Muco-adhesion; A Principle and Versatile Property of Chitosan

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Angela Landsman¹, Michael Ziebell¹, David Orr^1,2, Stephen Carter^1,3

Iterro Inc ¹, Medpoint², Zulia Biotech³

This white paper is a summary abstract from published literature and does not claim any therapeutic benefits.

Muco-adhesion, also referred to as bio-adhesion, is defined as the adherence of materials for an extended period with any given mucosal (mucus) surface layer ^[1,3]. The mucosal layer can be found in contact with the external environment, specifically the oral cavity, gastrointestinal tract, vaginal tract, nasal cavity, ocular cavities, intravesical, and lungs ^[2,4]. Muco-adhesion may be used to promote drug delivery to the body, either as a systemic or localized delivery. The greatest benefit to this drug delivery system is an increased drug residency time at the treatment site allowing for more predictable drug release rates from the site of application, and therefore presumably an improved timing and therapeutic effect of the drug ^[1,5]. Localized drug delivery may also be beneficial to the patient by delivering a bolus of drug to the target tissue and by avoiding a first-pass hepatic metabolism and modification of the medication that would lower the circulating drug concentration and therefore producing superior patient outcomes ^[1,4]. In short, mucoadhesive drug delivery systems have shown multiple advantages over conventional drug delivery systems to date ^[1,3].

Muco-adhesion may occur through multiple routes including wetting and swelling, mechanical inter-locking, diffusion or interpenetration, fracture, adsorption, and electron transfer ^[1]. It is understood that two or more theories are needed to completely explain the mechanisms of any given polymers’ muco-adhesion process ^[3].

Using muco-adhesion to improve the efficiency of drug delivery for a therapeutic would typically be formulated to have the drug molecule encapsulated by the cationic polymer (e.g., chitosan). This construct allows chitosan to serve as a delivery vehicle for the drug by adhering to the negatively charged tissue surface giving the drug molecule sufficient time to be transferred from the lumen of the chitosan ‘bubble’ to the interior of the cells of the tissue. The process of muco-adhesion occurs in two general steps: Contact and Consolidation ^[1,3]. In the contact stage the polymer comes into first contact with the mucosal membrane of interest ^[1,3]. The most common delivery routes of current interest are buccal (cheek and gum tissues), nasal, ocular, vaginal, rectal, and gastrointestinal ^[3]. Initially the polymer will dehydrate the mucosal layer by pulling moisture into itself ^[1,3]. The dehydration of the mucosa and the hydration of the polymer will allow it to spread, swell, and begin attachment ^[1,3]. Consolidation is complete when the polymer is hydrated and two or more of the above mechanisms are employed to secure the bond and begin the transfer of therapeutic drug delivery ^[1,3].

Multiple factors can affect the efficacy of muco-adhesion. A few factors to consider when designing a polymer for this purpose would be wetting and swelling rates (stereochemistry of the polymer, molecular weight), flexibility in the polymer chains (decreased density increases hydration rate), concentration of the polymer (1% to 2.5% of molecular mass), pH of the polymer at point of contact (can cause dissociation and hydration depending on ± charge), and mucin turnover at the site of interaction ^[1,4].

An ideal polymer formulated for muco-adhesion should be interact minimally with the drug to be transported, be non-toxic to the host, and provide sufficient bio-adhesion for the intended therapy to support optimal residence time ^[4]. Chitosan and its derivatives are currently widely used in different bio-adhesive applications due to its’ biocompatibility, ease of modification, biodegradability, and nontoxicity ^[4,5].

Currently there are three major design components to include: hydrophilicity or water-loving, being cationic in nature or positively charged, and the capability of forming hydrogen bonds ^[4,5]. Chitosan can be both hydrophilic and hydrophobic depending on its structure and modifications based on intended use ^[5]. Chitosan,  a cationic polymer in nature, makes it ideal for oral, ocular, nasal, and vaginal drug delivery in  part since the surfaces of these tissues are negatively charged creating a natural adhesion between the two agents ^[2]. It is also a promising prospect for gastrointestinal drug delivery due to its pH responsiveness and increasing the length of time in the small intestine for adsorption into the plasma for circulation^[2]. Lastly chitosan has potential to form hydrogen bonds due to both its N-acetyl groups and hydroxyl groups ^[1]. These bonds hold the polymer in place to aid in drug transfer ^[3].

The Degree of Deacetylation or DDA% is the measure of the percentage of the acetyl groups that have been removed from the chitin molecule to generate the positive charge. The greater the DDA%, the greater the cationic charge. The USP-NF Monograph establishes the identity of medical-grade or medical application chitosan as having a minimum of 70% DDA and a maximum of 95% DDA. trū Chitosan® offers chitosan products within that range to serve your application. Trū Chitosan’s DDA is measured by USP-NF mandated Nuclear Magnetic Resonance spectroscopy (NMR) and this value is memorialized for each lot on the Certificate of Analysis.

The USP-NF Monograph (Currently official 04-Jan-2022) only recognizes exoskeleton material from edible shrimp and edible crab as the acceptable sources of raw material for medical-grade, medical application chitosan. Unlike other chitosan producers, trū® Chitosan is the only vertically integrated producer of chitosan. The shrimp are reared in state-of-the-art indoor aquaculture technology to harvest the shell material providing a single species, single source of homogeneous exoskeleton tissue with complete chain-of-custody. The shells are not waste or a by-product; they are the product.

Crustaceans, such as shrimp, remain a dominant source of chitosan due to the quantity of chitin in the exoskeleton or shell ^[5].Tropomyosin is the protein that is responsible for generating the shellfish allergic response in some humans. In the production process to create trū® Chitosan, the exoskeleton tissue passes through an aggressive deproteinization reaction resulting in a finished chitosan with a protein content at or below the USP-NF limit of 0.20%. trū Chitosan goes a step beyond the USP Monograph and further tests for Tropomyosin using ELISA test #1130 to further confirm content of the allergen is < 1 ppm or below the level of detection. Results for each lot are memorialized on the Certificate of Analysis.

Endotoxin levels present a true and grave issue for the chitosan bio-adhesives. Chitosan polymers act like sponges in nature collecting endotoxins from contaminated environments and laboratory reagents due to the innate cationic nature of the chitosan polymer and the naturally negative charge of the endotoxin ^[2]. Endotoxin can cause great harm to the host including fever, hypotension, respiratory distress syndrome, septic shock, and more ^[2].

trū Chitosan’s captive and controlled indoor aquaculture production of shrimp exoskeleton results in the shrimp being raised in a low gram-negative bacteria environment and pollution free environment ensuring the resulting exoskeleton tissue is low in endotoxin and low in heavy metal content as opposed to wild-caught or ‘other’ farm-raised shrimp raised in ocean water. The “Ultra” option of trū Chitosan® provides an endotoxin content of < 1 EU/ml (<100 EU/g) or below the level of detection as measured by the mandated USP-NF Monograph Test 85. Undetectable endotoxin content means trū Chitosan biomaterial may be applied more broadly across med-tech and life science product applications.

Once chitosan has performed its intended purpose and it is removed from the hosts’ systems. It is naturally degraded by lysozymes that are produced in bodily secretions of tears, saliva, and serum ^[2,5]. Lysozymes primary function as an antimicrobial agent against the peptidoglycan wall of gram-positive bacteria and behaves similarly against chitosan ^[2]. Once digested, the hydrolyzed chitosan is either metabolized or excreted from the human body as glucosamine and chitooligosacharides with no harmful side effects ^[5].

Literature Cited

1.      Jawadi, Zina & Yang, Christine & Haidar, Ziyad & Maria, Peter & Massa, Solange. (2022). Bio-Inspired Muco-Adhesive Polymers for Drug Delivery Applications. Polymers. 14. 5459. 10.3390/polym14245459.

2.     Kulkarni, Radha & Fanse, Suraj & Burgess, Diane. (2023). Mucoadhesive drug delivery systems: A promising non-invasive approach to bioavailability enhancement. Part I: Biophysical considerations. Expert Opinion on Drug Delivery. 20. 10.1080/17425247.2023.2181331.

3.     Kulkarni, Radha & Fanse, Suraj & Burgess, Diane. (2023). Mucoadhesive drug delivery systems: A promising non-invasive approach to bioavailability enhancement. Part II: Formulation considerations. Expert Opinion on Drug Delivery. 20. 413-434. 10.1080/17425247.2023.2181332.

4.    Nandyala, Srinivas & Yelmame, Shankar & Gd'souza, Marina & Alluri, Pavani & Borse, Laxmikant. (2025). Entomological and marine sources of chitosan: A review of its properties and biopolymer applications. International Journal of Entomology Research. 10. 95-100.

5.    Reay, Sophie & Ferreira, Ana & Hilkens, Catharien & Novakovic, Katarina. (2024). The Paradoxical Immunomodulatory Effects of Chitosan in Biomedicine. Polymers. 17. 19. 10.3390/polym17010019