Unlocking the Use of Lipid-Based Formulations with Lipophilic Salts to Address Bioavailability Challenges in Small Molecule Drug Development

Drug developers have traditionally benefited from the ionizability of acidic or basic drugs to form ionic salts that increase water solubility.^1-3 However, this increased water solubility does not always relate to improved oral bioavailability, and therefore specialized technologies are needed to address bioavailability challenges. Lipid-based formulations (LBFs) are widely used in drug development to improve the oral absorption of poorly water-soluble drugs, which continue to dominate the development pipeline.^4,5 To render the target API more lipid-soluble and to reach the dose while unlocking the benefits of LBFs, a recent strategy has been to utilize a similar approach to ionic salts, but instead of pairing the ionized drug with a small inorganic or small organic counterion, a bulky, asymmetric non-polar organic counterion is utilized. These so-called lipophilic salts (LSs) may also be referred to as ionic liquids (ILs) or hydrophobic ion pairs (HIPs).

Lipid-Based Technology Applications

Lipid-based formulations using liquid-filled hard capsule or soft gel formats have been used extensively in the biopharma market to address a range of formulation challenges. Lipid- or liquid-based approaches have been used for better ensuring dose uniformity for low-dose applications, as well as to better ensure safe handling of highly potent API. LBF approaches – primarily soft gels – have also been extensively used in life cycle management strategies, especially in over-the-counter applications. Fixed-dose combinations and colonic delivery are additional areas of application. However, addressing bioavailability challenges remains the primary LBF application where lipid/solvent-based formulation approaches are especially effective in improving the solubility of highly lipophilic compounds. Neoral® (cyclosporine), Xtandi® (enzalutamide) and Lynparza® (olaparib) are only a few examples of marketed drugs utilizing lipid-based formulations to address poor or inconsistent solubility challenges.

These compounds that are well-suited to LBFs for oral absorption enhancement are often described as “grease ball” type drugs (Figure 1). Such drugs typically exhibit solvation-limited solubility and thus LBFs can improve their solubility by making changes to the local solubilization environment in the GI tract. The solvation-limited solubility of grease ball compounds is generally linked to a high partition coefficient (LogP), with a cut-off value of 2 to 3.6 Alternatively, for “brick dust” type drugs, where strong solid-state forces limit solubility, an amorphous formulation approach is advantageous. Generally the cut-off value for solid-state limited solubility of brick dust compounds is a melting temperature (Tm) of 200°C.⁶

In addition to improving drug micellar solubilization, an LBF may also increase drug absorption through bypassing drug dissolution, recruiting endogenous solubilizers such as biliary components to effectively shuttle drug to the site of absorption, and promoting the uptake of certain drugs into the lymphatic system.^7,8

A common problem in lipid solution development is difficulty identifying an LBF which can sufficiently dissolve a drug in order to reach a target concentration. This is defined by the maximal drug solubility in the LBF, while the target concentration is dependent on the target drug dose and the target drug-to-formulation ratio.

• The solubility of the drug in an LBF vehicle is key to the success of developing a viable lipid solution formulation. For example, in instances where solubility in a range of lipidic excipients is low, a lipid solution can only be developed if the target dose is low or if there is scope to utilize larger or multiple dosage units.
• The target drug dose is determined by the pharmacological potency of the molecule and oral bioavailability, with higher doses most often reflecting low potency. Unless there is scope to decrease the dose by increasing drug bioavailability, the dose is fixed and cannot be modified by the formulator. In the context of developing a lipid solution, a high dose will therefore usually translate to a need for a high target drug solubility in lipidic excipients.
• The target drug-to-formulation ratio defines the ideal dosage form size and number of dosage units per dose. The practicality of using a large number of dosage units (i.e., high pill burden) or large dosage form size is tempered by a number of drawbacks including the negative impact on compliance, increased risk of formulation induced adverse effects and basic administration challenges.⁹

Strategies to improve drug solubility, and therefore drug loading, in LBFs may therefore unlock the broader use and evaluation of LBFs for more drugs.

Salts Combined with LBFs to Enhance Oral Absorption

Lipophilic salts provide a promising approach to achieving higher solubility in lipids. Lipophilic salt forms of a drug typically exhibit depressed melting points relative to the free acid or base or traditional salt form and tend to exhibit substantially improved solubility in lipidic excipients without any structural changes to the drug. This allows also transforming ‘brick dust’ compounds into ‘grease balls,’ which are more amenable to LBFs. As a snapshot example, the relative solubility difference in a model LBF of erlotinib hydrochloride (marketed form, Tm = 244°C), erlotinib free base (Tm = 157°C) and erlotinib lipophilic salt (docusate form, Tm = 71°C) is depicted in Figure 2. Despite exhibiting low aqueous solubility and a clogP of 3.1, the hydrochloride salt form of erlotinib has very low solubility in the model LBF and as such ~90 g of formulation was required to dissolve a single dose. This equates to 110 size 00 capsules. In contrast, the same erlotinib dose can be delivered in a single capsule using a lipophilic salt approach.¹⁰

The overall benefits of increasing oral drug exposure include i. reduced dose, ii. reduced food effects, iii. reduced variability and iv. reduced effect of drug-drug absorption related interactions. LBFs can effectively improve the oral absorption of poorly water-soluble drugs. A performance synergy between lipophilic salts and LBFs can also exist, which in turn may lead to improved absorption from the fasted state.

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The first publication to describe this benefit when combining lipophilic salts and LBFs looked at cinnarizine and itraconazole.¹¹ In the case of cinnarizine, the lipophilic salt (decyl sulfate salt) solubility in an LBF containing medium-chain lipidic excipients was 3.5-fold higher than that of the free base and allowed dissolving the drug dose. The exposure obtained in rats from this formulation was over 3.5-fold higher than the exposure obtained using an aqueous suspension of the free base and nearly 2-fold higher than that of a suspension of cinnarizine free base in the same LBF, all dosed at the same free base equivalent dose. This boost in exposure when combining lipophilic salts and LBFs was attributed to the fact that dissolving the drug in the lipid vehicle using the LS approach was able to bypass traditional dissolution, which is likely to have limited exposure when using a suspended crystalline form of cinnarizine in the same LBF.

The benefit of using a dissolved lipophilic salt/LBF formulation on oral absorption was more pronounced for itraconazole.¹¹ In this case a Self-Emulsifying Drug Delivery Systems (SEDDS) containing longchain lipids and suspended itraconazole free base (Tm = 170°C, LogP = 5.66) yielded negligible exposure in rats, yet the same formulation containing the lipophilic salt (docusate, Tg = 47−53°C) in solution yielded an exposure level that was 2–3 fold higher than that of the currently marketed amorphous drug formulation (Sporanox®). This aspect highlights the performance benefit of using lipophilic salts in combination with LBFs.

The potential advantages of this technology have also been investigated for four model kinase inhibitors.¹⁰ There are now over 40 FDA-approved kinase inhibitors for the treatment of cancers and various auto-immune diseases, yet drugs in this class are plagued by instances of low aqueous solubility, low and variable absorption and food-affected pharmacokinetics.^12,13 Using simple “off-the-shelf” LBFs to provide an initial proof-of-concept, it was possible to achieve at least 100 mg/g drug loading in LBF when using docusate lipophilic salt forms of erlotinib and cabozantinib.

More recently the LS approach has been applied to lumefantrine, a model poorly water-soluble drug.¹⁴ In vivo studies found that the LS form, lumefantrine docusate, in a model SEDDS formulation with long chain-lipids showed significantly higher plasma exposure (up to 35-fold higher) compared to a free base aqueous suspension.

Conclusions

Years of experimentation have shown that transforming drugs into lipophilic salts is a viable strategy to increase the number of drugs with access to the absorption-enhancing benefits of LBFs. The underlying mechanisms for the performance benefit of the combination of lipophilic salts and LBF likely reflect the ability to deliver high drug concentrations molecularly dispersed (dissolved) in an LBF, thereby avoiding the potentially absorption-rate-limiting step of dissolution. In addition, the lipophilic salt showed increased solubility in dispersed and digested LBFs when compared to the free base or free acid, indicating that the presence of the lipophilic counterion can play an important role in promoting drug absorption.

The extent to which a lipophilic counterion improves solubility in the GI tract will be dependent on the extent of drug ionization, with maximal solubility gain in lipid-based colloids when both drug and counterion are fully ionized. An additional factor worth mentioning is that the higher lipid solubility of the lipophilic salts across a range of lipidic excipients unlocks the use of a broader range of lipidic excipients. Critically, for enhancing oral absorption, long-chain lipids are often more effective in solubilizing drug in the GI tract and promoting drug absorption than medium-chain lipid formulations or simple cosolvent systems.^15-17 But long-chain lipids have been historically limited by lower drug loading capacity in comparison to, for example, mediumchain lipidic excipients and cosolvents. The use of lipophilic salts may help to overcome this solubility limitation and help to increase bioavailability of ionizable small drugs and patient compliance by reducing pill burden and adverse effects.

Formulators may falter if they take a one-size-fits-all approach to enabling technology selection for improving low solubility and bioavailability. To determine whether lipophilic salts and LBF are the optimal technology approach for a bioavailability-challenged molecule, drug developers may benefit from a holistic tech selection approach that analyzes all dimensions of the drug’s problem statement. As bioavailability-challenged molecules continue to rise in number, having access to a range of enabling technologies, including LBF-based approaches, will be increasingly important for effective and timely drug development.

References

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