Getting clingy: Synthetic glycopolymer hydrogels as substrates to test mucoadhesion

The ability of drugs to adhere to the biological tissues in the human body can greatly affect their efficacy – and it is an ability typically evaluated using mucosal membranes taken from animals. Now, researchers from the University of Reading have developed novel glycopolymer hydrogels that could be used in place of animal tissues in the evaluation of adhesion and retention of dosage forms. 

Mucosal membranes in the human body are gaining more recognition as potential sites for drug administration. These include drug administration to the eyes, nasal cavity, the mouth, the gastrointestinal and the reproductive tracts. Improved residence of pharmaceutical dosage forms on mucosal membranes could potentially ensure better drug absorption and more efficient therapy.¹

The ability of pharmaceutical materials to adhere to mucosal tissues is defined as mucoadhesion. Many water-soluble polymers and other hydrophilic systems have mucoadhesive properties due to their ability to interact with mucosal surfaces. These are used in formulations for transmucosal drug administration. Examples of mucoadhesive drug delivery systems currently available on the market include some ophthalmic products (e.g. longer lasting eye drops containing mucoadhesive weakly cross-linked poly(acrylic acid) to relieve eye dryness and soreness) or buccal tablets and patches (e.g. Buccastem M tablets with prochlorperazine maleate to relieve nausea and vomiting).

Testing the ability of dosage forms to adhere to mucosal tissues or to retain on their surface is important for the development of efficient transmucosal drug delivery systems. This testing is usually done using freshly excised mucosal tissues obtained either from laboratory animals or from local abattoirs. Solid dosage forms are typically evaluated for their adhesion to mucosal tissues using tensile testing, when the mucoadhesive material is placed in contact with a biological tissue and then detached from it, measuring the mechanical characteristics of the process such as the maximal detachment force and the total work of adhesion. These experiments could be performed with the help of sensitive tensile testers such as Texture Analyser (Stable Microsystems, UK)¹.

Hall et al² reported the development of glycopolymer hydrogels composed of hydroxyethylmethacrylate (HEMA) and N-acryloyl glucosamine (AGA) copolymers, capable of mimicking porcine buccal mucosa. It was demonstrated that these hydrogels could be used as substrates for evaluation of mucoadhesive properties of tablets in place of animal buccal tissues. The detachment of mucoadhesive tablets from these hydrogels was found to resemble their detachment from animal mucosa (Figure 1). The retention of liquid or semi-solid dosage forms on mucosal tissues is typically tested using a simulated flow approach. This type of testing is more relevant for mucosal tissues affected by a continuous flow of biological fluids. A dosage form in this case is applied on a mucosal tissue and then is washed with artificial fluid relevant to the route of drug administration (e.g. simulated tear fluid for ocular drug delivery or simulated urine for retention on urinary bladder surface). The ability of the dosage form to withstand the wash off with a biological fluid and to retain on a mucosal surface is then viewed as a measure of mucoadhesion and could be evaluated using a variety of analytical methods (e.g. fluorescent microscopy and image analysis)1.

Recently, Cook et al³ have developed the mucosa-mimetic material by grafting the HEMA-AGA hydrogel on glass surface and demonstrated its applicability as a substrate for testing retention of liquid mucoadhesive systems (Figure 2).

It was established that the retention of three water-soluble polymers (pectin, chitosan and dextran) on HEMA-AGA (80:20 mol %) hydrogels was not significantly different from their retention on porcine gastric mucosa sourced from an abattoir, indicating that these artificial materials could be used as substrates in place of animal stomach tissue. It is believed that the mucosa-mimetic properties of the hydrogels are related to the specific interactions between the water-soluble polymers and the hydrogel, resulting from the presence of AGA glycomonomer in its structure. It should be noted that this hydrogel did not show the ability to mimic polymer retention on bovine cornea tissues.

Development of artificial materials that could be used in place of animal tissues for testing mucoadhesive dosage forms will be highly beneficial for researchers working in the area mucoadhesive materials and transmucosal drug delivery. The application of these materials could help to improve reproducibility of experimental results and also will lead to reduction of animal use in this area of pharmaceutical research. The advances in the area of mucosa-mimetic materials are reviewed in a recent review by Cook and Khutoryanskiy.? It is clear from the first examples of successfully developed mucosa-mimetic materials²,³ that not all types of hydrogels will exhibit good mucosa-mimetic properties. Only carefully designed systems with specific carbohydrate containing groups could be used for this purpose. Additionally, the materials designed to mimic one type of mucosal tissue (e.g. buccal mucosa) will not be suitable for testing adhesion/retention for a different route of transmucosal administration (e.g. ocular mucosa).

The author:

Vitaliy V. Khutoryanskiy is Professor of Formulation Science at the University of Reading’s school of Pharmacy

References

1. Khutoryanskiy VV. Advances in mucoadhesion and mucoadhesive polymers. Macromolecular bioscience 2011; 11: 748-764. 2. Hall DH, Khutoryanskaya OV, Khutoryanskiy VV. Developing synthetic mucosa-mimetic hydrogels to replace animal experimentation in characterisation of mucoadhesive drug delivery systems. Soft Matter 2011; 7: 9620–9623. 3. Cook MT, Smith SL, Khutoryanskiy VV. Novel glycopolymer hydrogels as mucosa-mimetic materials to reduce animal testing. Chem. Commun. 2015; 51: 14447-14450. 4. Cook MT, Khutoryanskiy VV. Mucoadhesion and mucosa-mimetic materials – a mini-review. Int. J. Pharm. 2015, doi:10.1016/j.ijpharm.2015.09.064