Oral Ingestion of Hemp Oil

 Pharmacokinetic studies have shown that when cannabis, or hemp oil products are ingested, only about 5%-10%
 of the cannabinoids get absorbed into the blood stream (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558665/), some of them are metabolized and degraded, but the majority is excreted unchanged in feces (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689518/). In order to have noticeable benefits from lipophilic compounds like CBD, it needs to accumulate in the body to specific levels, which could take weeks of every day use of a CBD oil tincture with a high concentration of at least 1000mg/30ml (33mg/ml). Now imagine if only 5% of this concentration goes systemic. This means that only 1.65mg/ml of CBD goes systemic and if taken once a day for 30 days, the absorbed CBD will reach 50mg. In the 2019 four randomized, double-blind, parallel-group, adjunctive-therapy clinical trials “Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy” published by Valentina Franco and Emilio Perucca (www.pubmed.ncbi.nlm.nih.gov/31372958/), it was determined that the therapeutic dose of CBD that stops seizures is 10mg/kg/day-20mg/kg/day. Lets consider a case of a 5 year old girl who has a weight of 18kg and has 40 seizures per day. She will need to absorb a dose of at least 180mg of CBD per day to prevent or reduce seizures. That is over 100 times the dose she would absorb from using an oil tincture with 1000mg of CBD per 30ml bottle. To achieve therapeutic dose, she would be forced to take very large amount of the oil to account for up to 95% loss of CBD in the body. This would lead to accumulation of oil in the body because the body can not quickly get rid of that much oil, which is not very healthy.

Topical Absorption of Hemp Oil

Absorption through an intact skin is an extremely complicated process and there are many conflicting clinical studies that exist. The main reason for varying results is that a drug transport through the skin depends on many factors and different compounds absorb via different routes. Transport of drugs though the skin happens either through the inter-cellular spaces/channels, or through hair follicle channels and sweat glands. The flux depends on parameters like the water activity of the drug delivery system as well as the skin, the composition of the drug delivery matrix and the drug compounds themselves and many other factors. Human skin is a layer that protects us from the environment outside the body, so naturally penetrating the top layer is extremely difficult.

Depending on the molecular weight and hydrophilicity/lipophilicity of the substance that comes in contact with the skin, the transport through it changes. According to the “500 Dalton” rule, if a substance has a molecular weight of more than 500 Dalton, it will not be able to penetrate the top layers of skin through the intercellular channels. If the substance is an oil and it has a molecular weight of less than 500 Dalton, it will penetrate through the intercellular channels because those channels are made of phospholipid bi-layer and so are lipophilic.
For example when CBD oil is applied on the skin, it never reaches the bloodstream, but can be absorbed through the top layers of the skin (stratum corneum) to interact with nearby cannabinoid receptors. In order to understand the transport of CBD oil through the skin we need to understand the layers of the skin and what those are composed of. The skin is composed of epidermis, dermis, and hypodermis (Pic. 1). The epidermis is composed of the layers of stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum and stratum basale (Pic. 2) (https://www.sciencedirect.com/topics/medicine-and-dentistry/epidermis).
The dermis has connective tissue, blood vessels, sweat glands, nerves, hair follicles, and other structures, which is why it is hydrophilic. CBD that has a molecular weight of 314 Dalton can penetrate through the stratum corneum via the intercellular channels, but will have a hard time penetrating further, and any water soluble compound has a hard time penetrating through stratum corneum, but will go systemic as soon as it’s in the dermis. This is why, studies show that CBD can penetrate as far as the sebaceous gland area which is the bottom of the epidermis, but it doesn’t goes systemic.
Luckily, for cosmetic purposes it is important for the oil to stay in the epidermis and interact with the cannabinoid receptors. This has been proven to be effective even for peripheral neuropathy pain relief (https://pubmed.ncbi.nlm.nih.gov/31793418/). However, if the pain is much deeper (muscles, joints,…) this will not help.
Pic. 1 The structure of the skin and it’s layers 
Pic. 2 The structure of the stratum corneum
For that kind of pain CBD will have to penetrate into the muscles, joints and connective tissue, for which, it must make it’s way into the blood, which then will carry it everywhere in the body including the muscles, joints and other tissues that need pain and inflammation relief.

GI Tract Bio-availability Improvement

In order to increase the bio-availability and absorption, the oil droplet size has to be decreased. In order to do that, some use devices like microfluidizers and others use ultra-sonification, however the one common thing is that an appropriate emulsifier system is needed in order to be successful. Most people use synthetic emulsifiers like Tween 80, Span 80, and solvents like Propylene Glycol and Ethanol to achieve a 100nm-200nm droplet size, which results in a milky nano-emulsion. Some small number of companies even achieve 50nm-100nm droplet size range. However, clinical studies performed on various Cyclosporine nano-emulsions (https://sci-hub.se/10.1002/jps.20057) found that the nano-droplet size correlates with the GI Tract bio-availability (blood concentration) in a following manner: In case of the oil droplet size range of 100nm-1000nm the bio-availability improves marginally and is similar to the bio-availability of the micro-emulsion. This is why, emulsions with droplet size of more than 100nm are considered micro-emulsions and not nano-emulsions. When the droplet size dips below 100nm there is a spike in bio-availability and the emulsion is considered a nano-emulsion. Most emulsifiers and technologies can only achieve a slightly sub 100nm droplet size, but some do reach 60nm-100nm sizes. In that range the bio-availability does not vary significantly and the nano-emulsion is still milky white, but as soon as the size drops to 60nm, the nano-emulsion is translucent and the bio-availability spikes again and changes significantly with the slightest change in the droplet size. See (Pic. 3) for the nano-emulsion translucency v.s. droplet size, and (Pic.4) for blood concentration v.s. droplet size.

Pic. 3 CBD nano-emulsion translucency v.s. oil droplet size.
Pic. 4 Blood concentration v.s. time for various nano-emulsion sizes, showing spikes in bio-availability for various oil droplet sizes. “Cyclosporine Nanoparticulate Lipospheres for Oral Administration”, T. Bekerman, J. Golenser, A. Domb, Journal of Pharmaceutical Sciences (2004), 93(5), 1264-1270. doi:10.1002/jps.20057.
Cyclosporine was used in the study above because of the lack of legitimate clinical studies performed with CBD oil. However, it is universally accepted that in terms of GI Tract bio-availability the size of the oil droplet is the most important parameter in determining the bio-availability of the oil.
  As can be seen from Pic. 3, below 60nm is when one can start seeing translucency, and below 30nm is when you can see through the nano-emulsion.

NanoFact Technologies Solution to the Absorption and Bio-availability Problems
  In order to solve the problems associated with low absorption of hemp oil through the gastro-intestinal tract and skin, we developed a unique solution that will work for both routes of cannabinoid administration. We use all natural (GRAS) Generally Recognized As Safe ingredients to increase the bio-availability of the hemp oil. As was shown above, the bio-availability directly correlates with the oil droplet size. The smaller the oil droplet size, the larger the bio-availability and absorption of the oil in the GI Tract. Lets look at the parameters that affect the oil droplet size independent of the oil type.
  The droplet size depends on the following critical parameters:
1. Concentration of the oil in the nano-emulsion
2. Carrier oil used
3. Type of emulsifiers used
4. Ratio of the emulsifiers to oil
5. Equipment used, time, batch temperature and many other batch parameters.
  NanoFact Technologies has been able to achieve droplet sizes of as low as 1.2nm (Pic. 5), and can control the size with high precision. In order to achieve a droplet size of 1nm-10nm the oil concentration will have to be low for a higher emulsifier : oil ratio. For droplet sizes in 10nm-50nm range, the parameters will have to be adjusted accordingly.
  We use ultrasonication in flow through mode to break down the oil droplets and make nano-emulsion batches in large scales of up to 25L/hour. The emulsifier we use is made of natural phospholipids, natural carrier oil and natural Vitamin E (not the synthetic Vitamin E TPGS). The natural Vitamin E keeps the emulsifier and the nano-emulsion self preserved without a need for preservatives.
  We make nano-emulsions with active ingredient concentrations from 10mg/ml to 50mg/ml, and there are no solvents used in the process except distilled water. Our nano-emulsions can be used to make pharmaceutical products, dietary supplements, foods and OTC products like gummies, candy, lozenges liquid tinctures, powders, pills and capsules, semi-solids like creams, gels, lotions and others, as well as trans-dermal and topical patches and tapes.
  NanoFact Technologies CBD nano-emulsion with 30mg/ml concentration and d50 of 25nm average droplet size and size distribution in the range of 10nm-50nm range is presented in (Pic. 6).
Pic. 5 Droplet size distribution we have been able to achieve with our proprietary process. Here, 3 sets of measurements were made using a Dynamic Light Scattering particle analyzer at the UCLA Chemistry Lab by a professor. This instrument can measure particle sizes from 1nm until 6um. Dynamic light scattering determines size from the fluctuations in scattered laser light intensity created by the particle's Brownian motion. The average droplet size is 1.2nm but in 2 out of 3 sets of measurements it stretches to up to about 3nm, and in the third one it's up to 13nm.
Pic. 6 Represented the transparency of a 30mg/ml CBD nano-emulsion of about 25nm average droplet size achieved by NanoFact Technologies.
Nano-droplet transport through the GI Tract
  As previously discussed the size of the oil droplet correlates with it’s bio-availability in the GI tract. That being said lets visualize the transport of the oil droplets through the GI tract epithelium wall. Epithelial wall representation can be seen in (Pic. 7) taken from https://www.ncbi.nlm.nih.gov/books/NBK54098/
Pic. 7 Architecture of the gut mucosal wall. Four-layered (mucosa, submucosa, muscularis mucosa, and serosa) organization of the digestive tract.
 Penetration through this epithelial mucosal wall is imperative for the oil to be absorbed by the gut. Hydrophilic compounds easily go through the wall and get absorbed, but lipophilic compounds like oils can not, so the body releases enzymes that break the oil down to be able to absorb at least some of it, and the rest is excreted unchanged. This process takes time and energy that negatively affect the human body, and our goal was to solve this problem. By nano-sizing the oil to sizes that are easily absorbed by the GI epithelial wall, the oil will penetrate the wall unimpeded, which will result in significantly higher bio-availability and easy absorption that prevents the strain digesting oil puts on the gut and the immune system. The next picture (Pic. 8) represents the nano-droplet micelles and a large oil droplet making contact with the GI epithelial wall. The “emulsion droplet” depicted in the picture is referring to the droplets achieved in the process of micro-emulsification, and micelles represent the nano-emulsified oil droplets that have a size of 10nm-30nm.
Pic. 8 Nano-droplet micelles and a large oil droplet making contact with the GI epithelial wall.
Nano-droplet transport through the skin
  As was discussed previously, there are 2 routes of drug delivery through the skin: Directly through the skin layers and through appendages (hair follicle channels and sweat glands). We have also discussed that because the intracellular channels are made of phospholipid bi-layer, which is lipophilic, oil chooses the route through those phospholipid channels (Pic. 9).
Pic. 9 Sketch of the morphology of human stratum corneum: The stratum corneum is composed out of rigid corneocytes (CC), dead cells densely packed with keratinous filaments in a matrix of connecting proteins and confined by the cornified envelope (CE), separated by the intercellular space (IS) filled with lipid compounds (fatty acids, ceramides etc.,) and aqueous films to form lamellar lipid bilayers (LLB). This was taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835875/
Studies showed, that oil-in-water micelle nano-emulsions and liposomes mostly prefer the route of the skin appendages (hair follicles and sweat glands), which lead directly into the blood. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835875/.
  Follicular and sweat gland channels are much larger than intercellular spaces and can accommodate nano-droplets easily. This means that nano-droplets can penetrate through the skin and go systemic without going through the layers of the skin, more notably stratum corneum which is the most powerful obstacle for them due to its lipophilic and barrier properties.
  To assist the nano-droplet penetration through the skin appendages, a hydrogel formulation is the most appropriate, because it hydrates the skin and fills the sweat glands with water, which becomes a better route of transport. This is what our trans-dermal patch technology is based on. Our hydrogel patches are designed to deliver a needed load of nano-emulsified CBD into the blood stream by trans-dermal drug delivery through skin appendages as well as directly through the skin layers, which is why the delivery system offers a very quick burst release, followed by a sustained release of CBD for days due to delivery via 2 different routes as well as the fact that the patch matrix has an expanded loading capacity and CBD slowly migrates from the back side of the patch to the front as the concentration of CBD at the front drops down due to penetration.
  Our Kinesiology Tapes are made using a proprietary acrylic matric technology, which allows for the tape to be stretched appropriately and allows for a similar delivery profile to the hydrogel patch technology.
  Our technologies are currently in a patent pending status.
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