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Chapter 78. Ocular Delivery of Tetrahydrocannabinol
Abstract
In recent years, discovery of the cannabinoid receptors in the ocular tissues has opened up the possible utility of tetrahydrocannabinol (THC) and other cannabinoids in the management of several ocular diseases and conditions. The biopharmaceutical characteristics of THC, however, do not favor transmembrane diffusion. Additional physiological barriers, atypical of ocular drug delivery, makes THC delivery to the ocular tissues through the topical route even more challenging. Thus, careful formulation design and consideration is needed to translate the potential of THC into the preclinical and clinical settings. This chapter reviews some of the ocular conditions that can be impacted by THC, and the barriers to its delivery through the topical route. Strategies to improve ocular penetration of THC have also been discussed.
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Purpose:
The overall goal of this project is to enhance ocular delivery of ∆(9)-Tetrahydrocannabinol (THC) through the topical route.
Methods:
Solubility, stability and in vitro transcorneal permeability of the relatively hydrophilic hemiglutarate ester derivative, THC-HG, was studied in the presence of surfactants. The solutions were characterized with respect to micelle size, zeta potential and solution viscosity. In vivo studies were carried out in New Zealand albino rabbits. A previously reported promising THC-HG ion-pair formulation was also studied in vivo.
Results:
Aqueous solubility and stability and in vitro transcorneal permeability of THC-HG was enhanced significantly in the presence of surfactants. THC levels in the ocular tissues (except cornea) were found to be below detection limits from mineral oil, surfactant or emulsion based formulations containing THC. In contrast, micellar and ion pair based THC-HG formulations produced significantly higher total THC concentrations in the anterior ocular chamber.
Conclusion:
In this study, although delivery of THC to the anterior chamber ocular tissues could be significantly increased through the prodrug and formulation approaches tested, further studies are needed to increase penetration to the back-of-the eye.
Mammalian tissues contain at least two types of cannabinoid receptor, CB1 and CB2 , both coupled to G proteins. CB1 receptors are expressed mainly by neurones of the central and peripheral nervous system whereas CB2 receptors occur in certain non-neuronal tissues, particularly in immune cells. The existence of endogenous ligands for cannabinoid receptors has also been demonstrated. The discovery of this 'endogenous cannabinoid system' has been paralleled by a renewed interest in possible therapeutic applications of cannabinoids, for example in the management of pain and in the suppression of muscle spasticity/spasm associated with multiple sclerosis or spinal cord injury. It has also prompted the development of a range of novel cannabinoid receptor ligands, including several that show marked selectivity for CB1 or CB2 receptors. This review summarizes current knowledge about the in vitro pharmacological properties of important CB1 and CB2 receptor ligands. Particular attention is paid to the binding properties of these ligands, to the efficacies of cannabinoid receptor agonists, as determined using cyclic AMP or [35S]GTPγS binding assays, and to selected examples of how these pharmacological properties can be influenced by chemical structure. The in vitro pharmacological properties of ligands that can potently and selectively oppose the actions of CB1 or CB2 receptor agonists are also described. When administered by themselves, some of these ligands produce effects in certain tissue preparations that are opposite in direction to those produced by cannabinoid receptor agonists and the possibility that the ligands producing such 'inverse cannabimimetic effects' are inverse agonists rather than pure antagonists is discussed.
Seventeen nonsmokers with heterogeneous glaucomas were tested with synthetic oral Δ9-THC in single-dose administrations. The intraocular pressure was decreased 7.8 ± 1.7 mm Hg after 5 hours in the 7 subjects tested with higher doses. These 7 subjects who received the higher doses (>20 mg) manifested severe alterations in sensorium including depersonalization, acute panic reactions, and paranoiac feelings. No significant differences in intraocular and blood pressures occurred after 5 or 10 mg Δ9-THC, though 1 subject who became severely hypotensive after 5 mg Δ9-THC is described.
To the Editor.—
It is accepted widely that the physiologic effects of smoking marihuana are not well known, despite an acknowledged high incidence of usage. Even the President of the United States has called for a major effort to study drug effects in a scientific manner. In an attempt to investigate the effects of marihuana smoking upon the human visual system, complete ocular examinations were performed in a group of youthful subjects, before and one hour after smoking. Selection of subjects, medical and other safeguards utilized, and details of the protocol will be presented in a later publication.The purpose of this letter is to present preliminary data concerning the most impressive change observed so far, namely, a substantial decrease in intraocular pressure observed in a large percentage of subjects. Applanation tonometry was performed by the same experienced examiner, using the same tonometer for each pair of observations. Marihuana was
Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pKa and cell permeability for two sets of four stereoisomers. Using computational chemistry and NMR spectroscopy we identified the formation of an intramolecular NH->NR3 hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pKa difference that accounts for the other structure-property relationships. Application of this knowledge could be of particular value to maintain the delicate balance of size, solubility and lipophilicity required for cell penetration and oral administration for chemical probes or therapeutics with properties at, or beyond, Lipinski's Rule of 5.
We have examined the effects of cannabinoid agonists on hyperalgesia in a model of neuropathic pain in the rat and investigated the possible sites of action. The antihyperalgesic activity of the cannabinoids was compared with their ability to elicit behavioural effects characteristic of central cannabinoid activity. WIN55,212-2 (0.3–10 mg kg−1), CP-55,940 (0.03–1 mg kg−1) and HU-210 (0.001–0.03 mg kg−1) were all active in a ‘tetrad’ of tests consisting of tail-flick, catalepsy, rotarod and hypothermia following subcutaneous administration, with a rank order of potency in each of HU-210>CP-55,940>WIN55,212-2. The effects of WIN55,212-2 in each assay were blocked by the Cannabinoid1 (CB1) antagonist SR141716A. In the partial sciatic ligation model of neuropathic pain WIN55,212-2, CP-55,940 and HU-210 produced complete reversal of mechanical hyperalgesia within 3 h of subcutaneous administration with D50 values of 0.52, 0.08 and 0.005 mg kg−1, respectively. In this model WIN55,212-2 was also effective against thermal hyperalgesia and mechanical allodynia. WIN55,212-2 produced pronounced reversal of mechanical hyperalgesia following intrathecal administration that was blocked by the CB1 antagonist SR141716A. Following intraplantar administration into the ipsilateral hindpaw, WIN55,212-2 produced up to 70% reversal of mechanical hyperalgesia, although activity was also observed at high doses following injection into the contralateral paw. The antihyperalgesic effect of WIN55,212-2 injected into the ipsilateral paw was blocked by subcutaneously administered SR141716A, but was not affected by intrathecally administered SR141716A. These data show that cannabinoids are highly potent and efficacious antihyperalgesic agents in a model of neuropathic pain. This activity is likely to be mediated via an action in both the CNS and in the periphery.
The delivery of the next generation of drugs, particularly polar peptides and proteins, will represent a major challenge to the pharmaceutical scientists. To successfully deliver these potential drugs to specific targets, strategies will have to be developed to circumvent epithelial (e.g., intestinal, buccal, nasal, epidermal) and endothelial (e.g., vascular) cells, which represent both physical and metabolic barriers. This presentation will focus on the possible utility of cultured epithelial and endothelial cells to screen the permeability properties of potential drug candidates, to elucidate transcellular transport mechanisms, to evaluate the potential cellular site of metabolism, and to test strategies to prevent metabolism and/or to enhance the permeability properties of drug candidates. Topics to be discussed include: (a) advantages and disadvantages of cell culture systems; (b) factors important in selecting an appropriate cell culture system which will mimic the in vivo biological barrier; (c) characterization and validation of in vitro cell culture model systems; (d) factors important in selecting a porous membrane and a diffusion apparatus for transcellular transport studies; (e) the effect of cell culturing conditions on the transport characteristics of cultured cells; and (f) factors important in interpretation of in vitro cell culture data.
The effect of indomethacin on the Δ9-tetrahydrocannabinol (Δ9-THC)-induced fall in rabbit intraocular pressure (IOP) was determined. A 2% suspension of indomethacin was given topically 1 h before intravenous injection of Δ9-THC. IOP was measured hourly and was compared between groups receiving either Δ9-THC alone or Δ9-THC plus indomethacin. A substantial attenuation of the IOP response to Δ9-THC was caused by indomethacin. Δ9-THC may influence IOP at least in part by a prostaglandin-mediated process. Involvement of the cyclooxygenase pathway offers a common explanation for linking several ocular cannabinoid effects. The latter include a fall in IOP, conjunctival hyperemia and minor inflammation.
The discovery of the endocannabinoid system (ECS; comprising of G-protein coupled cannabinoid 1 and 2 receptors, their endogenous lipid ligands or endocannabinoids, and synthetic and metabolizing enzymes, triggered an avalanche of experimental studies that have implicated the ECS in a growing number of physiological/pathological functions. They also suggested that modulating ECS activity holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders, obesity/metabolic syndrome, cachexia, chemotherapy-induced nausea and vomiting, tissue injury and pain, among others. However, clinical trials with globally acting CB1 antagonists in obesity/metabolic syndrome, and other studies with peripherally restricted CB1/2 agonists and inhibitors of the endocannabinoid metabolizing enzyme in pain introduced unexpected complexities, and suggested that better understanding of the pathophysiological role of the ECS is required in order to devise clinically successful treatment strategies, which will be critically reviewed in this brief synopsis. Journal compilation © 2013 FEBS. No claim to original US government works.
Objective:
To determine the effects of topically applied 2% delta-9-tetrahydrocannabinol (THC) ophthalmic solution on aqueous humor flow rate (AHFR) and intraocular pressure (IOP) in clinically normal dogs.
Animals:
21 clinically normal dogs.
Procedures:
A randomized longitudinal crossover design was used. Following acquisition of baseline IOP (morning and evening) and AHFR (afternoon only) data, dogs were randomly assigned to 2 treatment groups and received 1 drop of either 2% THC solution or a control treatment (olive oil vehicle) to 1 randomly selected eye every 12 hours for 9 doses. The IOPs and AHFRs were reassessed after the final treatment. Following a washout period of ≥ 7 days, dogs were administered the alternate treatment in the same eye, and measurements were repeated.
Results:
Mean ± SD IOPs in the morning were 15.86 ± 2.48 mm Hg at baseline, 12.54 ± 3.18 mm Hg after THC treatment, and 13.88 ± 3.28 mm Hg after control treatment. Mean ± SD IOPs in the evening were 13.69 ± 3.36 mm Hg at baseline, 11.69 ± 3.94 mm Hg after THC treatment, and 12.13 ± 2.99 mm Hg after control treatment. Mean IOPs were significantly decreased from baseline after administration of THC solution but not the control treatment. Changes in IOP varied substantially among individual dogs. Mean ± SD AHFRs were not significantly different from baseline for either treatment.
Conclusions and clinical relevance:
Topical application of 2% THC ophthalmic solution resulted in moderate reduction of mean IOP in clinically normal dogs. Further research is needed to determine efficacy in dogs with glaucoma.