Currently available cannabinoid dosage forms and innovative delivery systems in clinical evaluation

Cannabinoids, indeed, have poor oral bioavailability (estimated to be as low as 6% of a similar dose administered intravenously). Pure THC and CBD show similar plasma concentration-time profiles, with a delay of 120 min before reaching peak concentration [42]. Bioavailability increases when it is co-administered with food lipids. A cannabis formulation in sesame oil (a vehicle with long chain triglycerides [LCT], containing 42% oleic, 40% linoleic and 16% palmitic acids) significantly improved the bioavailability of cannabinoids [82].

The contribution of intestinal lymphatic transport is also worthy of note in the case of highly lipophilic compounds [83]. Indeed, the fatty acids generated by the lipolysis of medium and long chain triglycerides undergo several different processes: long chain fatty acids are associated to chylomicrons that are secreted into the lymphatic system instead of the portal vein. Thus, THC and CBD, used in combination with LCT, can bypass the liver, decreasing potential pre-systemic metabolism [41]. By avoiding loss in pre-systemic metabolism in the liver, cannabinoids can reach 22% bioavailability [84].

The role of high-fat meals on pharmacokinetic behaviour is also relevant. A formulation for CBD (administered as a single 1500 mg dose at 100 mg/mL in a sesame-oil vehicle) showed an absolute oral bioavailability of about 6% after intake in the fasting state, while co-administration with a high-fat meal would be expected to result in a bioavailability of about 25% and in reduced inter- and intra-subject variability, compared with the fasting state [40]. Moreover, THC showed similar bioavailability behaviour when administered with sesame oil [43].

Furthermore, the potential role of cannabinoid metabolites, especially active metabolites such as 7-hydroxy-CBD, should be considered, as outlined in recent studies in subjects with renal or hepatic impairments [85–87].

Oils that are formulated into capsule pellets and solid tablets currently allow pharmaceutical-grade compounds to be conveniently and accurately dosed.

Two important considerations to make when evaluating cannabinoid formulations are the pharmacokinetic goal and intended use. For example, if the indication is to treat acute pain, then a faster T_max and higher C_max may be desirable, while also potentially helping to decrease the risk of overdose via premature repeat self-administration. Alternatively, a larger AUC may be preferable for use as a chronic treatment if a user follows a regular dosing schedule.

Nevertheless, an ideal oral dosage form that has consistent delivery and high bioavailability is not yet available and is therefore warranted. Many companies have invested huge amounts of effort into improving pharmaceutical oral dosage. The different strategies taken have been detailed below, and have been marketed. The most advanced formulations have been summarised in Table ​Table2.2. Table ​Table33 summarises the ongoing clinical trials on pain treatments. Only the most recent reports on active research and the latest development phases are described. To complete the information and allow the reader to move more deeply into the composition and technology involved in the formulation procedures, the most significant data from related patents are also reported.

Continue at:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417625/

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