Oral Delivery of Liraglutide-Loaded Zein/Eudragit-Chitosan Nanoparticles Provides Pharmacokinetic and Glycemic Outcomes Comparable to Its Subcutaneous Injection in Rats

Introduction

It is estimated that the global incidence of diabetes mellitus (DM) in 2021 (latest global survey) will be 537 million people, representing 9.3% of adults aged between 20 and 79 years [1]. Projections indicate that this number is expected to increase to 783 million by 2045 [1,2]. It is worth noting that more than 90% of cases of diabetes mellitus correspond to type 2 [3,4,5]. Type 2 diabetes (T2D) represents a chronic metabolic condition characterized by insulin resistance and insufficient insulin production by pancreatic cells, associated with lifestyle factors such as inadequate diet and lack of physical activity [6].
The treatment of type 2 diabetes is approached comprehensively, incorporating strategies that aim to control blood glucose, improve insulin sensitivity and manage related risk factors [2]. A crucial initial intervention includes adopting a healthy lifestyle characterized by a balanced diet rich in complex carbohydrates, fiber, lean proteins and healthy fats, combined with regular physical activity [7].
In the context of the treatment of T2D, liraglutide (LIRA), a glucagon-like peptide-1 (GLP-1) receptor agonist, stands out as an effective option [8]. In addition to stimulating the release of insulin in response to high glucose, LIRA delays gastric emptying, promoting satiety and aiding weight loss [9]. These benefits contribute significantly to glycemic control and improved quality of life for patients [8,10]. The pharmacokinetic characteristics of LIRA allow for an extension of exposure for 24 h, meeting the need for glycemic control throughout the day with once-daily administration [10].

However, the use of LIRA faces challenges, especially with regard to adverse effects, such as nausea and diarrhea, in addition to causing liver and pancreatic problems [10,11,12]. There is also a need for administration by daily subcutaneous injection, which may impact treatment adherence [13]. Furthermore, oral forms would provide better adherence to treatment, however, as it is a protein, administration via this route is impossible due to the degradation of the molecule in gastric juice [10]

Pharmaceutical nanotechnology is an approach to improve the oral administration of molecules composed of proteins or peptides, overcoming absorption and gastrointestinal stability challenges [14,15]. The use of nanocarriers, such as nanoparticles (Nps) and liposomes, seeks to improve the bioavailability of these molecules, in addition to assisting in the pharmacokinetic and dynamic properties of the molecules, although it faces obstacles such as the mucosal barrier, enzymatic degradation and irregular absorption [16].
Within this context, zein emerges as a promising candidate in pharmaceutical nanotechnology. Zein, a protein derived from corn classified as prolamin, has distinct physicochemical characteristics with notable insolubility in water. However, its high solubility in organic solvents, such as ethanol, methanol and acetone, enables the formation of films and coatings from zein solutions [17]. This property has significant applications in coatings for pharmaceutical tablets, capsules and the formation of nanostructures for drug loading and targeting [18].
Zein demonstrates favorable compatibility with a variety of polymers, giving it versatility in blended formulations to meet specific requirements [19]. Additionally, its biodegradability, combined with renewable origin, contributes to its appeal in applications aimed at sustainable practices in the pharmaceutical industry and other areas [20]. Furthermore, zein exhibits satisfactory thermal stability at moderate temperatures, favoring formulation processes that involve controlled heating [20,21].

The use of zein in the formation of Nps serves as efficient vehicles for the controlled delivery of drugs, improving the solubility, bioavailability and stability of drugs, peptides or proteins in the gastrointestinal tract [20,22,23]. Through their solubility, the formation of nanoparticles occurs through self-assembly, promoting the encapsulation of various compounds, where the average diameter varies between 100 and 300 nm [22].

Eudragit RS100 (ERS100), a pH-sensitive synthetic polymer, is increasingly recognized for its application in drug formulation [24,25]. ERS100 is a favorable choice for producing zein nanoparticles owing to its notable resistance within the gastrointestinal tract and its efficacy in targeted drug delivery [25]. Additionally, chitosan (CS), a naturally occurring biodegradable polymer with low toxicity, is extensively utilized in nanotechnology, particularly for the encapsulation of biomolecules for oral administration, and its mucoadhesive properties and robust stability in the gastrointestinal environment make it an excellent stabilizer for zein Nps [26].
Within the scope of this work, we aimed to develop zein Nps for the encapsulation of LIRA, utilizing ERS100 and CS as stabilizers targeted for oral delivery. The performance of these Nps was assessed by analyzing their pharmacokinetic properties following oral administration in healthy rats, as well as their ability to regulate blood glucose levels in a T2D rat model.

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Materials

Liraglutide (injection, 3.0 mg) was purchased from Saxenda© (Novo Nordisk, São Paulo, Brazil). Zein, low molecular mass chitosan (50–190 kDa, 75–85% deacetylated), streptozotocin and formic acid were purchased from Sigma-Aldrich (St. Louis, MO, USA). Eudragit© RS100 was obtained from Evonik (Berlin, Germany). Absolute ethanol was purchased from Synth® (São Paulo, Brazil). HPLC-grade acetic acid was obtained from Vetec Química Fina (Duque de Caxias, Brazil). Purified water was obtained using a Milli-Q Plus system (Millipore, Burlington, MA, USA) with a conductivity of 18 MΩ.

Ziebarth, J.; da Silva, L.M.; Lorenzett, A.K.P.; Figueiredo, I.D.; Carlstrom, P.F.; Cardoso, F.N.; de Freitas, A.L.F.; Baviera, A.M.; Mainardes, R.M. Oral Delivery of Liraglutide-Loaded Zein/Eudragit-Chitosan Nanoparticles Provides Pharmacokinetic and Glycemic Outcomes Comparable to Its Subcutaneous Injection in Rats. Pharmaceutics 2024, 16, 634. https://doi.org/10.3390/pharmaceutics16050634

Read also our introduction article on Chitosan here:

Video: Chitosan as a natural excipient