Improving cannabinoids‘ solubility, thereby avoiding the limiting step in drug absorption – the slow dissolution from the crystalline state.
High-speed, convenient, predictable drug delivery
The current delivery methods for cannabinoids present various challenges. While smoking or vaping can offer rapid relief, these methods are often associated with health risks, inconsistent effects, difficulties in achieving precise doses, discomfort, and a certain degree of social stigma. On the other hand, oral delivery methods, although they provide safety and precise dosing, often fall short in terms of speed due to their slow onset and inadequate absorption.
In response to these challenges, and the need for a swift yet non-invasive solution, we have developed AdvanDrop®. This groundbreaking technology combines the benefits of both inhalation and oral delivery methods. It provides fast relief, mitigates the risks linked to inhalation, and simultaneously offers the precision, safety, and comfort of oral administration, without the associated delay in onset.Â
As a bridge between speed and precision, AdvanDrop® offers a game-changing solution for those seeking reliable, safe, and fast cannabinoid-based therapeutics.
Improving cannabinoids‘ solubility, thereby avoiding the limiting step in drug absorption – the slow dissolution from the crystalline state.
Enhancing the absorption of cannabinoids in the gastrointestinal tract (GIT) by greatly improving their transport across its layers.
Reducing the metabolism of cannabinoids by enterocytes during the digestion process.
Minimizing efflux processes that are responsible for the elimination of cannabinoids from the cells within the digestive system.
Reducing the first-pass metabolism of cannabinoids in the liver by promoting lymphatic drug transport.
If you are interested in licensing the rights to commercialize one or more of our groundbreaking cannabinoid delivery systems, please contact us using the form below. We would also be happy to discuss our platform in more detail and explore potential business development opportunities
Novel AdvanDrop® formulation significantly enhance bioavailability of Cannabidiol in-vivo.
T. Tronina 1,2*, P. Mituła 1,3, R. Gniłka 1, G. Kiełbowicz 1*,
1 Healthcann Ltd. Klecińska 123, 54-413 Wrocław, Poland
2 Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, C.K. Norwida 25, 50-375 Wrocław, Poland
3 Institute of Environmental Engineering, Wrocław University of Environmental and Life Sciences, Grunwaldzka 24, 50-363 Wrocław, Poland
* ttronina@healthcann.eu, gkielbowicz@healthcann.eu
Research at Healthcann Ltd has led to the development of several water-soluble formulations which significantly increase the oral bioavailability of cannabinoids including cannabidiol (CBD). Our remarkable technology AdvanDrop® shows a notably improvement of bioavailability and more rapid onset of action of CBD over traditional oil-based tinctures containing CBD. AdvanDrop® – the water soluble cannabinoids technology provides 26-fold faster absorption and 200% higher systemic exposure to CBD in body compared to CBD oils products.
Cannabis (Cannabis sativa L. – hemp) is one of the oldest cultivated plants purported to have unique medicinal properties. Due to dozens of bioactive compounds found in hemp, it is sometimes called as The Plant of the Thousand and One Molecules [1]. It has been proven that health-promoting and therapeutic properties of hemp are due to its phenolic compounds bonded with terpene moieties – cannabinoids, which bind to numerous receptors in the body, including endocannabinoid CB1 and CB2 receptors.
To date, more than 120 different cannabinoids have been identified in cannabis [2, 3]. The most abundant and most active cannabinoid of hemp is cannabidiol (CBD). CBD, unlike the another well-known cannabinoid of hemp tetrahydrocannabinol (Δ9-THC) does not have intoxicating properties. CBD exhibits broad spectrum of biological activities including anti-inflammatory, anti-oxidative and anti-necrotic protective effects [4].
There is evidence that CBD could be exploited in the treatment and symptom relief of various neurological disorders such as epilepsy and seizures [5, 6] psychosis [7], anxiety [8], movement disorders (e.g., Huntington’s disease and amyotrophic lateral sclerosis) [9, 10], and multiple sclerosis [11, 12]. CBD was also being used in clinical trials in Parkinson’s disease, Crohn’s disease and schizophrenia [13-15] showing promising results in these disorders [4]. In 2018 the Food and Drug Administration (FDA) has approved Epidiolex® – pure CBD for the treatment of severe, orphan, early-onset refractory epilepsy syndromes, which significantly reduces seizure frequency. Recent studies have also shown that CBD can be used as a potential preventive agent in the early stages of SARS-CoV-2 infection. CBD and its metabolite 7-OH-CBD, block the replication of SARS-CoV-2 in lung epithelial cells thus inhibiting its multiplication [16].
There are many ways to administer medicines such as injections or inhalations but the most common is oral administration which in comparison to intravenous or inhaled administration is not invasive and does not cause throat irritation or coughing. However, very often the high therapeutic potential of drugs administered orally is severely limited due to its low bioavailability, which is mainly caused by poor water solubility and therefore absorption from the gastrointestinal tract.
Therefore, one of the fundamental challenges associated with the use of CBD in treatment is to maximise the absorption of orally ingested CBD. One of useful tool to increase stability and bioavailability of poorly water-soluble compounds as CBD is use a formulation composed of lipids, surfactants and cosurfactants. If the composition is able to form a fine emulsion (micro/nano) in an aqueous environment e.g. gastrointestinal tract, the bioactive compound can be readily absorbed through the lymphatic pathway bypassing the first-pass effect of the liver thus bioavailability of drug is significantly increased. We would like to present a novel composition AdvanDrop® with CBD that notably increases and accelerates the absorption of this bioactive cannabinoid from the digestive system.
CBD was purchased form Mile High Labs (Belfast, Northern Ireland), MCT oil, Croda (East Cowick, UK) HPLC grade methanol and acetonitrile: Merck (Darmstadt, Germany), HPLC grade formic acid, acetic acid and ammonium formate: BDH Laboratory Supplies (Poole, UK). Other chemicals: Sigma Aldrich (Helsinki, Finland), the highest purity available. Water was in-house freshly prepared with a Direct-Q3 (Millipore Oy, Espoo, Finland) purification system and UP grade (ultra pure, 18.2 MW).
To measure the parameters of nanodroplets formed by dispersing AdvD M10 (10% CBD), 100 mg of the formulation containing 10 mg CBD was dropped into 350 ml of distilled water and gently stirred with a magnetic stirrer (250 rpm, 30 sec, IKA, Staufen im Breisgau, Germany).
The dispersion rate (sec), transparency of the solution (%T, λ=600 nm, UV-VIS Spectrophotometer Pharo 300 Spectroquant, Merck, Darmstadt, Germany), hydrodynamic diameter (DH) and particles polydispersity (polidispersity index -PDI) of the formed nanodroplets were examined in the dispersed solution. DH and PDI were measured by Dynamic Light Scattering (Zetasizer Nano ZS, Malvern Panalytical, Malvern, UK).
The dose of AdvD M10 (10.510% CBD (w/w)) formulation was prepared at the day of dosing by dilution of AdvD M10 with deionized water. As a control the oil based CBD (10.498 % CBD (w/w) in MCT oil) was use
Male rats (Sprague Dawley, Charles River Laboratories, Germany) aged 7-8 weeks, weighting between 174-276 g were housed in individually ventilated (IVC)-cages in groups of two rats. The cages were provided with aspen bedding (4HP and PM90L, Tapvei, Estonia) and paper strands (Sizzlenest, Datesand, UK or EnviroPak with Sizzlenest, Datesand or Bed r’nest, Datesand) as nesting material, and red polycarbonate cylinder (Datesand,
UK) and aspen brick (M-bricks, Tapvei, Estonia) as cage enrichment. The temperature (22±2˚C), humidity (55±10%) and air exchange rate (75 times/h) of the IVC-cages and 12/12-h light/dark cycle (500 lux lighting on at 6 a.m., 1.5 lux lighting on at 6 p.m.) of the animal holding room were automatically controlled and maintained. Animals were allowed to acclimatize to the site for at least five days prior to the study. Animals had ad libitum access to food (SDS diets, RM1 (E) 801002, Special Diets Services, UK) and tap water at all times, and their welfare was assured with daily observations.
Experiment using AdvD M10 and CBD in MCT oil ware conducted in 4 replicates, whereas control (blank without CBD) in triplicates. Each animal was given a dose of 12 mg CBD / kg body weight from a stock solution of: dispersed AdvD M10 formulation in water at 7.33 mg/g or stock solution of CBD in MCT at 105 mg/g.
A 1 ml syringe fitted with an 18 G ball point feeding needle was used to administer the material into the stomach. Blood samples were collected to K2EDTA tubes by saphenous venepuncture prior to dosage (0 min) and at 0.083, 0.25, 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0 and 24.0 hours thereafter. Within 30 min following the sampling, the blood was centrifuged for plasma separation (room temperature; 10 min; 2700g). The plasma samples were transferred into plastic tubes, frozen and stored at -20ËšC until analysis. Clinical signs and general behaviour of the animals were recorded when necessary, as was any deviation from the study plan.
The LC–MS/MS system was composed of a Waters Acquity UPLC + Waters TQ-XS triple quadrupole mass spectrometer equipped with an UniSpray (US) Ionization source. Data acquisition was performed with MassLynx 4.2 software.
Chromatographic separation was achieved on a Kinetex XB-C18 (2.1 × 100 mm, 1.7 µm, Phenomenex, USA) column protected by pre-column filter at 40 °C. The mobile phase consisted of 0.1% 1 mM Ammonium Fluoride in water (A) and mixture of Acetonitrile:Isopropanol (80:20) (B) using a gradient elution of 60% A → 10% A at 0.0-3.0 min (curve 6); 10% A → 2% A at 3.0–3.5 min (curve 1); 2% A → 60% A at 3.5–4.5 min (curve 1); The flow rate was 0.5 ml/min, and the injection volume was 2 µl. Mass spectrometer was operated in the negative mode. Quantification was obtained using multiple reaction monitoring (MRM) mode at m/z transitions of 313 → 173 (Collision Energy (CE) 30 eV) and 313 → 311 (CE 20 eV) for cannabidiol and 295 → 145 (CE 44 eV) and 295 → 267 (CE 32 eV) for an internal standard (Ethinylestradiol). The MS parameters were as follows: capillary voltage 3.0 kV; cone voltage 50 V; source temperature 150 °C; desolvation temperature 400 °C; nebuliser gas (nitrogen) 7 bar; collision gas (argon) 0.2 ml/min.
Deffinition of PharmacokineticTmax: Time to the maximum measured plasma concentration.
Cmax: Maximum measured plasma concentration over the time span specified.
T1/2: Final time taken for the plasma concentration to be reduced by half.
AUC0−last: The area under the plasma concentration vs. time curve, from time zero to time of last sampling.
AUC0−infinity: The area under the plasma concentration vs. time curve from zero to time calculated as AUC0−t plus the extrapolated amount from time t to infinity.
The pharmacokinetic parameters were calculated using Phoenix 64 (Build 6.4.0.768) WinNonlin (version 6.4) software, using non-compartmental methods (NCA). Nominal doses were used for all animals. The terminal phase half-life (T1/2) was calculated by least-squares regression analysis of the terminal linear part of the log concentration–time curve. The area under the plasma concentration–time curve (AUC) was determined with the linear trapezoidal rule for increasing values and log trapezoidal rule for decreasing values up to the last measurable concentration (AUC0-last), and extrapolation of the terminal elimination phase to infinity was used when possible to obtain AUC0-infinity; the following criteria were considered:
· Minimum of 3 points (not including Cmax) should be used to calculate lambda (with R2 adjusted >0.85)
· T1/2 should be shorter than the time-span used to calculate lambda
· AUC %Extrapolate should be < 20%
The maximum plasma concentration (Cmax) and the time to reach Cmax (Tmax) were derived directly from the plasma concentration data.
Like many lipophilic compounds, the oral bioavailability of CBD is known to be poor due to its limited absorption caused by very low water solubility and extensive first-pass metabolism [4, 17]. Studies in dogs have showed that 74% of CBD is metabolized in the liver [18]. The most popular oral CBD products on market are CBD oils, which are hemp CBD extracts (full or broad spectrum) or pure CBD isolate suspended in MCT oil (medium chain triglycerides), sesame oil or hemp oil. The use of CBD in these forms, due to its low bioavailability, can cause difficulties in achieving the desired therapeutic response through oral administration of CBD. Moreover, the oily form of these products, which are instilled sublingually, makes ingestion and dosage difficult. Therefore, new formulations that would enhance the absorption of lipophilic drugs such as CBD and unlike CBD oils, also be consumer-friendly are increasingly being sought. The novel formulation which notably increases and accelerates the absorption of CBD from the digestive system is AdvanDrop® (AdvD M10).
Among of dozens combination of composition consisting of API (different cannabinoids including e.g.: CBD, CBC, CBG, CBN, Δ9-THC, Δ8-THC, CBDV, CBL, acidic forms of cannabinoids: CBDA, THCA, CBGA, mixtures of cannabinoids as well as hemp extracts), lipids, surfactants, cosurfactants and cosolvents 68 formulation were tested, whereas for further tests AdvanDrop® AdvD M10 formulation was chosen. AdvD M10, developed using the DOE (Design of Experiment) method, showed the best parameters of nanodrops regardless of the cannabinoids used. In addition, the ingredients used in the AdvD M10 formulation are approved for the food industry in EU and US. AdvD M10 with CBD formed nanodroplets with a low dispersion rate – less than 3 seconds, hydrodynamic diameter DH = 36.4 nm ± 0.26 nm, polydispersity index PDI = 0.143 ± 0.003 and transparency %T = 98,7% ± 0.17%. Moreover nanodroplets obtained from AdvD M10 were stable and had desired parameters (small hydrodynamic diameter, monodispersity, high dilution resistance in aqueous environment ) in a wide range of pH from pH=8 to pH < 2. That makes the formulation AdvD M10 the perfect candidate for pharmacokinetics studies.
Pharmacokinetics of water solution of dispersed AdvD M10 with CBD concentration 10.510% as well as CBD oil (CBD 10.498% dissolved in MCT oil) as a control was tested in-vivo. Oral administration of CBD in formulation AdvD M10 and the oil-based formulation (CBD in MCT oil) in rats resulted in the pharmacokinetics profiles depicted in Figure 2.
Figure 2. Mean plasma concentration versus time curves for CBD administered in the AdvanDrop® formulation in comparison to CBD in MCT formulation.
| Time [h] /[min] | CBD in MCT oil Mean concentration (ng/ml) | AdvanDrop® Mean concentration (ng/ml) | Boost factor* |
| 0.083 h / 5 min | 0.45 ± 0.29 | 11.7 ± 1.72 | 26.09 ↑ |
| 0.25 h / 15 min | 5.55 ± 2.41 | 48.9 ± 12.0 | 8.81 ↑ |
| 0.5 h / 30 min | 32.1 ± 23.2 | 145.0 ±31.0 | 4.51 ↑ |
| 1 h / 60 min | 74.5 ± 35.6 | 226.7 ± 41.3 | 3.04 ↑ |
| 1.5 h / 90 min | 94.4 ± 79.1 | 184.0 ± 65.1 | 1.95 ↑ |
| 2 h / 120 min | 80.3 ± 39.8 | 140.4 ± 52.3 | 1.75 ↑ |
| 4 h / 240 min | 29.4 ± 22.4 | 50.3 ± 45.5 | 1.71 ↑ |
| 6 h / 360 min | 12.2 ± 5.2 | 27.8 ± 10.3 | 2.28 ↑ |
| 8 h / 480 min | 10.8 ± 3.7 | 15.0 ± 7.6 | 1.38 ↑ |
| 24 h / 1440 min** | 1.19 ± 0.35 | 6.0 ± 0.12 | 5.03 ↑ |
Table 1. Measured concentrations of CBD in rat plasma after oral administration at 12 mg/kg
* Calculated boost factor shows how the plasma CBD concentration of the AdvanDrop® formulation is multiplied compared to the plasma CBD concentration of the MCT oil formulation.
** Data not shown in figure 2.
The calculated pharmacokinetic parameters for CBD in rat plasma after oral administration of AdvanDrop® formulation and CBD in MCT oil formulation at both nominal CBD doses of 12 mg/kg are reported in Table 2.
| Formulation | Cmax (ug/ml) | Tmax (h) | T½ (h) | AUC0−last [ng*h/ml] | AUC0−infinity [ng*h/ml] |
| CBD in MCT oil | 123 ± 60.3 | 1.5 ± 0.41 | 5.27 ± 0.54 | 348 ± 149 | 357 ± 152 |
| AdvanDrop® | 236 ± 71.7 | 1.25 ± 0.29 | 4.82 ± 0.87 | 673 ± 64.6 | 686 ± 65.5 |
Table 2. The calculated pharmacokinetic parameters for CBD in rat plasma of tested formulations.
To sum-up, the AdvanDrop® is novel technology that notably increase bioavailability and bioeffectiveness of CBD by forming stable nanodroplets with CBD in an aqueous solutions. Due to the fact that the formulation was made of ingredients approved for food AdvanDrop® with CBD might be dissolved with water or any other beverage and consume in much more consumer friendly way than usage of oily CBD products. In comparison to traditional CBD product – CBD in MCT oil, AdvanDrop® technology provides at least 2-fold higher systemic exposure to CBD and very fast onset of action (concentration of CBD 5 minutes after oral administration is 26- fold higher in comparison to CBD in MCT oil).
Because the onset of action has fundamental importance in disorders such as epilepsy, severe pain, or anxiety, where CBD is often used as a medicine and must act immediately after administration, there is great potential of using the AdvanDrop® technology also as a carrier for CBD in therapies where a short onset of action is crucial.
The Smart Growth Operational Programme 2014-2020, Priority I: Support for R&D works by enterprises, Measure 1.3: Research and development works financed with the participation of capital funds, Sub-measure 1.3.1: Support for R&D projects in the pre-seed phase by proof of concept funds – BRIdge Alfa.
The study is conducted under the project licence ESAVI/20471/27/9/2019, approved by the national Animal Experiment Board of Finland under Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes, with the following national provisions: Act (497/2013) and Decree (564/2013) on the Protection of Animals Used for Scientific or Educational Purposes.
We are grateful to Janne Mannila PhD Juho Hokkanen PhD, Hanna-Maria Knaappila MSc for conducted pharmacokinetic experiments and report preparation.
Healthcann Ltd. approved the design of the pharmacokinetic studies but had no role in the collection and analyses of data and obtained results of pharmacokinetic studies. The authors declare no conflict of interest.
1. Andre, C. M.; Hausman, J.-F.; Guerriero, G.,
Cannabis sativa: the plant of the thousand and one molecules. Frontiers in plant science 2016, 7, 19.
2. Izzo, A. A.; Borrelli, F.; Capasso, R.; Di Marzo, V.; Mechoulam, R.,
Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences 2009, 30, (10), 515-527.
3. ElSohly, M. A.; Radwan, M. M.; Gul, W.; Chandra, S.; Galal, A.,
Phytochemistry of Cannabis sativa L. Phytocannabinoids 2017, 1-36.
4. Millar, S. A.; Stone, N. L.; Yates, A. S.; O’Sullivan, S. E.,
A systematic review on the pharmacokinetics of cannabidiol in humans. Frontiers in pharmacology 2018, 9, 1365.
5. Hofmann, M. E.; Frazier, C. J.,
Marijuana, endocannabinoids, and epilepsy: potential and challenges for improved therapeutic intervention. Experimental neurology 2013, 244, 43-50.
6. Jones, N. A.; Hill, A. J.; Smith, I.; Bevan, S. A.; Williams, C. M.; Whalley, B. J.; Stephens, G. J., Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. Journal of Pharmacology and Experimental Therapeutics 2010, 332, (2), 569-577.
7. Leweke, F. M.; Mueller, J. K.; Lange, B.; Rohleder, C.,
Therapeutic potential of cannabinoids in psychosis. Biological psychiatry 2016, 79, (7), 604-612.8.
8. Bergamaschi, M. M.; Queiroz, R. H. C.; Chagas, M. H. N.; De Oliveira, D. C. G.; De Martinis, B. S.; Kapczinski, F.; Quevedo, J.; Roesler, R.; Schröder, N.; Nardi, A. E.,
Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology 2011, 36, (6), 1219-1226.
9. Lago, E. d.; Fernandez-Ruiz, J.,
Cannabinoids and neuroprotection in motor-related disorders. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders) 2007, 6, (6), 377-387.
10. Iuvone, T.; Esposito, G.; De Filippis, D.; Scuderi, C.; Steardo, L.,
Cannabidiol: a promising drug for neurodegenerative disorders? CNS neuroscience & therapeutics 2009, 15, (1), 65-75.
11. National Academies of Sciences, E.; Medicine,
The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. 2017.
12. Lakhan, S. E.; Rowland, M.,
Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review. BMC neurology 2009, 9, (1), 1-6.
13. Leweke, F.; Piomelli, D.; Pahlisch, F.; Muhl, D.; Gerth, C.; Hoyer, C.; Klosterkötter, J.; Hellmich, M.; Koethe, D.,
Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Translational psychiatry 2012, 2, (3), e94-e94.
14. Chagas, M. H. N.; Zuardi, A. W.; Tumas, V.; Pena-Pereira, M. A.; Sobreira, E. T.; Bergamaschi, M. M.; dos Santos, A. C.; Teixeira, A. L.; Hallak, J. E.; Crippa, J. A. S.,
Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. Journal of Psychopharmacology 2014, 28, (11), 1088-1098.
15. Naftali, T.; Mechulam, R.; Marii, A.; Gabay, G.; Stein, A.; Bronshtain, M.; Laish, I.; Benjaminov, F.; Konikoff, F. M.,
Low-dose cannabidiol is safe but not effective in the treatment for Crohn’s disease, a randomized controlled trial. Digestive diseases and sciences 2017, 62, (6), 1615-1620.
16. van Breemen, R. B.; Muchiri, R. N.; Bates, T. A.; Weinstein, J. B.; Leier, H. C.; Farley, S.; Tafesse, F. G., Cannabinoids Block Cellular Entry of SARS-CoV-2 and the Emerging Variants. Journal of natural products 2022.
17. Perucca, E.; Bialer, M.,
Critical aspects affecting cannabidiol oral bioavailability and metabolic elimination, and related clinical implications. CNS drugs 2020, 34, (8), 795-800.
18. Samara, E.; Bialer, M.; Mechoulam, R.,
Pharmacokinetics of cannabidiol in dogs. Drug metabolism and disposition 1988, 16, (3), 469-472.
Project title: Development of innovative formulations of biologically active compounds  with increased oral bioavailability.
Aim of the project: The aim of the project is to develop a novel oral delivery product for  lipophilic active compounds from the cannabinoid group with improved bioavailability, absorption and convenience route of ingestion.
Total budget:Â Â 4 241 999,13 PLNÂ |Â Â Funding value:Â 3Â 226 079,98 PLN
Duration of the project:  1 December 2021 – 31 December 2023
Project contribution of European Funds
The project is co-financed from the European Regional Development Fund under Priority Axis III - Support for innovation in enterprises; Measure: 3.3. Support for innovation in enterprises; Measure: 3.3 Support for promotion and internationalisation of innovative enterprises, Operational Programme Intelligent Development 2014-2020; Contract no: UG-PMT/3342/1N/2022-USA Polish Bridges of Technology.
Healthcann S.A.
ul. Klecińska 123,  54-413 Wrocław
VAT No: 894 31 54 198
KRS: 0000979833