Multifaceted applications of bile salts in pharmacy: an emphasis on nanomedicine

Figures & data

Figure 1 Illustrative diagram summarizing (A) BS in human digestive system; (B) chemical structure of deoxycholic acid; (C) schematic representation of facial amphiphilic structure of conjugated deoxycholic acid with hydrophobic convex side and hydrophilic concave side; and (D) BS micelle.

Note: Modified from Maldonado-Valderrama et al² and Conacher et al.⁴

Abbreviations: BS, bile salt; CDCA, chenodeoxycholic acid.

Figure 2 Schematic representation of the absorption and digestion mechanisms of fats and fatty carrier (SEDDS) in the GIT.⁴⁶

Notes: (A) Drug diffusion from intact carrier; (B) nanoemulsion forms endogenous mixed micelle; (C) absorption of intact drug; loaded nanocarrier.

Abbreviations: TG, triglycerides; MG, monoglycerides; ME, microemulsion; FFA, free fatty acid; SEDDS, self-emulsifying drug delivery system; GIT, gastrointestinal tract; D, drug.

Figure 3 Diagrammatic representation summarizing the four major BS-integrated nanosystems.

Note: Modifed from Li et al⁵⁸ and Wilkhu et al.⁹⁹

Abbreviation: BS, bile salt.

Figure 4 Tumor targeting of paclitaxel-loaded PEGylated nanocarrier of cholic acid in ovarian cancer xenograft.⁵⁸

Abbreviation: PEG, polyethylene glycol.

Figure 5 (A) Geometric arrangements of bile salt and phospholipid molecules according to packing parameter (PP) value;⁵³ (B) pseudo-ternary phase diagram for silybin-sodium cholate/phospholipid-mixed micelles.⁷²

Table 1 Summary of versatile bilosomal formulations with different active ingredients and pharmaceutical findings

Drug	Bilosomal formulation	Imperative findings	Reference
Insulin	Cholesterol (CH)-bilosomes	• CH was required for higher drug entrapment	^Citation33
	Taurocholate bilosomes	• Evidence of higher oral stability • Size-dependent bioavailability	^Citation32, ^Citation40, ^Citation74
	Nanobilosomes with different bile salts	• Mechanism of bilosome enhanced bioavailability via transenterocytic internalization • Relative stabilizing and fluidizing effects of bile salts • Superiority of sodium glycocholate	^Citation40
Diphtheria vaccine	Sodium deoxycholate nanobilosomes	• Mucosal immunization	^Citation38
hepatitis B		• Comparable systemic immunization to IM injection	^Citation37
Baculovirus		• Without tolerance	^Citation34
Influenza vaccine	Sodium deoxycholate microbilosomes	• Large vesicles (≥6 μm) show higher accumulation in Peyer’s patches with higher mucosal immunization • Inverse relation between vesicle size and bile content	^Citation4
Bovine serum albumin	Cholera toxin conjugated bilosomes	• M-cell targeted by anchored toxin • Higher uptake and mucosal immunization	^Citation36, ^Citation39
Tetanus toxoid	Glucomannan-conjugated bilosomes	• Glucomannan targets receptors in APCs • Higher uptake, mucosal and systemic immunization	^Citation29
Calcein	Glycocholate bilosomes	• Comparatively higher stability of bilosomes versus liposomes in gastric enzymes was demonstrated	^Citation31
Cyclosporine A	Deoxycholate nanobilosomes	• Higher incorporation of lipophilic drug into PL bilayer thanks to SDC fluidizing effect	^Citation78
Fenofibrate		• Poor IVIV correlations regarding lipophilic drug release from bilosomes	^Citation41
Salmon calcitonin	Probilosomes	• Intraduodenal freeze-dried bilosomes showed a sevenfold increase in bioavailability • Theory of lipophilic ion-pair complex was proposed	^Citation81
Tacrolimus (FK506)	SGC and STC bilosomes	• Bilosomes could increase corneal drug permeation • Ocular toxicity of deoxycholate was reported	^Citation88
Clotrimazole	Cholate, deoxycholate nanovesicles	• Prolonged antifungal effect of occular bilosomes	^Citation100

Abbreviations: SGC, sodium glycocholate; STC, sodium taurocholate; SDC, sodium deoxycholate; PL, phospholipid; APCs, antigen presenting cells; IVIV, in-vitro in-vivo correlation; IM, intramuscular.

Figure 6 Diagrammatic representation of BS stabilizing effect of oral vesicles containing protein (A) ruptured liposomal vesicle prior to reaching M-cell; (B) intact bilosomes retaining antigen offering protection therefore continue to transit toward M-Cell.

Note: Modified from Wilkhu et al.⁹⁹

Table 2 Effects of various surfactants on the apical to basolateral permeability of sCT (300 μg/mL) and on TEER values in the Caco-2 cell monolayer (n=3–4)

Enhancers to sCT (w/v or v/v)	Papp (cm/s, mean ± SD)	Fold increase in Papp	Fold decrease in TEER	Merit index (mean ± SD)
No enhancer	1.35±0.21×10^−7	1.00	1.00	1.00±0.16
Sodium glycocholate (SGC) 0.1%	1.63±0.20×10^−7	1.21	1.23	0.98±0.12
Sodium taurocholate (STC) 0.1%	1.96±0.66×10^−7	1.45	1.27	1.14±0.39
Sodium dehydrocholate (SDHC) 0.1%	2.39±0.80×10^−7	1.77	1.53	1.16±0.38
Sodium cholate (SC) 0.1%	2.57±0.57×10^−7	1.90	1.67	1.14±0.25
Ursodeoxycholate (UDC) 0.1%	1.64±0.23×10^−7	1.21	1.03	1.18±0.17
Sodium tauroursodeoxycholate (STUDC) 0.1%	1.78±0.05×10^−7	1.32	1.02	1.29±0.35
Sodium taurochenodeoxycholate (STCDC) 0.1%	5.15±0.51×10^−7	3.82	2.30	1.66±0.17
Sodium deoxycholate (SDC) 0.1%	7.01±1.32×10^−7	5.19	3.97	1.31±0.25
Sodium glycodeoxycholate (SGDC) 0.1%	14.4±3.48×10^−7	10.66	4.57	2.33±0.56
Sodium taurodeoxycholate (STDC) 0.1%	14.6±1.91×10^−7	10.81	3.55	3.05±0.40
Sodium lauryl sulfate 0.01%	1.95±0.15×10^−7	1.44	2.49	0.58±0.04
Lauroyl carnitine chloride 0.01%	2.43±0.49×10^−7	1.80	1.46	1.23±0.25
Benzalkonium chloride 0.01%	4.10±1.40×10^−7	3.04	7.77	0.39±0.13
Benzethonium chloride 0.01%	8.61±1.01×10^−7	6.38	11.51	0.55±0.06
Triton X-100 0.01%	1.43±0.26×10^−7	1.06	1.04	1.02±0.18
Tween 80 0.01%	2.08±0.46×10^−7	1.54	1.40	1.10±0.24
Cremophor EL 0.01%	2.40±0.28×10^−7	1.78	1.39	1.28±0.15

Note: Modified from Song et al.⁸¹

Abbreviations: TEER, transepithelial electrical resistance; SD, standard deviation.

Figure 7 Schematic images of curcumin embedded in DPPC liposomes without bile salt (left image); in the presence of Na cholate (center image); and in the presence of Na deoxycholate (right image).⁵²

Abbreviation: DPPC, dipalmityl phosphatidyl choline.

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