Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update
Abstract
:1. Introduction
2. Permeation Enhancer (PE) Categories
3. Targets for Intestinal Permeation Enhancement: Beyond Insulin
4. Recent Highlights
4.1. Oral Semaglutide Reduces HBA1c in Type 2 Diabetics by over 1.5% in Phase II Trials
4.2. The Ionic Liquid Choline Geranate (CAGE) Has a Major Effect on Oral BA of Insulin
4.3. Mode of Action Studies on the PE, PIP 640
4.4. Application of Nanoparticles to Co-Localise Active and PE
4.5. Application of PEs in Delivery of Nutraceuticals
4.6. Can Non-Ionic Surfactants be More Effective than Ionizable Surfactants?
4.7. Can Physical Hydrophobization Improve Passive Intestinal Flux?
4.8. Mode of Action Studies are Required to Provide Evidence for a Paracellular Effect
4.9. Growing Need for Simulated Intestinal Fluid in PE Experiments
4.10. Improving PE Action in the Dynamic GI Tract
4.11. Intestinal Patches to Co-Localise PE and Active
4.12. Is Safety of PEs a Real Impediment to Translation?
4.13. Convergence between Delivery Concepts, Intestinal Physiology, and Formulation Science
5. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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Active | Mw | Dose | Frequency | Route | t½ | LogP † | BCS | Oral BA |
---|---|---|---|---|---|---|---|---|
Desmopressin | 1069 Da | 1–4 mcg | Daily | sc | ~2.8 h | −4 | III | 0.17% |
Octreotide | 1019 Da | 200 mcg | Thrice daily | sc | ~1.7 h | −1.4 | — | Phase 3 |
Cyclosporin | 1203 Da | 280 mg | Daily | iv inf. | ~8.4 h | 7.5 | II | 27% |
Vancomycin | 1449 Da | 1500 mg | Twice daily | iv inf. | ~7.2 h | −2.6 | III | Local |
Salmon calcitonin | 3432 Da | 16.7 mcg | Daily | sc | ~1.3 h | −16.6 | — | Phase 3 |
Semaglutide | 4114 Da | 500 mcg * | Weekly | sc | ~168 h | −5.8 | — | Phase 3 |
Exenatide | 4186 Da | 10 mcg | Daily | sc | ~2.4 h | −21 | — | Phase 1 |
Insulin degludec | 6108 Da | 350 mcg | Daily | sc | ~25 h | −4.9 | — | — |
Insulin aspart | 5832 Da | 1.8 mg ** | — | sc | ~1.4 h | — | — | — |
Formulation Additives | Disintegrant (% w/w) | Tableting Pressure (psi) | Disintegration Time (min) | Break Strength (N) |
---|---|---|---|---|
Labrasol and Neusilin® US2 (1:1) | 0 | 1000 | >60 | 29.1 ± 2.9 |
Labrasol and Neusilin® US2 (1:1) | 0 | 2000 | >60 | 68.8 ± 3.2 |
Labrasol and Neusilin® US2 (1:1) | 5 | 1000 | 5.5 ± 0.2 | 49.8 ± 6.2 |
Labrasol and Neusilin® US2 (1:1) | 5 | 2000 | 4.9 ± 0.3 | 72.4 ± 2.7 |
Anatomical/Physiological Property | Species | Influence on PE Action |
---|---|---|
Gastric emptying time (h) | Human: 1 h [130] Rat: 0.7–2.1 h [130] Dog: 3.9–5.3 h [130] Pig: 1.5–6 h [130] | For immediate release dosage forms, slower gastric emptying in pig and dog than in humans may increase gastric residence time of PE and payload, thus overestimating enhancement. For enteric dosage forms, slower gastric emptying, may delay dissolution in the GI tract and ultimately increase Tmax in these species versus humans. |
Gastric fluid volume (mL) | Human: 118 mL [137] Rat: 2.29 [137] Dog: 500–1000 mL [137] Pig: 278 mL [137] | For immediate release dosage forms, the larger volume in dogs may result in greater dilution of PE to below a threshold for enhancement action, thereby underestimating enhancement. |
Stomach pH | Human: 1.7 [128] Rat: 3.9 [138] Dog: 1.5 [128] Pig: 1.7 [128] | As many PEs that have progressed to clinical testing in oral formulations are weak acid surfactants, differences in solubility can be observed if there is variation in gastric pH. This gives rise to differences in enhancement as acidic surfactants are more effective in their ionizable form at high pH. |
Small intestine transit time (Fasted state) (time (h) and length (m)) | Human: 3–4 h [139] Human: 6.25 m [137] Rat: 4–5 h [128] Rat: 0.34 m [137] Dog: 1.5 h [137] Dog: 2.48 m [137] Pig: 3–4 h [137] Pig: 14.2 m [137] | Faster transit may reduce the exposure of PE and payload at the epithelium, thereby reducing enhancement, and potentially underestimating the effects of the PE. A short transit time does not strictly mean faster movement, as length of the small intestine is different in different species. |
Small intestine fluid volume (total and g/cm) | Human: 212 mL [137] Human: 0.6 g/cm [130] Rat: 3.9 mL [137] Rat: 0.06 g/cm [130] Dog: 300 mL [137] Dog: 0.9 [130] Pig: 476 mL [137] Pig: 0.62 [130] | Differences in fluid volume, or more specifically the volume and number of intestinal fluid pockets in the small intestine could lead to differences in the regional concentration of PE and payload, as well as differences in dissolution rate. This could lead to under- or overestimation of enhancement. |
Duodenal mucus thickness (µm) | Human: 15.5 µm [137] Rat: 30.6 µm [137] Dog: — Pig: 25.6 µm [137] | Difference in the thickness of the protective mucus gel layer overlying the epithelium has potential to modulate enhancement. |
Small intestine diameter | Human: 5 cm [137] Rat: 2.5–3 mm [137] Dog: — Pig: — | The diameter of the intestinal lumen may impact the proximity of enteric formulations to the epithelium and ultimately impact co-localization of PE and payload. |
Plasma membrane phospholipid composition of intestinal epithelium | Human: — Rat: — Dog: — Pig: — | There are differences in phospholipid composition in different species [128], which may impact sensitivity to perturbation by surfactant PEs |
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Maher, S.; Brayden, D.J.; Casettari, L.; Illum, L. Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update. Pharmaceutics 2019, 11, 41. https://doi.org/10.3390/pharmaceutics11010041
Maher S, Brayden DJ, Casettari L, Illum L. Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update. Pharmaceutics. 2019; 11(1):41. https://doi.org/10.3390/pharmaceutics11010041
Chicago/Turabian StyleMaher, Sam, David J. Brayden, Luca Casettari, and Lisbeth Illum. 2019. "Application of Permeation Enhancers in Oral Delivery of Macromolecules: An Update" Pharmaceutics 11, no. 1: 41. https://doi.org/10.3390/pharmaceutics11010041