Cannabinoid molecules and their love of lipid excipients

The generic term “cannabinoids” refers to different active pharmaceutical ingredients, the most popular being cannabidiol (CBD) which is non-psychoactive, and delta-9 tetrahydroxy cannabinol (THC) with psychoactive properties. With rapidly evolving regulations in many countries, a boom in cannabinoid products is observed. However, due to their physico-chemical properties, these molecules are very difficult to formulate. This article showcases how lipid excipients can solve cannabinoid formulation challenges with a particular focus on oral and topical dosage forms.

Cannabinoids cumulate many drawbacks such as low aqueous solubility, oxidation and temperature sensitivity, and high first-pass metabolism.1 Although cannabinoids have extremely low aqueous solubility and high lipophilicity (LogP around 6 to 8), they also have exceptional solubility in lipid excipients as shown in Table 1. Therefore, with lipid excipients, solubility is not a limitation.

These molecules are prone to oxidation; consequently, minimising the incorporation of air while mixing and adding antioxidants are compulsory to prevent molecule degradation. Because they are also extremely sensitive to temperature, cannabinoids must be handled and stored at the lowest temperature possible to stop them from being broken down.

Furthermore, due to an extensive first-pass metabolism, their bioavailability is low. However, this can be avoided by targeting the lymphatic pathway with appropriate excipients containing unsaturated long-chain fatty acids.

Although formulating with cannabinoids can be highly challenging, it is possible to overcome the various hurdles using lipid excipients.

Oral formulations

Tinctures, sublingual sprays and capsules are examples of dosage forms suitable for cannabinoids. However, one major drawback in oral formulations is the low bioavailability of cannabinoids. Using Maisine CC as an oily vehicle, either alone or in combination with other excipients, to form a self-emulsifying drug delivery system (SEDDS), enables a substantial increase in bioavailability.

In a human study, de Prá et al. compared formulations consisting of medium-chain fatty acids (MCT), Maisine CC, rich in long-chain fatty acids, and a SEDDS consisting of Maisine CC, polyoxyl castor oil and PEG 400.2 They obtained a significant increase in bioavailability thanks to the use of Maisine CC, both for the oily solution and the SEDDS formulation (see Table 2). Moreover, this excipient is derived from corn oil and has a pleasant taste. It naturally contains antioxidants, contributing to greater stability of the formulation.

Labrafil M 1944 CS is a self-emulsifying excipient, widely used in drops, for example with highly lipophilic vitamin D. Also derived from corn oil, it benefits from the same advantages as Maisine CC when added to an instantaneous dispersion, if the drops need to be diluted in a glass of water before intake.

Topical and transdermal formulations

Creams or lotions are common dosage forms used for local topical action. To prevent the degradation of cannabinoids in these formulations, careful attention must be paid to the process conditions to ensure molecules are incorporated at temperatures below 60°C.

Air incorporation must also be avoided during mixing.

Antioxidants should be added to topical and transdermal formulations to ensure their long-term stability. Tefose 63 is a versatile emulsifier suitable for topical dosage forms. An example of a formulation with CBD is included in Table 3.

Gels are also common preparations used for skin delivery. The powerful solubiliser Transcutol P is compatible with all types of gelling agents and can be used at a very high concentration in the gel without altering its structure.

Bi-gel is an innovative dosage form suitable for lipophilic and hydrophilic drugs. It is known to provide better drug absorption through the skin, providing a pleasant cooling and moisturising effect and with improved spreadability. A key ingredient used in the bi-gel formulation is the brand-new Emulfree Duo. It works as a stabilising agent for the oily phase of the bi-gel and as a PEG-free excipient, processable at room temperature.

Transdermal patches are also convenient for the delivery of cannabinoids when long-lasting action is required to alleviate pain. Transcutol P can be used in patches to solubilise and enhance the transdermal delivery of drugs. If you need more information on these solutions to formulate cannabinoids, connect with Gattefossé online by checking out the supplier’s dedicated webpage: https://bit.ly/3u8rSYE. These ingredients are available locally from Carst & Walker, the local agent for Gattefossé. •