PROCESS FOR STABILIZING A SOLUTION OF A CANNABINOID OR CANNABIS EXTRACT DISSOLVED IN OIL

Abstract

A process for stabilising a macerated oil comprising a liquid carrier and a compound soluble in said carrier and containing at least one cannabinoid, characterised in that it brings about a removal of oxygen from the liquid carrier before, during or after the dissolution of the soluble compound.

Description

1 / 23 PROCESS FOR STABILIZING A SOLUTION OF A CANNABINOID OR CANNABIS EXTRACT DISSOLVED IN OIL DESCRIPTION

[0001] The present invention relates to a process for stabilizing a macerated oil comprising a liquid carrier and a compound soluble in said carrier and containing at least one cannabinoid. PREVIOUS TECHNIQUE

[0002] Cannabidiol (CBD) is a cannabinoid, a terpenophenolic compound with multiple therapeutic potentialities and devoid of psychotropic activity. Thanks to its considerable therapeutic potential and good safety profile, associated with the absence of mind-altering activity, cannabidiol has been the subject of numerous studies aimed at outlining its mechanism of action and its interaction with the human endocannabinoid system.

[0003] The human endocannabinoid system was discovered after the identification of endocannabinoid receptors. Currently, the two main receptors belonging to the endocannabinoid system are represented by the CB1 and CB2 families and are capable of interacting with various endogenous ligands, generically called endocannabinoids. The endocannabinoid system is an ancestral and ubiquitous homeostatic regulatory system, capable of finely modulating vital functions such as hunger, sleep, and responses to various types of stress: CB1 and CB2 receptors are thus disseminated throughout all regions of the body, with a prevalence of CB1 receptors in the central nervous system, particularly in the areas responsible for motor control. Petition 870250066359, dated 07 / 30 / 2025, page 7 / 45 2 / 23 Emotional and behavioral responses and energy management. CB2 receptors, on the other hand, are more concentrated in the immune system. As the regulation of homeostasis is vital for an individual's survival, the human body exerts fine control over the endocannabinoid system through the action of enzymes from the FAAH family (fatty acid amide hydrolase), which have the role of regulating endocannabinoid levels in the human body.

[0004] The therapeutic effects of cannabidiol are primarily attributable to its interaction with the human endocannabinoid system: there is evidence that cannabidiol is able to allosterically modulate CB1 and CB2 receptors and bind to fatty acid amide hydrolases (FAAHs), thus modulating endocannabinoid levels. In addition, cannabidiol interacts with voltage-dependent TRPV family channels, responsible for pain sensation, and with many other ligands present in the serotonergic, GABAergic, and other systems.

[0005] Cannabidiol (CBD) is currently authorized as a medication for the adjunctive treatment of some forms of drug-resistant epilepsy and is used in extemporaneous off-label preparations for the treatment of some psychotic disorders, anxiety, depression, insomnia, diabetes, cardiovascular disorders, and chronic pain in several countries around the world. Of great interest are the various studies that attribute to CBD an antiblastic activity in relation to many forms of cancer.

[0006] In order to continue research on this promising molecule, it is necessary that the dosage forms through which cannabinoid administration occurs be Petition 870250066359, dated 07 / 30 / 2025, page 8 / 45 3 / 23 stable and do not undergo degradation or alteration phenomena over time.

[0007] Cannabidiol (CBD) is a cannabinoid that can be extracted from Cannabis sativa L., or obtained by synthesis, semi-synthesis, or fermentation, and can be dissolved in vegetable oils to obtain solutions with a known concentration of CBD. For the preparation of such solutions, it is possible to start with pure CBD or extracts of Cannabis sativa containing this cannabinoid. The oils that are generally used for the preparation of such macerated oils are: olive oil, corn oil, sesame oil, and, in general, all commercially available vegetable oils. A preferred oil for these types of preparations is oil obtained from medium-chain triglycerides (MCTs), which is very stable with respect to oxidation and therefore unlikely to become rancid, and for this reason, it is an ideal vehicle for the preparation of cannabinoid solutions, including pharmaceutical-grade ones.

[0008] Pure CBD appears as a white or off-white crystal which, if stored under appropriate conditions, is well known to be stable for several years in all climatic zones covered by the ICH Q1A (R2) guidelines, Stability Testing of New Substances and Drug Products. In contrast, under the same storage conditions, its oil solutions show fairly rapid degradation with the formation of oxidizing impurities in the presence of oxygen, catalyzed by exposure to light and heat. One of the best-known degradation products that form during the oxidation processes of CBD oil solutions is cannabidiol hydroxyquinone (CBD-HQ), also known as HU331. This substance has a very intense orange color (as Petition 870250066359, dated 07 / 30 / 2025, p. 9 / 45 4 / 23 Oxidation impurities in CBD are usually colored), easily recognizable in CBD solutions, which start out glassy and clear, and to which it imparts a yellow to red color, in proportion to the concentration of degradation products present in the macerated oil.

[0009] One attempt to prevent this degradation involves adding substances that inhibit the oxidation of cannabidiol: generally, the most common oil-soluble antioxidants, such as vitamin E, are used. The addition of preservatives creates a potential difficulty in further formulation steps, as well as compromising the chemical quality of a natural product that is highly sought after in the current health market. Furthermore, the introduction of antioxidants into CBD-infused oils does not appear to have a direct effect on the oxidation kinetics of the molecule, but rather on the stability of the oil carrier.

[0010] Thus, there is a perceived need to be able to obtain CBD oil solutions that are more stable without the addition of antioxidants.

[0011] The task of the present invention is, therefore, to provide a process for stabilizing a macerated oil that allows the disadvantages in the prior art to be overcome, without the addition of other substances that are not necessary for the cannabinoid activity.

[0012] Within the scope of this technical task, an objective of the present invention is to provide a process for rendering oil solutions containing cannabinoids that are more stable over time.

[0013] Another objective of the present invention is to provide a process for stabilizing a macerated oil that Petition 870250066359, dated 07 / 30 / 2025, p. 10 / 45 5 / 23 improve the quality and shelf life of pharmaceutical preparations based on oil solutions containing cannabinoids.

[0014] Yet another objective of the present invention is to provide a process for stabilizing a macerated oil that is simple, yet safe at the same time.

[0015] These and other objectives of the present invention are achieved by carrying out a process for stabilizing a macerated oil comprising a liquid carrier and a compound soluble in said carrier and containing at least one cannabinoid, characterized by causing a removal of oxygen from the liquid carrier before or during or after the dissolution of the soluble compound.

[0016] Preferably, the process for stabilizing a macerated oil comprises, before the oxygen removal step, a step of introducing said liquid vehicle into a containment device and, subsequently, the oxygen removal step by creating a vacuum within the containment device until the oxygen present in both the containment device and the liquid vehicle is removed.

[0017] Preferably, the containment device comprises a hermetically sealed, temperature-controlled reactor or a rotary evaporator.

[0018] Preferably, the vacuum is less than 400 mbar.

[0019] Preferably, the controlled temperature is between 12 °C and 200 °C.

[0020] The controlled temperature is preferably between 30 °C and 40 °C.

[0021] Advantageously, the process measures the oxygen present in the headspace of the containment device. Petition 870250066359, dated 07 / 30 / 2025, page 11 / 45 6 / 23 above the free surface of the liquid carrier, said measurement being indirectly correlated also with the dissolved oxygen in the liquid.

[0022] In particular, the process comprises mechanically agitating said liquid vehicle contained in said containment device to dissolve said cannabinoid in the liquid vehicle and facilitate the release of oxygen from the liquid vehicle.

[0023] More specifically, the process comprises carrying out, after the vacuum creation step, a blowing and extraction step of an inert gas to / from the containment device to remove residual oxygen contained in the liquid carrier.

[0024] Advantageously, the process cyclically repeats the steps of creating a vacuum and blowing and extracting an inert gas to / from the containment device until the measured oxygen is equal to zero or does not exceed a defined minimum level.

[0025] Preferably, the stabilized macerated oil is gravity-filled into airtight containers pre-filled with inert gas until it partially or completely replaces the latter.

[0026] Preferably, the inert gas comprises nitrogen and / or a noble gas.

[0027] Preferably, the cannabinoid is pure cannabidiol (CBD) obtained by extraction, fermentation, synthesis or semi-synthesis or an extract derived from Cannabis sativa L.

[0028] Preferably, the liquid carrier comprises MCT oil. Petition 870250066359, dated 07 / 30 / 2025, page 12 / 45 7 / 23

[0029] Additional features and advantages of the invention will become more apparent from the description of a preferred, but not exclusive, embodiment of the process for stabilizing a macerated oil illustrated by way of non-limiting example in the accompanying drawings. DESCRIPTION OF THE FIGURES

[0030] Figure 1: presents a visual analysis of CBD oil solutions as described in Table 1 after stress tests at 100 °C for three weeks; on the left side of Figure 1, the color changes in the non-inert macerated oils can be observed, at various CBD concentrations, and on the right the inert batches, which do not show the same color change as the non-inert analogues.

[0031] Figure 2: presents a quantification of the variation in CBD concentration (batch C01 in Table 1) at time 0, after 1 day, 3 days, 5 days, 10 days and 21 days, during the stress test study with storage at 100 °C for three weeks.

[0032] Figure 3: presents a quantification of the variation in CBD concentration (batch C02 in Table 1) at time 0, after 1 day, 3 days, 5 days, 10 days and 21 days, during the stress test study with storage at 100 °C for three weeks.

[0033] Figure 4: presents a quantification of the variation in CBD concentration (batch C05 in Table 1) at time 0, after 1 day, 3 days, 5 days, 10 days and 21 days, during the stress test study with storage at 100 °C for three weeks.

[0034] Figure 5: presents a quantification of the variation in CBD concentration (batch C10 in Table 1) over time Petition 870250066359, dated 07 / 30 / 2025, page 13 / 45 8 / 23 0, after 1 day, 3 days, 5 days, 10 days and 21 days, during the stress test study with storage at 100 °C for three weeks.

[0035] Figure 6: presents a quantification of the variation in CBD concentration (batch C20 in Table 1) at time 0, after 1 day, 3 days, 5 days, 10 days and 21 days, during the stress test study with storage at 100 °C for three weeks.

[0036] Figure 7: presents a quantification of the variation in CBD concentration (batch C40 in Table 1) at time 0, after 1 day, 3 days, 5 days, 10 days and 21 days, during the stress test study with storage at 100 °C for three weeks. DETAILED DESCRIPTION OF THE INVENTION

[0037] The present invention relates to a process for stabilizing a macerated oil comprising a liquid carrier and a compound soluble in said carrier and containing at least one cannabinoid, characterized by causing a removal of oxygen from the liquid carrier before, during or after the dissolution of the soluble compound.

[0038] Macerated oil is understood to be a solution of a cannabinoid dissolved in oil or a solution of a cannabis extract dissolved in oil.

[0039] In particular, according to a preferred embodiment of the invention, the liquid vehicle comprises MCT oil, since, as explained above, it is an oil that is very stable with respect to oxidation and therefore an ideal vehicle for the preparation of cannabinoid solutions.

[0040] According to a preferred embodiment of the invention, the cannabinoid is, in particular, cannabidiol (CBD). Petition 870250066359, dated 07 / 30 / 2025, page 14 / 45 9 / 23

[0041] The CBD according to the present invention may be purified or an extract of Cannabis sativa L. The process according to the present invention comprises a step of introducing the liquid vehicle into a containment device and a step of creating a vacuum inside it to eliminate the oxygen present in the upper space of the containment device above the free surface of the liquid vehicle and within the latter.

[0042] According to a first embodiment of the present invention, the containment device comprises a hermetically sealed, temperature-controlled reactor.

[0043] According to another embodiment of the present invention, the containment device comprises, instead, a rotary evaporator.

[0044] The vacuum to be applied must be lower than atmospheric pressure. In particular, according to a preferred embodiment of the invention, the vacuum is less than 400 mbar.

[0045] The temperature must be between the freezing point of the oil and its smoke point. In particular, the temperature is between 12 °C and 200 °C, preferably between 30 °C and 40 °C.

[0046] The vacuum condition specified above makes it possible to eliminate air from the reactor or evaporator, thus facilitating the release of air dissolved in the liquid carrier (MCT oil) by diffusion.

[0047] In particular, the containment device has a probe capable of measuring the presence of oxygen in the reactor headspace above the free surface of the liquid carrier. Petition 870250066359, dated 07 / 30 / 2025, page 15 / 45 10 / 23

[0048] Furthermore, thanks to the presence of a mixer within the containment device, the process allows the liquid vehicle contained in the reactor to be mechanically agitated to facilitate the dissolution of the cannabinoid in the liquid vehicle (if inertization occurs during the cannabinoid dissolution process) and to facilitate the release of oxygen from the MCT oil.

[0049] Advantageously, the process according to the present invention comprises carrying out, after the vacuum creation step, a blowing and extraction step of an inert gas to / from the reactor or evaporator to remove residual oxygen contained in the liquid carrier.

[0050] In fact, after a vacuum has been created in the reactor, the pressure is brought to values ​​close to atmospheric pressure by blowing into the inert gas, which is devoid of oxygen.

[0051] Advantageously, the process cyclically repeats the steps of creating a vacuum and blowing / extracting the inert gas to / from the reactor or evaporator until the measured oxygen is equal to zero or not above a defined minimum level.

[0052] According to a first embodiment of the invention, the stabilization process can be carried out directly in the MCT oil before the pure CBD or Cannabis sativa extract is dissolved in it.

[0053] According to a second embodiment of the invention, the stabilization process can be carried out during the dissolution of pure CBD or Cannabis sativa extract in MCT oil. Petition 870250066359, dated 07 / 30 / 2025, p. 16 / 45 11 / 23

[0054] According to a third embodiment of the invention, the stabilization process can be carried out after dissolving the pure CBD or Cannabis sativa extract in MCT oil.

[0055] Once the macerated oil is stabilized, it is gravity-filled into airtight containers that have also been pre-filled with the inert gas until it partially or completely replaces the inert gas.

[0056] According to a preferred embodiment of the present invention, the inert gas comprises nitrogen, but according to other embodiments, it may also comprise a noble gas. Materials and methods Stress Test

[0057] In order to demonstrate the effectiveness of the CBD stabilization process when placed in an oily solution, the results of several stress tests performed on CBD solutions at different concentrations, measuring the effectiveness of the stabilization process under extreme conditions, are reported below. CBD oil solutions prepared with the stabilization process of the present invention are compared with the same solutions prepared without the stabilization process and subjected to the same stress tests. MCT oil was chosen over other types of vegetable oils because, as previously described, it is resistant to oxidation.

[0058] The stress test was performed by placing the CBD solutions, indicated in Table 1, in hermetically sealed glass test tubes at 100 °C for Petition 870250066359, dated 07 / 30 / 2025, page 17 / 45 12 / 23 three weeks; CBD concentration was measured at time 0, after 1 day, 3 days, 5 days, 10 days and 21 days.

[0059] Analysis of the decrease in CBD concentration (Figures 1 to 7) demonstrates that solutions in contact with atmospheric oxygen undergo continuous degradation, while in those with an inert atmosphere (i.e., treated with the method of the present invention) an initial degradation is measured, which then stops: this initial deterioration is presumably due to the consumption of traces of oxygen present in the solutions and stops after its exhaustion.

[0060] Table 1 below shows the batches used for the stress test: Code Lot Concentration of CBD (%) Manufacturer CBD* CBD 76718009 99.8 LINNEA Medium-chain triglyceride MCTs* MCT 1223 na Gattefossé C40 C40 6342 40.13 LINNEA C20 C20 6342 20.64 LINNEA C10 C10 6342 10.44 LINNEA C05 C05 6342 5.22 LINNEA C02 C02 6342 2.58 LINNEA C01 C01 6342 1.06 LINNEA *MCT and CBD: refer to the batches used to prepare the CBD solutions. Table (1)

[0061] Table 1: Description of the batches used for the stress test. The stress test was performed in duplicate (on inertized and non-inertized macerated oils) at 100 °C for three weeks. Petition 870250066359, dated 07 / 30 / 2025, page 18 / 45 13 / 23

[0062] Studies conducted using the high-temperature stress test revealed that the same macerated oil undergoes a different degradation process depending on the presence or absence of oxygen within it. Stability under normal conditions of use

[0063] In order to demonstrate that the stabilization process of the macerated oil does not occur only at high temperatures, stability tests were performed on a 10% CBD solution in MCT oil; the first solution was prepared without using the stabilization process described in the present invention (Table 2), while the second solution was prepared using the stabilization process according to the present invention (Table 3). Both solutions were placed in climate chambers at 25 °C and 60% humidity for 36 months. Tables 2 and 3 below present the results of the analyses performed during the stability tests.

[0064] Table 2 below: stability study of CBD solution in MCT oil with a concentration of 10%, prepared without the inertization step described in this patent, placed in climate chambers at 25 °C and 60% humidity for 36 months and analyzed at regular intervals. Test Analysis Period (months) 0 3 6 9 12 18 24 36 Appearance In compliance In compliance In compliance In compliance In compliance In compliance In compliance Color (abs at 410 nm) 0.160 0.236 0.458 0.671 0.841 1.29 1.582 2.293 Concentration of 102 mg / ml 102 mg / ml 100 mg / ml 101 mg / ml 100 mg / ml 106 mg / ml 105 mg / ml 104 mg / ml Petition 870250066359, dated 07 / 30 / 2025, page 19 / 45 14 / 23 HPLC: CBD A9-THC <0.05% <0.05% <0.05% <0.05% <0.05% <0.05% <0.05% <0.05% CBDV 0.38% 0.37% 0.35% 0.38% 0.36% 0.38% 0.37% 0.39% CBD-C4 0.15% 0.14% 0.14% 0.15% 0.15% 0.15% 0.16% 0.15% CBD-HQ < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% 0.06% 0.08% 0.18% Other related substances (each) < 0.05% < 0.05% < 0.05% 0.07% 0.13% 0.12% 0.05% 0.14% 0.07% 0.07% Sum of related substances 0.6% 0.5% 0.5% 0.6% 0.7% 0.8% 0.9% 0.8% Table (2)

[0065] Table 3 below: Stability study of a CBD solution in MCT oil with a concentration of 10%, prepared with the inertization step described in this patent, placed in climatic chambers at 25 °C and 60% humidity for 36 months and analyzed at regular intervals. Test Analysis Period (months) 0 3 6 9 12 18 24 36 Appearance In compliance In compliance In compliance In compliance In compliance In compliance In compliance Color (abs at 410 nm) 0.3788 0.2198 0.4825 0.4778 0.4188 0.4549 0.4484 0.5048 Concentrate 100.4 99.4 97.9 99.1 97.7 97.6 99.1% 99.6% Petition 870250066359, dated 07 / 30 / 2025, page 20 / 45 15 / 23 HPLC analysis: CBD A9-THC < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% CBDV 0.30% 0.30% 0.32% 0.30% 0.29% 0.30% 0.30% 0.30% CBD-C4 0.16% 0.16% 0.17% 0.16% 0.16% 0.16% 0.16% 0.20% CBD-HQ < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% Other related substances (each) < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% < 0.05% Sum of related substances 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% 0.5% Table (3)

[0066] Table 2 shows that from the test performed at nine months, a new impurity was formed. Subsequent tests showed additional impurities that revealed the instability of the solution. Table 3, on the other hand, demonstrates that the use of the inertization process makes the solution stable without the formation of new impurities until the last moment of the test.

[0067] The high effectiveness of the stabilization process of the present invention in eliminating oxygen from CBD solutions in MCT oil has thus been demonstrated. Oxygen is, in fact, the main cause of oxidation of CBD solutions in oil.

[0068] The elimination of oxygen thanks to the invention process actually makes it possible to limit the formation Petition 870250066359, dated 07 / 30 / 2025, page 21 / 45 16 / 23 of degradation products that cause oxidation of solutions, thus improving quality and stability over time and preventing the formation of contaminants that are potentially hazardous to health.

[0069] A comparative study is reported below which attests to the surprising effect of applying a vacuum of less than 400 mbar to remove the oxygen responsible for the degradation of cannabinoids: the elimination of oxygen in these ways, as will be demonstrated, allows the shelf life of macerated oils to be extended considerably. Comparative study

[0070] Evaluation of the inertization process at different pressure values: below 400 mbar, 400 mbar and above 400 mbar, and respective thermal stress tests on 20% CBD solutions in MCT oil.

[0071] The inertization process related to the preparation of oils macerated with cannabis extracts is based on the elimination of oxygen from the macerated oil; this operation is achieved by performing vacuum cycles that allow oxygen to be removed from the oil, followed by pressurizing the receptacle containing the macerated oil with an inert gas, usually nitrogen. Pressurization with the inert gas allows the macerated oil to become saturated, making it difficult for any oxygen that might come into contact with it to dissolve.

[0072] The oxygen removal process has a stabilizing effect on the solution and, in particular, on the cannabinoids present within it, preventing oxidation reactions. Petition 870250066359, dated 07 / 30 / 2025, page 22 / 45 17 / 23

[0073] This report highlights the results of a trial aimed at demonstrating the technical effect obtained using a pressure lower than, equal to, or higher than 400 mbar during the vacuum stage of the aforementioned cycles. In particular, at pressures higher than 400 mbar, the stabilization of the macerated oil has a smaller effect, since the amount of oxygen removed is insufficient. In order to demonstrate the difference in stability, thermal stress tests are performed on 20% CBD solutions in MCT oil prepared with vacuum and pressurization cycles carried out at values ​​lower than, equal to, or higher than 400 mbar.

[0074] In particular, the following four tests are performed. Test #1: refers to the inerting process carried out by depressurizing the solution to the maximum possible value; Test #2: refers to the inerting process carried out by depressurizing the solution to a value of 400 mbar; Test #3: refers to the inerting process carried out by depressurizing the solution to a value of 800 mbar; Test #4: refers to the preparation of the solution without the vacuum and inert gas pressurization cycles.

[0075] Table 4 shows the conditions used for the preparation and inertization of the macerated oil; the other operating conditions not shown in the table were kept identical for all four tests. Test No. 1 Number of Vacuum Cycles (minutes) Pressure Reached Dissolution Temperature Petition 870250066359, dated 07 / 30 / 2025, p. 23 / 45 18 / 23 with nitrogen (mbar) CBD (°C) Vacuum 1 10 24 38 Pressurization 5 800 Vacuum 2 10 40 Pressurization 5 800 Vacuum 3 10 14 Pressurization 5 800 Vacuum 4 10 20 Pressurization 5 800 Vacuum 5 10 20 Pressurization 5 Atmospheric pressure Test No. 2 Vacuum 1 10 400 38 Pressurization 5 800 Vacuum 2 10 400 Pressurization 5 800 Vacuum 3 10 400 Pressurization 5 800 Vacuum 4 10 400 Pressurization 5 800 Vacuum 5 10 400 Pressurization 5 Atmospheric pressure Test No. 3 Vacuum 1 10 800 38 Pressurization 5,900 Vacuum 2,108,000 Pressurization 5,900 Vacuum 3,108,000 Petition 870250066359, dated 07 / 30 / 2025, page 24 / 45 19 / 23 Pressurization 5,900 Vacuum 4,10,800 Pressurization 5,900 Vacuum 5,10,800 Pressurization 5 Atmospheric pressure Test No. 4 None None Atmospheric pressure 38 Table (4)

[0076] The solutions relating to the four tests are maintained at 120 °C for a total of four days, with samples being taken at regular intervals of 1, 4, 8, 24 and 96 hours. All samples are analyzed by HPLC analysis to assess the impurity profile at each time point and the CBD concentration for the 24-hour and 96-hour time points, as well as for the baseline before heat stress.

[0077] The test results are shown in Tables 5a and 5b. Impurity to test 1 test 2 T0 1 h 4 h 8h 24 h 96 h T0 1 h 4h 8 h 24 h 96 h 1 2 3 4 5 0.02 6 0.02 0.09 0.01 0.02 0.15 7 0.03 0.08 8 0.02 0.03 0.02 0.02 0.02 0.02 0.02 0.02 0.03 0.03 0.02 0.01 9 10 0.01 0.03 11 0.02 Petition 870250066359, dated 07 / 30 / 2025, page 25 / 45 20 / 23 12 13 0.01 14 0.05 0.05 0.05 0.05 0.05 0.07 0.05 0.05 0.05 0.05 0.05 0.07 15 16 0.02 0.04 17 0.01 0.02 0.04 80.04 19 0.02 0.07 0.01 0.17 CBD 20.5 1 20.5 3 20.2 4 20.4 9 20.4 8 19.7 21 22 0.01 0.04 0.01 0.1 23 0.03 0.03 Table (5a) Petition 870250066359, of 30 / 07 / 2025, p. 26 / 45 21 / 23 Impurity tests 3 tests 4 T0 1 h 4h 8 h 24 h 96 h T0 1 h 4 h 8 h 24 h 96 h 0.04 0.08 0.14 0.61 7 0.08 0.02 0.05 0.27 8 0.02 0.02 0.03 0.03 0.02 0.02 0.03 0.02 0.02 0.02 9 0.04 0.03 0.03 0.02 0.09 11 0.02 0.01 0.06 12 0.01 13 0.01 0.05 14 0.05 0.05 0.05 0.05 0.05 0.07 0.05 0.05 0.05 0.050 50.60 0.02 16 0.04 0.01 0.03 0.14 17 0.02 0.01 0.02 18 0.04 0.02 0.07 19 0.01 0.2 0.02 0.06 0.17 0.99 CBD 20.5 20.66 20.51 19.55 15.95 21 0.02 22 0.01 0.1 0.01 0.03 0.09 0.4 23 0.01 24 0.02 Table (5b)

[0078] Currently, solutions for the four tests, columns T0 in Tables 5a and 5b of the preparation of the four HPLC analyses (see 5b) show that, in addition to CBD, Petition 870250066359, dated 07 / 30 / 2025, p. 27 / 45 22 / 23 only impurities 8 and 14 are present. These impurities are present at all time points and their concentration does not change, indicating that they are neither degraded nor increase in concentration during heat stress.

[0079] However, the formation of new impurities is noted, the concentration of which increases with increasing time.

[0080] With regard to CBD concentration, degradation is observed over time, which becomes more pronounced depending on the type of inertization test.

[0081] Before the onset of thermal stress in the four solutions (T0), the CBD concentration is almost identical for the four tests; after 24 and 96 hours, degradation is increasingly evident, but is directly correlated with the inertization procedure performed in the four tests.

[0082] In particular, Test 1 shows the least degradation, probably due to the single thermal effect (120 °C), while the result of test 4 is the worst.

[0083] The results of inertization performed with vacuum cycles greater than or equal to 400 mbar (test 3 and test 2, respectively) are also much worse compared to test 1 (after 96 hours, the CBD concentration decreased by 1.3% in test 1, 3.9% in test 2, 4.2% in test 3 and 22.2% in test 4).

[0084] CBD degradation is not the only observable effect during thermal degradation, as many impurities are also formed, in a non-negligible concentration.

[0085] Degradation increases over time, but is directly correlated with the type of inertization test; test 1 generates more stable solutions in Petition 870250066359, dated 07 / 30 / 2025, page 28 / 45 23 / 23 comparison with tests performed without inerting or with partial inerting (vacuum greater than or equal to 400 mbar). Conclusions of the comparative study

[0086] The degradation of cannabinoids in oil solutions, particularly CBD in MCT oil, depends on the oxygen dissolved in the oil. Eliminating this oxygen makes it possible to render cannabinoid solutions much more stable against degradation and increase their shelf life.

[0087] The four tests performed demonstrate that the degradation of the solutions depends on the amount of oxygen remaining within the solution and, in particular, that vacuum values ​​below 400 mbar can allow for the almost complete elimination of oxygen.

[0088] The ultimate goal to be achieved is, therefore, the complete elimination of dissolved oxygen.

[0089] It was decided to use 20% CBD solutions to have a simple matrix to study with little interference due to other cannabinoids or other components of more complex matrices.

[0090] The process for stabilizing a conceived macerated oil is susceptible to numerous modifications and variants, all encompassed within the scope of the inventive concept, as disclosed and claimed. Petition 870250066359, dated 07 / 30 / 2025, page 29 / 45

Claims

1 / 3 CLAIMS 1. A process for stabilizing a liquid vehicle in combination with a compound soluble in said vehicle and containing at least one cannabinoid, characterized by causing oxygen removal from the liquid vehicle before, during or after the dissolution of the soluble compound and by, before the oxygen removal step, comprising a step of introducing said liquid vehicle into a containment device and, subsequently, said oxygen removal step being carried out by creating a vacuum of less than 400 mbar within the containment device until the oxygen present in both the containment device and within the liquid vehicle is removed.

2. Process for stabilizing a liquid vehicle in combination with a soluble compound, according to claim 1, characterized in that said containment device comprises a hermetically sealed temperature-controlled reactor or a rotary evaporator.

3. Process for stabilizing a liquid vehicle in combination with a soluble compound, according to claim 2, characterized in that said controlled temperature is between 12 °C and 200 °C.

4. Process for stabilizing a liquid vehicle in combination with a soluble compound, according to claim 3, characterized in that said controlled temperature is between 30 °C and 40 °C.

5. Process for stabilizing a liquid vehicle in combination with a soluble compound, according to any of the preceding claims, characterized by measuring the oxygen present in the headspace of the containment device above the free surface of the liquid vehicle, said measurement being indirectly correlated also with the oxygen dissolved in the liquid.

6. Process for stabilizing a liquid vehicle in combination with a soluble compound, according to any of the preceding claims, characterized in that said liquid vehicle contained in said containment device is mechanically agitated to facilitate the release of oxygen from the liquid and to allow the dissolution of said cannabinoid in said liquid vehicle if inertization occurs during the dissolution of the cannabinoid in the liquid vehicle.

7. Process for stabilizing a liquid vehicle in combination with a soluble compound, according to any of the preceding claims, characterized in that, after the vacuum creation step, a blowing and extraction step of an inert gas into / out of the containment device is performed to remove residual oxygen contained in the liquid vehicle.

8. Process for stabilizing a liquid vehicle in combination with a soluble compound, according to any of the preceding claims, characterized in that said steps of creating a vacuum and blowing / extracting the inert gas in the containment device are carried out until the measured oxygen is equal to zero or not exceeding a defined minimum level.

9. Process for stabilizing a liquid vehicle in combination with a soluble compound, according to any of the preceding claims, characterized in that the liquid vehicle in combination with the stabilized soluble compound gravity fills pre-filled hermetic containers (Petition 870250066359, dated 07 / 30 / 2025, page 31 / 45 3 / 3) with inert gas until it partially or completely replaces the latter.

10. Process for stabilizing a liquid vehicle in combination with a soluble compound, according to any of the preceding claims, characterized in that said inert gas comprises nitrogen and / or a noble gas.

11. Process for stabilizing a liquid vehicle in combination with a soluble compound, according to any of the preceding claims, characterized in that said cannabinoid is pure cannabidiol (CBD) obtained by extraction, fermentation, synthesis or semi-synthesis or an extract of Cannabis sativa.

12. Process for stabilizing a liquid vehicle in combination with a soluble compound, according to any of the preceding claims, characterized in that said liquid vehicle comprises MCT oil. Petition 870250066359, dated 07 / 30 / 2025, pp. 32 / 45

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