Evaluation of the impact of the polymer end groups and molecular weight on in vitro and in vivo performances of PLGA based in situ forming implants for ketoprofen

Introduction

In situ forming implants (ISFIs) are attractive dosage forms for prolonged drug release. ISFIs are typically injected as low viscous solutions and then form a gel or solid depot at the injection site in the body. Different triggers have been reported to enable this solution to depot transformation, e.g., in situ cross-linking stimulated by photo, physical or chemical factors, in situ solidifying organogels, in situ phase separation induced by pH, temperature or solvent exchange.1 Among all these technologies, only in situ polymer precipitation systems based on solvent removal have established their commercial dominance.1 These in situ polymer based systems are polymeric delivery systems consisting of a water insoluble polymer (e.g. Poly(DL-lactide-coglycolide) or PLGA, Poly(DL-lactide) or PLA) dissolved in a biocompatible water miscible solvent (e.g. N-methyl-s-pyridone or NMP, polyethylene glycols or PEGs). The drug is either suspended or dissolved in the polymer solution. When injected into the body, e.g. subcutaneously, the water miscible solvent diffuses from the injection site while water permeates into the polymer matrix. Since the polymer is not soluble in water, it precipitates or coagulates upon contact with aqueous body fluid to form a solid implant which slowly releases its drug as the polymer degrades over time. An example of such technology is “Atrigel”.2 Several extended release in situ forming implant drug products approved by FDA between 1998 and 2018 are based on this technology, e.g. Atridox® (doxycycline hyclate, approved in 1998, drug released up to 7 days), Eligard® (leuprolide acetate suspension, approved in 2002), Sublocade® (buprenorphine solution, approved in 2017), Perseris® (risperidone suspension, approved in 2018), Fensolvi® (leuprolide acetate suspension, approved in 2020, administered every 6 month).2,3 Except for Atridox®, all these products are administered at least monthly via subcutaneous route of administration, leading to decreased dosing frequency, enhanced patient convenience, and improved patient compliance.

In the field of research, ISFIs has been an area with great interest since 1990, demonstrating a consistent growth in publications referencing “in situ implants” in last three decades. The number of publications citing this term increased rapidly and peaked at around 3000 between 2013 and 2015. Since then, the prevalence of publications on this topic has remained steady. Research on ISFIs includes development of novel polymeric or non-polymeric excipients for such formulations, as well as investigations of critical formulation factors, process parameters, and dosing parameters and their impact on product performance.4, 5, 6 Another crucial area of intense research in recent years has been the development and evaluation of biorelevant in vitro release methods.4, 5, 6 The chemical modalities reported for in situ forming implants (ISFIs) span from large molecules such as peptides and proteins to small molecules.7,8 The broader potential applications of this technology offer a significant opportunity to transform the poorly soluble small molecules in the current drug discovery and development pipelines into chronic treatments via alternative routes of administration, as opposed to oral solid dosage forms. The recently approved Perseris® serves as a great example of this.9 Perseris® contains a poorly soluble atypical antipsychotic molecule, risperidone. To enhance patient compliance, Perseris® offers a monthly subcutaneous injection as an alternative to daily oral administration. Utilizing the Atrigel delivery system (an extended-release polymer 80:20 poly(D, L-lactide-co-glycolide) dissolved in NMP with the risperidone powder suspended in the polymer solution), Perseris® achieved sustained, dose-proportional systemic exposures over a 28-day period in both rats and dogs. Additionally, less than 7% and 10% of the total systemic exposure of risperidone was released in rats and dogs, respectively, from the in situ implant within the first 24 hours after injection, followed by a trough during the first week and subsequent rise to a plateau that persisted until Day 28. This type of sustained drug release profiles over a 28-day period following subcutaneous administration present significant potential in drug discovery and research especially as we encounter an increasing number of poorly soluble molecules at this stage of development.

In drug discovery, local injections (intramuscular, intraperitoneal, subcutaneous) are often utilized to achieve sustained target coverage in preclinical animal models.10 Daily subcutaneous injections necessitate injection site rotation to reduce injection site reactions and animal stress. Conversely, sustained release depot formulations can circumvent such shortcomings, making them highly appealing at this stage of development. Previously, we discussed the opportunities and challenges of developing subcutaneous thermos-sensitive in situ gel depots for small molecules in drug discovery.10 In our previous report, we endeavored to develop thermos-sensitive in situ gel depot (thermogel) extended-release formulations for ketoprofen. Extended drug release profiles were observed in vitro up to 5 or 9 days for two different polymers; however, rapid in vivo drug absorption was noted from both formulations. Furthermore, despite differentiated in vitro drug release profiles between the two polymers evaluated, no difference was observed in the rat pharmacokinetic profiles. These observations underscored a significant gap for the in vitro-in vivo relationship for ketoprofen thermogel formulations. The next intriguing extend-release formulation type to explore in drug discovery would be in situ forming implant formulations as they present as a liquid at room temperature, making them suitable for dosing animals with syringes in drug discovery.

The main objective of this article is to showcase the development of extended-release subcutaneous in situ forming implants for ketoprofen using commercially available triblock polymers such as poly (lactic-co-glycolic acid)-poly (ethylene glycol)-poly (lactic-co-glycolic acid), featuring different type of end groups and molecular weights (PLGA-PEG-PLGA, Resomer® RG 502H, 502, 753H, 753S). The study involves analytical characterization of the in situ forming implants and a comparative analysis of the in vitro ketoprofen release profiles of the selected copolymers with their in vivo performance following subcutaneous administration in rats. Furthermore, the article discusses the in vitro-in vivo relationship for ketoprofen in situ implant formulations and emphasizes the key challenges and opportunities associated with the development and assessment of in situ implant formulations.

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Materials

Resomer® RG 502H, 502, 753H and 753S Poly(D,L-lactide-co-glycolide) (PLGA) were sourced from Evonik, NJ, USA. Ketoprofen was purchased from Sigma-Aldrich, MO, USA. N-Methyl-2-pyrrolidone (NMP) was purchased from Acros Organics, NJ, USA. Phosphate-buffered saline pH 7.4 (PBS, GibcoTM) was obtained from Thermo Fisher Scientific, USA. All these reagents were procured commercially and used without further purification.

Sanjib Saha, Xinhao Lin, Liping Zhou, Aixiang Xue, Eric Gosselin, Paresh P. Chothe, Mittal Darji, Xiuling Lu, Wenzhan Yang, Evaluation of the impact of the polymer end groups and molecular weight on in vitro and in vivo performances of PLGA based in situ forming implants for ketoprofen, Journal of Pharmaceutical Sciences, 2024, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2024.10.019.

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