Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_101_библиотеки_им_акад_М_И_Перельмана

Insulin holds the distinction of being the rst biopharmaceutical accepted for subcutaneous use. Intravenous bolus or infusion remains the most common route for medications necessitating pre­cise dosing calculations, particularly oncology drugs, and is typically administered by healthcare professionals. However, there has been a recent shift from intravenous to subcutaneous administra­tion due to economic reasons. After the introduction of subcutaneous formulations of trastuzumab and rituximab in Europe between 2013 and 2014, numerous medications are now reformulated as subcutaneous dosage forms, moving away from intravenous administration. This shift enables self­injection of therapies for rheumatoid arthritis, multiple sclerosis, or primary immunodeciency, where mixed dosing (not based on body weight) is recommended.

Inhalable insulin, a powdered form of insulin, is inhaled and absorbed through the lungs. Inhaled insulins work faster than subcutaneously injected ones, resulting in a higher peak blood concentra­tion and faster metabolism. Pzer introduced Exubera, the rst inhaled insulin medication, in 2006, initially developed by Inhale Therapeutics (later renamed Nektar Therapeutics). However, due to poor sales, it was withdrawn in 2007. The FDA approved Mannkind’s monomeric inhaled insulin, Afrezza, in 2014. Dypreza inhaled insulin by Highlands Pharmaceuticals received approval for sale in Europe in 2013 and in the United States in 2016. Achieving precise dosing with inhalable insulin can be challenging, particularly when administered through a specic system.

Two products, an anti- vascular endothelial growth factor (anti- VEGF) aptamer and a monoclonal antibody (Lucentis; Ranibizumab), have gained approval for ocular delivery. Traditional topically applied dosage forms, such as eye drops, suffer from low bioavailability and therapeutic efcacy. Hence, new strategies have emerged to overcome ocular delivery barriers and enhance protein bio­availability through the ocular route. For instance, coadministration of chemical chaperones and recombinant human hyaluronidase facilitates protein delivery via the ocular path. To address protein aggregation concerns in ocular disease treatment, a novel strategy involving chemical chaperones, which act as protein aggregation inhibitors, has been devised to prevent misfolding and self- assembly of aggregation- prone protein sequences. Additionally, combining recombinant hyaluronidases with biopharmaceutical drugs has long been practiced to enhance drug penetration through ocular tissue barriers by breaking down hyaluronic acid, a vital tissue component. Research into nanocarriers like polymeric micelles, liposomes, nanospheres, nano wafers, and dendrimers focuses on controlled and targeted protein delivery through the ocular route, aiming to overcome ocular delivery barriers. Table 12.15 lists drugs administered through the eyes.

Protein drugs, highly susceptible to physicochemical and enzymatic destabilization, benet from absorption enhancers, protease inhibitors, prodrugs, and nano formulations. Insulin, heparin, calci­tonin, recombinant human granulocyte colony- stimulating factor (rhGCSF), and human chorionic gonadotrophin require absorption enhancers. However, certain enhancers used in rectal drug delivery may cause irritation and damage to the mucous membrane. Protease inhibitors enhance rectal bio­availability by minimizing protein degradation. Using prodrugs shields proteins from peptidases and mucosal enzyme degradation, boosting protein and peptide absorption. Nanotechnology- based formulation methods further aid in enhancing protein drug delivery via rectal administration.

Nanoparticles exhibit lipid- uidizing properties, which inuence skin permeability by altering the extracellular lipids in the stratum corneum.

Lipid- based nanocarriers, such as liposomes, solid lipid nanoparticles, and nanostructured lipid carriers, have been studied extensively for ocular protein delivery. Prolonged drug release may help reduce the risk of ocular complications associated with multiple intravitreal injections, such as vit­reous hemorrhage, endophthalmitis, retinal detachment, and cataracts.

Niosomes, self- assembling nanovesicles composed of nonionic surfactants resembling liposomes, are preferred for topical ocular drug delivery due to their chemical stability, biodegradability, bio­compatibility, lack of immunogenicity, and low toxicity. They exhibit structural exibility, encap­sulating both lipophilic and hydrophilic drugs. Discomes, a type of niosome with wide structures (12– 16 mm) as a result of the addition of Solulan C24 (nonionic surfactant), are advantageous for ocular administration, preventing drainage into the systemic pool due to their size and shape, tting comfortably into the eye’s cul- de- sac. However, their development is still in the early stages.

Liposomes serve as carriers to encapsulate proteins within the aqueous core, enhancing membrane permeability for protein drugs. The structural similarity of liposomes to cellular membranes aids in intestinal absorption. However, they do have drawbacks as oral protein carriers due to chemical and enzymatic instability in the gastrointestinal tract. To address stability issues, surface coating becomes essential for oral drug delivery in liposomes. Various approaches, such as altering the liposomal surface using ligands interacting with specic receptors on cellular membranes, present promising possibilities. Lectins, a type of plant- derived glycoprotein, are a potential ligand for spe­cic binding to mucosal carbohydrate receptors.