Monoclonal antibody formulations: a quantitative analysis of marketed products and patents

ABSTRACT

Since the approval of OKT3® in 1986, monoclonal antibodies (mAbs) have become a cornerstone of modern therapeutics. However, their complex physicochemical properties pose challenges, particularly for high-concentration formulation and subcutaneous administration. Excipient selection is crucial for maintaining mAb stability and efficacy, yet existing studies often lack systematic, cross-source analyses. This study integrates data from marketed products and patents to investigate formulation trends and excipient preferences. Data were retrieved from the Drugs@FDA databases, CAS Formulations Database and Derwent Innovation as of December 31, 2024. Extracted information included target, indication, dosage form, route of administration, and formulation composition. The associations between formulation-related factors (e.g., antibody concentration, route of administration) and excipient selection were evaluated using proportion tests. A total of 6,119 patent records and 108 marketed mAb products (covering 388 patented and 141 marketed formulations) were analyzed. Proportion tests revealed significant associations between antibody concentration and the use of histidine (marketed p = 0.0017) and citric acid (marketed p = 0.0047). The route of administration also influenced excipient choice, notably for hyaluronidase (marketed p = 0.0167; patent p = 0.0056). In addition, lyophilized formulations accounted for a relatively small fraction of both marketed (14.18%) and patented (14.69%) products, with sucrose emerging as the predominant lyoprotectant. This study analyzed excipient usage in marketed and patent formulations by time, concentration, and administration route. High-concentration products more frequently included histidine, arginine, and hyaluronidase, while low-concentration ones used citric/phosphoric acid, trehalose, and NaCl. Intravenous formulations commonly used phosphate/citric buffers, while histidine, arginine, hyaluronidase, and methionine buffers were favored for subcutaneous administration. Lyophilized formulations consistently contained sucrose as the main excipient to mitigate freeze-drying stresses. Additionally, surfactants were essential across formulations to prevent surface-induced aggregation. Patent data could provide early indications of emerging formulation strategies, though further validation is needed to confirm their predictive value.

1. Introduction

Since the approval of OKT3® (muromonab-CD3), the first monoclonal antibody (mAb) authorized for human use, in 1986, mAbs have revolutionized therapeutic strategies across oncology, autoimmune diseases, cardiovascular disorders, and viral infections such as SARS-CoV-2.^1,2 Their rapid clinical adoption and expanding indications have propelled the global mAb market toward a projected USD 494.53 billion by 2030, underscoring their increasing medical and commercial value.³

Despite their clinical success, mAbs present formulation challenges due to their large molecular size, structural sensitivity, and vulnerability to environmental stressors such as temperature changes, agitation, light, and interfacial adsorption.^4,5 These vulnerabilities are particularly pronounced in high-concentration and subcutaneous (SC) formulations, which are increasingly favored for patient convenience and dose volume reduction. It is well known that excipient selection plays a pivotal role in maintaining mAb stability and efficacy throughout the product lifecycle.^6,7 Furthermore, the role of pH and concentration on product stability has been examined in mAb formulation studies. Reviews of commercially available antibody formulations have highlighted significant shifts in formulation practices, such as the convergence toward standardized excipient usage and pH values across different product types.^8,9

Based on the previous studies, we introduce here a novel approach that integrates commercial and patent data, applying quantitative analysis to show key patterns and emerging trends in formulation design. Specifically, we investigated how excipient selection correlates with antibody concentration and route of administration, and whether patent data can serve as an early indicator of formulation trends. By bridging commercial and intellectual property data, this work seeks to inform formulation design strategies and support more efficient development of mAb therapeutics.

It is worth noting that the integration of patent data offers particular value in this context. Patents not only provide legal protections for innovation, but also serve as valuable data sources that bridge academic research and industrial application. They also serve as early signals for emerging trends and technologies.^10–12 While patents can be complex due to technical language and legal terminology, they remain an indispensable resource for understanding innovations in mAb formulation.

Consequently, this study focuses on the rational selection and optimization of excipients-key components that stabilize mAbs and ensure safe and effective delivery. We developed a systematic comparative approach featuring three key characteristics. First, to enhance data completeness and reliability, we curated and cross-validated marketed mAb formulations from Food and Drug Administration (FDA) drug labels, the CAS Formulations Database, and published literature. Second, to investigate excipient usage preferences, we conducted statistical proportion tests under different formulation conditions. Third, to overcome the limitations of single-source data, we performed an integrated analysis of both marketed products and patents, enabling a more comprehensive perspective on formulation design throughout the product development lifecycle.

2. Results

Patent and market data collection followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹³ After initial screening, 294 patent documents were identified, representing 6,119 INPADOC patent families and 388 patented mAb formulations. In parallel, 108 marketed mAb drugs were retrieved from the Drugs@FDA database, yielding 141 marketed formulations (Figure 1; Supplementary Material 1).

Figure 1.

Flow diagram of data. (a) Patented formulations; (b) marketed formulations.

Analysis of these data revealed that patent activity was limited before 2002, but increased rapidly thereafter, peaking between 2010 and 2020 (Figure 2(a)), reflecting intensified innovation and investment in mAb formulation development. In contrast, FDA-approved mAb products and their formulations increased more gradually, showing a lag relative to patent filings, consistent with the extended development timelines of biologics. Among the 388 patented formulations, only 12 (~3.1%) were incorporated into approved marketed products (Figure 2(b)). This suggests a potential gap between patent activity and clinical translation in mAb formulation development: while patenting activity is diverse and prolific, the rate of successful conversion into clinically approved formulations remains low.

Figure 2.

Trends and compositions of mAb formulation patents and products. (a) Temporal trends in mAb formulation patent applications and product approvals; (b) relationship between formulation patents and approved mAb products.

Among the 141 approved formulations analyzed, 20 were lyophilized (14.18%), while 57 of the 388 patented formulations (14.69%) referred to lyophilization as a possible dosage form. Unlike liquid formulations, lyophilized products are exposed to freeze concentration and drying stresses during drug product processing, which necessitates additional stabilization strategies. Analysis of excipients in these lyophilized formulations reveals that sucrose is the predominant lyoprotectant: it was used in 15 of the 20 marketed lyophilized products (75%) and in 33 of the 57 patent formulations. These findings highlight that sucrose consistently serves as the primary excipient to mitigate stresses unique to the freeze-drying process, thereby ensuring protein stability.

2.1. Formulation analysis

We investigated the use of formulation excipients, such as buffers, stabilizers, surfactants, and other functional components, in relation to different antibody concentrations and routes of administration. By analyzing both patented and marketed formulations, we aimed to identify preferred excipient types and usage patterns for various formulations. The findings focus on the excipient selection trends across high- versus low-concentration antibodies, as well as among major administration routes such as intravenous (IV) and SC. The results without statistically significant differences are summarized separately in Supplementary Material 2. The corresponding P-values from the proportion tests are provided in Supplementary Material 3.

2.1.1. Buffers

Proportion tests indicated that buffer selection in marketed mAb formulations was significantly associated with both antibody concentration and route of administration. As shown in Figure 3, histidine buffer was used in 66.67% of high-concentration antibody products (HCAPs, ≥100 mg/mL), compared to only 34.52% in low-concentration products (p = 0.0017). Similarly, histidine buffer was more frequently used in SC (56.45%) than in IV formulations (38.16%, p = 0.0486). These findings suggest a clear preference for histidine buffers in high-concentration and SC-administration mAb formulations.

Figure 3.

Comparison of buffer usage proportions in mAb formulations. (a-c) Histidine, citrate, and phosphate buffers in high vs. Low antibody concentrations; (d-f) histidine, citrate, and phosphate buffers in SC vs. IV administration routes. Orange: patented formulation data; Green: marketed formulation data. *p < 0.05, **p < 0.01.

In contrast, citrate and phosphate buffers were more commonly used in low-concentration and IV products. Specifically, citrate was present in 22.62% of low-concentration formulations but only in 5.26% of high-concentration ones (p = 0.0047), while phosphate appeared in 17.86% of low-concentration vs. 1.75% of high-concentration products (p = 0.0071). Regarding the administration route, citrate was used in 23.68% of IV and 6.45% of SC formulations (p = 0.0118), while phosphate was found in 19.74% and 1.61% of IV and SC formulations (p = 0.0024), respectively. Notably, such trends are not observed in the formulation data extracted from patents, indicating a divergence between experimental or conceptual formulations in the patent literature and the strategies adopted in approved commercial products. Additionally, among the 141 marketed formulations collected, only one high-concentration antibody product (Humira®) was identified without an added buffer ( < 1%). In this case, the buffering capacity is provided by the antibody itself, thereby obviating the need for additional buffering excipients. By contrast, all patent formulations analyzed in this study explicitly contained buffer components.

The longitudinal variation in formulation pH under buffer adjustment is presented in Figure 4. It is clear from Figure 4(a) that the pH of low-concentration marketed mAb formulations has exhibited a pronounced downward trend over time. However, during the past five years, the pH values of both high- and low-concentration formulations, whether marketed or patented, have gradually converged to a range of 5.75–6. Figure 4(b) depicts the trend of pH changes in formulations differentiated by route of administration. A similar pattern was observed: over the past five years, the pH of both IV and SC mAb formulations, in marketed products as well as in patents, has consistently converged to the range of 5.75–6.

Figure 4.

Overlay of average formulation pH by year for all market and patented formulations. (a) Antibody concentration: HCAP and HCAF(high concentration mAb, ≥100 mg/ml,), LCAP and LCAF(low concentration mAb, <100 mg/ml); (b) administration route.

2.1.2. Stabilizers

Preferential patterns were observed in the selection of excipients for stabilizers in the mAb formulations with respect to antibody concentration and administration route (Figure 5). Proportion tests based on patented formulation data indicated that arginine was used more frequently in high-concentration (33.33%) than in low-concentration (17.12%) formulations (p = 0.0002). Similarly, its use was higher in SC (33.02%) than in IV (21.94%) preparations (p = 0.0273). This preference may be attributed to arginine’s ability to reduce viscosity and enhance solubility at high protein concentrations.^14–17 This property is particularly beneficial for SC administration, where volume limitations apply.

Figure 5.

Comparison of stabilizer usage proportions in mAb formulations. (a-b) Arginine and trehalose in high vs. low antibody concentrations; (c-d) arginine and trehalose in SC vs. IV administration routes. Orange: patented formulation data; Green: marketed formulation data. *p < 0.05, **p < 0.01, ***p < 0.001.

In contrast, trehalose was used more commonly in low-concentration than in high-concentration formulations (26.85% vs 13.84%, p = 0.0027). This result may be attributed to its well-documented role in protein stabilization through preferential exclusion mechanisms. Although these trends are prominent in the patent data, they are not significantly reflected in the compositions of approved mAb products. This finding further underscores the discrepancy between experimental formulations during development and those ultimately authorized for clinical use.

2.1.3. Surfactant

Surfactants are critical excipients in mAb formulations, primarily serving to mitigate protein adsorption at gas-liquid interfaces and to prevent aggregation.¹⁸ Among the 388 patented formulations analyzed, 367 (94.6%) contained a surfactant, most commonly polysorbate 80, polysorbate 20, and poloxamer 188. A similar pattern was observed in marketed products: 131 of 141 mAb formulations (92.9%) contained surfactants, with polysorbate 80 (n = 96), polysorbate 20 (n = 30), and poloxamer 188 (n = 5) being the most frequently employed. Proportion tests for these three surfactants indicated no significant association between their usage frequency and either the route of administration or antibody concentration (Figure 6).

Figure 6.

Comparison of surfactant usage proportions in mAb formulations. (a-c) Polysorbate 80, polysorbate 20, and poloxamer 188 in high vs. low antibody concentrations; (d-f) polysorbate 80, polysorbate 20, and poloxamer 188 in SC vs. IV administration routes. Orange: patented formulation data; Green: marketed formulation data. *p < 0.05, **p < 0.01.

2.1.4. Other excipients

Some other excipients were still found to have usage preferences in relation to antibody concentration and administration route through the proportional tests conducted in this study, with the results shown in Figure 7. It is clear from Figure 7a that sodium chloride (NaCl) was more frequently used in low-concentration products among approved mAb formulations, with usage rates of 38.10% and 15.79% in low- and high-concentration formulations (p = 0.0075), respectively. This preference may be attributed to NaCl’s ability to maintain isotonicity and ionic strength in dilute protein solutions without significantly impacting solubility or stability at lower concentrations.

Figure 7.

Comparison of other excipient usage proportions in mAb formulations. (a-c) NaCl, rHuph20, and methionine in high vs. low antibody concentrations; (d-f) NaCl, rHuph20, and methionine in SC vs. IV administration routes. Orange: patented formulation data; Green: marketed formulation data. *p < 0.05, **p < 0.01, ***p < 0.001.

In contrast, patented formulation data indicated that recombinant human hyaluronidase PH20 (rHuPH20) was more commonly used in high-concentration preparations (7.55% in high-concentration vs. 0.39% in low-concentration preparations, P<0.0001). This is likely due to its known function in facilitating SC absorption by transiently degrading hyaluronan in the extracellular matrix, thereby reducing the viscoelastic resistance of the interstitial tissue, improving the dispersion of concentrated biologics and enabling larger SC injection volumes.^19–21 No apparent concentration-dependent trends were observed for the other excipients.

With respect to administration route, the patented and marketed mAb formulation data consistently showed preferences for methionine and hyaluronidase in SC formulations. Specifically, methionine was used more frequently in SC than in IV formulations: 18.87% vs. 8.71% in patents (p = 0.0075) and 17.74% vs. 3.95% in marketed products (p = 0.017), respectively. This result may be due to methionine’s role as an antioxidant, protecting proteins from oxidation during prolonged SC residence.^22,23 At the same time, rHuPH20 showed similar trends, with higher frequencies in SC formulations: 7.55% vs. 1.61% in patents (p = 0.0056) and 8.06% vs. 0% in approved products (p = 0.0167), respectively. Additionally, NaCl was more prevalent in IV than in SC formulations of approved products (38.16% vs 19.35%, respectively, p = 0.027). Furthermore, the use of inorganic salts, particularly chlorides, such as NaCl and potassium chloride (KCl), has slightly declined since 2000 (Figure 8). In both patented and marketed mAb formulations, the proportion containing NaCl and KCl in the past five years has remained at approximately 20–30%.

Figure 8.

NaCl and KCl usage over time. Orange: patented formulation data; Green: marketed formulation data.

2.1.5. Patent data as an early signal

We extended our analysis by incorporating a temporal dimension to explore whether formulation trends in patent data precede those in marketed products. Figures 9(a,b) show that high-concentration mAb formulations were consistently recorded in patents since 2008, with a notable surge in 2013, whereas marketed products did not appear regularly until 2015, marking the peak in growth for high-concentration formulations. Similarly, for SC formulations (Figures 9(c,d)), while patents have documented their continuous use since 2010, sustained and stable approvals in the market began in 2015, with patent activity peaking in 2013, about two years before the commercial market growth.

Figure 9.

Formulation percentages over time. (a, b) Formulations categorized by antibody concentration (marketed (a) and patented (b)); (c, d) formulations categorized by administration route (marketed (c) and patented (d)).

We compared the timeline of four excipients-arginine, acetate buffer, lysine, and succinic acid buffer-across patents and marketed formulations, as shown in Figure 10. Arginine was present in patents as early as 2005, but did not appear in approved products until 2011 (Figure 10(a)). Acetate buffer entered the commercial landscape in 2006, but only gained widespread use after 2015 (Figure 10(b)), despite being filed in patents almost annually since 2008. Lysine and succinic acid buffer emerged in marketed formulations much later, in 2021 and 2016, respectively, while both had been used in patent filings significantly earlier (2013 and 1996, respectively; Figures 10(c,d)).

Figure 10.

Occurrence of excipients in patented and marketed formulations. (a) Arginine; (b) acetate buffer; (c) succinate buffer; (d) lysine.

In addition, the overall temporal trends indicated that the peak of patent activity for mAb formulations occurred significantly earlier than that in approved products (Figure 2(a)). This observation further supports the notion that patent data can serve as an early indicator of formulation trends, which may later be translated into commercially approved products. To further characterize the temporal relationship between patent filings and market approvals, we quantified the time lag between the initial consistent appearance of representative excipients or formulation features in patents and their subsequent adoption in commercial products. Based on selected examples, such as arginine, acetate buffer, lysine, and succinic acid, the average lag was approximately 7.4 years, although this interval varied across excipient types and formulation attributes. This observation reinforces the utility of patent data as a forward-looking resource in anticipating formulation trends.

3. Discussion

By systematically analyzing 6,119 mAb formulation-related patents and 141 marketed formulations, this study delineates formulation trends across antibody concentration, administration routes, and temporal evolution. A marked increase in patent activity was observed after 2002, reflecting intensified innovation in mAb formulation technologies. High-concentration and SC formulations showed clear excipient preferences, highlighting the formulation-specific challenges at play. Furthermore, the alignment between early patent filings and subsequent product compositions underscores the potential of patent data to signal emerging formulation strategies. These patterns are explored in the following sections.

3.1. Effect of antibody concentration on formulation adjuvant selection

Our analysis suggests that antibody concentration can influence excipient selection in patented and marketed mAb formulations. High-concentration mAb formulations pose specific challenges, such as elevated viscosity, increased protein – protein interactions, and heightened risks of aggregation and solubility limitations.^24,25 Thus, to address these issues, excipients that can reduce viscosity or stabilize the protein structure are preferentially selected. Conversely, excipients with unfavorable properties under such conditions are less frequently used, leading to discernible usage preferences.²⁶

The results, as depicted in Figures 3(a) and 5(a), further exhibited that histidine and arginine are more frequently used in high-concentration mAb formulations, likely due to their physicochemical benefits. This observation is consistent with previous experimental studies demonstrating the stabilizing effects of these excipients.^27,28 For example, histidine provides effective buffering capacity within the pH range of 5.0–7.0 and does not exert destabilizing effects on mAbs.²⁹ Moreover, molecular dynamics simulations and contact free energy calculations conducted by Saurabh et al. demonstrated that histidine can interact with hydrophobic regions on the protein surface, thereby mitigating protein – protein interactions and reducing aggregation.³⁰ These mechanisms are particularly valuable for maintaining formulation stability and minimizing immunogenicity risks associated with high-concentration mAb products. Arginine hydrochloride has been shown to reduce attractive electrostatic interactions between antibody molecules, thereby suppressing aggregation and phase separation, two major challenges in high-concentration antibody formulations.¹⁷ Specifically, Oki et al. reported the superior performance of arginine in reducing emulsion turbidity and inhibiting aggregation in high-concentration antibody preparations than that of other amino acid stabilizers.³¹ These findings support the observed trend of histidine use in HCAPs. A few high-concentration mAb formulations without added buffers were developed. For example, Humira® was initially formulated at 50 mg/mL with a citrate – phosphate buffer, but a later high-concentration version (100 mg/mL) omitted these buffer excipients. This approach leverages the self-buffering properties of concentrated antibody solutions, as reported in previous studies.^32,33 However, relying solely on the antibody for buffering capacity can pose risks, including reduced pH stability and increased aggregation.³⁴ These considerations could explain why most marketed products and patented formulations continue to include buffer systems. Interestingly, we did not identify buffer-free cases in patent data. This likely reflects the nature of patent disclosures, which generally specify excipients included, but seldom emphasize the absence of components. By contrast, regulatory documents, such as FDA drug labels, require complete disclosure of all formulation components, making them a more reliable source for identifying buffer-free products.

In contrast to high-concentration formulations, low-concentration mAb preparations demonstrate a distinct preference for excipients such as citric acid, phosphoric acid, trehalose, and NaCl (Figures 3(b,c) 5(b) and 7(a)). This preference can be attributed to their ability to maintain physicochemical stability in diluted environments, especially when the intrinsic buffering capacity of the antibody is limited.³⁴ For instance, citrate and phosphate buffers are particularly effective in the mildly acidic to neutral pH range, which corresponds closely with the stability profiles of numerous therapeutic antibodies.⁹ In addition to maintaining the buffer system, these excipients generally possess the capacity to effectively preserve the stability of mAb preparations and suppress the aggregation of mAbs.^35,36 Trehalose is a widely used stabilizer that inhibits antibody aggregation by forming hydrogen bonds with the Fab region, as demonstrated in the computational study by Deepika et al..³⁷ They identified an optimal trehalose-to-trastuzumab (Tmab) weight ratio of 0.2–2.4, corresponding to a stable formulation at a Tmab concentration of 21 mg/mL and 55 mM trehalose. This concentration range aligns with the low-concentration formulation defined in our study, although further validation using additional monoclonal antibodies is warranted to confirm its general applicability. In low-concentration mAb formulations, NaCl is commonly used to regulate ionic strength and osmolarity, thereby enhancing colloidal and conformational stability.³⁸ Furthermore, NaCl has been reported to reduce viscosity and aggregation in antibodies with highly negatively charged Fv regions.^36,39 Nevertheless, isolated reports indicate that, in certain aggregation-prone mAbs, NaCl may instead diminish electrostatic repulsion, ultimately facilitating self-association and increasing aggregation under stress conditions.^40,41

Apart from the mechanism study, the observed excipient preferences are supported by formulation analyses of marketed mAb products. For example, Ghosh et al. investigated 46 high-concentration antibody formulation products in the United States. Among these, histidine buffer was used in 27 product formulations, while arginine hydrochloride was found in 6 of 30 formulations using amino acids.²⁴ Additionally, Mieczkowski’s 2023 review found a sharp decline in NaCl use in antibody formulations over the past three decades, consistent with our results (Figure 8).⁸ Mieczkowski further noted a downward trend in formulation pH over time, with the most pronounced decreases observed in low-concentration and intravenous preparations.⁸ This trend aligns with our analysis of pH variation in marketed and patented formulations (Figure 4). This convergence of empirical data and market trends lends credibility to our statistical findings.

3.2. Effect of administration route on formulation adjuvant selection

The administration route emerged as another critical variable in excipient selection, with SC and IV formulations demonstrating distinct compositional patterns. The SC route, now favored for patient-centric delivery and home-use compatibility, presents constraints, such as limited injection volume (≤2 mL) and high viscosity-conditions that demand specialized excipient strategies.^20,42

Our analysis indicates that SC preparations are more inclined to use excipients, such as rHuPH20, histidine and methionine (Figures 3 and 7). These excipients are selected to address the unique challenges posed by SC administration, including limited injection volume, local tissue permeability, and the need for high protein concentration and stability.²⁹ Specifically, rHuPH20 facilitates the dispersion and absorption of SC-injected macromolecules by temporarily depolymerizing hyaluronan in the extracellular matrix.⁴³ This enzymatic degradation significantly reduces the resistance to bulk fluid flow, thereby enabling the administration of larger injection volumes or higher-concentration mAbs that would otherwise be impractical via the SC route.^44,45 This strategy has been employed in several recent FDA-approved SC formulations, including Opdivo® Qvantig™ (nivolumab) and Tecentriq® Hybryza™ (atezolizumab), both of which incorporate rHuPH20. In head-to-head clinical studies comparing these SC products with their intravenous counterparts, rHuPH20-containing formulations demonstrated comparable efficacy, while offering enhanced bioavailability and improved patient adherence.^46,47 These findings underscore rHuPH20’s growing role in overcoming volume and absorption barriers in SC biologic delivery, making it a critical excipient in the formulation of next-generation antibody therapies.

Histidine is frequently used as a buffering agent in SC mAb formulations due to its favorable pKa (~6.0), which enables the maintenance of mildly acidic pH conditions commonly preferred in these preparations.²⁹ Beyond its buffering capacity, histidine has also been reported to contribute to the stabilization of mAbs through multiple mechanisms.²⁹ Specifically, it can promote electrostatic repulsion between protein molecules, thereby reducing self-association and lowering solution viscosity-both critical factors for ensuring syringeability and minimizing injection-site discomfort.⁴⁸ These multifunctional roles make histidine a particularly valuable excipient in the development of stable and patient-friendly SC mAb formulations. The use of phosphoric acid in SC formulations has become less prevalent (Figure 3). For example, a recent analysis of marketed antibody products as of January 2023 found a marked decline in the inclusion of phosphoric acid in antibody preparations.⁸ This trend reflects formulation preferences for alternative buffer systems that could better accommodate SC administration. Methionine, a sacrificial antioxidant, serves to preserve protein integrity by undergoing oxidation preferentially over methionine residues within therapeutic proteins.⁴⁹ It is widely incorporated as a stabilizing agent in mAb formulations.²⁴ Our research shows that methionine was more frequently used in SC formulations (Figure 7(f)). This is mainly because SC administration requires high-concentration protein solutions to achieve therapeutic doses within small injection volumes. Compared with dilute IV formulations, such concentrated systems are more prone to viscosity increase, aggregation, and chemical degradation, with oxidation being a major degradation pathway.^{22,23,50–52} While lower concentrations might intuitively seem more unstable due to higher molecular mobility, in reality the strong intermolecular interactions at high concentration exacerbate oxidation-related instability, which explains the greater reliance on methionine as an antioxidant excipient. However, there is currently a lack of systematic studies investigating the specific role of oxidation in the stability of SC biopharmaceuticals.²⁰ Future research should explore whether oxidative degradation is a critical determinant of SC formulation stability, which can provide valuable insights for optimizing formulation strategies in this increasingly important route of administration.

In contrast to the excipients that are preferentially employed in SC formulations, certain traditional buffers such as citrate and phosphate are increasingly avoided due to their unfavorable physicochemical or biological effects in the subcutaneous environment. Citrate buffers, although proven effective in maintaining pH stability, are now less favored in SC mAb products due to their association with injection site pain and local irritation.⁵³ This discomfort is thought to result from citrate’s calcium-chelating properties and its ability to activate pain-related sensory neurons in the subcutaneous tissue.⁵⁴ Our own dataset corroborates this trend (Figure 3(e)), showing a noticeably higher frequency of citric acid buffers in IV formulations, where direct systemic administration circumvents local tissue irritation. Isotonic agents are added to protein preparations to create solutions suitable for IV injection, as non-isotonic solutions can cause tissue damage or pain at the injection site.^55,56 NaCl, a common isotonic agent, is frequently used in IV mAb preparations (Figure 7), which is consistent with previous reports.^41,55 This trend reflects the increasing complexity of SC formulation science, where excipients are often selected to balance molecular stability and clinical acceptability.

3.3. Other formulation analysis

Our analysis indicates that lyophilized formulations account for only a relatively small proportion compared with liquid formulations. This is consistent with the findings of Mieczkowski, who reported that freeze-dried products represented only 7% of approved antibody formulations from 2021 to January 2023. Liquid formulations, particularly high-concentration antibodies, remain the dominant focus of development.⁸ At the same time, our results highlight the critical role of sucrose in lyophilized preparations. Its frequent use can be attributed to its dual function: stabilizing antibodies and acting as a lyoprotectant during freeze-drying, which makes sucrose one of the most important excipients in freeze-dried mAb formulations.^57,58

Other polyols such as sorbitol and mannitol are also commonly used as stabilizers in mAb formulations (Supplementary Material 2). They reduce protein aggregation primarily by promoting preferential hydration, and by stabilizing proteins through water-mediated effects, including increasing the surface tension or surface free energy of water, thereby indirectly enhancing protein thermal stability.^59,60 Moreover, Abbas reported that polyols can also reduce attractive intermolecular interactions by directly interacting with exposed hydrophobic patches on the protein surface.⁶¹

Surfactants are indispensable stabilizers in mAb formulations, as they reduce surface-induced aggregation and protect proteins from mechanical stresses encountered during manufacturing, storage, and administration.^62,63 This widespread reliance is consistent with previous studies, which report that more than 95% of marketed formulations contain polysorbate 20 or polysorbate 80.⁸ Although the quality and instability of surfactants, such as polysorbate 80, are a hot topic in this field,^64,65 they are still widely used in marketed products.

Our integrated analysis of both patents and marketed mAb formulations shows that patent documents can reflect emerging formulation trends prior to product launch. Specifically, trends such as the increasing adoption of SC delivery routes, the development of high-concentration antibody formulations, and the use of novel excipients (e.g., arginine, succinate buffer) were consistently observed in patent filings approximately 7.4 years before corresponding products reached the market (Figures 2, Figures 9, 10). This observation aligns with prior studies that highlight the role of patents as early indicators of innovation.^66,67 For example, Wagner et al. emphasized the predictive value of patent activity in R&D-intensive sectors, linking it to subsequent commercialization outcomes.⁶⁸ Similarly, Zhang et al.⁶⁹ concluded that patents serve as signals in financial markets, highlighting the value of patent analysis as a predictive tool for strategic planning. In the context of biological formulations, this utility is further enhanced by the granularity of patent disclosures, which often provide details regarding excipient composition, concentration ranges, and administration routes, technical attributes that are not always visible in early-stage publications or clinical trial databases.⁷⁰ It is worth noting that, although our comprehensive analysis generally supports the role of patents as early signal of formulation innovation, the intravitreal administration case appears to be an exception. In this context, companies may strategically withhold formulation details, particularly excipient compositions, to safeguard proprietary knowledge and mitigate the risk of generic competition. Such information can therefore be maintained as trade secrets rather than disclosed in patent databases, leading to apparent cases where marketed products precede corresponding formulation patents.⁷¹

Importantly, this study demonstrates the methodological advantage of combining patent and commercial data sources. While market data reflect the final formulation decisions under regulatory and clinical constraints, patent documents offer earlier and more granular insights into formulation hypotheses, excipient functions, and concentration ranges. This dual-source strategy allows for a more systematic and time-sensitive mapping of formulation trends than either source alone. For example, some excipient preferences, such as the frequent use of arginine in mildly acidic SC formulations (Figure 5), were first revealed in patent filings, whereas others, like the predominance of histidine in approved SC products (Figure 3), were more apparent from marketed data. Inconsistencies between the two sources may reflect strategic patent drafting, formulation optimization during development, or differences in disclosure requirements. Rather than being a limitation, these differences underscore the complementary nature of the two data sources. Furthermore, this study applies proportional analysis to quantitatively examine excipient preference, advancing beyond descriptive statistics to provide theoretical support for formulation strategy.

Excipient selection in mAb formulations is fundamentally context-dependent, governed by the interplay of concentration, administration route, dosage form, and time. High-concentration and SC products preferentially use histidine, arginine, methionine (and rHuPH20 where applicable) to mitigate viscosity, self-association, and oxidative risk under volume constraints, whereas low-concentration and intravenous products more often contain citrate/phosphate buffers, NaCl, and trehalose. Lyophilized formulations, although a minority, consistently depend on sucrose (with other polyols) as lyoprotectants, and surfactants remain near-universal against interfacial stress. Apparent discrepancies between patents and labels, such as the rarity of buffer-free disclosures in patents, reflect disclosure practices and development optimization rather than true contradictions.

Practically, our data support a risk-led formulation logic: align excipient mechanisms with the dominant failure mode (viscosity/self-association, oxidation, injection pain/volume limits, interfacial stress) and justify choices using convergent evidence across sources. Future work should prospectively validate patent-derived signals and evaluate next-generation excipients and surfactant systems under clinically relevant stresses to inform formulation design and regulatory strategy. While certain challenges remain, such as the inherent publication lag of patent documents, the integrated approach used in this study offers valuable theoretical support for understanding excipient preferences. More importantly, it provides a practical framework for anticipating formulation trends and informing excipient optimization strategies in mAb development.

4. Data sources and methods

4.1. Data source

Patent data were retrieved from Derwent Innovation (https://derwentinnovation.clarivate.com.cn/login/), a comprehensive database offering enhanced full-text patent information from 77 jurisdictions, along with bibliographic data from 106 jurisdictions, covering over 161 million patent documents. A systematic search was conducted for patents published or granted up to 31 December 2024.

The search was performed against the titles, abstracts, and claims of patent documents. Search terms combined: 1) keywords related to monoclonal antibodies (including full names, abbreviations, and synonyms), 2) formulation-related terms, and 3) International Patent Classification (IPC) codes relevant to antibody formulations (e.g., A61K0039395). The search term was AB=(monoclonal ADJ antibody) AND CL=(formulation) AND ICR=(A61K0039395). To improve reproducibility, patents were grouped into INPADOC families, ensuring that multiple filings of the same invention across jurisdictions were treated as a single record. Ambiguous or broad claims were manually reviewed, and only patents with clearly defined mAb formulations were included.

Marketed product data were collected through a systematic search of PubMed, Web of Science, CAS formulations database, and publicly available industry news sources, identifying mAb drugs approved for clinical use as of 31 December 2024. Corresponding formulation data were extracted from the Drugs@FDA database (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm), which provides detailed regulatory and formulation information on FDA-approved drugs. Extracted data were manually curated and cross-validated with other databases and literature sources to ensure accuracy.

Patents were included if they specifically described mAb formulations, contained description of formulation components, and were not general protein formulations. We excluded non-antibody products, combination therapies not focusing on mAb, and deleted duplicate information. Marketed formulations were similarly filtered for completeness and clarity of reported composition. All patent and marketed data were searched based on the PRISMA statement. The overview of search schematics is provided in Figure 1.

4.2. Data collection

The following data were extracted: antibody target, antibody isotype and subtype (if applicable), indication, concentration (mg/mL), dosage form, route of administration, and detailed formulation components (buffer, surfactant, amino acid stabilizers, non-amino acid stabilizers, viscosity modifiers, chelators, antioxidants, tonicity-modifying agents), as well as pH. The final extracted indicators are shown in Figure 11.

Figure 11.

Summary of key metrics.

4.3. Statistical analysis

To investigate whether specific excipients were preferentially used under different formulation conditions, we applied two-sample tests for equality of proportions (chi-square tests). These analyses were conducted separately for marketed formulations and patented formulations. Two formulation-related factors were examined: (i) antibody concentration (low: < 100 mg/mL; high: ≥100 mg/mL) and (ii) route of administration (IV vs. SC). For each excipient, its frequency of occurrence was compared between the two groups defined by each factor. Exact p-values for significant findings are reported in the Results section, while the test statistics and p-values for comparisons is provided in Supplementary Material 3. Statistical significance was considered at *p < 0.05, **p < 0.01, and ***p < 0.001.

5. Conclusion

This study compared excipient usage patterns in marketed and patent formulations, focusing on temporal trends, antibody concentration, and administration route. The analysis identified trends in excipient usage under different conditions. In particular, histidine buffer, arginine, and hyaluronidase were more frequently employed in high-concentration formulations, whereas citric acid, phosphoric acid, trehalose, and NaCl were predominantly used in low-concentration products. In terms of administration routes, phosphate and citric acid buffers were more commonly found in IV formulations, while histidine buffer, arginine, hyaluronidase, and methionine were favored in SC preparations. Lyophilized formulations consistently relied on sucrose as the main excipient to mitigate freeze-drying stresses. Additionally, surfactants remain essential across formulations to prevent surface-induced aggregation. Furthermore, the analysis of patent data can offer early indicators of formulation strategies, potentially supporting more efficient development and screening processes in future mAb product development.

Funding Statement

This research was funded by the Science and Technology Development Fund of Macau SAR [No.: 005/2023/SKL, SKL-QRCM(UM)-2023-2025, and 0049/2024/AGJ], and by the University of Macau [No: MYRG-CRG2023-00007-ICMS-IAS, and MYRG-GRG2024-00268-ICMS].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplementary material is available online and includes additional figures, tables, and experimental details supporting the findings of this study.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19420862.2025.2580696

Abbreviations

mAb

Monoclonal antibody

SC

Subcutaneous

IV

Intravenous

R&D

Research and development

FDA

Food and Drug Administration

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

HCAPs

High-concentration antibody products

NaCl

Sodium chloride

KCl

Potassium chloride

rHuPH20

Recombinant human hyaluronidase PH20

IPC

International Patent Classification