Methods and compositions for delivery of a therapeutic agent
View Patent ↗Compositions of hyaluronic acid (HA) conjugated with antibiotics are disclosed for a rapid release antibiotic delivery system into a closed space to achieve rapid therapeutic range within 24 hours and effective elimination of the antibiotic within 80-120 hours. In particular, this invention is directed to compositions, method of preparation, and method of treatment to prevent invention using porous and non-porous embodiments of hyaluronic acid polymer conjugated with antibiotics or other therapeutic agents for rapid therapeutic delivery and controlled reduction of therapeutic dosages of antibiotics to prevent invention and reduce antibiotic resistance. Low concentration of crosslinkers conjugated with HA as well as using porogens and functional group modifiers allow other therapeutic to be conjugated to HA such as sugars and steroids. Suspension of HA conjugates in chitosan enable additional treatment means. Anti-cancer therapeutic agents may also be conjugated for controlled release using this system.
1 . A biologically active rapid release therapeutic agent polymer composition comprising:
a hyaluronic acid (HA) polymer formed of HA particles, the HA particles comprising HA repeating units;
a therapeutic agent covalently bound to the HA polymer; and,
a crosslinking agent present at less than 20% mole relative to the HA repeating units;
wherein the HA particles are porous HA particles formed by crosslinking at said less than 20% mole amount by dispersing an aqueous HA solution in a sodium bis(2-ethylhexyl) sulfosuccinate (AOT) solution in isooctane, the porous HA particles having an average surface area between 0.32 m2/g and 21.54 m2/g, an average pore volume of between 0.86 cm3/g and 7.92 cm3/g, and an average pore size between 5.4 nm and 8.3 nm;
wherein the HA polymer is adapted to release the therapeutic agent to achieve a therapeutic range within approximately 24 hours after administration; and
wherein the therapeutic agent is substantially released from the HA-polymer within 80-120 hours after administration.
2 . The composition of claim 1 wherein the therapeutic agent is an antibiotic and wherein the therapeutic agent is substantially released from the HA polymer within 80-120 hours after administration, and wherein the AOT solution is a 0.2M AOT solution used during synthesis in isooctane, wherein the HA polymer is adapted to release the antibiotic to achieve a therapeutic range within approximately 24 hours after administration.
3 . The composition of claim 2 , wherein the crosslinking agent is divinyl sulfone (DVS).
4 . The composition of claim 3 , wherein the amount of crosslinking agent is present at less than 10% mole relative to the HA repeating units.
5 . The composition of claim 3 , wherein the amount of crosslinking agent is present at less than 5% mole relative to the HA repeating units.
6 . The composition of claim 3 , wherein the amount of crosslinking agent is present at less than 2.5% mole relative to the HA repeating units.
7 . The composition of claim 2 , wherein the HA polymer further includes a simple carbohydrate conjugated to the HA-polymer, wherein the HA polymer is an HA-carbohydrate-antibiotic polymer, whereby the simple carbohydrate attracts bacteria to proximate of the antibiotic.
8 . The composition of claim 7 , wherein the simple carbohydrate is sucrose.
9 . The composition of claim 8 , wherein the HA repeating units are modified HA repeating units having at least one of modified functional groups of —OH, —NH 2 , —COOH, —SH, —SO 3 H, and —CN, thereby increasing conjugation sites on the HA polymer for the therapeutic agent.
10 . The composition of claim 1 , wherein the therapeutic agent is selected from the group consisting of Mitomycin C, 5-Fluorouacil and Cisplatin.
11 . The composition of claim 1 , wherein the therapeutic agent is selected from the group consisting of interferons and insulin.