An Overview of Galenic Preparation Methods for Medicinal Cannabis
Luigi Romano and Arno Hazekamp
Current Bioactive Compounds, 2018, 14,
In recent years, the Cannabis plant (Cannabis sativa L.) has been rediscovered as a source of new medicines around the world. Despite the fact that a number of registered medicines have been developed on the basis of purified cannabis components, there is a rapid increasing acceptance and use of cannabis in its herbal form. Licensed producers of high quality cannabis plants now operate in various countries including The Netherlands, Canada, Israel, and Australia, and in many US states. The legal availability of cannabis flowers allows to prescribe and prepare different cannabis galenic preparations by pharmacists. It is believed that synergy between cannabis components, known as “entourage effect”, may be responsible for the superior effects of using herbal cannabis versus isolated compounds. So far, only a few cannabis components have been properly characterized for their therapeutic potential, making it unclear which of the isolated compounds should be further developed into registered medicines. Until such products become available, simple and accessible galenic preparations from the cannabis plant could play an important role. In cannabis, phytochemical and pharmacological attention has been attributed mainly to four major cannabinoids (9- tetrahydrocannabinol, cannabidiol, cannabigerol and cannabichromene) and to terpene components. This means a basic knowledge of these compounds and their bioavailability in different administration forms is useful for producers as well as prescribers of galenic preparations. This work will outline the most important aspects of cannabinoids and terpenes, and their behaviors during preparation and use of various administration forms including vaporizing, cannabis oils and extracts, tea, and skin creams.
Keywords : Medicinal cannabis, cannabinoids, terpenes, extracts, decarboxylation, galenic preparations.
Cannabis sativa L. is one of the oldest known medicinal plants in human culture. Originating from Central Asia, it was cultivated and consumed long before the appearance of writing [McKim W. A., 2000]. According to archeological discoveries, it has been known in China at least since the Neolithic period, around 4000 BC [McKim W. A., 2000]. The scientific interest of the occidental world for the therapeutic potential of the cannabis plant started only in 1839 when William O’ Shaughnessy, a British physician and surgeon working in India, discovered the analgesic, appetite stimulant, antiemetic, muscle relaxant and anticonvulsant properties of cannabis [O’ Shaugnessy W. B., 1838-1840]. In 1854, Cannabis was listed in the United States Dispensatory [Robson P., 2001] and it was sold freely in pharmacies of Western countries. It would be available in the British Pharmacopoeia in extract and tincture form for over 100 years [Iversen L., 2000].
Only in 1964 the psychoactive component of Cannabis , delta-9-tetrahydrocannabinol (also: 9-THC or THC), was isolated [Gaoni Y. and Mechoulam R., 1971] and since 1986 a registered form of THC has been available and prescribed to patients under the name Marinol® (Abbott Products, Inc.). This product contains a synthetically made version of THC, also known by its INN (international non-proprietary name) dronabinol. Another prescribed cannabinoid is Nabilone (marketed as Cesamet® since 1981, Valeant Pharmaceuticals International) [WHO 2006]. Both products are registered for the symptomatic treatment of nausea and vomiting associated with cancer chemotherapy, while dronabinol is also approved for treating anorexia and cachexia related to HIV/AIDS. The patent on Marinol® expired in 2011, and an authorized generic version has become available from Watson Pharmaceuticals. A generic formulation of Nabilone is now available in Canada from Pharmascience Inc. In Germany, generic THC is supplied by two companies (THC Pharm and Bionorica Ethics) from which pharmacies can prepare capsules and solutions (in oil or alcohol) [WHO 2006].
Nabiximols (marketed as Sativex® since 2005 by GW Pharmaceuticals, UK, and partners) is a sublingually administered oromucosal spray. Sativex is currently registered in Canada and received regulatory approval in 30 countries so far (outside the United States). In Canada, it is approved for the relief of neuropathic pain and advanced cancer pain. In Europe, Sativex has now received marketing authorization in 21 countries for the treatment of spasticity (muscle stiffness/ spasm) due to MS, which include: Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Iceland, Ireland, Italy, Lichtenstein, Luxembourg, Netherlands, Norway, Poland, Portugal, Slovakia, Spain, Sweden, Switzerland and the United Kingdom. Beyond Europe, Sativex has received full regulatory approval for MS spasticity in Canada, Australia, New Zealand, Brazil, Colombia, Chile, UAE & Kuwait and achieved approval in Israel for the indications of MS Spasticity and pain and for chronic cancer pain [GW Pharmaceuticals 2016].
In recent years, the official introduction of pharmaceutical grade cannabis flowers for medicinal purpose opened up the possibility for physicians and pharmacists to legally prepare and prescribe cannabis-based products. Throughout Europe, several countries have introduced specific regulations and guidelines regarding medicinal cannabis, including the Netherlands, Italy, Germany, Czech Republic, Croatia
and Finland. These regulations detail for example which medical conditions cannabis may be prescribed for, and which administration forms are allowed. In a few cases, e.g. in Italy, physicians and pharmacists have the legal possibility to prescribe and prepare, respectively, different kinds of cannabis- based galenic preparations.
This started on March 2014 with a Law Decree promoted by Italian Health Minister Beatrice Lorenzin [Beatrice Lorenzin, Law Decree 20th March 2014, n. 36] which was then converted in an effective law that allows the use of cannabis and cannabis-based products (such as extracts, tinctures, etc) based on the preparations described by Romano and Hazekamp [Romano L. L. and Hazekamp A., 2013]. In November 2015 a Ministerial Decree obligated the analysis by HPLC or GC-FID of every single galenic preparation and the results must be shared with the prescribing physician for the evaluation of the dosage [Health Minister Decree 9th November 2015]. In September 2016, the Italian Society of Pharmacists (SIFAP) proposed a new method for the preparation of cannabis oleic extract: 5 g of cannabis – Bedrocan inflorescences with a THC content between 19 and 22% (derived from the sum of THC and THCA content) – extracted in 50 ml of olive oil to obtain a final extract with a THC content
equal to 1.7 ± 0.3% (w/w) and a THCA content <0.1% (w/w) [SIFAP news letter, 29th September 2016]. The suggested analytical method for quality control of these types of cannabis-based preparations has been developed by Citti and colleagues [Citti C. et al, 2016] by using high performance liquid chromatography coupled to diode array detection. In order to evaluate the identity and purity of the analytes, a high-resolution mass spectrometry (HPLC-ESI-QTOF) analysis was also carried out. Full method validation has been performed in terms of specificity, selectivity, linearity, recovery, dilution integrity and thermal stability according to EMA [European Medicine Agency] guidelines suggesting that any pharmacist could analyze his own cannabis-based medicines by employing the LC-UV and LC-MS methodology. An alternative extraction method has since then been proposed in order to preserve more cannabis monoterpene components in the final extract. Nevertheless, there is no official law yet which recognizes the use of this extraction or analytic method.
Other countries have chosen different approaches to access to medicinal cannabis products. In The Netherlands, the Transvaal pharmacy in The Hague is one of the compounding pharmacies in the country where patients can obtain cannabis inflorescence oil of guaranteed quality. Pharmacistsextract the flowers from different varieties of cannabis with pharmaceutical grade ethanol and heat the extract in an oven to obtain the decarboxylated cannabinoids. Ph. Eur. quality Arachis (peanut) oil is used to dilute the extract to the desired final concentration and to soften the bitter taste. At the moment, the oil is almost exclusively prescribed to patients who do not respond to regular medication. In Germany, the Federal Institute for Drugs and Medical Devices has authorized the medicinal use of cannabis for special cases, which was strongly encouraged by the Federal Administrative Court in 2005. Currently, about 300 German patients with severe medical conditions are allowed to buy cannabis products at pharmacies to relieve their pain [Bifulco M. and Pisanti S., 2015]. Germany is currently in the process of setting up its own program for cultivating medicinal cannabis by a number of licensed producers. Spain is lagging behind Italy and Germany in terms of legalizing medicinal cannabis use. The possession and use of
cannabis is still illegal, but it has been decriminalized. As such, people can grow and use the plant for personal and medical use without fear of being prosecuted. The semiautonomous region of Catalonia in particular is pressing the Spanish government to legalize medical cannabis to treat pain and nausea resulting from cancer – or chemotherapy treatments against it – AIDS, and other diseases that cause chronic pain or appetite loss [Bifulco M. and Pisanti S., 2015].
In the Czech Republic, the State Agency for Medical Cannabis was established as a special department of the State Institute of Drug Control. Use of medical cannabis products is only possible in line with the Ministerial Notice of 2013, and the prescription should state the mode of use and cannabinoids concentration of the prescribed product. At the time of writing this manuscript, only 16 specially qualified doctors, such as oncologists and psychologists, were authorized to prescribe cannabis, and only 26 pharmacies could dispense it. The first domestic harvest of cannabis was distributed to pharmacies in March 2016 [EMCDDA, 2017].
In Croatia, new regulations entered into force in October 2015 that amended the Ordinance on classifying, prescribing and dispensing medicines, to allow the use of cannabis for medical purposes. Following the recommendation of certain medical specialists in neurology, infectious diseases or cancer, medicines containing THC, dronabinol or nabilone can An Overview of Galenic Preparation Methods for Medicinal Cannabis Current Bioactive Compounds 2018, Vol. 14, No. 00 3 be prescribed, on non-repeatable prescription. . They may be used in various forms such as teas, ointments and other extracts including galenic preparations, whilesmoking or vaping herbal cannabis is not permitted. The prescription should state the amount of THC in a single dose, the number of individual doses, drug form, dosage and method of use.[EMCDDA, 2017].
Herbal medical cannabis is also legal in some forms in Finland. In 2008, the Finnish government drafted legislation permitting the prescription of medical cannabis on a case-bycase basis, which was to be delivered in the form of herbal cannabis imported from The Netherlands. Since then, the authorities have awarded several dozen individuals the right to access this source of cannabis. Cannabis is only prescribed when all other treatment options have failed, and is only approved for a very small range of conditions including cancer pain, multiple sclerosis, spinal cord injury, and treatment of glaucoma. An extremely limited group of medicinal users (223 in 2014) are permitted to purchase Sativex mouth spray and/or Dutch herbal cannabis from one of 27 apothecaries that have the permit to sell medical cannabis [Akuutti, Health Magazine].
It can be concluded that each country is finding its way to medicinal cannabis or cannabinoids in a different manner. Despite the fact that the scientific literature still lacks in clear information, and there is little uniformity in European and National laws, there is an increasing interest from patients, doctors and regulators to prepare and use simple and accessible cannabis formulations. The aim of this review is to discuss and clarify some major topics related to galenic preparations of medicinal cannabis such as: decarboxylation, cannabis tea, cannabinoids vaporization, and cannabis concentrated solvent extracts.
The cannabis plant contains a large range of identified compounds (Table 1). The main active principles are represented by the cannabinoids. These are C21 terpenophenolic compounds that have been detected not only in cannabis species [Mechoulam R. and Hanus L., 2000; Mechoulam R. et al, 2007], but also in a few other plant species like Helichrysum [Bohlmann F. and Hoffmann E., 1979; Pollastro F. et al, 2017] and Rhododendron [Iwata N. and Kitanaka S., 2011; Hakeem Said I. et al, 2017].