Compositions and methods using a cannabinoid to enhance bioavailability of a statin
Inventors
Smeeding, James • Sherwood, Mathew
Assignees
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Publication Number
US-11786482-B2
Publication Date
2023-10-17
Expiration Date
Abstract
The invention relates to pharmaceutical compositions comprising a statin and a cannabinoid, and their use for the treatment of hypercholesterolemia and atherosclerosis. It has been found that compositions combining a statin and a cannabinoid are improved over existing statin formulations. The compositions of the invention for example allow for a lower effective dose of statin and a reduction of the adverse effects seen with statins taken alone. Dosing ranges and formulations suitable for oral, buccal, and sublingual administration are disclosed. Various specific cannabinoids such as cannabidiol and synthetic cannabidiols selected for their anti-inflammatory, antioxidant, and anti-atherosclerotic effect are shown to be particularly advantageous.
Core Innovation
The invention relates to a pharmaceutical composition for once daily dosing and a method for enhancing the bioavailability upon oral administration of a statin to a human patient. The approach combines a reduced daily dosage amount of the statin with a phytocannabinoid, wherein the reduced statin dosage amount is less than the standard daily dosage amount for the statin when taken alone. The disclosed aim is to enhance oral bioavailability while enabling the statin to be administered at a lower daily dose.
The disclosed pharmaceutical composition is formulated for oral administration and is supported by a CYP-mediated mechanism linking the phytocannabinoid and the statin through hepatic metabolism and first-pass metabolism. The document describes that CBD can act as a CYP inhibitor and is metabolized via CYP3A4, with to a lesser extent CYP2C19. The document further describes that statins are metabolized through specific CYP isoforms, including CYP3A4 for atorvastatin, lovastatin, and simvastatin, and CYP2C19 and CYP2C9 for rosuvastatin, fluvastatin, and pitavastatin.
The disclosed invention includes pairing selections and formulation considerations to match CYP substrate/inhibition behavior between the statin and the phytocannabinoid. The document emphasizes reduced-psychoactive or non-psychoactive formulations, including reduced or absent THC, and describes multiple oral administration routes including oral administration and orally-disintegrating dosage forms, as well as buccal and sublingual administration. The disclosure includes an example dose reduction for atorvastatin combined with CBD, with reduced dosing amounts described as 50% or 75% depending on CYP3A4 affinity.
Claims Coverage
The independent claims are clm-00001 and clm-00011. Across these, the coverage centers on two inventive aspects: a once-daily oral pharmaceutical composition or method that combines a phytocannabinoid with a reduced statin daily dosage to enhance oral bioavailability, and narrowing via CYP-enzyme substrate relationships and specific CYP isoforms, notably CYP3A4, that connect the statin and phytocannabinoid.
Once-daily oral reduced-dose statin plus phytocannabinoid composition for enhanced bioavailability
A pharmaceutical composition for once daily dosing for enhancing oral bioavailability upon oral administration to a human, comprising a reduced daily dosage amount of the statin and a phytocannabinoid, wherein the reduced daily dosage amount of the statin is less than the standard daily dosage amount for the statin when taken alone.
Oral co-administration reduced-dose statin plus phytocannabinoid to enhance bioavailability
A method of enhancing bioavailability upon oral administration to a human of a statin by orally co-administering the statin in a reduced daily dosage amount and a phytocannabinoid, wherein the reduced daily dosage amount of the statin is less than the standard daily dosage amount for the statin when taken alone.
CYP enzyme substrate pairing for statin and phytocannabinoid
The pharmaceutical composition or method wherein the statin and the phytocannabinoid are both substrates of a CYP enzyme.
CYP3A4 narrowed CYP enzyme relationship
The pharmaceutical composition or method wherein the CYP enzyme is CYP3A4.
Atorvastatin, lovastatin, or simvastatin under CYP3A4 constraint
The pharmaceutical composition or method wherein the statin component is atorvastatin, lovastatin, or simvastatin.
Rosuvastatin under CYP2C19-associated subset
The pharmaceutical composition or method wherein the statin is rosuvastatin.
The claims cover compositions and methods that enhance statin oral bioavailability using a phytocannabinoid together with a reduced daily statin dose, and further narrow the relationship by requiring both statin and phytocannabinoid to be CYP substrates, including CYP3A4 and specific statin selections such as atorvastatin, lovastatin, simvastatin, and rosuvastatin.
Stated Advantages
Enhancing oral bioavailability upon oral administration of a statin.
Enabling a reduced daily dosage amount of the statin compared with the standard daily dosage amount when taken alone.
Reducing statin-associated adverse effects, including myopathy and rhabdomyolysis, and associated kidney injury or acute renal failure.
Documented Applications
Treatment approaches for hypercholesterolemia and atherosclerosis using a statin combined with a phytocannabinoid to enhance oral bioavailability.
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