Implantable pharmaceutical composition prepared from components consisting of calcium sulfate alpha-hemihydrate, vancomycin and gentamicin
Inventors
Aiken, Sean Sydney • Laycock, Phillip Anthony • Cooper, John Joseph • Bratt, John Stephen • Harris, Michael Christopher James
Assignees
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Publication Number
US-12133862-B2
Publication Date
2024-11-05
Expiration Date
Abstract
The present disclosure concerns a composition for an implantable pharmaceutical composition prepared from components consisting only of calcium sulfate α-hemihydrate in combination with two antibiotics, vancomycin and gentamicin, for the treatment of infection in bone and soft tissue.
Core Innovation
The disclosed invention relates to an implantable pharmaceutical composition for drug delivery that consists of phase pure calcium sulfate α-hemihydrate and dual antibiotics, vancomycin hydrochloride and gentamicin sulfate. The composition is formed so that calcium sulfate α-hemihydrate is excipient-free, and the gentamicin sulfate is in the form of a solution. The formulation is intended to control water demand, porosity/pore size, setting time, and mechanical strength, thereby controlling dissolution and elution and reducing the risk of overly rapid release.
The invention further provides a route for preparing the calcium sulfate α-hemihydrate using conversion steps from calcium sulfate dihydrate to soluble calcium sulfate anhydrite and then back to calcium sulfate α-hemihydrate. A source of pharmaceutical grade calcium sulfate dihydrate is converted to soluble calcium sulfate anhydrite by hydrothermal treatment in suspension, and the resulting soluble anhydrous calcium sulfate is converted to calcium sulfate α-hemihydrate through sequential autoclave rehydration to calcium sulfate dihydrate followed by a further conversion autoclave step.
The disclosed invention combines the prepared phase pure α-hemihydrate with vancomycin hydrochloride and gentamicin sulfate, and forms the mixture into implantable beads or pellets. The document reports in vitro synergistic inhibition of vancomycin plus gentamicin compared to single antibiotic, including inhibition for gram-positive bacteria including MRSA, and the beads or pellets are described by characteristic shapes and measured properties including BET specific surface area, BJH pore diameters, and compressive strength.
Claims Coverage
The independent claims are directed to a pharmaceutical composition and a method of manufacturing an implantable drug delivery composition. Across the independent claims, four principal inventive features recur: phase-pure calcium sulfate α-hemihydrate prepared via the specified hydrothermal/autoclave conversion route, combination with vancomycin hydrochloride and gentamicin sulfate (gentamicin sulfate being in the form of a solution/liquid) in defined amounts, formulation into implantable beads or pellets, and process conditions for producing the beads or pellets from the mixed suspension and α-hemihydrate powder.
Dual-antibiotic implantable calcium sulfate α-hemihydrate composition
A pharmaceutical composition prepared from components consisting of pharmaceutical grade, phase pure calcium sulfate α-hemihydrate, vancomycin hydrochloride, and gentamicin sulfate, the gentamicin sulfate in the form of a solution.
Hydrothermal/autoclave route to phase-pure calcium sulfate α-hemihydrate
The calcium sulfate α-hemihydrate is prepared by converting a source of pharmaceutical grade calcium sulfate dihydrate to soluble calcium sulfate anhydrite by hydrothermal treatment in suspension, and then converting the resulting soluble anhydrous calcium sulfate to calcium sulfate α-hemihydrate by sequential autoclave rehydration and a further conversion autoclave step.
Beads or pellets formed from mixed suspension and α-hemihydrate powder
A method of manufacturing a composition for delivery of an implantable drug by mixing vancomycin hydrochloride with gentamicin sulfate, combining the suspension with pharmaceutical grade, phase pure calcium sulfate α-hemihydrate powder to form a mixture, forming the mixture into beads or pellets, and allowing the beads or pellets to set and solidify using molds.
The claim set centers on an implantable dual-antibiotic composition using phase pure, excipient-free calcium sulfate α-hemihydrate produced via a defined hydrothermal/autoclave conversion route, combined with vancomycin hydrochloride and gentamicin sulfate. The composition is provided and/or manufactured as beads or pellets formed from a suspension combined with α-hemihydrate powder and set or solidified to obtain the implantable drug delivery form.
Stated Advantages
Controls water demand, porosity/pore size, setting time, and mechanical strength, thereby controlling dissolution and elution and reducing the risk of overly rapid release.
Provides synergistic inhibition for vancomycin plus gentamicin versus single antibiotic in vitro.
Documented Applications
Administering the composition into a surgical void to treat an infection in bone and soft tissue.
Delivery of an implantable drug for an implantable drug delivery composition using the described beads or pellets.
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