Injectable and biodegradable polymer formulations for controlled release of bioactive agents
View Patent ↗The present disclosure is directed to injectable formulations that include biodegradable polymers based on trimethylene carbonate (TMC) with mole fractions of polylactic acid (PLA) and/or polyglycolic acid (PGA) that are used to deliver a bioactive agent to a targeted site. Excipients such as polyethylene glycol (PEG) may be added to the formulations to reduce the injection force and/or to modulate the release of the bioactive agent. Suitable biodegradable polymers for use in the injectable formulations include D,L-PLA:TMC, D-PLA:TMC, L-PLA:TMC, TMC:PLA:PGA and variations thereof. Additionally, copolymers of TMC and PLA and terpolymers of TMC:PLA:PGA may be formed into nanoparticles and delivered to the target site with an injectable crosslinkable polyethylene glycol system. In at least one embodiment, the injectable formulations are used to treat ocular diseases.
1. An injectable sustained-release formulation comprising:
an injectable bioabsorbable polymer comprising
a polylactide (PLA), trimethylene carbonate (TMC), polyglycolic acid, (PGA) terpolymer, wherein the terpolymer comprises from 3-19 wt. % PGA and wherein the PLA:TMC weight ratio is from 3.25:1 to 0.75:1;
a pharmaceutically acceptable excipient;
at least one solvent selected from 1,2 3-triacetoxypropane, acetyltributyl citrate, triethyl citrate, tributyl citrate, and acetyl triethyl citrate; and
a bioactive agent;
wherein said terpolymer is in the form of an injectable liquid;
wherein the injectable liquid solidifies in a tissue bed in the form of a solid mass,
wherein the tissue bed is an eye, and
wherein said formulation is configured to maintain a normalized average intraocular pressure (IOP) in the eye at or below 100% for 14 weeks.
2. The injectable formulation of claim 1 , wherein the bioactive agent is incorporated in said injectable bioabsorbable polymer and said bioactive agent has a half-life of release from said injectable bioabsorbable polymer of greater than 30 days.
3. The injectable formulation of claim 1 , wherein said excipient is selected from polyethylene glycol, poloxamers, and polyvinyl alcohol.
4. The injectable formulation of claim 1 , wherein said terpolymer has a number average molecular weight from 25,000 to 40,000 g/mol.
5. The injectable formulation of claim 1 , wherein the bioactive agent is incorporated in said injectable bioabsorbable polymer.
6. The injectable formulation of claim 1 , wherein the injectable sustained-release formulation is a delayed-release formulation in vivo or in situ.
7. The formulation of claim 1 , wherein said solid mass allows for delayed release of the bioactive agent.
8. The injectable formulation of claim 1 , wherein said formulation is used to treat ocular diseases.
9. An injectable sustained-release formulation comprising:
a first portion comprising nanoparticles formed from a copolymer of polylactic acid (PLA) and trimethylene carbonate (TMC) in an injectable cross-linkable polyethylene glycol (PEG), wherein the first portion is contained within a first barrel of a syringe, and
a second portion comprising a cross-linkable polyethylene glycol (PEG) contained within a second barrel of the syringe; and
a bioactive agent encapsulated in said nanoparticles of said first portion,
wherein said copolymer comprises from 60 to 90 wt. % PLA and from 10 to 40 wt. % TMC,
wherein the first and second barrels are configured to inject the first and second portions into an eye
wherein the first portion and the second portion are configured to mix and solidify as a rigid hydrogel with the nanoparticles entrapped therein in the eye, and
wherein said formulation is configured to maintain a normalized average intraocular pressure (IOP) in the eye at or below 100% for 14 weeks.
10. The injectable formulation of claim 9 , wherein said bioactive agent has a half life of release from said nanoparticles of greater than 30 days.
11. The injectable formulation of claim 9 , wherein the injectable sustained-release formulation is a delayed-release formulation in vivo or in situ.
12. An injectable sustained-release formulation comprising:
a first portion comprising nanoparticles formed from a copolymer of polylactic acid (PLA) and trimethylene carbonate (TMC) in an injectable cross-linkable polyethylene glycol (PEG), the first portion contained within a first barrel of a syringe
a second portion comprising a cross-linkable polyethylene glycol, the second portion contained within a second barrel of the syringe; and
a bioactive agent encapsulated in said nanoparticles of said first portion,
wherein the first and second barrels are configured to inject the first and second portions simultaneously or nearly simultaneously,
wherein a combination of the first portion and the second portion in a tissue bed forms a rigid hydrogel with the nanoparticle entrapped therein,
wherein the tissue bed is an eye, and
wherein said formulation is configured to maintain a normalized average intraocular pressure (IOP) in the eye at or below 100% for 14 weeks.
13. The injectable formulation of claim 12 , wherein said bioactive agent has a half life of release from said nanoparticles of greater than 30 days.
14. The injectable formulation of claim 12 , wherein the injectable sustained-release formulation is a delayed-release formulation in vivo or in situ.
15. The injectable formulation of claim 12 , wherein the cross-linkable polyethylene glycol of the first portion comprises a polyethylene glycol amine and the cross-linkable polyethylene glycol of the second portion comprises a polyethylene glycol succinimidyl glutarate.
16. An injectable sustained-release formulation comprising:
an injectable bioabsorbable polymer comprising
a D/L-polylactide (D/L-PLA), trimethylene carbonate (TMC), and polyglycolic acid (PGA) terpolymer, wherein the terpolymer comprises from 3-19 wt. % PGA and wherein the D/L-PLA:TMC weight ratio is from 3.25:1 to 0.75:1;
a pharmaceutically acceptable excipient;
a solvent; and
a bioactive agent,
wherein the injectable bioabsorbable polymer solidifies in a tissue bed in the form of a solid mass,
wherein the tissue bed is an eye, and
wherein said formulation is configured to maintain a normalized average intraocular pressure (IOP) in the eye at or below 100% for 14 weeks.
17. The injectable formulation of claim 16 , wherein the solvent comprises 1,2,3-triacetoxypropane, acetyltributyl citrate, triethyl citrate, tributyl citrate, or acetyl triethyl citrate.