solubilizer for full spectrum cbd oil

LifeSense Product C8 KetoMCT solubilizes CBD

Introduction. In this invited review, we are honored to have Dr/Professor Alvin Berger describe the current challenge of poor bioavailability of CBD, and how bioavailability can be improved by various means, including use of medium chain triglycerides (MCTs). Dr. Berger is a published expert on lipids including MCTs, with academic, industrial and commercial experience. He has also published landmark papers on endocannabinoids and phytocannabinoids in prestigious journals with Raphael Mechoulam and Vincenzo Di Marzo, leaders in the cannabinoid field.

Definitions of solubility, absorption, and bioavailability. Solubility is the ability of a substance to be dissolved. Some nutrients are not dissolved, but evenly dispersed as fine particles with mixing or sonication. Bioavailability is the uptake of a drug or nutrient by our organs. As it is challenging to measure levels of a nutrient in an organ (requiring a biopsy in humans), a surrogate is to measure levels in whole blood, plasma, or serum. Once the molecule of interest is in the blood circulation, it can exert biological actions by binding to receptors (such as cannabinoid receptors CB1 and CB2 in the endocannabinoid system ; and non-cannabinoid receptors like serotonin receptor 5-HT1A, GPR55, and μ- and δ-opioid receptors). If a nutrient is not properly solubilized or dispersed, this can contribute to poor bioavailability. Other factors contributing to poor bioavailability are: poor absorption during digestion (uptake of nutrient from the digestive tract to the blood circulation); degradation during digestion; excretion to the stool or urine; and being metabolized or broken down before reaching target organs. In recent years, drugs and nutrients (such as CBD) have become more lipophilic (fat loving), with poor solubility, unless special emulsifiers and other technologies are employed.

CBD focus. CBD has attracted significant interest due to lack of psychotropic activity, and anti-inflammatory, anti-oxidative, anti-necrotic, pro-sleep, anticonvulsant, anxiolytic, and anti-pain properties [1]. CBD displays a favorable safety and tolerability profile in humans making it a promising candidate for combatting epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, Crohn’s disease, society anxiety disorder, and schizophrenia. In June 2018, highly purified CBD Epidiolex ® , a CBD oil preparation, was approved by the FDA for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome. CBD is widely used as a popular food supplements and also topically for a range of complaints. The CBD market will grow to $2.1 billion for US consumer sales by 2020.

Bioavailability of CBDs. CBD can be obtained orally, sub-lingually (under the tongue), and by injection, vaporization, rectal suppositories, and inhalation. Oral bioavailability of CBD is very low (13–19%) [2] due to: limited aqueous solubility; extensive first pass metabolism (after passing through the intestine, the substance is converted to an inactive form at the liver); and renal (kidney) excretion of metabolites [3]. Despite extensive use of CBD, there is little data on its absorption, distribution, metabolism, and excretion, and rates thereof (together, known as pharmacokinetics or PK). Understanding PK is necessary to optimize bioavailability. A challenge in determining bioavailability is high intra (within)- and inter (between)-subject absorption [4], which can relate to genetic differences, foods consumed with the preparations, and more. Companies must optimize solubility and bioavailability to provide customers with an efficacious product to differentiate themselves from competitors in this increasingly saturated and soon commoditized space. With higher bioavailability, consumers can consume less product to achieve equivalent benefits, and better taste. If CBD crystallizes out of solution, this imparts a bitter and undesirable taste.

Dose effects on bioavailability. Not surprisingly, consuming more CBD leads to a higher blood concentration. But there is a saturation or plateauing (leveling off) effect. For example, maximum blood concentration was similar with 400 mg and 800 mg doses [5]. Moreover, physiological benefits exist at low and high doses (bimodal effects); and these effects can be opposite at different doses, vastly complicating decisions on the optimal dose to consume. At this time, lack of understanding of dose to consume for different conditions is a huge concern, and not a problem easily solved.

Meal effects on bioavailability. Consuming fatty foods (nut butters, oils, full fat dairy, avocado, etc.) prior to consuming a lipophilic substance (like CBD) generally improves absorption and hence bioavailability. Adding oils to CBDs makes the mixture more lipophilic (fat-loving), driving absorption to the chylomicron-lymphatic absorption path, increasing overall bioavailability versus absorption via the hepatic (liver) portal route (system for absorbing hydrophilic [water-loving] substances from the gut to the liver). In one study, consuming a standard breakfast one hour before consuming CBD capsules increased bioavailability [5]. Co-consumption with fatty foods may also lipase activity, which is valuable when lipid components must be cleaved off a molecule’s backbone for maximal absorption (for example, absorption of the fatty acids from the glycerol backbone in triglycerides, the main form of fat in nature); and may increase biliary flow which helps solubilize fatty nutrients in the gut. Consuming CBD with a fatty meal may also decrease any gastrointestinal discomfort basis results with other fatty molecules. Despite the current craze to add lipophilic nutrients to coffee (“bullet-proof”), this is generally ill advised due to more propensity for gastrointestinal absorption and possibly less solubility and associated bioavailability (not to mention, undesirable effects of consuming acidic coffee on an empty stomach).

Methods to increase solubility of CBDs. These include: self-emulsifying drug delivery system (SEDDS) [6]; self nano-emulsifying drug delivery systems (SNEDDS) [7]; utilization of liposomes and lipospheres (coating CBD in lipid particles) [4]; and solubilizing CBDs in oils such medium chain triglycerides (MCT) and other oils [8]. An emulsion is a thermodynamically stable system comprising oil, water, and a surfactant or emulsifier, and have been used to effectively deliver highly lipophilic drugs and nutrients. Solubilization in MCTs will be our focus herein.

MCTs defined. MCTs consist of fatty acids of chain length 6-10 carbons, esterifed (attached) to a glycerol (glycerin) backbone. In a typical triglyceride in a vegetable oil, the chain lengths would be 16-20 carbons. Fatty acids of chain length 6-10 are classified as a saturated fat for labeling purposes, but do not behave like longer chain fatty acids with 12 or more carbons, because medium chain fatty acids (MCFA) are absorbed via the hepatic portal system; whereas longer chain fatty acids are absorbed via the lymphatic system. MCFA are rapidly and efficiently absorbed, and MCT have been used since the 1980s by athletes, and in recent years by the masses for weight management, energy, cognition and increasingly solubilization of hard to solubilize nutrients (and drugs). MCTs are used topically (labeled as caprylic-capric tryglycerides- C8/10) to increase penetration through the skin’s stratum corneum outer layer.

Solubilizing CBDs in MCT oils. Bioavailability of CBDs can be improved with various techniques. MCTs advantage is providing a healthy oil that is not stored as body fat, but rather burned for energy at the liver or preferentially converted to beneficial ketone bodies, providing sustained energy, glycemic control, weight management, and cognitive benefits. These benefits may be additive or possibly synergistic (greater than the sum of the parts) with CBDs. MCTs can increase bioavailability of CBDs by increasing solubilization in liquid products and in the gut [9], and by minimizing first pass metabolism (liver degradation) . MCTs and their derivatives can also increase bioavailability by forming SEDDS and SNEDDS with drugs and nutrients [10-12]. A practical advantage of solubilizing CBDs with MCTs are the very long shelf life of MCTs, with typical re-test dates being 3 years. Stability is high because there are no double bonds in high quality C8/10 MCTs to oxidize. Oxidation is a major concern with some vegetable oils and fish oils, imparting bad taste and undesirable health effects. Despite reports in lay media, there is little evidence MCTs have anti-microbial properties; rather it is the monoglyceride or fatty acid component of MCTs that have anti-microbial properties [13, 14].

Types of MCTs used to solubilize CBD. Companies purchasing LifeSense Products’CBD Solubilizer (containing C8 MCTs) report they have internal data demonstrating C8 MCTs solubilize CBDs better than C8/10 MCTs; and claim better bioavailability with the former. Dr. Berger is not aware of formal studies proving this. However, C8 fatty acids and C8 MCTs do have different polarity than those from C8/10, so such differences are conceivable. Another advantage of C8 over mixtures of C8/10 is the former leads to larger increases in beneficial plasma ketone bodies, which is expected to translate to better weight management, sustained energy, cognition and other conditions correlated with increased ketone bodies [15].

Solubilizing CBDs in coconut oil. Despite marketing claims from the Coconut Oil Board and companies with vested interests, coconut oil is not a rich source of MCTs (and should not be called an MCT oil) as it contains predominately the longer chain C12 fatty acid (lauric acid; esterified to glycerol), and C12 is less polar (more hydrophobic, water resisting) than the C8 and C10 fatty acids (esterified to glycerol) found in true MCT oils [14]. Coconut oil contains only 5-15% C8/10 fatty acids. C8 MCTs (such as LifeSense Products’ CBD solubilizer) contain 95+ percent C8, with up to 5% C10, and minimal C6 and C12. In C8/10 MCTs, the ratio of C8:C10 is 60:40 or 70:30. It is very likely coconut oil would solubilize CBDs differently than C8/10 MCTs; and physiologically coconut oil behaves mostly like other long chain fats, accumulating in adipose tissue and having adverse affects on LDL (bad) cholesterol in high amounts; moreover, coconut oil can impart a soapy taste to products [14].

Water soluble CBD and powdered CBD. Using previously described techniques, water soluble CBD oil appeared on the market beginning in 2016. CBD added to oil would appear as oil droplets in the water. To produce a single phase, CBD can be dispersed into oil to create an emulsion by: using surfactants to lower surface tension between two liquids; and by using emulsifiers to mix the two liquids. An emulsifier such as lecithin contains a hydrophilic head (the polar group in lecithin) and a hydrophobic tail (fatty acid chains in lecithin). The head contacts the water, the tail contacts the oil. If additional emulsifiers are added to MCT oil, an added benefit may be further increases in CBD absorption and bioavailability, tracking with greater increases in ketone bodies and plasma C8/C10 fatty acids (and also less stomach upset in sensitive individuals [16]. Similarly, mixtures of powdered CBD and powdered C8 MCT oil (the latter from LifeSense Products) are manufactured with emulsifiers for addition to aqueous vehicles, offering the convenience of a powder. Such powders can be mixed with other nutritional powders.

Solubilizing different phytocannabinoids in MCT. Cannabis sativa plant contains more than a hundred different phytocannabinoid compounds, CBD being one. Hemp seed oil and full spectrum CBDs contain numerous phytocannabinoids and terpenoids. Some of these are structurally similar with similar polarity (charge) and may have similar solubility as CBD; but not all phytocannabinoids and terpenoids can be expected to solubilize equivalently in a given oil or bioavailability enhancer system. Thus, companies should make solubility measurements on their complex mixtures in MCTs. On the biological side, an advantage of complex phytocannabinoid systems are the “entourage” effects where non-receptor binding lipids decrease degradation of receptor-binding phytocannabinoids [17, 18]. As THC is structurally similar to CBD, systems that maximize solubility and bioavailability of CBD may do the same for THC and levels of blood THC should ideally be measured for each formulation developed [1].

Conclusions. MCTs alone and in SEDDs formulations are increasingly used to increase solubility and oral bioavailability of CBDs. This allows manufacturers to provide a product that is more potent biologically (also providing a competitive commercial advantage); and at the same time, provides for the independent (possibly synergistic) benefits of C8/10 MCT oils.

Sonomechanics Blog

Water-Soluble Cannabis Oils: Microemulsion, Liposomes or Nanoemulsion?

[fa icon=”calendar”] Nov 24, 2016 9:00:00 AM / by Alexey Peshkovsky, Ph.D.

Industrial Sonomechanics is launching a series of blog posts dedicated to describing the main principles of developing water-compatible cannabis extract formulations, also known as water-soluble CBD and THC. As explained in our earlier blog post, since medical marijuana extracts are oils and, as such, not soluble in water, they have to be specially formulated in order to become water-compatible and acquire the appearance of being water-soluble. There are three formulation classes that can provide this property: microemulsions, liposomes and nanoemulsions.

Microemulsions and nanoemulsions are described in our earlier article as well as in this free eBook:

However, due to a large number of questions we have been receiving on this subject, we though that it deserves to be expanded upon in this separate article.

Oil-in-water emulsions are visually homogeneous mixtures that combine the properties of both oil and water, wherein water is the continuous phase and oil is the dispersed phase, stabilized by at least one surfactant (emulsifier). There are three main types of oil-in-water emulsions: macroemulsions, microemulsions and nanoemulsions. Liposomes can be used to create similar types of oil and water mixtures with some notable differences, as explained below.

Macroemulsions are common emulsions with droplets averaging over 1 micron in diameter and generally having wide droplet size distributions. They are unstable and tend to separate into an oil layer at the top and a water layer at the bottom, sometimes with a mixed layer in between. Due to their lack of stability, macroemulsions are generally not suitable as water-compatible cannabinoid delivery vehicles.

Microemulsions are translucent and thermodynamically stable mixtures of oil, water and surfactants having average droplet diameters below 100 nm. They can be spontaneously formed by “solubilizing” the oil in water or a beverage by very high amounts of surfactants – substantially higher than the amount of the oil. Because of many undesirable side-effects caused by concentrated surfactants (health issues, taste deterioration, etc.), the use of microemulsion-based, water-compatible cannabis oil formulations is disadvantageous. Furthermore, it is frequently impossible to achieve the desired cannabinoid concentration in a beverage without exceeding maximum permitted surfactant levels.

A typical microemulsion precursor (before the addition to a beverage) formulation is presented below [1]:

  1. Active ingredient (e.g., cannabis oil extract) ————- 10.00 %
  2. Carrier oil (e.g., Miglyol 812) ——————————- 30.00 %
  3. Surfactant 1 (e.g., oleic acid) ——————————- 15.00 %
  4. Surfactant 2 (e.g., Tween 80) ——————————- 33.75 %
  5. Surfactant 3 (e.g., Cremophor RH 40) ——————– 11.25 %

For a typical cannabinoid dose of 10 – 15 mg, about 20 – 30 mg of cannabis oil extract (assuming 50 – 70 % cannabinoid concentration) needs to be mixed into a beverage. With the microemulsion-type formulation, the same beverage will also end up with about 120 – 180 mg of surfactants, making it taste soapy and (for many surfactants) bitter, as well as potentially leading to regulatory compliance issues.

Liposomes are spherical structures with diameters from about 50 to 5000 nm formed by one or more concentric phospholipid bilayers with an aqueous phase inside and in-between the bilayers. Liposomes can entrap water-soluble (hydrophilic) active ingredients in their internal water compartment and water-insoluble (hydrophobic) active ingredients in their bilayer membrane. The latter property makes it possible to use liposomes to formulate water-compatible cannabis extracts. This, however, involves complex preparation procedures and, as with microemulsions, very high surfactant (lecithin phospholipids) concentrations. In addition, it is difficult to produce liposomal formulations using natural cannabis extracts, requiring the use of synthetic or isolated cannabinoids instead.

A typical liposome precursor (before the addition to a beverage) formulation is presented below [2]:

  1. Active ingredient (e.g., synthetic cannabinoids) ——– 18.90 %
  2. Surfactants (e.g., lecithin phospholipids) —————– 75.60 %
  3. Encapsulant (e.g., sodium alginate) ———————— 5.50 %

Nanoemulsions are emulsions with narrow droplet size distributions centered below approximately 250 nm. Nanoemulsion-based formulations in which all droplets are smaller than 100 nm are optically translucent, achieving progressively higher degree of clarity as the droplet sizes are diminished. These formulations have several attractive properties, including low viscosity, high interfacial surface area and long-term kinetic stability. Nanoemulsions are made using significantly (about 10 times) lower surfactant amounts than microemulsions or liposomes. They are completely water-compatible and can be easily mixed into water or any beverage.

A typical nanoemulsion concentrate (with some water, but before the addition to a beverage) formulation is presented below [3]:

  1. Active ingredient (e.g., cannabis oil extract) ————- 5.40 %
  2. Carrier oil (e.g., olive oil) ———————————— 7.20 %
  3. Surfactant (e.g., Quillaja saponin) ————————- 2.00 %
  4. Water ———————————————————–85.4%

For a typical cannabinoid dose of 10 – 15 mg, requiring 20 – 30 mg of cannabis oil extract to be present in a beverage, a nanoemulsion-type formulation will only contain about 7 – 11 mg of surfactant, making the beverage much easier to bring into compliance with regulations and helping it retain its original taste. In addition, nanoemulsions can be produced using natural surfactants (formulation shown above), which avoids having any synthetic ingredients in the resulting products.

The reason that cannabis oil nanoemulsions require much lower surfactant concentrations than the alternatives is that the driving force for their formation is mainly mechanical instead of chemical. Nanoemulsions can be produced by utilizing ultrasonic cavitation-derived high shear forces, able to break the oil droplets down to nanometer sizes.

Laboratory, bench and industrial-scale ultrasonic liquid processors specially designed for the production of high-quality nanoemulsions are available from Industrial Sonomechanics. We also offer help with the development of formulations for “nano-cannabinoids” starting from different types of cannabis extracts or cannabinoid isolates.

Formulating with Cannabis

The cannabis market continues to burgeon, both domestically and globally. As of 2019, North America holds the largest revenue share at 88.4%, but the global legal marijuana market size is expected to reach USD $73.6 billion by 2027, according to Grand View Research. 1 And although the global market is slated to expand at a compound annual growth rate (CAGR) of 18.1%, the market still faces hurdles when it comes to formulating new cannabis products.

Formulation Challenges

Many factors affect formulation—from efficacy to taste—and much of it depends on the delivery form. For example, edibles have the issue of taste. Masking the taste of actives or minimizing the taste of surfactants and emulsifiers presents a challenge. Another factor is that different cannabinoids exhibit their own formulating characteristics. For instance, cannabidiol (CBD) and tetrahydrocannabinol (THC)—full- and broad-spectrum CBD and THC—will formulate similarly; however, the other bioactives found in cannabis extracts, such as terpenes, sterols, fiber, etc., may strongly impact the formulations and their functionality, solubility, and taste. But overall, according to Alice Hirschel, PhD, nutritional business director at ABITEC, the two major challenges that product developers face are improving solubility and ensuring absorption of the cannabis actives.

Solubility

“Cannabis extracts, including all forms of CBD and THC, are hydrophobic, meaning they are not soluble in water,” Dr. Hirschel explains. “This creates a challenge when formulating a variety of delivery forms.”

To overcome this, emulsions are used to solubilize cannabis extracts so they can be included in more delivery forms, including edibles, functional beverages, gummies, personal care products, etc. For example, data supports ABITEC’s CAPTEX ® 8000, a caprylic acid medium-chain triglyceride oil, achieving up to 40% w/w solubility of CBD. Its CAPMUL ® GMO-50 and CAPMUL ® MCM C8 ingredients have a high capacity to solubilize cannabis extracts, and they also function as emulsifiers. Moreover, CAPMUL ® ingredients function as food preservatives due to their ability to provide protection, stability, and increase shelf-life.

Bioavailability

Beyond solubility is bioavailability. “As lipophilic (lipid-loving) actives, cannabis extracts need to be solubilized in lipids, and these lipids may also facilitate in their absorption upon ingestion,” Dr. Hirschel says. “Lipid delivery systems have been used for decades to deliver hydrophobic actives in easy-to-use, convenient delivery forms that also support absorption.”

ABITEC’s SENDS formulations—which include a solubilizer, an emulsifier, and a surfactant and/or co-surfactant—enhance solubility and promote emulsification of active nutraceutical ingredients (ANIs), such as cannabis extracts, leading to greater bioavailability.

“The combination of these ingredients and steps for formulating a SENDS ™ will vary based on the ingredients of the end-use product,” Dr. Hirschel explains. “Each SENDS ™ formulation is custom designed to optimize the ANI. Optimization can include increased bioavailability, enhanced formulation efficiency to reduce dose, and protection of the ANI during processing and in the gastrointestinal environment while reducing food effect.”

Transdermal Penetration and Lymphatic Transfer

Topical applications present a unique challenge to absorption. “Transdermal-penetrating formulations require the optimized concentration of carrying excipients and penetration-enhancing excipients to produce the desired flux across the stratum corneum (the outer layer of the skin) to the site of release,” says John Tillotson, RPh, PhD, pharmaceutical and nutraceutical technical business director at ABITEC. Many of ABITEC’s CAPMUL ® ingredients can increase transdermal penetration by hydrating the stratum corneum, allowing for the transdermal administration of CBD and THC.

For oral products, “To increase bioavailability, some or all of the active ingredients may need to be driven into the lymphatic system to avoid first-pass metabolism,” Dr. Tillotson says. Long-chain lipids, such as CAPTEX ® GTO and CAPMUL ® GMO-50 from ABITEC, help drive lymphatic transport of CBD and THC, leading to decreased first-pass metabolism and improved bioavailability.

As companies like ABITEC continue to create solutions for solubility and bioavailability in cannabis formulations, product developers are using these solutions to engineer new, innovative delivery forms and label-friendly formulations that satisfy consumers’ needs and growing market demands.

Reference

Grand View Research. “Legal Marijuana Market Size Worth $73.6 Billion by 2027 | CAGR 18.1%.” Published February 2020.