Innovative rheology modifiers for mucosal formulations

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  • January 10, 2019
  • 3 mins of read time

Innovative rheology modifiers for mucosal formulations

Alice Denis [1], Christie Coudert [1,2], Catherine Bulcourt [1], Juliette Ben Arous [1], Alicia Roso [1]
2019, Formulation Days

Formulation development for mucosal applications is progressing nowadays with the raise of topical forms.From the oral cavity to the vaginal and perianal regions, several active ingredients can be delivered. To overcome washout from biological liquids such as saliva, mucoadhesive excipients are selected to allow prolonged contact with the targeted site, thus improving drug availability and treatment efficiency. Mucoadhesion is the ability of a material to adhere to a mucous membrane, resulting from interactions with the mucins. In this context, conventional polyelectrolytes [1] are known to provide mucoadhesive hydrogels.However, their ionic interactions with mucin are affected by physiological pH variations, especially in acidic conditions such as in the vaginal area, as well as in low pH formulations driven by API efficacy concerns. Innovative polyelectrolytes rheology modifiers were developed to achieve more robust structures, largely ionized on a wide range of pH in order to optimize API stabilization and mucoadhesion. The objective of this study was to challenge the mucoadhesive properties and mucosal tolerance of new

ingredients, at realistic use levels in semi-solid and liquid formulations. The three rheology modifiers chosen were synthetized by two polymerization routes providing liquid or powder final appearance. Robust structures versus pH variations were achieved by introduction of a monomer containing a strong acid group. A comparative method was developed to assess mucoadhesion with a texture analyzer [2]. In addition, tolerance of the selected polymers was evaluated at a pre-clinical step on reconstructed mucosa.

Materials & Methods.

1. Mucoadhesion

The measurement is based on detachment force principle using TA-XTplus texture analyzer (Stable Micro Systems, Surrey, UK). Mucin disks from porcine stomach (type II) were prepared by compression and fixed to the lower end of the probe. The samples were placed inside the Pelletier cabinet at 25°C and the probe was lowered until it reached the hydrogel surface. The probe was then withdrawn until complete detachment to record the work of adhesion (three replicates). The results were plotted against polymer concentration in aqueous gels.

2. Tolerance

Tolerance is scored with in vitro reconstructed 3D models (Skinethic TM mucosa, supplied by Episkin).

  • Gingival epithelium composed of normal human gingival cells cultivated in a defined medium.
  • Vaginal epithelium from human vulva epidermoid carcinoma cells line cultivated in a defined medium.

30μl of each hydrogel are applied on the epithelium surface and cell viability is measured through a MTT test after different times of contact. Negative and positive controls were selected to validate the methodology and results.

Results.

1. Mucoadhesion measurement

The mucoadhesion against the concentration of three polymers depends on polymer structure. Polymer 3, including hydrophobic groups provided a positive response at low doses only.

2. Tolerance assessment

In the validation step, controls’ response demonstrated a selective model sensitivity, according to the gingival or vaginal target, indicating relevance of the models to screen mucosa tolerance of ingredients. The three selected polymers resulted in high cellular viability after 24h of contact and appeared well tolerated at efficient use levels.

Conclusions.

The dermopharmacy rheology modifiers proved to be highly tolerated on mucosal epithelia. The mucoadhesive performance of the three polymers have been confirmed in a wide range of pH, in accordance with their chemical structure. Moreover, the pH robustness of the polymers improves APIs’ stabilization. The innovative rheology modifiers are promising versatile materials for all mucosal applications The next perspective is to assess mucoadhesion of finished products to evaluate the influence of other excipients on the adhesive properties.

References
[1] Mythri G., Kavitha K., Rupesh Kumar M., Jagadeesh Singh Sd., (2011), Novel Mucoadhesive Polymers A Review. Journal of Applied Pharmaceutical Science 01 (08), 37-42.
[2] Das Neves J., Amaral M. H., Bahia M. F., (2008), Performance of an in vitro mucoadhesion testing method for vaginal semisolids: Influence of different testing conditions and instrumental parameters. European Journal of Pharmaceutics and Biopharmaceutics 69, 622–632.

[1] Seppic, 22 Terrasse Bellini - Paris La Défense, 92800 Puteaux, France [2] Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918 - 69100 Villeurbanne, France