Advancements in drug delivery systems, challenges and future opportunities

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Why is oral delivery the desired route for delivery of most drugs? It is due to enhanced patient compliance, lower cost and less side effects. However several problems must be overcome including solubility, low solubility then low bioavailability.

Digestion: e.g. peptide based drugs could be digested by the proteolytic enzymes in the stomach and the small intestine. Absorption: overall charge is important for absorption and the drug must pass easily through the SI mucus layer. The stomach is not an absorptive organ and may need to be protected from damage by the drug. Lipid formulations consisting of oils/triglycerides and surfactants can increase solubility of lipid soluble drugs, which can be dispersed as emulsions (self emulsifying drug delivery systems, SEDDS) in the aqueous environment of the GI tract (7). A downside is that the lipids can be digested in the intestine via pancreatic lipases which could lead to release of some of the active with reduced solubility. However if surfactants are present this can result in the creation of micelles, which can be absorbed as mixed micelles formed into chylomicrons in the enterocytes and enter the lymphatic system and so miss the hepatic first pass increasing bioavailability (8). Lipid formulations can also protect the stomach as there is little lipase activity in the adult stomach the lipid formulations should pass through unaltered. We have demonstrated in the Aelius biotech model the effects of lipid formulations of ibuprofen on the gastric mucosa. The model consists of a transwell system containing a monolayer of CRL1739 human gastric cells coated with a physiologically relevant gastric mucus layer and topped with gastric digestive fluids (acid and pepsin). If no mucus is present, we have shown that free ibuprofen kills the cells. A lipid formulation will reduce cell death. Application of a mucus layer reduces damage from the free compound and no damage occurs when the lipid formulation is applied. Oral delivery of proteins and peptides, currently a growing market, raises further problems (9). Consider Semaglutide, an analogue of human glucagon-like peptide 1, secreted by endocrine L cells of the intestinal ileum: It binds to the GLP receptor and stimulates insulin secretion, decreases glucagon secretion and slows gastric emptying.

Semaglutide is delivered either subcutaneously or via the oral route. The problem with oral delivery is limited bioavailability (0.4-1.0%). Semaglutide has been formulated with SNAC (sodium N-(8-(2-hydroxybenzoyl)amino)caprylate), to increase gastric absorption . However the stomach is not an absorptive organ. In addition semaglutide is a modified peptide and as such will be damaged by the acidic environment of the stomach and digested by pepsin. Further digestion can occur in the small intestine via the action of pancreatic proteases.

 

For absorption to then occur, the active must pass through the mucus layer; being a small peptide Mol wt 4,113 (31 amino acids) and not highly charged, it will pass easily through the mucus pores and access the enterocytes for absorption via a peptide carrier or by a paracellular pathway. However inside the cell other proteases can further digest the peptide.
Delivery can be enhanced of proteins and peptides; some examples:

 

• Enhance survival using chemical modification, e.g. PEGylation which increases half-life by reducing proteolytic digestion.
• Absorption enhancers SNAC
• Enteric coating to prevent release in the stomach
• Mucolytic agents, but could lead to damage to the mucosa from digestive fluids. In addition passage through mucus and absorption can be enhanced by changes in charge. Mucus is negatively charged and nanoparticles loaded with drug, with surface phosphate groups making them negative will pass through the mucus. At the intestinal cell surface alkaline phosphatase will remove the phosphate giving the nanoparticle an overall positive charge enhancing absorption.
• Prodrugs. These are compounds with no pharmacological activity but have labile groups which when removed in vivo release the active drug. Also prodrugs can be activated by ultrasound or magnetic fields. Prodrugs are an increasingly used method of delivery, between 2008 and 2018 12% of all small molecules approved by the FDA were prodrugs (10).

Advances in terms of increasing efficacy and reducing side effects of injectables can be achieved using technologies that can deliver to specific cells or tissues. These could be drugs that involve antibodies or ligands. High energy radiation could be delivered to cancer cells using this technology.

 

Finally current treatments proposed for obesity involve injections of semaglutide or trizepatide which are effective in promoting weight loss via their action as GLP-1 and GIP analogues, however they do come with side effects. In terms of green chemistry these compounds are chemically synthesised and it may be possible to use natural products from plants and algae as substitutes. They can be used orally with minimal side effects, as metabolic and thermogenic stimulators e. g. green tea extracts, appetite regulators e.g. extracts of Hoodia gordonii, regulators of insulin sensitivity and inducers of hypoglycaemia e.g. procyanidins, pancreatic lipase and amylase inhibitors e.g. alginates from seaweed and inhibitors of adipogenisis e.g. esculetin (11, 12).

 

References and notes

1. J, Lou et al. Advances in oral drug delivery systems: Challengers and opportunities. 2023, Pharmaceutics: 15; 484.
2. S. Dave, D. Shriyan, P. Gujjar. Newer drug delivery systems in anaesthesia. 2017 J. Anaesthesiology Clin. Pharm: 33; 157-163.
3. J. K. Vasir, K. Tambwekar, S. Garg. Bioadhesive microspheres as a controlled drug delivery system. 2023, Int. J. Pharmaceutics: 255; 13-32.
4. S. M. Bierma-Zeinstra at al. A new lipid formulation of low dose ibuprofen shows non-inferiority to high dose standard ibuprofen. 2017, Osteoarthritis and cartilage: 25; 1942-1951.
5. K. Stanforth et al. In vitro modelling of the mucosa of the oesophagus and upper digestive tract. 2021, Annals of esophagus. http://dx.doi.org/1021037/aoe-2020-ebmg-06
6. BCC Publishing. Global Markets for Media, Sera and Reagents in Biotechnology. s.l. : BCC Research, 2021.
7. Shrestha, H. Bala, R. Arora, S. Lipid based drug delivery systems. 2014, J. Pharmaceutics http://dx.doi.org/10.1155/2014/801820
8. Mahajan, N. et al. Self-emulsifying drug delivery system for enhanced oral delivery of Tenofovir: formulation, physiochemical characterization, and bioavailability assessment. 2024, ACS Omega: 9; 8139-8150.
9. Chen, G. et al. Oral delivery of protein and peptide drugs: from non-specific formulation approaches to intestinal cell targeting strategies. 2022, Theranostics: 12; 1419-1439.
10. Rautio, R. Meanwell, N A. Hageman, M J. The expanding role of prodrugs in contemporary drug design and development. 2018, Nature reviews drug discovery: 17; 559-587.
11. Sayed, U F S M. et al. Natural products as novel anti-obesity agents: insights into mechanisms of action and potential therapeutic management. 2023, Frontiers in Pharmacology: Volume 14;  https://doi.org/10.3389/fphar.2023.1182937
12. Wilcox, M D. Brownlee, I A. Richardson, C J. Dettmar, P W. Pearson, J P. The modulation of pancreatic lipase activity by alginates. 2014, Food Chemistry: 146; 479-484.