In the realm of medicinal cannabinoid development, the choice of excipients plays a pivotal role in formulating effective solutions. This article delves into the extensive formulation possibilities offered by Gattefossé excipients across various administration routes, including oral, topical, transdermal and alternative methods. Understanding the potential of these excipients opens up new horizons for optimising cannabinoid delivery and enhancing therapeutic outcomes

Medicinal Cannabinoids

The integration of the cannabis plant into Western medicine dates back to the 19th century, initially as an additive to patented medicines. However, the progress of cannabis-based therapies faced a significant setback in the 1970s, following the enactment of laws that classified cannabis as a scheduled (narcotic) substance.

Despite these regulatory constraints, researchers have identified over one hundred active molecules (phytocannabinoids) within the plant. Additionally, synthetic forms of cannabinoids like dronabinol, nabilone and cannabidiol have been developed and are now marketed for treating nausea associated with chemotherapy, as well as myoclonic seizures in patients aged two and older.

It wasn’t until 2018 that the US FDA granted approval for Epidiolex®, the first purified phytocannabinoid isolated from the cannabis plant. This breakthrough medication is specifically indicated for severe forms of epilepsy, namely Lennox-Gastaut and Dravet syndromes.

Given the growing understanding of the medicinal benefits and the easing of regulations worldwide, there is a pressing demand for science-backed, precisely dosed and age-appropriate cannabinoid medicines.

The benefits of medicinal cannabinoids include:

• Controlled and measured dosing
• Age appropriate, patient-centric dosage forms
• Alternatives to unhealthy modes of intake such as vaping or smoking.

Properties of Cannabinoids

Among the hundreds of phytocannabinoids and terpenes isolated from cannabis, two very lipophilic molecules stand out: tetrahydrocannabinol (THC); and cannabidiol (CBD). Amounting between 30% and 50% of a single plant’s weight, they are known to affect physiological processes such as mood, memory, appetite and pain sensation. They function by activating the endocannabinoid receptors of the nervous system which are found throughout the body, including in the brain.

THC and CBD have been extensively studied and are found to have unique qualities of their own.

Figure 1. Primary constituents of cannabis extract

THC is responsible for the euphoric and psychoactive effects of cannabis and has applications as medicine for treatment of chronic pain and nausea associated with chemotherapy. Another indication for THC is the treatment of amyotrophic lateral sclerosis (ALS), i.e. potential delay in the progression of the disease and alleviation of the ALS symptoms. CBD on the other hand, is a non-psychoactive, anti-inflammatory medicine. It is preferred over THC by patients in need of treatment for arthritis, mood disorders and nausea.

Studies have shown that THC and CBD have oral bioavailability of approximately 3% to 8% and this varies by formulation and type of vehicles used. This poor bioavailability is in part attributed to the poor gastrointestinal (GI) solubility of these compounds resulting in erratic and variable absorption from the GI tract. Additionally, a significant first pass metabolism may ensue in the liver following GI absorption. These properties render cannabinoids as excellent candidates for Lipid-Based Drug Delivery (LBDD).

The benefits of lipid excipients in oral drug delivery

Lipid formulations are shown to improve the bioavailability of cannabinoids by improving solubility, intestinal permeability and enhancement of the lymphatic route of absorption. Among the key mechanisms associated with oral lipid formulations in enhancing bioavailability is the improved drug wettability and dispersion in the GI fluids, through natural digestion mechanisms that help maintain drug solubilisation in vivo. However, not all lipids are equal in the nature of their impact on permeability and absorption.
Due to their unique properties and versatility, lipid formulations may be designed to tackle several of the below listed bioavailability objectives in a single lipid formulation:

• Solubilisation of the API in the dose
• Drug dispersion and dissolution in the GI tract
• Enhanced permeability across enterocytes and wider absorption window
• Enhanced lymphatic transport of lipophilic drugs.

Excipients for oral delivery

Gattefossé offers a range of excipients for achieving one or more of the objectives listed above. They may be categorised by physical state (liquid vs. solid), melting point, HLB value, as well as biopharmaceutical aspects.

Table 1. Excipients by function, category and suitability for oral dosage forms

Lymphatic vs. hepatic absorption

Since absorption by the lymph means bypassing the liver, formulation with unsaturated LCFA can be a promising strategy for cannabinoids, which are metabolised extensively in the liver. Moreover, lipid excipients may be selected for their surfactive and often self-emulsification properties. Self- emulsification refers to the unique property of certain lipids that disperse spontaneously in aqueous media, forming micellar and lamellar self-assemblies, which are key in maintaining solubility and improving permeability of poorly soluble drugs such as cannabinoids.

SEDDS/SMEDDS

With careful selection of the excipients having the right fatty acid chain length, melting point, and emulsification properties, it is possible to design sophisticated dosage forms. As an example, self (micro) emulsifying drug delivery systems known as SEDDS and SMEDDS are a suitable solution to improving oral drug delivery of poorly soluble and low permeability drugs.

Formulation guidelines

Further practical information regarding formulation considerations for lipid formulations can be found in our Formulation Guidelines: Developing Lipid Based Formulations for Oral Bioavailability Enhancement.

Additionally, it is possible to develop unique combinations of excipients to simultaneously achieve enhanced bioavailability and sustained delivery. Additional information on sustained release development is available in our Sustained Release Formulation Guidelines.

The benefits of lipid excipients in dermal drug delivery

• Dosage Forms

In certain cases, cannabinoids need to be applied locally on the skin for various purposes such as anti-acne, anti-psoriatic, anti-fungal, analgesics and anti-inflammatory applications. These may be in topical dosage forms having various sensorial properties / textures and a range of viscosities.

• Excipients for topical formulations

An overview of Gattefossé emulsifiers, consistency agents and solubilisers suitable for topical preparations is provided in Figure 2. With excellent tolerance / safety profiles and long history of use, these are products of choice for developing stable and luxurious textures.

Table 2. Excipients by function, category and suitability for topical dosage forms

Penetration and permeation enhancers – Transcutol® P

Transcutol® P is globally known to solubilise and enhance the penetration of many drugs, notably THC and delivery across skin layers.

Figure 2. Effect of formulation on the skin distribution of THC from PEG 400, Transcutol® P and propylene glycol:ethanol formulations

Transcutol® P is a safe and effective solubiliser of both hydrophilic and lipophilic compounds. It acts as an enhancer by inducing a transient swelling of the hydrophilic regions of the stratum corneum, rendering it permeable similar to fully hydrated skin. By diffusing into the skin layers, Transcutol® P improves the drug solubility in the skin and its partitioning into the deeper hydrophilic regions of the dermis (Osborne, 2018).

The benefits of lipid excipients in alternative drug delivery routes

A highly effective and yet unexploited approach to difficult drugs is mucosal delivery. The possibilities include nasal, buccal, rectal and vaginal routes of administration. In addition to circumventing exposure to the GI tract where drug degradation may occur by digestive enzymes, bile sales and/or pH related effects, this approach helps eliminate any first pass (hepatic elimination) risks for drugs like cannabinoids.

Mucosal delivery

Mucosal delivery is a unique alternative for administration of drug to patients with special needs. Examples include children suffering from recurring seizures, patients unable to take oral medication, and those in palliative care who may receive medicine as nasal sprays or suppositories.

Click here to download the detailed brochure from Gattefosse on Lipid Excipients for Cannabinoid Drug Products, which outlines the various lipid excipients available together with their applications and benefits.

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