aqueous phase.”
Furthermore, Vincent Plassat, lead product development scientist, Catalent, emphasizes that by delivering drugs in a solubilized form, dose-uniformity can be improved, minimizing patient-to-patient variability. “There is a lot of precedent for the use of lipid-based drug delivery systems as a result of their value to drug developers and ultimately to patients. LBDDS are extremely versatile because there are many excipients and combinations of excipients that can be used in their development,” he explains.
Along with improved dose uniformity, LBDDS are also capable of mitigating food effects (1), Plassat confirms. “For very lipophilic drugs with a LogP value greater than five, formulation of long chain fatty acids can improve lymphatic uptake and bypass the liver. In addition, lipid-based formulations can maintain their solubility throughout the entire journey of the API through the GI tract, allowing higher absorption,” he says. “This is unlike non-lipid-based formulations, which exhibit supersaturation, decreased solubility, and lower absorption.”
Administration of lipid-based formulations is possible across several routes-oral, injectable, and topical-and depending on the lipophilic nature of a drug, it is possible to determine the optimal lipid delivery system using the Lipid-Formulation Classification System (2), explains Kodipyaka. Employing a suitable lipid excipient component can also aid in modulation of drug release. “The greater the hydrophobicity of the lipid excipient the slower the drug release due to reduced water penetration,” he adds.
Being able to control drug release is important so that rapid, high drug plasma level peaks are avoided, which can cause unwanted side effects in patients, notes Ellie Au, product development scientist, Catalent. “A slower release may also protect the drug from degradation in the stomach and facilitate release of the drug throughout the GI tract to improve absorption. Self-emulsifying lipid formulations typically have faster drug release than those lipid formulations that require digestion. The use of waxes, which are solid at room temperature, creates a matrix for modified release. The drug is therefore released with a controlled kinetic as the matrix slowly erodes,” she says.
“Drug release can be further modulated by incorporating pore formers, hydrophilic polymers, and surfactants in the composition or by virtue of a process that creates a more porous structure,” Kodipyaka comments. “Drug release is the important determinant to ensure maximum bioavailability at the site of action. Thus, lipid formulations could be tailored to achieve desired drug-release kinetics by careful selection of lipid excipients.”
Lipid-based formulations offer versatility and compatibility in terms of generally recognized safety, route of administration, and capability to overcome bioavailability issues. However, with this versatility, some challenges with LBDDS arise, such as stability issues and drug loading, reveals Karunakar Sukuru, vice-president, Product Development (US & EU) Softgel & Oral Technologies, Catalent.
Drug loading, for example, can be quite low in LBDDS as a result of the improved solubility offered. “Nevertheless, drug loading is a challenge faced by many other bioavailability enhancing technologies,” Sukuru adds.
For Kodipyaka, a common challenge associated with lipid-formulations is ingredient stability issues, particularly when using liquid formulations rather than solid forms, and drug precipitation during storage or contact with in-vivo GI fluids. “After administration, dilution and digestion effects will lead to a reduction in the solvent capacity of the lipid formulation. As a result, the API that was initially in solution may precipitate, and this may reduce the bioavailability-enhancing potential of the formulation,” agrees Speybroeck. “While lipid formulations are generally less susceptible to these effects than those based on water-miscible solvents, some precipitation may still occur. The magnitude of this effect can be assessed using in-vitro techniques that consider the effect of formulation digestion.”
Therefore, appropriate design of LBDDS is necessary to ensure that drug precipitation upon exposure to GI fluids is indeed avoided, Sukuru confirms. “Understanding the mechanism and predicting in-vivo performance of LBDDS has gained a lot of attention recently,” he says. “Many lipid excipients are naturally derived and contain multiple lipids (e.g., mixtures of mono-, di-, and triglycerides). There may be issues as ratios of lipid components change from batch-to-batch. Because of these variables, it is recommended that drug developers work with experts who have extensive experience and knowledge of the development of LBDDS.”
Another challenge experienced with lipid-based formulations is that of Ostwald ripening, which is where small particles dissolve and then re-deposit onto larger particles due to surface energy instability. “Ostwald ripening is a major challenge for lipid-based formulations, particularly for injectable products,” says Kodipyaka. “There are a limited number of approved, safe emulsifiers commercially available that can stabilize the emulsion system; hence, it would be very challenging to develop emulsion systems with the desired target product profile.”
“Finally, while the excipients used to construct lipid formulations are usually quite inert, many of these contain impurities, such as peroxides, aldehydes, or formic acid, that may trigger degradation pathways that are not seen when the same API is formulated in a solid formulation,” specifies Speybroeck.
Assessing the precipitation risk of lipid-based formulations as a result of dilution and digestion is possible using in-vitro experiments. These tests are more complex than standard dissolution tests but are capable of providing a more reliable indicator of lipid formulation performance, notes Speybroeck.
“In-vitro lipolysis experiments have been the traditional experiment to study a LBDDS mechanism and correlate it with in-vivo performance,” confirms Au. “Newer approaches, such as kinetic solubility measurements, are gaining interest to correlate with in-vivo behavior of LBDDS.”
Sukuru adds that a main limitation of current techniques that are aimed at overcoming challenges associated with lipid-based formulations is that all the work is undertaken in a closed system, whereas the human body is dynamic and always in motion. “A variety of new techniques and tools are available to quickly evaluate lipid-based formulations. One such tool is fiber optic dissolution testing, which allows for monitoring of dissolution profiles in real-time in a variety of biorelevant media and makes it easier to compare the performance of the formulation without the need for complex and lengthy analytical methods. It is also easier to asses any impact of the media modification,” he says. “With such advances in analytical instrumentation, product development can be expedited and made more robust through the generation of data and providing the opportunity to challenge different parameters of the formulation earlier in development.”
There is also the emergence of technologies in the field to enhance API loading of lipid-based formulations, adds Speybroeck. “Some researchers have reported on the use of supersaturated lipid formulations (3), whereby the API loading is increased by subjecting the lipid formulation to a heat-cool cycle,” he states. “This way, the concentration of API in the formulation is increased beyond its equilibrium solubility, which may lead to several-fold increases in API loading. This technique may be a viable option to reduce administration volume in preclinical and early clinical development. However, the utility for commercial products is more limited given the risk of API precipitation during storage, as the API is present at concentrations above its equilibrium solubility in the formulation.”
Regarding ingredients, Speybroeck notes that lipophilic salts are developing within the industry. “While traditional pharmaceutical salt forms are usually developed using small, hydrophilic counterions in an attempt to increase aqueous solubility, lipophilic salts are constructed with large, lipophilic counterions,” he says. “These salts may exhibit greatly depressed melting temperatures relative to the free form of the API and therefore also exhibit much higher solubility in lipophilic vehicles.”
In terms of unsaturated lipid components, which are prone to lipid peroxidation, formulators can employ saturated medium chain triglycerides along with appropriate antioxidants, explains Kodipyaka. “Excipient compatibility and stress stability studies during early stage development help formulators choose the right excipients according to the degradation pathway of the drug,” he says. “Decreased mobility by making semi-solid formulations also can help to physically and chemically stabilize the formulation.”
Additionally, alternative ingredients for capsules are coming to the fore, such as the use of hydroxypropyl methylcellulose (HPMC) or polyvinyl alcohol, instead of traditional gelatin-based capsules. “These ingredients are chemically and thermally stable and are less prone to humidity compared to gelatin-based capsules,” Kodipyaka confirms. “Furthermore, with the invention of liquid encapsulated micro-spray sealing technology, problems that were common with the conventional banding approach have been resolved.”
As molecules entering the drug development pipeline are increasing in size and becoming more lipophilic and chemically diverse, solubility challenges are also rising and can lead to a higher level of drug susceptibility to food effects, notes Au. “The broad range of lipid excipients available offer many options to customize formulations to meet the specific needs of the molecule,” she says. “Investing time and effort early in the development of a LBDDS can result in significant savings in time and overall development costs, and often with a better outcome.”
With an expanding proportion of drugs gaining fast-track designation, particularly for those therapies aimed at unmet medical needs, the benefits of LBDDS, which were primarily used to introduce life-saving drugs such as HIV proteases and anti-cancer treatments, are apparent, notes Plassat. “For example, within the industry, there has been a growing interest in peptides and other macromolecules due to their high specificity and potency,” he states. “The molecules are usually more sensitive to degradation, and lipid-based formulations can provide them with a better environment for long-term stability, and/or protect them from degradation in the GI tract.”
Yet, developing a lipid-based formulation essentially remains an empirical endeavor, notes Speybroeck. “Given the plethora of lipids and lipophilic excipients available, initiating a lipid formulation development may seem like a daunting task,” he adds. “However, great progress is being made in in-silico (computer-assisted) prediction of solubility. Adoption of such techniques may dramatically reduce the initial development effort.”
Thanks to these formulation design advancements in addition to new technologies that can enhance API loading and an improved understanding of how lipid-based formulations perform in-vivo, Speybroeck anticipates an enhanced adoption of the lipid approach in the future. “I believe we will witness a steady increase in the use of lipid formulations in clinical and commercial drug products going forward,” he says.
Taking a lipid-based approach for the formulation and delivery of new molecules with large molecular weights and high lipophilicity has shown great promise, stresses Kodipyaka. “However, technology development and implementation in the area of lipid drug delivery needs to be expedited to catch up with the discovery pace,” he summarizes. “A multi-disciplinary approach is required to overcome limitations pertaining to development of lipid formulations for poorly soluble molecules. Knowledge of lipid chemistry, predictive in-silico models, nanotechnology, and bio-pharmaceutics coupled with advanced characterization techniques would be helpful in resolving complex issues moving forward.”
1. R. Savla, et al., Drug Dev. Ind. Pharm., 43 (11) 1743–1758 (2017).
2. V. Jannin, et al., Indian J. Pharm. Sci., 80 (6) 1011–1020 (2018).
3. J. Brouwers, M.E. Brewster, and P. Augustijns, J. Pharm. Sci., 98 (8) 2549–2572 (2009).
Vol. 43, No. 10
When referring to this article, please cite it as F. Thomas, “Overcoming Bioavailability ‘Roadblocks’ with LBDDS,” Pharmaceutical Technology 43 (10) 2019.