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Publication Number
US-10987304-B2
Publication Date
2021-04-27
Expiration Date
Abstract
The present invention relates to an aqueous composition comprising a macrolide immunosuppressant drug at a concentration of less than 2% w/v and an amphiphilic carbohydrate compound having a molecular weight in the range 1-50 kDa, for use in treatment of an eye disorder by topical application to the eye, wherein the amphiphilic carbohydrate compound is present at a concentration below 10% w/v of the composition. A preferred carbohydrate compound is quaternary ammonium palmitoyl glycol chitosan (GCPQ). Pharmaceutical compositions and methods of treatment are also provided. The treatment may be for instance dry eye syndromes (DES), vernal keratoconjunctivitis (VKC), eczema, atopic keratoconjunctivitis (AKC), Sjögren syndrome, post-operative refractive surgery, corneal transplant or contact lens intolerance.
Core Innovation
The invention relates to an aqueous topical ocular formulation comprising a macrolide immunosuppressant drug selected from sirolimus, cyclosporine A, tacrolimus, and everolimus. The macrolide immunosuppressant is present at a concentration of less than 2% w/v, and the formulation uses quaternary ammonium palmitoyl glycol chitosan (GCPQ) at a concentration below 10% w/v with a GCPQ to drug concentration ratio greater than 5:1. The formulation has a pH from 6.5 to 7.4.
GCPQ is defined to have a palmitoylation level between 10 mole % and 40 mole % and a quaternization level between 6 mole % and 20 mole %. The amphiphilic carbohydrate compound self-assembles into positively charged nanoparticles/micelles that encapsulate the drug without requiring lipids or emulsions. The formulation is described as forming positively charged muco-adhesive carriers that encapsulate the macrolide immunosuppressant.
In the described examples, the composition includes one or more pharmaceutically acceptable excipients in a topical ocular pharmaceutical composition. The formulation is characterized with stability under thermal and freeze-thaw conditions, and rabbit in vivo topical dosing data are described showing drug levels in cornea/conjunctiva that are higher than Restasis® with plasma levels below quantification.
Claims Coverage
The patent includes two independent claims. Both independent claims share the same core inventive parameter set: a topical ocular formulation or pharmaceutical composition with a macrolide immunosuppressant drug selected from sirolimus, cyclosporine A, tacrolimus, and everolimus; GCPQ concentration limits; a GCPQ-to-drug concentration ratio greater than 5:1; defined palmitoylation and quaternization levels; and a formulation pH from 6.5 to 7.4. One independent claim additionally requires pharmaceutically acceptable excipients.
Aqueous topical ocular formulation with defined macrolide immunosuppressant and GCPQ functional levels
A topical ocular formulation comprising an aqueous composition comprising a macrolide immunosuppressant drug selected from sirolimus, cyclosporine A, tacrolimus, and everolimus at a concentration of less than 2% w/v and quaternary ammonium palmitoyl glycol chitosan (GCPQ) at a concentration below 10% w/v, wherein the ratio of the concentration in w/v of GCPQ to the drug is greater than 5:1, and wherein GCPQ has a palmitoylation level between 10 mole % and 40 mole % and a quaternization level between 6 mole % and 20 mole %, wherein the formulation has a pH from 6.5 to 7.4.
Topical ocular pharmaceutical composition with pharmaceutically acceptable excipients and defined macrolide immunosuppressant and GCPQ functional levels
A pharmaceutical composition that is a topical ocular formulation comprising one or more pharmaceutically acceptable excipients, a macrolide immunosuppressant drug selected from sirolimus, cyclosporine A, tacrolimus, and everolimus at a concentration of less than 2% w/v, and a quaternary ammonium palmitoyl glycol chitosan (GCPQ) at a concentration of less than 10% w/v, wherein the ratio of the concentration in w/v of GCPQ to the drug is greater than 5:1, and wherein GCPQ has a palmitoylation level between 10 mole % and 40 mole % and a quaternization level between 6 mole % and 20 mole %, wherein the formulation has a pH from 6.5 to 7.4.
Across both independent claims, the main claimed inventive concept is an aqueous topical ocular formulation or composition that combines a macrolide immunosuppressant at less than 2% w/v with GCPQ at less than 10% w/v, where the GCPQ to drug concentration ratio is greater than 5:1. The claims further require GCPQ functionalization by palmitoylation and quaternization within defined ranges and require a formulation pH of 6.5 to 7.4, with one independent claim additionally requiring pharmaceutically acceptable excipients.
Stated Advantages
Improved ocular delivery supported by drug levels in cornea/conjunctiva that are higher than Restasis®.
Reduced systemic exposure supported by plasma levels below quantification.
Stability under thermal and freeze-thaw conditions.
Documented Applications
Use in treating ocular conditions associated with hydrophobic macrolide immunosuppressants, including dry eye syndrome (DES)/keratoconjunctivitis sicca, vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), and Sjögren syndrome.
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