Improved small molecule drug release fromin situforming poly(lactic-co-glycolic acid) scaffolds incorporating poly(β-amino ester) and hydroxyapatite microparticles

Abstract

In situ forming implants are an attractive choice for controlled drug release into a fixed location. Currently, rapidly solidifying solvent exchange systems suffer from a high initial burst, and sustained release behavior is tied to polymer precipitation and degradation rate. The present studies investigated addition of hydroxyapatite (HA) and drug-loaded poly(β-amino ester) (PBAE) microparticles to in situ forming poly(lactic-co-glycolic acid) (PLGA)–based systems to prolong release and reduce burst. PBAEs were synthesized, imbibed with simvastatin (osteogenic) or clodronate (anti-resorptive), and then ground into microparticles. Microparticles were mixed with or without HA into a PLGA solution, and the mixture was injected into buffer, leading to precipitation and creating solid scaffolds with embedded HA and PBAE microparticles. Simvastatin release was prolonged through 30 days, and burst release was reduced from 81% to 39% when loaded into PBAE microparticles. Clodronate burst was reduced from 49% to 32% after addition of HA filler, but release kinetics were unaffected after loading into PBAE microparticles. Scaffold dry mass remained unchanged through day 15, with a pronounced increase in degradation rate after day 30, while wet scaffolds experienced a mass increase through day 25 due to swelling. Porosity and pore size changed throughout degradation, likely due to a combination of swelling and degradation. The system offers improved release kinetics, multiple release profiles, and rapid solidification compared to traditional in situ forming implants.

Degradation of poly(β‐amino ester) gels in alcohols through transesterification: Method to conjugate drugs to polymer matrices

“…It was initially observed that PβAEs synthesized using single step approach were unstable in ethanol. This was different from previously reported data, where ethanol was used as a stable washing solvent . Originally, it was believed that degradation was due to the water content in the solvent.…”

Modelling of combination therapy using implantable anticancer drug delivery with thermal ablation in solid tumor

“…For example, in-situ forming implants (ISFIs) have a dual-release pattern with a large undesirable burst release, which may cause major toxicity problems and consume the loaded drug in the implants rapidly 10 . Designing this type of implants with a minimum initial burst release becomes an attractive challenge, and one of the key issues in the design of ISFIs 11 . Moreover, some drug-loaded implants can be designed in a controlled way to have a dual-release profile to release a large amount of drug early, i.e., burst release, to rapidly reach the effective therapeutic concentration at the target site while keeping drug concentration within the effective level during the sustained release phase 12 .…”

PNIPAAM modified mesoporous hydroxyapatite for sustained osteogenic drug release and promoting cell attachment

“…For microspheres, PLGA is considered to be a good drug carrier owning to its excellent biocompatibility and biodegradability [16,17]. However, PLGA microspheres provide a large initial burst release [18]. Therefore, to overcome this problem, polymers such as poly(β-amino ester) (PBAE) [18], polyethylene glycol (PEG) [19], and poly(L-lactic acid) (PLLA) [20] were added to adjust the release profile of the drug.…”

“…However, PLGA microspheres provide a large initial burst release [18]. Therefore, to overcome this problem, polymers such as poly(β-amino ester) (PBAE) [18], polyethylene glycol (PEG) [19], and poly(L-lactic acid) (PLLA) [20] were added to adjust the release profile of the drug. Inorganic porous materials were also used as bone substitutes, such as α-tricalcium phosphate (α-TCP) [21], β-tricalcium phosphate (β-TCP) [22–24], and hydroxyapatite (HA) [18].…”