Methods to reduce complications of intra-articular steroid
Inventors
Shih, Sheue-Fang • Chang, Po-Chun • Wu, Ming-Ju
Assignees
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Publication Number
US-12083138-B2
Publication Date
2024-09-10
Expiration Date
Abstract
Provided are methods of treating joint pain, comprising administering to a subject in need of joint pain treatment an effective amount of a pharmaceutical composition comprising a lipid mixture comprising one or more lipids; and an effective amount of an intra-articular steroid or a pharmaceutically acceptable salt thereof, wherein the therapeutic efficacy of the intra-articular steroid is sustained but the side effects associated with the intra-articular steroid are reduced.
Core Innovation
The invention relates to compositions and methods for sustaining therapeutic efficacy of an intra-articular (IA) steroid for treating joint pain while reducing steroid-induced cartilage side effects. The background problem is steroid-induced cartilage side effects, including chondrocyte damage/apoptosis and proteoglycan loss, which can lead to cysts in articular cartilage, articular cartilage degradation, joint destruction, and toxicity.
The disclosed approach uses a pharmaceutical composition that includes a lipid mixture and an IA steroid or pharmaceutically acceptable salt thereof. The lipid mixture is a nano-/liposomal lipid mixture or liposomes formed by mixing lipids including phospholipids and optionally cholesterol and/or polymers, with the IA steroid loaded for immediate- or extended-release components, including steady state release.
The document emphasizes a dosing regimen with at least two intra-articular injections and a dosing interval of at least four weeks. It describes IA steroid concentration at about 15 mM to about 40 mM and includes examples such as dexamethasone sodium phosphate (DSP), including a DOPC/DOPG/cholesterol lipid mixture. Preclinical results discussed in the document include reduced proteoglycan loss after a single IA injection of liposomal DSP versus saline or vehicle and prolonged synovial fluid exposure of dexamethasone phosphate (DP) with reduced or no marked cartilage toxicity in dogs and rabbits, in contrast to increased proteoglycan loss and chondrotoxicity associated with triamcinolone acetonide (TA) and triamcinolone acetonide extended-release (ER-TA).
Claims Coverage
The independent claim set covers a treatment method and a pharmaceutical composition. Across the independent claims, there are five inventive features centered on the lipid mixture composition, IA steroid concentration and dose, and a dosing regimen with at least two intra-articular injections separated by at least four weeks.
Lipid mixture with defined phospholipid and cholesterol mole-percent ratio
A pharmaceutical composition including a lipid mixture comprising a first phospholipid, a second phospholipid and a cholesterol at a mole percent ratio of 29.5% to 90%:3% to 37.5%:10% to 33%.
Intra-articular steroid concentration range in the composition
An effective amount of the IA steroid or a pharmaceutically acceptable salt thereof, wherein the IA steroid or pharmaceutically acceptable salt thereof is at a concentration ranging from about 15 mM to about 40 mM.
At least two intra-articular injections with at least a four-week interval
A dosing regimen having at least two intra-articular injections with a dosing interval of at least four weeks.
Specified DOPC/DOPG/cholesterol lipid mixture
A pharmaceutical composition comprising a lipid mixture comprising DOPC, DOPG and cholesterol at a mole percent ratio of 29.5% to 90%:3% to 37.5%:10% to 33%.
Dexamethasone sodium phosphate dose and concentration ranges
An IA steroid comprising dexamethasone sodium phosphate at a dose ranging from 10 mg to 14 mg with a concentration ranging from about 15 mM to about 40 mM.
Coverage centers on an IA steroid formulation that combines a defined phospholipid/cholesterol mole-percent lipid mixture with an IA steroid at about 15 mM to about 40 mM, and in one composition claim dexamethasone sodium phosphate at 10 mg to 14 mg, administered as at least two intra-articular injections separated by at least four weeks.
Stated Advantages
Reducing steroid-induced cartilage side effects, including chondrocyte damage/apoptosis and proteoglycan loss.
Reducing progression to cysts in articular cartilage, articular cartilage degradation, and joint destruction.
Sustaining therapeutic efficacy of an intra-articular steroid.
Prolonging high synovial-fluid dexamethasone phosphate exposure while showing no marked cartilage toxicity after dosing as described in the document.
Documented Applications
Treating joint pain in a subject in need of treatment for joint pain, while reducing side effects induced by an intra-articular steroid.
Treating joint pain or inflammation using a pharmaceutical composition that includes a specified lipid mixture and an intra-articular steroid, administered via a dosing regimen with at least two intra-articular injections spaced by at least four weeks.
Preclinical evaluation in dogs and rabbits, including assessment of proteoglycan loss and synovial-fluid dexamethasone phosphate exposure after intra-articular dosing, with comparisons versus saline/vehicle and versus triamcinolone acetonide and triamcinolone acetonide extended-release.
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