(M1430-02-10) Effects of Monomer on PLGA Based Long-Acting Injectables’ Release and Stability

Purpose: Long acting injectables (LAI’s) frequently utilize bio-resorbable polymers to control the release of active pharmaceutical ingredients via tunable degradation rates. One commonly used bioresorbable polymer is poly (lactic-co-glycolic acid), or PLGA because they allow for tuning of co-monomer ratio, molecular weight, and end capping group to meet a characteristic degradation rate¹. Degradation rates, geometric constraints and, API characteristics such as hydrophobicity and loading help determine the pharmacokinetic profile of the long-acting injectable product². A less studied aspect of PLGA bio-resorbable polymers is the effect monomers can have on the degradation rate and drug stability. The purpose of this study is to examine the effects monomer has on long-acting injectable formulations release and stability and how to minimize these effects.

Methods: Analysis of the development of an acidic microenvironment was performed using Viatel™ DL 02 A and DL 07 E both with varying level of monomer were cast into thin films by solubilizing 1.0 g polymer in acetone and removing the solvent using elevated temperature and vacuum. The cast films were incubated at 37 °C for an extended duration in a 20mL scintillation vials with 15 mL of 10 mM phosphate buffer at pH 6.95. The pH profile was measured twice a week and the study was terminated after no significant change in pH was observed. API stability was assessed using solutions composed of Pharmasolve™ (NMP), DL 02 A with varying levels of monomer and 100 mg/g atorvastatin to assess degradation of the API over 3 days. In situ forming depots were composed of Pharmasolve™ (NMP), DL 07 E with relatively low and high levels of residual monomer and atorvastatin to assess the burst release of the API, by directly injecting the depot forming solution into a bath containing 900 mL pH 7.4 PBS and stirring at 100 rpm after initially forming the depot. The assay and related substance profile was quantified by employing HPLC coupled with a photodiode array detector over 7 hours.

Results: In the cases of both thin films a significant drop in pH is observed immediately for samples containing elevated monomer which is to be expected as the monomer hydrolyses to lactic acid in solution. The high monomer sample also has a more erratic and rapid degradation compared to the low monomer sample that degrades in a more gradual and controlled manner as seen in figures 1 and 2. For DL 07 E little acidification is seen over 13 weeks. Stability of the in situ system shows the degradation of atorvastatin was far more pronounced with increasing concentrations of monomer compared to the low monomer equivalent. At 72 hours nearly 10% of API had been degraded in the high monomer sample compared to < 2% in the low monomer sample, Fig. 3. Release of atorvastatin was monitored up to 7 hours from in situ depot systems containing high and low monomer. The high monomer depot demonstrates initial burst of 7% at T0 and > 35% by 7 hours. The low monomer sample had released only 5 % at T0 which increases to 29% drug released at 7 hours, a difference of 7% in the time analyzed to demonstrate burst release in Fig. 4.

Conclusion: The presence of monomer contributes to acid-catalyzed hydrolysis of the PLGA backbone accelerating the degradation rate by means of molecular weight drop and influencing burst release and API stability. This effect may contribute to dissolution profiles observed in products on the market and must be accounted for in product design and deformulation. Polymers with very low monomer content yield a dissolution and release profile that best demonstrates the effects exerted by composition and API characteristics alone.

References: 1] Makadia HK, Siegel SJ. Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. Polymers (Basel). 2011 Sep 1;3(3):1377-1397. doi: 10.3390/polym3031377. Epub 2011 Aug 26. PMID: 22577513; PMCID: PMC3347861.
2] Steven J. Siegel, Jonathan B. Kahn, Kayla Metzger, Karen I. Winey, Kathryn Werner, Nily Dan. Effect of drug type on the degradation rate of PLGA matrices. European Journal of Pharmaceutics and Biopharmaceutics. Volume 64, Issue 3, 2006, Pages 287-293, ISSN 0939-6411,https://doi.org/10.1016/j.ejpb.2006.06.009.
3] Houchin, M.L. and Topp, E.M. (2009), Physical properties of PLGA films during polymer degradation. J. Appl. Polym. Sci., 114: 2848-2854. https://doi.org/10.1002/app.30813

Figure 2: DL 07 E: Acidification of 10 mM, pH 6.95 phosphate buffer

Figure 3: Atorvastatin recovery after exposure to in situ system, shows substantial degradation with high monomer content.

Figure 4: in vitro release of atorvastatin through 7 hours, indicating burst release in high monomer sample. 900 mL pH 7.4 PBS, 37C, 100 rpm