May 7, 2024

The role of bile acid as excipients in drug delivery

Bile salts include a large family of amphiphilic steroids with 4 or 5 rings, derived, by the liver, from cholesterol with very unique physical-chemical (and biological) characteristics. 

Compared to their chemical structure, bile acids (BAs) are steroidal molecules that contain a saturated tetracyclic hydrocarbon cyclopentanoperhydrophenanthrene ring and consist of:

  • three 6-membered rings and a 5-membered ring, 
  • a short aliphatic side chain,
  • a tough steroid nucleus.  

They have been used in drug delivery research due to their biocompatibility and unique chemical properties.

What are the health benefits of bile acids as drug absorption enhancers?

Bile acids can work as drug absorption enhancers which is the property to act as both drug solubilizing and permeation-modifying agents. Therefore, they act as drug carrier systems, improving bioavailability of drugs with poor aqueous solubility or low membrane permeability.[1]

The main advantages of using BAs as drug absorption enhancers are:

  • interaction with target cells,
  • activation of intracellular pathways,
  • structural integrity at different pH (essential for the oral dosage),
  • improving of transcellular permeability,
  • biocompatibility by not stimulating the host’s immune response. 

Synthesized in the body of all vertebrates and produced by the liver, bile acids, in human are:

  • deposited in the vertebrates, 
  • delivered in the intestine, 
  • taken into the bloodstream,
  • absorbed in the liver.

BAs as oral excipients

Bile acids can be utilized as absorption enhancer for oral drug delivery, both in the formulation of conventional dosage forms, and in Polymeric Micellar Systems, a kind of “smart” drug delivery realized with micellar vesicular or polymer-based therapeutic systems. 

As shown in the figure, bile acids’ polymeric micelles can work as carriers aiding uptake of many poorly soluble actives, that can be integrated into the hydrophobic core of the micelles due to these benefits and their tiny size. 

This is very helpful, because about 60–70% of all drug molecules in the market are insufficiently soluble to be absorbed from the gastrointestinal tract following oral administration.[2]

BAs have different chemical structures, for example, hydrophobicity decreases in the following order: lithocholic acid (LCA) > deoxycholic acid (DCA)> chenodeoxycholic acid (CDCA) > cholic acid (CA) > ursodeoxycholic acid (UDCA) > muricholic acid (MCA). 

Chemical structure can change also the critical micellar concentration, depending on the type of BA, their micelle can have anywhere from 4 to 50 molecules.[3]

What are the advantages of BAs as topical excipients?

BAs promote paracellular and transcellular drug absorption by widening tight junctions between cells and transport liposoluble drugs through membranes in the form of micelles. They can also be used as topical penetration-enhancing excipients,[4] which is a benefit in enhancing drug delivery. Penetration enhancement can overcome the disadvantages of conventional topical pharmaceutical formulations’ skin permeability which limits their therapeutic efficacy.

BAs as formulation excipients for cell encapsulation

Cell encapsulation is a strategy for 3D cell culture in which cells are isolated by a semipermeable material that permits diffusion of nutrients, gases, and metabolites. It is used for example, for genetically engineered cells or artificial tissues.

Microencapsulation is also used to deliver chemicals for a long period. 

BAs are appearing as a perfect excipient in microencapsulation, to enhance delivery and offering protection from the immune system.[5]

The roles of BAs as targets for drug development

Bile acid-related drugs play important roles in regulating metabolism. Drug development based on these targets could provide new hope for patients with a relative lower cost.[6] 

BAs can be used to build a prodrug, which is a biologically inactive molecule that undergoes chemical transformations once introduced into the body. By doing so, the pharmaceutical profile of parent drugs is refined through utilizing bile acid transporters.

Enhancing the core structure of ACV (antiherpetic drug acyclovir) with bile acids can deliver prodrugs with amplified antiviral activity:  ACV-cholate had an eight-fold higher activity than ACV alone.[7]

Bile acids drug carrier systems, as mixed micelles, bilosomes and drug conjugates are nanocarriers used in many fields.

In oncology, for example, the cytotoxic properties of hydrophobic BAs have been engineered to develop novel chemotherapy drugs, Furthermore, some bile acid derivatives have demonstrated anti-proliferative activities against a wide variety of human cancer cell lines including.

  • breast, 
  • prostate, 
  • cervical, 
  • colon,
  • liver cancer cells.

They have recently been optimized through conjugation with hydrophilic polymers, which has led to the development of bile acid-based nanoparticles with tunable sizes[8]

The future for these impressive excipients is to build a new precision medicine, which means to realize personalized medicines to each patient.

[1]Pavlović N, Goločorbin-Kon S, Ðanić M, Stanimirov B, Al-Salami H, Stankov K, Mikov M. Bile Acids and Their Derivatives as Potential Modifiers of Drug Release and Pharmacokinetic Profiles. Front Pharmacol. 2018 Nov 8;9:1283.

[2]Pavlović N, Goločorbin-Kon S, Ðanić M, Stanimirov B, Al-Salami H, Stankov K, Mikov M. Bile Acids and Their Derivatives as Potential Modifiers of Drug Release and Pharmacokinetic Profiles. Front Pharmacol. 2018 Nov 8;9:1283.

[3]Kovacevic B, Jones M, Ionescu C, Walker D, Wagle S, Chester J, Foster T, Brown D, Mikov M, asMooranian A, Al-Salami H. The emerging role of bile acids as critical components in nanotechnology and bioengineering: Pharmacology, formulation optimizers and hydrogel-biomaterial applications. Biomaterials. 2022 Apr;283:121459.

[4]Zaklan D, Nešić D, Mitrović D, Lazarević S, Đanić M, Mikov M, Pavlović N. Influence of Bile Acids on Clindamycin Hydrochloride Skin Permeability: In Vitro and In Silico Preliminary Study. Eur J Drug Metab Pharmacokinet. 2024 Feb 8.

[5]Mooranian A, Jones M, Ionescu CM, Walker D, Wagle SR, Kovacevic B, Chester J, Foster T, Johnston E, Mikov M, Al-Salami H. Pharmaceutical formulation and polymer chemistry for cell encapsulation applied to the creation of a lab-on-a-chip bio-microsystem. Ther Deliv. 2022 Jan;13(1):51-65.

[6]Shen H, Ding L, Baig M, Tian J, Wang Y, Huang W. Improving glucose and lipids metabolism: drug development based on bile acid related targets. Cell Stress. 2021 Jan 5;5(1):1-18.

[7]Chayrov RL, Stylos EK, Chatziathanasiadou MV, Chuchkov KN, Tencheva AI, Kostagianni AD, Milkova TS, Angelova AL, Galabov AS, Shishkov SA, Todorov DG, Tzakos AG, Stankova IG. Tailoring acyclovir prodrugs with enhanced antiviral activity: rational design, synthesis, human plasma stability and in vitro evaluation. Amino Acids. 2018 Aug;50(8):1131-1143.

[8]Faustino C, Serafim C, Rijo P, Reis CP. Bile acids and bile acid derivatives: use in drug delivery systems and as therapeutic agents. Expert Opin Drug Deliv. 2016 Aug;13(8):1133-48.