The Development of Oral Amphotericin B to Treat Systemic Fungal and Parasitic Infections: Has the Myth Been Finally Realized?
Abstract
:1. Preamble
2. Purpose
3. Chemistry of AmB
3.1. Structure Overview
3.2. Structure-Activity Relationship
3.3. Mechanism of Action of AmB
3.4. Bioavailability of AmB
4. Treating Visceral Leishmaniasis (VL)
4.1. Amphotericin B Parenteral Formulations
4.2. Visceral Leishmaniasis Treatment Options and Limitations
5. Oral Formulations of AmB Currently in Development
5.1. Solid Lipid Nanoparticles
5.2. PLGA–PEG Nanoparticles
5.3. Chitosan-Coated Nanostructured Lipid Carriers
5.4. Lecithin-Based Mixed Polymeric Micelles
5.5. O/W Microemulsion
5.6. Pickering Emulsion
5.7. Tragacanth/Acrylic Acid Copolymer
5.8. Chitosan (CS) and Porphyrin (POR) Polymeric Nanocarrier
5.9. Chitosan–Ethylenediamine Tetraacetic Acid (EDTA) Microparticles
5.10. Carbon Nanotubes
5.11. Cubosomes
5.12. GCPQ Nanoparticles (Quaternary Ammonium Palmitoyl Glycol Chitosan)
5.13. Cochleates
5.14. SEDDS (iCo-010/019)
6. Discussion and Concluding Remarks
Funding
Conflicts of Interest
Abbreviations
Acrylic acid | AAc | Anhydrogalactose | AGR |
Amphotericin B | AmB | Blood urea nitrogen | BUN |
Amphotericin B cochleates | CAMB | Colony forming units | CFU |
Chitosan | CS | 1,2-distearoyl-sn-glycero-3-phosphoethanolamine- N-methoxy(poly(ethylene glycol)-2000 | DSPE-PEG 2K |
Carbon nanotubes | CNTs | Ethylenediaminetet-raacetic acid | EDTA |
Gut associated lymphatic tissue | GALT | Oral bioavailability | Fo |
Hydrophilic–lipophilic balances | HLBs | Gastrointestinal tract | GIT |
Oil-in-water microemulsion | O/W ME | Minimum inhibitory concentration | MIC |
Polyelectrolyte complexation | PEC | Poly(lactide-co-glycolide)–poly(ethylene glycol) | PLGA–PEG |
Phamacokinetics | PK | Porphyrin | POR |
Quaternary ammonium palmitoyl glycol chitosan | GCPQ | Reactive oxygen species | ROS |
Self-emulsifying drug delivery system | SEDDS | Simulated intestinal fluid | SIF |
Solid lipid nanoparticles | SLNs | Visceral leishmaniasis | VL |
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AmB oral formulation | Efficacy | Stability |
---|---|---|
Solid lipid nanoparticle [47] | Lower kidney tissue concentration, | 2–8 °C for 3 months, |
105% Fo of Fungizone® | 15 days ≥ 25 °C | |
PLGA–PEG nanoparticle [43,48] | Increase antifungal activity 4-fold in vitro | N/A |
Inhibit parasite load by 93.2% compared with free AmB group (74.6%) | ||
130% Fo of Fungizone® | ||
Chitosan-coated nanostructured lipid carriers [42] | N/A | 63.9% AmB retained encapsulated after 30 min incubation in SIF |
Lecithin-based mixed polymeric micelles [49] | Less toxic in HT29 cells | Increase solubility |
150% Fo of Fungizone® | ||
O/W microemulsion [50] | Slightly less toxic than free DMSO | Increase the solubility by 1000 folds |
Pickering emulsion [51] | N/A | Stable one month under refrigeration |
Tragacanth/acrylic acid copolymer [52] | No mortality observed in mice comparing with free AmB | N/A |
Improve oral bioavailability comparing with free AmB | ||
Chitosan and porphyrin polymeric nanocarrier [53] | 23-fold antifungal activity than Ambisome® | Less degradation in SIF and a superior release profile for up to 12 h |
Slightly less toxic than Fungizone® | ||
Chitosan–EDTA microparticles [54] | N/A | 12-fold improvement in in vitro dissolution relative to pure AmB |
Carbon Nanotubes [55,56] | Inhibit the parasite load in a dose-dependent manner | N/A |
No evidence of toxicity in mice and hamster models | ||
Cubosomes (cubic liquid crystal nanoparticles) [57] | low dose of AmB-loaded cubosomes shows low kidney concentration than Fungizone® | 74% detectable AmB after 3h in SIF |
285% bioavailability of Fungizone® | ||
GCPQ nanoparticles [58] | Absolute Fo is 24.7% | Stable for a year on storage |
Higher concentration in liver, lung and spleen | ||
Cochleate–CAMB/MAT2203 [59,60] | 100% survival comparing with Fungizone® and AmBisome® | Stable for 4 months at 4 °C |
No serious adverse event in Phase I study | ||
SEDDS (iCo-010/019) [66] | <99% reduction in parasitic infection in a murine model | >75% over 60 days in 30 °C; >95% after 4 h in SIF |
95% inhibition when compared to control |
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Cuddihy, G.; Wasan, E.K.; Di, Y.; Wasan, K.M. The Development of Oral Amphotericin B to Treat Systemic Fungal and Parasitic Infections: Has the Myth Been Finally Realized? Pharmaceutics 2019, 11, 99. https://doi.org/10.3390/pharmaceutics11030099
Cuddihy G, Wasan EK, Di Y, Wasan KM. The Development of Oral Amphotericin B to Treat Systemic Fungal and Parasitic Infections: Has the Myth Been Finally Realized? Pharmaceutics. 2019; 11(3):99. https://doi.org/10.3390/pharmaceutics11030099
Chicago/Turabian StyleCuddihy, Grace, Ellen K. Wasan, Yunyun Di, and Kishor M. Wasan. 2019. "The Development of Oral Amphotericin B to Treat Systemic Fungal and Parasitic Infections: Has the Myth Been Finally Realized?" Pharmaceutics 11, no. 3: 99. https://doi.org/10.3390/pharmaceutics11030099
APA StyleCuddihy, G., Wasan, E. K., Di, Y., & Wasan, K. M. (2019). The Development of Oral Amphotericin B to Treat Systemic Fungal and Parasitic Infections: Has the Myth Been Finally Realized? Pharmaceutics, 11(3), 99. https://doi.org/10.3390/pharmaceutics11030099