(W0930-11-73) Oral Tablets Containing a Model Protein API – Impacts of Excipient Selection, API Loading, Unit Operation, and Manufacturing Process Parameters on Tablet Properties, Performance, and Stability

Purpose: Establish fundamental understanding of how excipients, unit operations, and process parameters impact formulation, manufacture, properties, performance, and stability of tablets containing a model protein active pharmaceutical ingredient (API). Model protein concentration was varied to simulate APIs spanning a dose / potency range. Both immediate-release (IR) and modified-release (MR) formulations were investigated.

Methods: Concentration of the model protein API, lactoferrin¹, was varied from high-dose (HD, 45%) to medium-dose (MD, 30%) to low-dose (LD, 15%). Four formulations were made at each lactoferrin dosage level: 1) IR with only microcrystalline cellulose (MCC) plastic-deforming binder; 2) IR with MCC and 2.5% croscarmellose (xCMC) superdisintegrant; 3) IR with 1:1 MCC / lactose (LAC, brittle-fracture binder); and 4) MR with 30% hydroxypropyl methylcellulose (HPMC) 2208, 100 mPa-s. Added to each formulation were 0.5% glidant (silicon dioxide) and 0.5% lubricant (sodium stearyl fumarate, SSF). Formulations were tableted by both direct compression and after roller compaction. Biconvex round 8-mm tablets were compressed at 2 kN compression force, but certain formulations were also compressed at 22 kN, particularly those containing LAC. Targeted total tablet weight was 200 mg / tablet. Tablet weight, tensile strength, and friability were measured. Lactoferrin content was assayed via UV spectrophotometry. Tablet disintegration and lactoferrin release (Type 2 USP paddle method) were also measured. Intact lactoferrin content was assayed via ELISA to determine API – excipient compatibility over time and impact of compression force on lactoferrin.

Results: Except for those containing LAC, formulations could be compressed at 2 kN force, producing tablets with at least 1 MPa average tensile strength and friability ≤ 0.6%. At 2 kN, IR tablets containing 1:1 MCC/LAC were < 0.8 MPa in tensile strength and > 0.75% in friability – in one instance up to 1.4% friability. Increasing compression force to 22 kN with formulations containing LAC increased tensile strength and reduced friability. For example, friability of MD/MCC/LAC tablets decreased from 0.54% and 0.82% to 0.1% and 0% for direct-compressed and roller-compacted tablets compressed at 2 and 22 kN, respectively. Tablet weight targets were attained for all 12 formulations via both direct compression and roller compaction. Suitable range was 90-110% of nominal target weight, 200 mg / tablet. Tablet weight RSD was ≤ 5%. Except for one formulation containing LAC, lactoferrin content was assayed at ≤ 5% RSD, indicating suitable content uniformity for the HD, MD, and LD formulations. Content uniformity generally improved for tablets produced via roller compaction². For example, content assay from the LD/MCC/xCMC IR formulation was 4% vs. 1% RSD in direct-compressed vs. roller-compacted tablets, respectively (Figure 1). Tablet disintegration and lactoferrin release could be adjusted by excipient choice. In Figure 2, MR over 5 h was attained with HPMC 2208, 100 mPa-s in the formulation. IR within ≤ 30 min was attained with either 1:1 MCC / LAC or MCC and 2.5% xCMC. Using solely MCC as dry binder resulted in lactoferrin release over ~2.5 h. Using MCC with 2.5% xCMC resulted in IR within 30 min, with the added benefit of suitably strong, low friability tablets at 2 kN compression force vs. those containing 1:1 MCC / LAC. At 2 vs. 22 kN compression force, disintegration time from the MD/MCC IR formulation increased from 1 to 2.5 h, respectively, and lactoferrin release kinetics decreased accordingly. Substituting 2.5% of MCC with xCMC reduced tablet disintegration times to 0.5 and 1 h at 2 vs. 22 kN compression force, respectively, and allowed more comparable IR of lactoferrin within the shorter timeframe. Compression force did not significantly impact MR from the HPMC matrix tablets (Figure 3). Spot-check ELISA has been conducted thus far out to 11 months on tablets stored in sealed bags on the laboratory bench at ambient room conditions. There is no indication of lactoferrin degradation or incompatibility with the various excipients or processes used.

Conclusion: Suitable tablet strength and friability were attained at low compression force for all tablets except those containing LAC. Increasing compression force an order of magnitude delivered suitable properties for tablets containing LAC. Inclusion of xCMC imparted more rapid IR, and inclusion of HPMC imparted MR. Low level of xCMC, 2.5%, also minimized compression force impact on IR tablets containing MCC and delivered suitable tablet strength and friability at lower compression force. Roller compaction minimally impacted tablet disintegration and release and generally improved content uniformity. Lactoferrin content was suitable across a broad API loading range spanning from 45 to 15%. Suitable API – excipient compatibility is thus far attained out to 11 months.

References: 1. Kell DB, Heyden EL, Pretorius E (2020) The biology of lactoferrin, an iron-binding protein that can help defend against viruses and bacteria, Frontiers in Immunology 11, https://www.frontiersin.org/articles/10.3389/fimmu.2020.01221
2. am Ende MT, Moses SK, Carella AJ, Gadkari RA, Graul TW, Otano AL, Timpano RJ (2007) Improving the content uniformity of a low-dose tablet formulation through roller compaction optimization, Pharm Dev Technol 12(4), 391-404.

Acknowledgements: The authors have no disclaimers, funding, or conflicts of interest statements to disclose.

Figure 1. Lactoferrin content uniformity.

Figure 2. Range of lactoferrin release attained depending on excipient choice.

Figure 3. Impact of compression force on lactoferrin release.