Therapeutic agent formulations for implanted devices
An injectable formulation of therapeutic agent may comprise the therapeutic agent and a stabilizer such that a substantial portion of the stabilizer remains in the therapeutic device to stabilize the therapeutic agent when the therapeutic agent is released from the therapeutic device. The injectable formulation may comprise one or more of binding agent particles or erodible material particles, such that the formulation can be injected into the therapeutic device. The binding agent particles can bind reversibly to the therapeutic agent so as to modulate release of the therapeutic agent, and the erodible material particles can generate protons of an acid so as to increase stability of the therapeutic agent and may modulate release of the therapeutic agent. The therapeutic agent can be combined with one or more of the stabilizer, the binding agent particles or the erodible particles to increase stability of the therapeutic agent and may modulate release.
1. An aqueous composition comprising:
(i) a therapeutic agent;
(ii) a stabilizer having a molecular weight of at least 2 kilodaltons, wherein the molecular weight of the stabilizer is at least 25% of the molecular weight of the therapeutic agent; and
(iii) a complex comprising the therapeutic agent and the stabilizer;
wherein the therapeutic agent, the stabilizer, and the complex are in equilibrium in the aqueous composition.
2. The aqueous composition of claim 1 , wherein the therapeutic agent, the stabilizer, and the complex are in solution in the aqueous composition.
3. The aqueous composition of claim 1 , wherein the therapeutic agent is an antibody or a Fab antibody fragment.
4. The aqueous composition of claim 1 , wherein the stabilizer has a plurality of hydrophilic functional groups.
5. The aqueous composition of claim 1 , wherein the stabilizer has a molecular weight of at least 5 kilodaltons.
6. The aqueous composition of claim 5 , wherein the stabilizer has a molecular weight of at least 10 kilodaltons.
7. The aqueous composition of claim 1 , wherein the stabilizer is a metal ion, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, chitosan, hyaluronic acid, a histidine polymer, polyethylene oxide, or a combination of two or more thereof.
8. The aqueous composition of claim 1 , further comprising a particulate binding agent that is capable of reversibly binding with the therapeutic agent.
9. The aqueous composition of claim 8 , wherein the particulate binding agent is non-biodegradable.
10. The aqueous composition of claim 8 , wherein the particulate binding agent is a chromatographic binding agent.
11. The aqueous composition of claim 1 , further comprising an erodible polymer.
12. The aqueous composition of claim 11 , wherein the erodible polymer is polylactic acid, polyglutamic acid, polylactic acid/polyglutamic acid copolymer, polyglycolic acid, or poly(lactide-co-glycolide) copolymer.
13. The aqueous composition of claim 1 , further comprising a surfactant.
14. The aqueous composition of claim 13 , wherein the surfactant is polysorbate 20, polysorbate 80, an ethylene oxide-propylene oxide block copolymer, an ethoxylated emulsifier, or a combination of two or more thereof.
15. The aqueous composition of claim 1 , further comprising a buffer.
16. The aqueous composition of claim 15 , wherein the buffer is an acetate buffer, a succinate buffer, a gluconate buffer, a histidine buffer, or a citrate buffer.