Nabiximols API Manufacturers

General Description:

Nabiximols, identified by CAS number 56575-23-6, is a notable compound with significant therapeutic applications. Nabiximols (tradename Sativex®) is a whole plant extract from the Cannabis species _Cannabis sativa L._ that has been purified into the active components CBD (cannabidiol) and THC (delta-9-tetrahydrocannabinol). For trademark purposes, purified CBD is branded as Nabidiolex®, while THC is purified as the product Tetrabinex®. Sativex® is available in a 1:1 formulation of THC:CBD as an oro-mucosal pump spray used for treatment of neuropathic pain from Multiple Sclerosis (MS) and for intractable cancer pain. Although still largely debated, Cannabis has been shown to have analgesic, anticonvulsant, muscle relaxant, anxiolytic, neuroprotective, anti-oxidant, and anti-psychotic activity . From a pharmacological perspective, Cannabis' diverse receptor profile explains its potential application for such a wide variety of medical conditions. Cannabis contains more than 400 different chemical compounds, of which 61 are considered cannabinoids, a class of compounds that act upon cannabinoid receptors of the body . Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two types of cannabinoids found naturally in the resin of the marijuana plant, both of which interact with the cannabinoid receptors found in the human body. While both CBD and THC are used for medicinal purposes, they have different receptor activity, function, and physiological effects. While cannabis in its natural plant form is currently used "off-label" for the management of many medical conditions, THC is currently commercially available in synthetic form as , as purified isomer as , or in a 1:1 formulation with CBD from purified plant extract as . The primary psychoactive component of Cannabis, delta 9-tetrahydrocannabinol (Δ9-THC), demonstrates its effects through weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors. This activity results in the well-known effects of smoking cannabis such as increased appetite, reduced pain, and changes in emotional and cognitive processes. In contrast to THC's weak agonist activity, CBD has been shown to act as a negative allosteric modulator of the cannabinoid CB1 receptor, the most abundant G-Protein Coupled Receptor (GPCR) in the body . Allosteric regulation is achieved through the modulation of receptor activity on a functionally distinct site from the agonist or antagonist binding site. The negative allosteric modulatory effects of CBD are therapeutically important as direct agonists are limited by their psychomimetic effects while direct antagonists are limited by their depressant effects . In Canada, Sativex® has received a Notice of Compliance (NOC) for use as an as adjunctive treatment for symptomatic relief of spasticity in patients with multiple sclerosis (MS) who have not responded adequately to other therapy and who demonstrate meaningful improvement during an initial trial of therapy. Sativex® has also received a Notice of Compliance with Conditions (NOC/c) for use as an adjunctive treatment for the symptomatic relief of neuropathic pain in adult patients with multiple sclerosis (MS) and as adjunctive analgesic treatment in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain.

Indications:

This drug is primarily indicated for: In Canada, Sativex has received a Notice of Compliance (NOC) for use as an as adjunctive treatment for symptomatic relief of spasticity in patients with multiple sclerosis (MS) who have not responded adequately to other therapy and who demonstrate meaningful improvement during an initial trial of therapy. Sativex has also received a Notice of Compliance with Conditions (NOC/c) for use as an adjunctive treatment for the symptomatic relief of neuropathic pain in adult patients with multiple sclerosis (MS) and as adjunctive analgesic treatment in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain. Marketing authorisations with conditions reflect the promising nature of the clinical evidence and the need for confirmatory studies to verify the clinical benefit. Patients should be advised of the conditional nature of the authorizations with conditions. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Nabiximols undergoes metabolic processing primarily in: THC and CBD are metabolized in the liver by a number of cytochrome P450 isoenzymes, including CYP2C9, CYP2C19, CYP2D6 and CYP3A4. They may be stored for as long as four weeks in the fatty tissues from which they are slowly released at sub-therapeutic levels back into the blood stream and metabolized via the renal and biliary systems. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Nabiximols are crucial for its therapeutic efficacy: Individual subject plasma concentration data and pharmacokinetic parameters show a high degree of inter-subject variability. Following a single buccal administration, maximum plasma concentrations of both CBD and THC typically occur within two to four hours. When administered buccally, blood levels of THC and other cannabinoids are lower compared with inhalation of smoked cannabis. The resultant concentrations in the blood are lower than those obtained by inhaling the same dose because absorption is slower, redistribution into fatty tissues is rapid and additionally some of the THC undergoes hepatic first-pass metabolism to 11-OH-THC, a psycho-active metabolite. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Nabiximols is an important consideration for its dosing schedule: Elimination from plasma is bi-exponential with an initial half-life of one to two hours. The terminal elimination half-lives are of the order of 24 to 36 hours or longer. This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Nabiximols from the body primarily occurs through: Nabiximols is excreted in the urine and faeces. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Nabiximols is distributed throughout the body with a volume of distribution of: Cannabinoids are distributed throughout the body; they are highly lipid soluble and accumulate in fatty tissue. The release of cannabinoids from fatty tissue is responsible for the prolonged terminal elimination half-life. This metric indicates how extensively the drug permeates into body tissues.

Pharmacodynamics:

Nabiximols exerts its therapeutic effects through: The principal pharmacological effects of THC include analgesic, muscle relaxant, antiemetic, appetite stimulant and psychoactive effects. CBD has analgesic, anticonvulsant, muscle relaxant, anxiolytic, neuroprotective, anti-oxidant and anti-psychotic activity. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Nabiximols functions by: The primary psychoactive component of Cannabis, delta 9-tetrahydrocannabinol (Δ9-THC), demonstrates its effects through weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors. This activity results in the well-known effects of smoking cannabis such as increased appetite, reduced pain, and changes in emotional and cognitive processes. In contrast to THC's weak agonist activity, CBD has been shown to act as a negative allosteric modulator of the cannabinoid CB1 receptor, the most abundant G-Protein Coupled Receptor (GPCR) in the body . Allosteric regulation is achieved through the modulation of receptor activity on a functionally distinct site from the agonist or antagonist binding site. The negative allosteric modulatory effects of CBD are therapeutically important as direct agonists are limited by their psychomimetic effects while direct antagonists are limited by their depressant effects . There is further evidence that CBD also activates 5-HT1A serotonergic and TRPV1–2 vanilloid receptors, antagonizes alpha-1 adrenergic and µ-opioid receptors, inhibits synaptosomal uptake of noradrenaline, dopamine, serotonin and gaminobutyric acid and cellular uptake of anandamide, acts on mitochondria Ca2 stores, blocks low-voltage-activated (T-type) Ca2 channels, stimulates activity of the inhibitory glycine-receptor, and inhibits activity of fatty amide hydrolase (FAAH) . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Categories:

Nabiximols is categorized under the following therapeutic classes: Agents producing tachycardia, Analgesics, BCRP/ABCG2 Inhibitors, Cannabinoid Receptor Agonists, Cannabinoids and similars, Central Nervous System Agents, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors (strength unknown), Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP2D6 Inhibitors, Cytochrome P-450 CYP2D6 Inhibitors (strength unknown), Cytochrome P-450 CYP2D6 Substrates, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Inhibitors, Cytochrome P-450 CYP3A5 Inhibitors (strength unknown), Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 CYP3A7 Inhibitors, Cytochrome P-450 CYP3A7 Inhibitors (strength unknown), Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Peripheral Nervous System Agents, Pharmaceutical Preparations, Sensory System Agents, Terpenes. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.