(178aa) Injectable in situ crosslinkable depots for ultra-long-acting delivery of hydrophilic therapeutics

Patient adherence to medications is a major obstacle towards achieving effective treatment of numerous diseases, especially for chronic conditions that require treatment throughout life. Sustained release technologies, including long-acting injectables (LAIs) and implants simplify dosing schedules and enhance treatment regimen adherence, which is particularly advantageous in low resource settings with limited healthcare infrastructure.

Multiple LAIs and implants are in clinical use for the treatment and prevention of different diseases.^{1, 2} Conventional LAI approaches such as microparticles,³ in situ-forming implants (ISFI), and wet milled particles have been documented to achieve prolonged release of hydrophobic drugs for several months but have poor ability to achieve similar ultra-long-term release of hydrophilic drugs^4-7. In the case of ISFI, which typically consists of a hydrophobic polymer, poly(lactic-co-glycolic acid) (PLGA) dissolved in N-methyl-2-pyrrolidone (NMP), solvent efflux during phase conversion tends to release a significant amount of drug as initial burst, which increases with the hydrophilicity of the drug.⁶ Additionally, previously developed LAI approches promote significant influx and efflux of water due to their large pores, leading to fast diffusion of hydrophilic drugs.^{3, 6, 8} Wet milling – a commonly employed approach for formulating LAIs^{9, 10} require the drug to be hydropbohic and are fundamentally incompatible with hydrophilic drugs.^{1, 11, 12} Although implantable devices have shown success for long-term delivery of both hydrophobic¹³ and hydrophilic drugs^{14, 15}, they require invasive, time-consuming medical procedures for insertion, which may pose significant challenges, particularly in low resource settings and low-middle income countries. Furthermore, implants in general tend to be more susceptible to local inflammation when compared to injectable alternatives.^{16, 17}

Hydrophilic drugs constitute a major fraction of all the drugs used for the prevention, treatment and management of chronic conditions. Examples include anti-psychotics, anti-depressants, anti-convulsants, antibiotics, and drugs for the treatment of substance abuse disorder (SUD). Although a few hydrophilic drugs have clinically approved LAI formulations, their release typically last for only a month. For example, Vivitrol®, an LAI suspension of naltrexone-loaded PLGA microspheres for treating SUD, provides 30 days of drug release,¹⁸ which is sub-optimal since SUD often requires therapy for several years. Therefore, there is an unmet need to develop an injectable platform that enables ultra-long-term delivery of hydrophilic drugs for several months. Additionally, the platform should be designed to be biodegradable for safe breakdown and clearance from the body while also being retrievable in the event of local or systemic drug toxicity.

We report an injectable platform that addresses the aforementioned limitations of current LAI approaches, thereby resulting in ultra-long-term release of encapsulated hydrophilic drugs for at-least 6 months. This platform is derived from an ultra-low-molecular-weight liquid pre-polymer – polycaprolactone (PCL), which has been used previously in multiple FDA approved products. PCL is chemically modified with methacrylate groups, enabling it to undergo cross-linking upon injection. The liquid pre-polymer can effectively suspend or dissolve both hydrophilic and hydrophobic drugs, and can be easily injected through a standard 18-23 gauge needle. Upon co-injection with clinically used radical initiator and accelerator, benzoyl peroxide (BPO) and N,N-dimethylparatoluidine (DMT), the pre-polymer mixture undergoes a time-dependent (1-10 minutes) cross-linking in situ. The cross-linking process involves radical polymerization of methacrylated PCL creating new carbon-carbon bonds. This process encapsulates the drugs physically, creating a solid monolithic structure hereafter referered to as an in situ cross-linked depot (ISCD). Hydrolysis of the polymer ester bonds allows gradual erosion of the depot over time, obviating the need for surgical removal after depot exhaustion, and ensuring safe clearance from the body.

ISCD has two key features, which enable it to achieve ultra-long-term release of hydrophilic drugs. These include a solvent-free design and a dense mesh network, both attributed to the use of ultra-low-molecular weight PCL. The liquid state of the pre-polymer obviates the need for a solvent, minimizing the risk of high burst release, commonly associated with solvent exchange processes in ISFI.⁷ Being ultra-low molecular weight, methacrylated PCL forms a dense mesh upon cross-linking, which limits water influx/efflux and hence the drug release.

We have demonstrated sustained release of multiple hydrophilic drugs with varying water solubilities ranging from 5.63-112 mg/mL and belonging to a diverse class of therapeutics, including anti-retrovirals, opioid antagonists and antibiotics. ISCD showed sustained release of all the drugs for at least 6-10 months in vitro, suggesting the versatality of the platform. We also demonstrated ultra-long-term release of two proof-of-concept hydrophilic drugs - tenofovir alafenamide (TAF) and naltrexone (NAL) in vivo in rats. A single subcutaneous injection of ISCD formulations loaded with TAF or NAL resulted in sustained plasma concentration for at least 6-7 months. ISCD outperformed the conventional ISFI platform in TAF delivery, exhibiting notably lower burst release compared to ISFI, and providing a prolonged drug release duration of up to 7 months. ISCD also showed ultra-long-term release of a hydrophobic drug – Tacrolimus (TAC) for at least 6 months in rats. Pharmacokinetic (PK) modeling predicted sustained delivery of NAL and TAC in humans, achievable with ISCD. We also identified design parameters that can tailor the polymer network to tune drug release kinetics of ISCD. Notably, modulating the intrinsic factors, including decreasing the concentrations of BPO and DMT, or using a higher molecular weight of methacrylated PCL results in a lower cross-linking density within the polymer network, thereby increasing the drug release. Additionally, integrating external polymeric additives such as polyethylene glycol (PEG) alongside methylacrylated PCL can modulate the depot’s hydrophilicity, increasing drug release. External additives with varying degree of methacrylation (mono, di or tri) can also modulate drug release by altering the cross-linking density of the polymer network. Finally, we also demonstrated the feasibility of achieving ultra-long-term release of clinically relevant combination regimens of hydrophilic drugs, encapsulated in a single depot, and demomstrated the biocompatibility and retrievability of ISCD.

Together, our findings underscore the potential of ISCD as a versatile platform to enable ultra-long-term delivery of both hydrophilic and hydrophobic drugs. This approach has holds potential to revolutionize therapy options across a variety of chronic conditions where patient adherence is critical. To our knowledge, this is the first report demonstrating ultra-long-term delivery of hydrophilic drugs using an injectable system.

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