Peptides face unique challenges when introduced into biological systems due to their size, polarity, enzymatic sensitivity, and limited membrane permeability. As a result, the route of administration and formulation strategy profoundly influences stability, absorption, and overall pharmacokinetic performance. This chapter explores the biochemical and physical principles underlying peptide delivery, highlighting the strengths and limitations of each route.
6.1 Why Route of Administration Matters
Because peptides are hydrophilic, enzymatically degradable molecules, their performance varies significantly between administration routes. Oral delivery often fails due to digestive proteases, while parenteral routes bypass these barriers. Understanding these distinctions is essential for interpreting research outcomes (NCBI – peptide delivery overview).
6.2 Subcutaneous (SubQ) Administration
SubQ delivery is the most common method used in peptide research because it provides:
- Slow, sustained absorption from the interstitial fluid.
- Reduced enzymatic degradation compared to oral routes.
- High bioavailability for most small-to-medium peptides.
- Compatibility with depot formulations and sustained-release matrices.
Absorption occurs via diffusion and lymphatic uptake, influenced by lipophilicity, charge, and molecular size. Hydrophobic or lipidated peptides exhibit slower absorption and extended exposure (British Journal of Pharmacology – absorption kinetics).
6.3 Intramuscular (IM) Administration
IM administration delivers peptides deeper into well-perfused muscle tissue. Compared to SubQ:
- Absorption is faster due to greater blood flow.
- Peak concentrations are typically higher.
- Suitable for peptides requiring rapid systemic exposure.
However, IM injections may be more painful and less suitable for frequent administration.
6.4 Intranasal Delivery (IN)
Intranasal administration offers a non-invasive option that bypasses first-pass hepatic metabolism. Small, lipophilic, or receptor-targeted peptides can exploit olfactory and trigeminal pathways for rapid absorption. Factors influencing success include:
- Peptide size and charge.
- Solvent system and pH.
- Permeation enhancers (e.g., cyclodextrins, chitosan derivatives).
- Formulation viscosity and spray pattern.
Absorption through the nasal mucosa is documented in numerous pharmacological studies (PubMed – nasal peptide delivery).
6.5 Oral Delivery: Why It Usually Fails
Oral peptide delivery is limited by:
- Proteolytic degradation in stomach acid and intestinal fluid.
- Poor membrane permeability across intestinal epithelium.
- First-pass hepatic metabolism, eliminating circulating peptide.
Only a small number of peptides have demonstrated successful oral bioavailability, usually with advanced formulation techniques such as microencapsulation, enteric coatings, enzyme inhibitors, or permeation enhancers (Nature – oral peptide chemistry).
6.6 Advanced Delivery Systems and Enhancers
To enhance absorption or stability, researchers use:
- Cyclization to resist proteolysis.
- D-amino acid substitution to increase stability.
- Lipidation to slow clearance and enhance membrane interaction.
- Nanoparticle carriers for controlled release.
- PEGylation to increase hydrodynamic radius.
- Depot (slow-release) matrices for sustained exposure.
- pH-buffered nasal formulations for improved mucosal absorption.
Many of these methods are directly derived from pharmaceutical peptide research (ACS – peptide formulation strategies).
6.7 Formulation Considerations
Proper formulation improves peptide stability, solubility, and bioavailability. Important parameters include:
- pH – impacts solubility and degradation rate.
- Buffer composition – citrate, acetate, phosphate, or histidine-based.
- Solvents – sterile water, saline, or mixed aqueous-organic systems.
- Tonicity agents – prevent irritation during injection.
- Preservatives – only appropriate for multi-dose research formulations.
A well-designed formulation minimizes aggregation, oxidation, and precipitation (Chromatography Online – formulation stability).
6.8 Summary of Chapter 6
Peptide delivery requires careful consideration of enzymatic stability, membrane permeability, pH, solvent systems, and physiological barriers. SubQ and IM routes offer the most reliable systemic absorption, while intranasal delivery provides a viable non-invasive alternative for select peptides. Due to harsh digestive conditions, oral delivery remains challenging unless paired with advanced formulation strategies. Understanding these factors is essential for interpreting peptide behavior and optimizing experimental results.
