Micelles are colloidal particles composed of amphiphilic molecules (molecules that have hydrophilic heads and hydrophobic tails). In an aqueous solution, these molecules assemble into nanosized structures (spherical, ellipsoid, cylindrical, or unilamellar) with a hydrophobic core and hydrophilic shell (1,2). Other hydrophobic compounds, such as CBD, can be loaded into the hydrophobic core. Micelles demonstrate several desirable properties as drug carriers and are often used as pharmaceutical carriers for water-insoluble drugs (1).

1. Torchilin, V. P. Micellar Nanocarriers: Pharmaceutical Perspectives. Pharm. Res. 24, 1 (2006).
2. Hanafy, N. A. N., El-Kemary, M. & Leporatti, S. Micelles Structure Development as a Strategy to Improve Smart Cancer Therapy. Cancers (Basel). 10, 238 (2018).

There are several bioavailability-enhancing techniques, including Lipid-Based Drug Delivery Systems (LBDDSs), chemical modifications, crystal modifications, and inclusion complexes. However, non-LBDDS techniques have multiple potential downsides, including that they have complex processes, are cost and energy-intensive, result in low stability, and produce limited dosage forms (1). On the other hand, Micellae’s LBDDS technology, O2W, has a simple and inexpensive production process, is highly stable, and can be used to produce an unmatched variety of dosage forms. O2W was engineered to significantly enhance the solubility, bioavailability, and time of onset of fat-soluble compounds, including cannabinoids. Free of PEGs and medium/short-chain alcohols, O2W is the only self-dispersing and fully water-dilutable Self-Microemulsifying Drug Delivery System (SMEDDS) made with food-grade excipients.

1. Nouraei, M. An Introduction to Micellar Solubilization Technology. 1–11 (2020).

LBDDSs are composed of a variety of oils and oil-like ingredients, emulsifiers, and sometimes water (1). They can be liquid (emulsions, nanoemulsions, microemulsions (μE) and SEDDS/SMEDDS), solid (solid-liquid nanoparticles and solid SMEDDS), and semi-solid (organogels).

SMEDDSs are the most superior type of liquid LBDDSs based on several measures of overall performance. (Please see “What is a SMEDDS”) Emulsions are the largest in size (1-20 µm) and provide the lowest increase in bioavailability. Contrary to the name, microemulsion particles are much smaller in size than nanoemulsion particles and provide the highest increase in bioavailability. Furthermore, nanoemulsions require a large input of energy, necessitating complex and energy-intensive equipment to make them kinetically stable, whereas microemulsions (and SMEDDSs) are thermodynamically stable and can be formed in a simple mixing vessel (1). Self-emulsifying LBDDSs such as SEDDSs/SMEDDSs are isotropic mixtures of oil and surfactant/cosurfactant that spontaneously form nanoemulsions/microemulsions upon mild agitation in an aqueous solvent. SMEDDSs may be defined as a concentrated microemulsion or latent μE. Since SMEDDSs are also water-free they have higher stability and consequently, they have a longer shelf-life than diluted microemulsions (1).

1. Nouraei, M. An Introduction to Micellar Solubilization Technology. 1–11 (2020).

Self-Microemulsifying Drug Delivery Systems (SMEDDSs) are water-free concentrate systems of oil(s) and surfactant(s) that upon exposure to an aqueous phase (e.g., gastrointestinal fluid) with mild agitation, spontaneously form microemulsions that function as a carrier for drugs. (Please see “What is a SMEDDS”)

Microemulsions are thermodynamically stable, self-assembling, transparent/translucent, and optically homogeneous (but microscopically heterogeneous) dispersions of an aqueous phase and oil phase, stabilized by an interfacial film of amphiphilic molecules.

1. Solubilization Enhancement: Quick and thermodynamically favored micellization significantly enhances the solubilization of the active pharmaceutical ingredient (API).
2. Ease of Manufacturing and Scale-up: Self-microemulsification is a thermodynamically favored process that occurs spontaneously with little to no energy input. No homogenizers, no sonicators, no pump or sheers are needed!
   In contrast, for conventional emulsions, energy is needed to break down the oil droplets and to create new surfaces. However, due to the high surface energy, the droplets tend to merge again.
3. Smaller Dosage Forms and Longer Shelf-life: The absence of water in SMEDDSs enhances the stability and shelf-life of both the formulation itself, as well as the API, compared to microemulsions.

For other advantages of O2W, please see our “O2W Advantage” section.

Despite their effectiveness in increasing the solubility of poorly soluble ingredients, there are numerous challenges in formulating SMEDDSs that limits their wide-spread use. The two main challenges of designing SMEDDSs are achieving full-dilutability and using only food-grade excipients.

Full-dilutability, or phase continuity over dilution, is a key factor in designing SMEDDSs. Full-dilutability is the ability of a drug delivery system to produce formulations that can be dissolved in any volume without phase separation. Full-dilutability is important because oral administration results in serial dilutions of compounds within the digestive system, thus it is critical for the formulation to remain stable at any water volume for optimum absorption.

Engineering fully dilutable microemulsions with food-grade and alcohol-free compounds is particularly challenging due to the limited choices for surfactants. Currently available microemulsions/SMEDDS contain Polyethylene Glycols (PEG) and short/medium-chain alcohol compounds. It is important because PEGs are petroleum-based compounds that are widely used in cosmetics as thickeners, solvents, softeners, and moisture-carriers. PEGs are not environmental-friendly and may present long-term safety concerns. Our PEG-free, food-grade formulation improves long-term safety.

According to the Biopharmaceutics Classification System (BCS), the two major limiting factors for absorption of an active ingredient are solubility and permeability. Accordingly, the substances are classified into four groups of which type II and IV compounds are of particular interest.

Certain chemical compounds can provide immense therapeutic benefit in vitro but may not demonstrate the same efficacy in vivo. This poor efficacy in vivo can often be attributed to the poor water solubility and bioavailability characteristics. In fact, pharmaceutical drug pipelines are seeing a rise in poorly water-soluble and bioavailable drug candidates, necessitating an effective solution (1).

One of the most effective solutions to tackle solubility and bioavailability concerns are drug delivery systems. Drug delivery systems are specifically designed to optimize the desired therapeutic effect(s) of hydrophobic compounds by substantially enhancing their water solubility, permeability, and bioavailability (2).

Recently, drug delivery systems have started to garner attention from their ability to promote effective immunization in COVID-19 vaccines. Specifically, all COVID-19 mRNA vaccines are delivered using lipid nanoparticles (LNPs), which efficiently encapsulate, condense, and increase cellular uptake of mRNA to reach cell cytosol (3).

1. J, B., ME, B. & P, A. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J. Pharm. Sci. 98, 2549–2572 (2009).
2. Wen, H., Jung, H. & Li, X. Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges. AAPS J. 17, 1327 (2015).
3. Park, K. S., Sun, X., Aikins, M. E. & Moon, J. J. Non-viral COVID-19 vaccine delivery systems. Adv. Drug Deliv. Rev. 169, 137 (2021).

Studies suggest that cannabinoids have a wide range of benefits ranging from treating rare forms of epilepsy to reducing anxiety (1). However, cannabinoids are considered to have low oral bioavailability, with only 4%-12% being absorbed in the gastrointestinal tract and reaching the bloodstream. Given this, the need for an effective drug delivery system is paramount to increasing the bioavailability of cannabinoids. O2W is a water-solubilizing and potency enhancing drug delivery system designed to substantially increase the bioavailability of poorly bioavailable compounds, such as cannabinoids. O2W does not alter the cannabinoids chemically but instead acts as a vehicle to encapsulate the active ingredient and deliver it to its intended destination.

Pamplona, F. A., da Silva, L. R. & Coan, A. C. Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis. Front. Neurol. 0, 759 (2018).

One of the important characteristics of O2W is its turnability. Based on the need of the client, we can deliver a wide range of release profiles (immediate, delayed, extended).

Our concentrate platform is high-potency and fast-acting, allowing for high bioavailability and a rapid onset of action. Our powder formulation platform is extra high-potency and tunable release, allowing for extra high bioavailability and tunable immediate, delayed, or extended release. Our gel formulation platform is high-potency and extended-release, allowing for high bioavailability and tunable controlled release. (Please see “Breakthrough Product Platforms”)

Some examples of final products include extra high-potency, tunable-release tablets; high-potency, fast-acting capsules; high-potency, tunable extended-release capsules; instant, high-potency concentrate drops; and more. (Please see “Unlimited Product Options”)

Micellae’s powder platform is based on the process of solidification of the O2W liquid platform in which fine liquid droplets are microencapsulated to combine the advantages of the conventional liquid SMEDDSs with those of the solid dosage forms.

Microencapsulation is the process of coating one or more active ingredients with a (mixture of) polymer(s), forming a shell, with the objective of providing a physical barrier between the active ingredient and other components of the product to protect it from environmental factors like humidity, light, and air.

In a simplistic form, a microcapsule is a small sphere with an inner core containing one or more active compounds covered with a coating material sometimes called shell, membrane, coat, or wall. The coating materials are usually polymers from natural or synthetic sources, selected depending on the compound to be coated, the characteristics desired in the final capsules, and the type of release required. Depending on the coating material, many triggers can be used to activate the release of the encapsulated compounds: temperature, pH change (enteric and anti-enteric coating), enzymatic activity, time, etc.

While the conventional microencapsulation process involves coating the active ingredients, Micellae’s microcapsule coats the droplets of the CBD-loaded liquid delivery system.

Solidification of SEDDSs affords a multitude of benefits compared to precursor liquid-SEDDSs, which can be summarised within the following categorical advantages:

1. Improved drug solubilisation and dissolution,
2. Improved safety,
3. Controlled drug release, and
4. Industrial and commercial benefits (1)

First, it allows our clients to make formulated tablet or loose powder dosage forms, the favourite mode of administration by doctors and patients. Pre-encapsulation of the whole dose into capsules/tablets provides more accurate and precise dosing in comparison to administering a prescribed volume of a suspension using a syringe or spoon and allows us to create different release profiles (immediate, delayed, controlled). It also results in better patient compliance (i.e., it is generally preferred by adult patients to administer capsules/tablets rather than a liquid formulation). The ease of use and tunability of the platform brings unique advantages to this platform in addition to the advantages of our conventional liquid SMEDDS.

Furthermore, the solidification of SMEDDSs enables simpler handling and manufacturing processes using more economic and conventional equipment (better suited to large-scale production). Solidification imparts physicochemical stability and reduces production costs while retaining, or optimising, the pharmacokinetic benefits of liquid SMEDDSs. Additionally, it avoids drug-packaging interactions, potential leakage, and migration of the excipients into the capsule shell.

This approach has given successful results for the enhancement of solubility and bioavailability of a variety of BCS class II drugs with results significantly superior to those obtained with the pure drug during in vitro and in vivo studies. It enhances intestinal solubilisation and improves drug permeability.

It is useful to protect compounds from environmental factors like humidity, light, and oxygen. It is also useful to protect compounds that are orally administered and need to pass the gastrointestinal tract without being affected by the stomach pH and the enzymatic action. The resulting microcapsules are more stable products and easy to handle and transport, with extended shelf-life.

1. Joyce, P. et al. Solidification to improve the biopharmaceutical performance of SEDDS: Opportunities and challenges. Adv. Drug Deliv. Rev. 142, 102–117 (2019).

Yes, Micellae is based on 15 years of research and has performed both in vivo and in vitro studies.

In 2021, Micellae performed a single-dose pharmacokinetic (PK) study in rats through an independent CRO. This study demonstrated the efficiency of our O2W powder and concentrate formulations compared to a traditional CBD Oil Solution. The pharmacokinetic parameters of Area Under the Curve (AUC), maximum concentration (Cmax), and time where the maximum concentration is reached (Tmax) were all significantly increased showing a greatly improved bioavailability of CBD at an unmatched speed. (Please see “Unprecedented Performance”)

Micellae has also performed a single-dose PK study in rats comparing O2W-Ibuprofen concentrate and with Ibuprofen in water. We found a 4x higher AUC, 3.6x higher Cmax, and significantly shorter Tmax. (Please see “Unprecedented Performance”)

Micellae out-licenses our patent-protected O2W technology to our partners. We will manufacture the customized blank pre-mixed formulation (intermediate product) with the help of a co-packer and will sell it to the licensee. (Please see “Services”) You (the manufacturer/cannabis producer) will add the cannabis extract in your facility and integrate a simple mixing step to your manufacturing process. (Please see “Manufacturing”)

Micellae is a business-to-business company with the objective of becoming the most valuable partner of high-quality pharmaceutical, medical, and recreational cannabis producers. Our mission is to provide the most advanced Drug Delivery System to significantly improve the solubility and bioavailability of cannabinoids.

Micellae out-licenses our patent-protected O2W technology to our partners. If you are interested in partnering with us, the first step is to contact our team, indicating the product you would like to create or enhance. Based on your desired product and release profile, we can help you select the optimal product platform (concentrate, powered, or gel) and develop a pricing estimate.

Yes, Micellae’s technology has seven current patents and one patent pending. The patents were filed by Dr. Edgar Acosta and Dr. Mehdi Nouraei. They are property of the University of Toronto and have been filed with the US Patent Office (Please see “Patents”).

O2W’s long-term toxicity study demonstrated long-term safety in rats with β-Carotene. In this study, male Sprague-Dawley rats were fed either a regular diet with no SMEDDS (control group), a diet enriched with 1% SMEDDS, or a diet enriched with 5% SMEDDS (n=6/group). The SMEDDS was loaded with 1000 ppm β-carotene.

During the 6-week period, the animals were monitored both physically and psychologically. At the end of the 6-week period, body dimensions were measured with no significant differences between groups. Furthermore, blood and tissue samples were collected for analysis. A Complete Blood Test (CBT) showed white blood cells (lymphocytes, monocytes, and neutrophils) were in the normal range for all three groups, indicating that the diet has no adverse impact on the immune system. Furthermore, the red blood cell, hemoglobin, and hematocrit for the control were below the normal ranges, while the results for the two test groups fell within the normal ranges. When weighing organs, no significant differences were found except for the 5% SMEDDS diet kidney being smaller.