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ProPharma Group talk through how to chew THC cannabis gum

ProPharma Group talk us through the process of creating a trial using chewing gum containing THC.

ProPharma Group has a global network of experts to support you in development of drug product, entering clinical studies and help you to get approval for a medical cannabis product in your country.

This article will provide an example of how we successfully supported a client with an idea of using chewing gums with THC for medicinal purposes.

Introduction to cannabis

The medicinal cannabis industry is rapidly maturing.

The cultivation of Cannabis sativa plants has increased substantially over the last few years and extraction techniques have been developed.

Therefore, THC and CBD are now readily available both as the pure compounds and as full spectrum cannabis extract in which most of the cannabinoids that have identified in the cannabis sativa plant are present including terpenes.

Simultaneously, several clinical studies have been conducted to understand whether cannabinoids can treat conditions or help alleviate symptoms. In only a few cases have they resulted in successful outcomes and approval was obtained from the health authorities.

Well-known examples are: Marinol (in the US, chemically synthesised THC to treat loss of appetite in people with AIDS and nausea in cancer patients), Sativex (1:1 ratio of full spectrum THC and CBD to improve symptoms of spasticity in MS patients ) and epidyolex (a CBD oral solution to treat rare but serious forms of childhood onset epilepsy).

The latter product surprisingly acts – at least partly – through de-activating a number of CYP-enzymes in the liver responsible for metabolising Clobazam, which is often a co prescribed drug in those patients.

The primary metabolite of Clobazam is active as well and its further metabolism is delayed due to the inhibition of a CYP-enzyme. The built-up of the primary metabolite may well be partly responsible for the favourable outcome. Further research is ongoing to unravel the mechanism of action.

Other studies in a range of conditions have not shown significant effect compared to placebo; at least not statistically significant. Many factors may have contributed to this such as the study was not significantly powered (i.e. the number of patients was not sufficient to demonstrate efficacy over placebo), or the type of the medicinal product used (i.e. pure cannabinoids or mixtures, such as full spectrum cannabis extracts with or without terpenes).

On top of that, many different types of route of administration have been used: inhalers for pulmonary administration, oromucosal and oral administration, as well as topical formulations. Another question that may arise is, have the inhaler devices and vaporisers been studied to a level that accurate and consistent dose delivery is guaranteed? All these variables make it hard to compare one study to another and to find out why there is anything more to treatment with cannabinoids than the aforementioned products.

Whether extracts or purified cannabinoids are used during these studies, there are several possibilities to administer active substances to patients; each with their own pros and cons.
When working with medicinal cannabis, it is important to start with the patient in mind and define requirements that will treat a patient in the most comfortable / appropriate way possible.

There are quite a few patient groups strongly advocating the use of THC, CBD or mixtures for treatment of various conditions such as PTSS, ADHD and pain. They often report that they have found in cannabinoids an effective treatment for their ailment after a long search for the best combination of active substance, administration route and delivery device. Can we consider cannabinoids as possible personalised medicines in which for every patient a unique combination is needed? To continue the studies to discover more about treatment with cannabinoids, it is important to be able to navigate the field with an expert to support the processes.

We can only progress the use of cannabinoids as a drug through sound, science-based research using selected patient groups and employing standardised medicine. We are a consultancy company offering support for the pharmaceutical industry in the areas of life cycle management, regulatory affairs, pharmacovigilance and medical information.

We have supported many cannabis pharmaceutical companies in building quality systems, participation in tender procedures, import of medical cannabis from Canada and other non-European countries into Europe and support in filing CTAs and INDs for clinical studies using cannabis. In the last couple of years, we have also been involved in the development of a medicinal cannabis chewing gum.

Let me walk you through this adventurous journey.

Problem statement

The client is a virtual company lacking deep knowledge of developing a product towards clinical studies. They wanted to develop a formulation for oromucosal administration of THC or CBD or combination of both. A chewing gum formulation was chosen as the active substance would be administered in the buccal/oromucosal area thereby avoiding the oral route.

The oral route is known to deliver only low amounts of THC due to a first pass effect i.e. clearance of THC by the liver, which results in a bioavailability through the oral route of only 15%. It was speculated that mastication (chewing) would also have a positive effect on pain one of the possible indications. The use of other modes of oromucosal delivery were excluded as those would not require mastications. On this basis, ProPharma Group was asked to develop an overall development plan including formulation, regulatory and clinical strategies.

How did we approach this project?

Target product profile

The approach of ProPharma Group in developing a product is to start with the target product profile. It in fact defines the future labelling of the product and thereby helps focusing the development efforts. It is an important starting document and will be adapted during development based on the findings.

We defined the following aspects for the chewing gum:
  • Product description: bio-comparable to existing marketed products in the field such as Marinol and Sativex. Striving for bio-equivalency was considered too daring as the formulation is so different from the oral and sprayed oromucosal formulations. There was also a wish to have higher dosages of CBD to treat PTSS (Post-Traumatic Stress Syndrome);
  • Formulation: a gum of two grams containing up to 20 mg of THC and up to 400 mg of CBD;
  • Release: preferably slowly but within five to 10 minutes;
  • Stability: at least two years; and
  • Markets: primarily US but also Europe.
Project team

After deciding on the TPP, a dedicated project team was set up to address all the activities needed to progress to the first clinical study which would be a PK/PD-study with the chewing gum containing THC. ProPharma Group has a network of over 1,100 in-house and external subject matter experts on formulation and analytical as well as on quality and regulatory aspects and clinical.

Complemented with project management services, we can support all activities in the quality and regulatory field needed to bring a product to clinical studies and beyond. As an independent partner, ProPharma Group can support you in navigating and managing all parties you need to involve such as regulatory bodies, manufacturing partners and contract research labs. On top of that we have a database with trusted vendors. External input was required to address the needs of this project. We defined four work streams necessary to support the development of this product.

  • CMC (chemistry, manufacturing and controls ): consisting of experts in the field of extracting the plant and producing purified API’s (active pharmaceutical products) and formulation development as well as manufacturing exerts capable of carrying out the production of both the API and the chewing gum;
  • QA (quality): consisting of experts who built a quality management system from scratch, covering both CMC and GCP aspects of the project. This team was also responsible for obtaining a manufacturing licence as well as the controlled substance licences to support the import and export of cannabinoid products as well as the storage of these products at CMO/CRO’s;
  • RA (regulatory affairs): consisting of experts in the field who could support the development of the product throughout its journey; from developing the regulatory strategy to scientific advice at regulatory bodies as well as compiling and filing dossiers to support clinical study applications; and
  • Clinical: consisting of experts who were responsible for drafting the clinical protocols and participant facing documents and were also in charge of executing the clinical study in healthy volunteers.

Each work stream was led by a project lead who represented his or her specialty within the core project team. The team was completed with a sponsor representative and a Project Manager. The core team was mainly focused on overall planning and resolving of issues, rather than on the technical aspects of the project. Technical aspects were dealt within the sub-teams and issues were escalated if these could impact the timelines, budget or compromise the desired outcome of the project. The team structure is depicted in the scheme below.

The team of those experts ran the daily operations of the sub teams. One example of such a sub-team is also given in the picture below.

The journey

With the goal set, the team composition secured, and the project plan written, all the elements were present to start the journey of developing a chewing gum containing cannabinoids.

Initial experiments defined the extraction procedure as well as the decarboxylation of both THC and CBD containing plant materials. This is in reverse to what is regularly done in this industry; first decarboxylation of THC and CBD while it is still present as the acid in the dried buds. This method has the advantage that via an acid/base extraction, terpenes can easily be removed and thus the purified cannabinoids can be obtained by usual purification methods.

Scaling up of this method proved to be possible and therefore we were soon able to obtain sufficient amounts of API (active pharmaceutical ingredient or drug substance) to fully start the development work of the chewing gum. Analytical methods for the API were developed including methods to demonstrate the absence of terpenes.

During development of the chewing gum, it soon became apparent that this was by no means an easy task. Both CBD and THC have a strongly lipophilic character and on top of that are unstable under oxygen and light conditions (except when CBD is in its crystalline form). It is well established that THC decomposes by a radical oxidative process. This precludes the simple mixing of ingredients to form a chewing gum as would typically be done in a tableting process. The lipophilic character of both the chewing gum and the APIs form a combination that will not easily separate and dissolve into the hydrophilic environment of saliva. On top of that, the unprotected APIs would not survive in such an oxygen-rich environment.

How did ProPharma Group meet this challenge from a development perspective? We selected three methods to protect the THC and/or CBD and to still be able to make it available for dissolution. A method based of self-emulsifying principles two distinctly different types of microspheres.

The formed intermediates would then need to be mixed with chewing gum base and further excipients to form a chewing gum. The selection of the best intermediate was done on the basis of stability, ability to release of API, prior IP and manufacturability. One of the microsphere options was chosen as the best way forward and scaled-up.

Tableting of the intermediate with chewing gum base and excipients proved quite uneventful. The only questions remained at which ratio of intermediate versus chewing gum base, the chewing gum still has the texture of a chewing gum. By performing some chewing tests with different ratios of chewing gum and a placebo intermediate product (the microsphere) a preferred ratio could be established which still provided the texture of a chewing gum.

The chewing gum would lose its texture and disintegrate rapidly. With that knowledge, it was clear that the amount of THC or CBD in the gum should be limited and the delivery of hundreds of milligrams of CBD into the chewing gum would not be possible in this way.

The analytical methods were developed and validated and in particular the method to test the release of API from the chewing gum. A chewing gum tester as per European Pharmacopoeia was used to demonstrate that release from such a complex matrix is possible and this method was also validated according to ICH-guidelines.

GMP production of both the API and the drug product went as planned and the material was now ready to start a first clinical trial to establish the PK/PD-profile.

Quality assurance

The customer assigned all QA activities to ProPharma Group. The following activities were included:

• Setting up a quality management system (QMS), a site master file (SMF) and the standard operating procedures needed to work under GMP-conditions;

• Performing audits at the CMO/CRO’s to the sponsor such as the clinical site and the development and manufacturing sites. This included audits at the clinical CRO and the sites where the API and the drug product were manufactured as well as the transporter of the clinical trial material;

• Manufacturing licence was required and ProPharma performed the relevant submission and was responsible for the communication with the authorities during the inspection; and
• Applying for the controlled substance licence. Although not physically handled by the Client, the inspection indicated that the client should also apply for such a licence as they are the owner of the THC-containing product.

These activities were all successfully completed which opened another door to conduct the clinical study.

Regulatory affairs

As with the QA activities, the RA-activities were also assigned to ProPharma Group. First, scientific advice was requested from regulatory authorities to make sure that we were on the right track comparing the chewing gum formulation to existing cannabis containing products. This was done by providing a detailed briefing document to the authorities, which included mostly questions on the clinical development of the product as well as questions on CMC aspects such as the specification of the chewing gum.

During execution of the CMC development plan, reports that formed the basis for the quality part of the IMPD were written by Propharma Group. In addition, non-clinical and clinical parts of the Investigator’s Brochure (IB) were also prepared. The IMPD together with the Investigators Brochure, the clinical protocol and other supporting documentation form the clinical trial application which is the basis of the assessment by the Ethical Committee to grant approval to conduct the clinical study.

All three activities were delivered successfully and on time.

Clinical

The clinical study will be conducted by a clinical CRO. The CRO developed the clinical protocol and supporting plans and related documents around data management, safety reporting, lab assessments, monitoring, etc. The sponsor/client maintains overall responsibility for the conduct of the study. Competent authorities advised that GCP compliance should be supported by an external person to ensure no bias towards the results and possible issues during the study. ProPharma Group GCP expert will support this aspect of the project.

Work streams coming together

Now that all work streams have delivered their objectives, the scene is finally set for a beautiful ending. Currently, the research ethics committee is reviewing our responses to questions they had after their first review and it is likely that the clinical study will start in the next few months.

Conclusion

This example shows that ProPharma Group has a good track record in supporting the complex activities needed to bring a product into clinical studies in the area of cannabinoids.

We set up a project team consisting of four different expertise areas, populated those with relevant SMEs and saw the project through to the initial stages of the clinical study. Now we look forward to the results of this first study in healthy volunteers, which will show us the way to further develop this product.

Jan Zorgdrager, PhD
Principal Consultant
ProPharma Group
+31 (0) 6 15 070 348
[email protected]
Tweet @ProPharmaGroup
www.ProPharmaGroup.com

This article appeared in the first issue of Medical Cannabis Network which was out in January. Click here to subscribe.

ProPharma Group talk us through the process of creating a trial using chewing gum containing THC.

How To Make Cannabis Gummy Bears

Published : Dec 21, 2018
Categories : Cannabis recipes

Cannabis gummy bears are very popular for a lot of reasons: They are small, so you can dose accurately. You can suck on them, so they do work faster than other edibles. And of course, they taste super awesome! Find out how you can make your own cannabis gummy bears!

Cannabis gummy bears are a classic among edibles and they are still hugely popular among stoners all over the world. The sweet little teddy bears make a great way to get your dose of weed and they are perfect for whether you’re a medical user or enjoy cannabis for recreational (aka: fun and chill) purposes. Here is how you can make them yourself!

SOME REASONS WHY CANNABIS GUMS ARE SO POPULAR

As compared to other edibles such as pot brownies and also when compared to smoking weed, cannabis gums have some advantages, which explains why they’re still a favourite treat for many cannabis enthusiasts.

THEY TASTE GREAT

First of all, and this is perhaps the most obvious thing, they simply taste awesome. Honestly, who doesn’t like gums? There is just something about their sweet and sometimes a little sour taste that makes them irresistible. For many, weed gums simply taste better. With other edibles, the weed in them can sometimes make for a somewhat “grassy” taste that may come across as off. Maybe it’s the sweetness of the gums covering up the weedy taste which makes them taste better.

CANNABIS GUMMY BEARS ARE EASIER (AND MORE ACCURATE) TO DOSE

Cannabis gummy bears are smaller than your average weed cookie, which can make them easier to dose. With brownies and cookies, you often don’t know how much cannabis you are getting, and this is why you normally break them into portions. But this isn’t exactly the most accurate way for dosing weed. Gummy bears make dosing a lot easier and more accurate. This can be important for medicinal cannabis users and also for anyone else, if they want to get just the right effect from their weed.

THEY DISSOLVE IN YOUR MOUTH, WHICH MAKES THEM MORE EFFICIENT

This is one of the biggest advantages of cannabis gums: You can just suck on them, so they dissolve slowly in your mouth. When the gums melt away slowly under your tongue, this is one of the most effective ways to get the goodness of cannabis into your body. The reason for this is that the mucosal membranes in the mouth are in particular dense so that cannabinoids can directly enter the bloodstream. Other types of cannabis edibles first need to be metabolised in the body when you eat them. Because of this they are normally taking much longer until their effect kicks in. Cannabis gummy bears are a lot more effective!

YOU CAN STORE CANNABIS GUMS EASIER AND THEY STAY FRESH LONGER

Just like your grandma’s Christmas cookies, weed cookies and other edibles can easily get stale when you store them. They can also crumble and break. Not good! Weed gums are much easier to store. The only thing that can happen to your gums when you store them is that they might stick together. But you can just toss them in icing sugar, so they won’t stick. You can then simply put your gums into a container and place them in the fridge. This way, they will keep fresh for some weeks until you’re ready to consume them.

YOU CAN EASILY MAKE CANNABIS GUMMY BEARS YOURSELF

And here is the best part of it: You can easily make cannabis gummy bears yourself! Unlike gums that you get from a store or the weed gums from your dispensary, they won’t contain artificial colouring, flavours, or other (potentially unhealthy) additives. You can make them with natural ingredients that you can get anywhere. In addition to that, you can also save some nice coin when you’re making your batch of tasty cannabis gummy bears. Here is how you can make your own cannabis-infused gummy bears!

PREPARATIONS FOR YOUR CANNABIS-INFUSED GUMMY BEARS

ACTIVATING (DECARBOXYLATING) YOUR WEED

For making your cannabis gums, you first need to “activate” your weed. This process is called decarbing or decarboxylation. It sounds complicated, but it really isn’t. The reason why you need to activate (decarb) your weed, is that fresh weed won’t get you high. The THCA in cannabis first needs to become THC, which is the compound in cannabis that gives you the high. And this happens when you apply heat to your weed. When you smoke weed, the heat from smoking activates the THC, so you don’t need to do this. But for things like making a cannabis tincture that we’ll be using to make our gums, we need to activate the weed first.

Here is how you do it: Take your buds and crumble them into large pieces. Wrap the weed pieces in tin foil. Place your wrapped weed pieces on a baking dish. Set your oven to 105°C (220°F) and bake your weed for about 45 minutes. This is the temperature at which cannabis begins to decarboxylate, converting the inactive THCA in it into THC!

MAKE A CANNABIS TINCTURE

After you have activated your weed so that it can give you an effect, you need to make it into a tincture. For this you put your decarbed weed into a jar with a lid and cover the weed in the jar with high-proof food-grade alcohol such as Everclear. The alcohol extracts the active compounds from your weed. If you want to make a potent cannabis tincture, you should keep the jar with the alcohol and the weed in a dark place for a week or so. Shake the jar every day for a more effective extraction. If you’re impatient, you can speed up the process; you just have to shake the jar vigorously so that the cannabinoids are better absorbed into the alcohol. But for a potent tincture, it is best if you allow at least a few days for the extraction.

You can also keep the lid open for some hours each day to allow some of the alcohol to evaporate. This way you can get a thicker and more potent cannabis tincture. When the extraction is done after some days, strain the tincture through a cheese cloth or a fine sieve to get rid of all the plant material. You can pour your cannabis tincture into a bottle and store it in the fridge to keep it fresh.

CANNABIS-INFUSED GUMS RECIPE

Now with your cannabis tincture ready, we can get to the fun part: How to make your cannabis-infused gums!

INGREDIENTS

⅔ cup fruit puree, thawed
⅓ cup water
3 tbsp. gelatine
1 tbsp. lemon juice
2–3 tsp. (10–15ml) cannabis tincture
Sugar

HARDWARE

Medium-sized saucepan
Dropper bottle
Baking dish or silicon baking moulds
Cooking spray
Whisk

INSTRUCTIONS

1. Take a medium-sized saucepan and add the fruit puree, water and lemon juice. Put your stove on medium heat. Cook and stir the mix for a few minutes until it is nice and smooth.

2. With a whisk, add 2–3 teaspoons of your cannabis tincture to the mix.

3. Slowly add the gelatine to the mix and continue whisking until you have a smooth mix.

4. Remove the saucepan from the stove. With the dropper of the bottle, transfer the mixture onto a baking dish or into silicon moulds.

5. Put the sheet or the moulds into your fridge and allow to cool for 15 minutes.

6. Remove the gums from the moulds and cut into small bite-sized pieces.

7. Toss your cannabis gums in icing sugar to keep them from sticking together. Tip: If you like your gums sour, you can also toss them in a mix of sugar and citric acid!

8. Place your gums in a container with a lid and store in a cool, dark location. You can keep them fresh for 2–3 weeks.

HOW TO DOSE YOUR CANNABIS GUMS

With most other edibles, the effect from cannabis will normally take longer until it kicks in—up to 30 minutes to an hour. When you’re slowly eating your cannabis gums and let them dissolve in your mouth under your tongue, they will be very potent and you will feel an effect much earlier.

Of course, everyone is different, and what works for one may not work for someone else. It can be recommended that you start with one gummy first and wait some time, so you see about the effect. You should also know that edibles are usually working for much longer as if when you’re smoking weed, which would be another thing that you may want to consider if you’re planning for some good time.

The best way to find your perfect dose is when you keep it safe. Always start with lower doses and listen to your body. If you have found the right dosage for your weed gums, it can help when you note down how much you had. This can also be useful if you had too much, so you can simply try a lower dose next time.

Enjoy your own yummy cannabis-infused gums!

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Cannabis gummies make great edibles. They taste awesome and have many other advantages. Find out how you can make your own cannabis gummy bears! ]]>