Innovative Rheology Modifiers for Mucosal Drug Formulations

This study builds on the fundamental principles of improving the stability of topical formulations, with a specific focus on their use in mucosal environments. The development of topical drugs for mucosal areas such as the oral cavity, vagina, and perianal region requires innovative formulation strategies due to a widespread biophysical challenge, namely rapid clearance caused by washout from biological fluids.

In mucosal applications, washout refers to the premature removal of a formulation from the target site as a result of high biological fluid turnover and natural mechanical clearance processes, including swallowing or ciliary movement. The continuous presence of fluids and complex macromolecules, such as mucin, significantly reduces the residence time of formulations at the application site. As a result, drug concentration decreases and delivery kinetics are negatively affected, ultimately limiting therapeutic effectiveness.

Addressing this persistent issue requires the development of mucoadhesive excipients capable of forming strong and durable interactions with the mucosal surface. These interactions provide scientifically demonstrated prolonged contact time and maintain functional integrity within highly dynamic physiological environments.

The scope of mucosal applications

Mucosal surfaces examples

The need for strong mucoadhesion and formulation stability is not confined to a single tissue type but extends across a wide range of sensitive drug delivery sites. Mucosal applications play a critical role in pharmaceutical development due to their rapid cellular renewal and high fluid turnover rates.

Vaginal delivery: Requires stability in acidic pH (3.5–4.5) to treat infections or hormone deficiencies, necessitating mucoadhesion to resist natural clearance.
Oral/Gingival delivery: Used for localized treatments where the formulation must withstand salivary wash and mechanical stress.
Rectal/Perianal delivery: Important for treating localized conditions where prolonged contact time is paramount for efficacy.

Formulations for mucosal administration

The development of topical formulations for mucosal administration, ranging from the oral cavity to vaginal and perianal sites, has become a major focus within dermo-pharmaceutical research. The primary biophysical limitation of these dosage forms is the rapid washout caused by biological fluids. This challenge necessitates the use of mucoadhesive excipients to extend residence time at the target site, thereby enhancing drug availability and treatment effectiveness.

In this context, two innovative rheology modifiers were investigated and shown to be promising, versatile materials suitable for a broad range of mucosal applications. These polymers were evaluated in various formulations, including liquid preparations such as aqueous gels. A key finding was their strong resistance to pH variation, which is particularly beneficial in acidic physiological environments like the vaginal area, where conventional excipients often exhibit performance limitations.

The mechanics of mucoadhesion

Effective mucoadhesion requires the polymer to overcome the biological environment’s natural tendency to reject foreign bodies. This relies on specific mechanisms:

Electrostatic interaction: The formation of ionic or hydrogen bonds between the polymer and the mucin glycoprotein layer.
Mechanical interlocking: The physical entanglement of the polymer chains within the mucus network.

Limitations of traditional excipients in dynamic environments

Conventional polymers commonly rely on ionization mechanisms to generate viscosity. While effective under controlled laboratory conditions, these materials are prone to ionic collapse when exposed to fluctuating pH levels, such as those found in the acidic vaginal environment with a pH of 3.5 to 4.5, or in the presence of high electrolyte concentrations encountered in vivo. This instability, combined with high shear forces and changing osmolarity at the application site, results in a rapid loss of structural integrity and adhesive properties. Consequently, drug retention is reduced and premature washout of the formulation occurs.

The need for innovative mucoadhesive polymers

The demand for advanced rheology modifiers arises from the inherent shortcomings of conventional polymers when exposed to mucosal conditions. As discussed in our foundational article on stability factors, traditional excipients often fail to preserve their structural integrity under variable processing and physiological conditions.

Technical validation: Performance and robustness data

Materials and methods

The objectives of this study were to assess the mucoadhesive performance and mucosal tolerance of two innovative polymers at realistic usage levels, to develop an in vitro method for predicting the mucoadhesion of aqueous gels, and to evaluate the tolerance of selected polymers on reconstructed mucosa models at a preclinical stage.

The study focused on two innovative polymers:

Polymer 1 (Polyacrylate Crosspolymer-6) in powder form : SEPINEO™ PRD 100
Polymer 2 (Hydroxyethyl Acrylate/ Sodium Acryloyl Dimethyl Taurate Copolymer) in powder form: SEPINEO™ D.E.R.M

In vitro mucoadhesion method

An in vitro method was established using a TA-XT plus texture analyzer (Stable Micro Systems) equipped with a Peltier cabinet maintained at 25°C. Mucin disks derived from porcine stomach (Type II), prepared by compression, were attached to the lower end of the probe.

The detachment force was measured by retracting the probe until complete separation, enabling the calculation of the work of adhesion. Measurements were performed in triplicate.

Mucoadhesive properties were also compared as a function of gel viscosity.

In vitro tolerance approach (Partnership with IDEA lab)

The tolerance of selected polymers was evaluated on 3D reconstructed mucosa models:

HGE (in vitro Reconstructed Gingival Epithelium – SkinEthic®): Cellular viability was assessed using the MTT test after 10 minutes, 1 hour, 3 hours, and 24 hours of contact (30µl of product/epithelium).
HVE (in vitro Reconstructed Vaginal Epithelium – SkinEthic®): Cellular viability was assessed using the MTT test after 10 minutes, 1 hour, 3 hours, and 24 hours of contact (30µl of product/epithelium).

The cellular viability results (MTT test) determined the conclusion: Irritant if viability is <50%, according to SkinEthic® recommendations.

Key findings

The study produced significant results related to both safety and efficacy. Regarding in vitro tolerance, SEPINEO™ PRD 100 and SEPINEO™ DERM, tested at effective concentrations, were classified as non irritant on both reconstructed gingival and vaginal epithelia after 24 hours of exposure. These findings confirm their excellent safety profile on reconstructed mucosal tissues.

In terms of in vitro mucoadhesion, both polymers demonstrated strong resistance to pH variation across pH ranges of 3.5 to 4 and 5 to 5.5. This resistance is essential for maintaining functional viscosity in situ and represents a clear advantage over conventional polyelectrolytes such as carbomers, particularly under acidic physiological conditions like those of the vaginal environment. Although mucoadhesion is influenced by concentration and polymer structure, SEPINEO™ PRD 100 exhibited higher mucoadhesion than SEPINEO™ DERM at equivalent concentrations.

When evaluated based on gel viscosity, SEPINEO™ PRD 100 at its standard dosage achieved the highest mucoadhesion, whereas the tested carbomer 980 displayed a notably low mucoadhesive performance.

Measurements of work of adhesion directly demonstrate the superior ability of these innovative excipients to establish and maintain contact with mucosal surfaces compared with traditional materials.

Critical technical advantage: pH robustness

The performance data confirm the technical advantages of these polymers over legacy excipients. Their exceptional resistance to pH variation within the clinically relevant range of 3.5 to 5.5 ensures that both adhesive performance and critical viscosity are preserved in situ, even under fluctuating physiological conditions. This pH robustness enhances API chemical stability and ensures consistent dose retention by preventing the ionic collapse and premature viscosity loss commonly observed with conventional polymers. In addition, the high mucoadhesion demonstrated, particularly by SEPINEO™ PRD 100, provides a reliable and predictable platform for advanced topical drug formulations.

Safety and patient compliance validation

The demonstrated efficacy is supported by an excellent safety profile confirmed through in vitro testing. The consistent classification of both polymers as non irritant on gingival and vaginal epithelium models confirms their suitability for use in highly sensitive mucosal applications.

Overall, this investigation conclusively validates SEPINEO™ PRD 100 and SEPINEO™ DERM as versatile and robust polymers for advanced mucosal applications, effectively addressing the challenge of rapid drug clearance. Both rheology modifiers exhibit excellent tissue compatibility and maintain critical pH stability across a wide physiological range. This pH robustness significantly enhances API stabilization while ensuring in situ viscosity retention, positioning these polymers as strong candidates for complex topical formulations. Their use is further supported by comprehensive technical and regulatory documentation, including Type IV DMF, fulfilling the requirements for topical drug delivery systems.

The article was supplied by Seppic

Sources

Denis, A., Coudert, C., Despax, S., Ben Arous, J., Bulcourt, C., & Roso, A., Innovative Rheology Modifiers for Mucosal Formulations, Seppic Research & Innovation (Paris, France), 2024.
Smart, J. D., The basics and underlying mechanisms of mucoadhesion, Advanced Drug Delivery Reviews, 57(11), 1556-1568, 2005.
Stable Micro Systems, Determining Mucoadhesive Properties of Semi-solids using Texture Profile Analysis, SMS Ltd (London, UK), 2023.
International Journal of Drug Delivery Technology, Formulation Challenges in Dermal Drug Delivery Systems: A Comprehensive Review of Physicochemical Properties and Advanced Delivery Strategies, Volume 14, Issue 4, 2024.