Abstract:
Background: Obesity and diabetes are chronic conditions that need continuing care and it is crucial to ensure patient compliance with the medication to maintain the plasma drug concentration constant. For controlled and sustained delivery of medications, Long-Acting Injectables (LAIs) have been developed. LAIs have several advantages over traditional administration methods, including improving patient compliance, minimizing adverse effects (AEs), and maintaining the plasma drug concentration within therapeutic windows for predetermined time frames, thus maximizing therapeutic efficacy.
In recent years, semaglutide has received extensive interest due to its high effectiveness in managing both diabetes and obesity. It functions as a glucagon-like peptide-1 (GLP-1) receptor agonist, stimulating glucose-dependent insulin release, inhibiting inappropriate post-meal glucagon release and reducing food intake. Nevertheless, it frequently causes gastrointestinal (GI) AEs (e.g., nausea, vomiting), which are less common with LAIs than short-acting ones and the extent of them is known to be related to the dose strength. To maximize therapeutic efficacy while minimizing AEs, it is essential to employ LAI-mediated semaglutide administration with meticulous regulation of in situ drug release. However, encapsulating semaglutide, a high molecular and hydrophilic peptide requiring a narrow therapeutic window, into the LAI had remained a challenging project.
Herein, a novel subcutaneously administered, one-month LAI of semaglutide called IVL3021 is described. The LAI was developed and manufactured by IVL-DrugFluidics® technology using microfluidics, enabling precise drug release control through size-, morphology-, nanostructure-regulated microspheres. In the current study, the physicochemical properties of IVL3021 were characterized, and the pharmacokinetic (PK) profiles in SD rat models were investigated.
Methods: IVL3021 were prepared by Inventage Lab’s microfluidics-based manufacturing technology, IVL-DrugFluidics® technology. The morphology of IVL3021 was examined by scanning electron microscopy (SEM), and the size distribution of the microparticles was measured by a laser particle size analyzer (PSA). The size distributions were expressed as span value and CV(%). The amount of semaglutide encapsulated in the microspheres were determined by HPLC, and encapsulation efficiency (EE, %) was calculated. Non-clinical models were used to optimize the formulation and to evaluate their pharmacokinetic properties. IVL3021 was administered to male SD Rats, and plasma concentrations were monitored for 6 weeks.
Results: The SEM images of the IVL3021 showed smooth spherical microspheres. The EE(%) of the microspheres was over 97.0% and the solvents used for manufacturing met the FDA's residual solvent guideline. The span value was less than 0.32% and the CV (%) was less than 11.17%, confirming that the particle size distribution was uniform. In the preclinical PK study, the plasma concentrations of semaglutide were maintained without an initial burst release over 4 weeks.
Conclusions: The IVL3021, size-controlled semaglutide-encapsulating PLGA microspheres have been successfully developed using IVL-DrugFludics® Technology. Including the size, and topology of the vehicle particles, EE and PK of IVL3021 behaviors were characterized for further clinical investigation. In conclusion, the findings of the study indicate IVL3021 holds great potential to improve compliance and the quality of life in long-term treatment regimens for obese and diabetic patients.
Audience take-away:
- The concept of microparticle-based LAI and its advantages in the obesity and diabetes treatment
- Superiority of microfluidics-based LAI-manufacturing technology over conventional technology
- Well-controlled and well-characterized microparticle-based drug release system
- Pharmacokinetics of LAI-mediated semaglutide in animal models: Comparison between conventionally delivered and LAI-mediated delivered active semaglutide
