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7 Things to Consider in Medicinal Cannabis Development
14-12-2018

#7 Things to Consider in Medicinal Cannabis Development

Mention the word cannabis and the confusion starts; legal or illegal, nutraceutical or medicinal product, psychoactive or non-psycho-active, clinically significant or not. At the same time, the cannabis industry is booming and attracting many investors. Currently mainly focused on the growing of the plant and exploiting the benefits of medicinal cannabis but more and more the focus shifts to the use of purified cannabinoids into medical products. In this blog, you will find out more about the regulations regarding medicinal cannabis and what to expect of it in the near future.


1. Cannabis

The first thing to set straight is the name cannabis. This is not a specific type of plant or product but more an all-encompassing term of a number of plants, materials, and products. The two common active substances (cannabinoids are called THC and CBD and are representative for the majority of endeavors in cannabinoid product development. THC and CBD are quite different from one another and in the table below you can see a comparison. Next to these two, there are over a hundred other known cannabinoids with slightly different chemical structures.

 

 

THC

CBD

Psychoactive

Yes

No

Legal status

Listed in narcotic laws, exemption needed1

Not listed in most countries (except US, UK, and some others)1

Origin

Weed plant

Hemp (grown for fiber)2,3

Growing location

Hot and humid climate/greenhouses

Moderate climate2

Products

Medicinal/recreational

Nutraceutical/medicinal

Appearance in pure form

Sticky oil/resin

Crystalline material

Stability

Unstable towards oxygen and light

Stable

Receptor activity

CB1/CB2 partial-agonist

CB1/CB2 antagonist

Proven clinical effects

Relieving chronic pain, muscle spasms, nausea

Epilepsy

Products

Marinol, Sativex (in combination with CBD)

Epidiolex (Lennox-Gastaut and Dravet Syndrome)

  1. please check the legal status if you embark on a cannabis project
  2. specially bred CBD-containing plants are grown in greenhouses. These are mainly intended for medicinal products
  3. if hemp is grown to isolate CBD, an exemption from the narcotics law is required in most countries

2. Regulations

So how is medicinal cannabis regulated? Currently, there are 27 countries, mainly in Europe and the Americas, where medicinal cannabis is permitted. It is usually prescribed by GPs and provided by pharmacies. Pharmacies obtain their packaged product from wholesalers and those from growers of cannabis plants. Both the growers and the distributors require licenses from local governments to be allowed to work with this plant material. To obtain such a license you’ll need to demonstrate aspects such as:

  • protective measures to prevent cannabis material from going missing
  • the exact handling of the material
  • growing,
  • importing,
  • re-packing,
  • storage,
  • distribution,
  • R&D-activities,

Currently more than 100 producers have been successful in obtaining the license, mainly in Canada. Having said that, it’s complicated to work in several countries at the same time because each country has its own set of regulations.


3. Quality Standards

When producing medicinal cannabis, Health Authorities may require a product to comply with the standards described in the Good Manufacturing Practice guidelines (GMP), e.g EU countries. This is managed by clearly defining specifications for possible quality risk factors like:

  • content
  • moisture
  • foreign matter
  • microbiology

Information on GMPs can be found in EU GMP “Eudralex 4” or the United States FDA 21CFR part 210 and 211

Interestingly, the GMP isn’t required for planting or seeding of cannabis plants. Instead, this typically requires Good Agricultural Practice (GAP which secures a constant quality of the plant material and is often done in a secured greenhouse).  GMP usually starts at harvest of plant buds.


4. Extract or purified substance?

Currently, the cannabis industry’s focus is still on plant material possibly because the terpenes exert a beneficial effect and dried buds are easy to get by and use. Besides this, the actual use of plant material ranges from tea made from the leaves to smoking it. It comes as no surprise that standardizing the use of cannabis to secure constant dosing for patients is key and it’s certainly worthwhile to investigate more advanced ways of delivering cannabinoids.  For instance, by presenting an extract or purified THC / CBD to patients you increase your control over the contents and dosing becomes more accurate, opening possibilities to investigate treatment efficacy in clinical trials. A number of companies are already using purified THC and CBD (essentially pure active substances) in clinical studies aimed at obtaining marketing authorization.

Example:  Sativex. By extracting the active materials from the plant and formulating it as a spray, GW Pharma obtained a marketing authorization in the EU and Australia. They did the same to register CBD in the US for treatment of rare epilepsy syndromes.

This is remarkable because the extracts used for Sativex still contain a large number of other cannabinoids as well as terpenes. Although we assume it’s because of the THC and CBD, it is not clear which components are actually responsible for the efficacy in pain reduction or reduction of seizures.


5. Formulation

Whether extracts or purified cannabinoids are used, there is a number of possibilities to administer these active substances to patients; each with their own pros and cons. Therefore, when embarking on a cannabis project (or any project in fact) it is useful to start with the patient in mind and define requirements that will treat a patient in the most comfortable way possible.

Some of the formulations:
 

 

Pros

Cons

Oral tablet

Easy to use

High first pass effect (extensive metabolism by the liver)

Cumbersome manufacturing

Inhalation

Demonstrated way of delivery (recreational use)

High plasma level leading to psycho-active effects

Patch

Easy to use

Only low doses can be given

Mouth spray

Immediate delivery

Only low doses can be given

Chewing gum/pastilles/lozenges

Easy to use

Cumbersome manufacturing


6. Stability

One aspect that needs to be considered when extracting and purifying THC is its stability, or rather its instability. Unlike CBD, THC is vulnerable to oxygen, light, and possibly moisture and it is readily decomposed by radical oxidation. This means standard formulation techniques aren’t sufficient to provide a stable drug product and instead requires encapsulation techniques. Methods have been developed to protect the THC by encapsulation into a polymeric or a liposome matrix. Surprisingly, the dissolution in aqueous ethanol mixture also exerts a stabilizing effect as demonstrated by the Sativex spray developed by GW Pharma.


7. Clinical studies

As previously stated, a number of treatments have been approved by Health Authorities. These are mainly in the area of pain reduction, emesis, nausea and symptom reduction in MS-patients. It is known that cannabinoids act on a multitude of different receptors in the body, either as agonists or antagonists, and could potentially interfere with disease mechanisms. Therefore, cannabinoids are thought to have the potential to treat or cure also diseases such as cancer (see e.g. the excellent review paper of Massi et al.)


Future

So, why haven’t we found more cures to date? Is it possible that the multi-compound containing plant material has hampered the progression of cannabinoids in approved treatments? As indicated before, these are ill-defined materials of a number of cannabinoids and terpenes and with a multitude of administration routes. So, claims using medicinal cannabis can’t be substantiated with clinical evidence. With THC and CBD now readily available as GMP-material, the scientific community is more suitably equipped to perform clinical studies. Hopefully resulting in approved drug products that treat patients safely and effectively.

Blog by: Jan Zorgdrager & Marc Stegeman


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