Cannabis-Based Oral Formulations for Medical Purposes : Preparation, Quality and Stability
Francesca Baratta, Marco Simiele, Irene Pignata, Lorenzo Ravetto Enri, Antonio D’Avolio, Riccardo Torta, Anna De Luca, Massimo Collino and Paola Brusa
Pharmaceuticals, 2021, 14, 171, 1-13.
Doi : 10.3390/ph14020171
Current legislation in Italy provides that medical Cannabis may be administered orally or by inhalation. One of the fundamental criteria for the administration of oral formulations is that they deliver a known consistent quantity of the active ingredients to ensure uniform therapies leading to the optimisation of the risks/benefits. In 2018, our group developed an improved Cannabis oil extraction technique. The objective of the present work was to carry out a stability study for the oil extracts obtained by this method. Furthermore, in order to facilitate the consumption of the prescribed medical Cannabis therapy by patients, a standard procedure was defined for the preparation of a single-dose preparation for oral use (hard capsules) containing the oil extract; thereafter, the quality and stability were evaluated. The hard capsules loaded with the oil extract were analysed and found to be uniform in content. The encapsulation process did not alter the quantity of the active molecule present in the oil. The stability tests yielded excellent results. Since the capsule dosage form is easily transported and administered, has pleasant organoleptic properties and is stable at room temperature for extended periods of time, this would facilitate the adherence to therapy by patients in treatment.
Keywords : medical Cannabis; Cannabis oil; THC; CBD; standard procedures; stability
Before the last century, when it became illegal in most Countries, Cannabis was widely used in medicine. The reason for the restriction in its availability as a therapeutic agent was its growing notoriety as a psychotropic agent and its consequent abuse [1,2]. In recent years, however, there has been a resurgence in support for the legalisation of cannabinoids for medical use as a result of media attention as well as expectations of their efficacy, albeit, this is not always supported by scientific evidence [3–5].
The phytocomplex of the Cannabis plant contains over 500 different molecules, of which approximately a hundred belong to the cannabinoid chemical class; among these, small differences in molecular structure may induce widely different effects . The molecules of greatest pharmacological interest from the point of view of their effects are the decarboxylated forms of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) as these are easily absorbed in the intestine . Hence, the determination of the quantities of these compounds present in medications to be administered to patients is a fundamental prerequisite.
In the last few years, reforms in Italy have opened the door to the use of medical Cannabis in tightly regulated cases. Consequently, Cannabis is now available for this purpose. In Italy medical Cannabis is produced by the Stabilimento Chimico Farmaceutico Militare (Pharmaceutical Chemical Military Facility) in Florence.
Since 2016, a variety of Cannabis, FM2, has been available. This is supplied as dried, ground Cannabis inflorescences containing delta-9-tetrahydrocannabinol in quantities ranging from 5% to 8% and cannabidiol in percentages from 7.5% to 12%. Since 2018, another variety of Cannabis, FM1, has also been made available; this contains delta-9-tetrahydrocannabinol in quantities from 13% to 20% while the cannabidiol content is lower than 1%. Note that the percentages reported refer to the “total” content: that is, the sum of the molecule in both acid form (delta-9-tetrahydrocannabinolic acid—THCA-and cannabidiolic acid—CBDA) and decarboxylated form (delta-9-tetrahydrocannabinol—THC and
Currently in Italy, the law states that medical Cannabis may be administered orally or by inhalation. The administration by inhaler is to be considered the second-choice option and must only be selected when oral administration does not produce the desired pharmacological effects or when the physician considers it opportune [9,11].
Concerning oral administration, in accordance with Minister of Health directives, decoctions represent the first-choice pharmaceutical form. The decoction must be prepared in compliance with the official procedure reported in “Recommendations for doctors prescribing FM2 Cannabis inflorescence derivatives” . In a previous study, our research group demonstrated that the prescription of decoction-based formulations, considering the low yields of THC and CBD and, consequently, the high volume that a patient would have to consume as well as the high costs of processing the raw material to obtain the required quantity of active molecule, should not be recommended .
As well as the decoction for oral administration, the legislation in effect in Italy specifies that medical Cannabis may also be administered as an oil extract (hereafter, oil) on condition that this has been previously titrated for the active molecule using the proper instrumentation as set out by the current regulations (gas or liquid chromatography coupled with mass spectroscopy) [9,11]. The administration of formulations containing known quantities of active molecule is essential to ensure the uniformity of therapies leading to the consequent optimisation of the risks/benefits. On this point, it is important to note that although a number of preparation methods have been reported in scientific literature [13–16], the situation for oils, in particular, was that an exhaustive comparative study was lacking which investigated the technical aspects of preparation procedures for Cannabis-based formulations for medical purposes.
In light of this, in 2018, our research group developed a novel preparation method (denominated -4) that allowed us to obtain a significantly higher amount of THC and CBD than those for water extraction (decoction) or an oil extraction using the previously known methods most widely used in Italy .
Having optimised the extraction procedure, the objective of the present study was to conduct stability studies on the oils obtained through the -4 method. In addition, considering that oils have received considerable attention due to their easier dose management during the treatment period, but their organoleptic characteristics are particularly unpleasant, in order to facilitate the consumption of the prescribed medical Cannabis therapy by a patient in treatment, a standard procedure was defined for the preparation of a single-dose preparation for oral use (hard capsules) using the oil-based formulation. Both the oil and the capsules were then evaluated for quality and stability. Furthermore, the preparation of a pharmaceutical form that masks the organoleptic characteristics of the oil has the advantage of allowing the establishment of a control/placebo group in a clinical trial.