PeptideJournal
Research14 min read

Peptide Bioavailability Research: Routes of Administration

Getting a peptide into the body is only half the problem. Getting it to work once it arrives — that is the real challenge.

Getting a peptide into the body is only half the problem. Getting it to work once it arrives — that is the real challenge.

Bioavailability, the fraction of an administered drug that reaches systemic circulation in active form, determines whether a peptide therapy succeeds or fails. And bioavailability depends heavily on how the peptide gets in. A subcutaneous injection might deliver 80-95% of the dose. The same peptide taken as a pill? Often less than 1%.

This gap has shaped the entire peptide therapeutics field. It explains why most of the 80+ FDA-approved peptide drugs require injections. It also explains why billions of research dollars are flowing into alternative delivery methods — from microneedle patches to robotic pills to nanoparticle carriers.

Here is what the research tells us about each route, what the numbers actually look like, and where things are heading.

Table of Contents

Why Peptide Bioavailability Is So Low {#why-peptide-bioavailability-is-so-low}

Peptides face a gauntlet of biological barriers that small-molecule drugs largely avoid. Understanding these barriers explains why delivery route matters so much.

Enzymatic degradation. The body is full of proteases — enzymes whose job is to break down proteins and peptides. The gastrointestinal tract is especially hostile. Pepsin in the stomach, trypsin and chymotrypsin in the small intestine, and membrane-bound brush border enzymes all attack peptide bonds. Most unprotected peptides are destroyed within minutes of oral ingestion (Pharmaceutics, 2025).

Poor membrane permeability. Peptides are typically large (molecular weight above 500-1,000 Da), hydrophilic, and carry multiple charges. These properties make it difficult for them to cross the lipid-rich cell membranes of epithelial barriers. Fewer than 10% of approved peptides target intracellular pathways, largely because of this permeability problem (Nature Signal Transduction and Targeted Therapy, 2025).

First-pass metabolism. Peptides absorbed through the intestine travel through the portal vein to the liver before reaching systemic circulation. Hepatic enzymes can degrade a substantial portion of the absorbed dose, further reducing what is available to the body.

Short plasma half-life. Even after a peptide reaches the bloodstream, rapid renal clearance and continued enzymatic breakdown limit how long it remains active. Many native peptides have plasma half-lives measured in minutes, requiring frequent dosing or structural modifications.

Molecular size. The kidneys filter molecules below roughly 60 kDa quite efficiently. Most therapeutic peptides are well below this threshold, which means they are cleared quickly from circulation unless they are modified or bound to carrier proteins.

Route-by-Route Bioavailability Comparison {#route-by-route-bioavailability-comparison}

The following table summarizes what research has found across major delivery routes. These are representative ranges — specific numbers vary by peptide, formulation, and study design.

RouteTypical BioavailabilityOnset of ActionKey BarrierPatient Convenience
Intravenous100% (by definition)ImmediateNone (direct to blood)Low (requires IV access)
Subcutaneous50-95%15-60 minutesLocal enzyme activityModerate (self-injection possible)
Intramuscular50-100%10-30 minutesLocal enzyme activityModerate
Pulmonary (inhaled)10-50%5-15 minutesMucociliary clearance, macrophagesModerate-High
Intranasal<5% (most peptides)1-30 minutesMucosal barrier, enzymatic activityHigh
Transdermal (microneedles)46-100% (relative to SC)15-60 minutesStratum corneumHigh
Buccal/Sublingual1-2%15-30 minutesEpithelial barrier, saliva washoutHigh
Oral<1-2%30-120 minutesGI enzymes, permeability, first-passVery High

Sources: Bachem peptide bioavailability review; PMC comprehensive review, 2025; Springer Nature pulmonary review, 2022

Subcutaneous and Intramuscular Injection {#subcutaneous-and-intramuscular-injection}

Injectable routes remain the workhorse of peptide therapy. Roughly 78% of approved peptide drugs use parenteral (injectable) administration, and subcutaneous injection alone accounts for about 36% of all peptide formulations (PMC review, 2023).

Why Injections Work So Well

Subcutaneous and intramuscular injections bypass the GI tract entirely, avoiding the triple threat of acid degradation, enzymatic breakdown, and poor intestinal permeability. They also skip first-pass hepatic metabolism. The result is bioavailability that typically ranges from 50% to 95%, depending on the specific peptide and injection site.

Subcutaneous vs. Intramuscular

The two routes are not identical. Subcutaneous injections deliver peptides into the fatty tissue beneath the skin, producing a slower, more sustained absorption curve. Intramuscular injections place the drug directly into muscle tissue, where higher blood flow leads to faster absorption and quicker onset.

For peptides like semaglutide (injectable Ozempic/Wegovy), subcutaneous delivery provides consistent weekly exposure with a half-life of approximately 168 hours — long enough for once-weekly dosing.

The Patient Compliance Problem

The main drawback of injections is adherence. Studies consistently show that patients dislike needles, and many skip doses or discontinue treatment. For chronic conditions requiring months or years of therapy — metabolic disease, growth hormone deficiency, osteoporosis — injection burden is a real clinical problem. This is the driving force behind research into every other delivery route on this list.

Oral Administration {#oral-administration}

Oral delivery is what patients want. It is also where peptide bioavailability hits its lowest point.

The Scale of the Problem

Unmodified peptides taken by mouth typically show bioavailability below 1-2%. With rare exceptions like cyclosporine (which benefits from unusual lipophilicity and a cyclic structure), the GI tract destroys or blocks nearly all of the administered dose (Frontiers in Nutrition, 2024).

Peptides face a multi-layered obstacle course in the gut:

  1. Stomach acid (pH 1-3) denatures many peptide structures
  2. Pepsin attacks peptide bonds in the stomach
  3. Pancreatic proteases (trypsin, chymotrypsin, elastase) continue degradation in the duodenum
  4. Brush border membrane enzymes add another layer of breakdown at the intestinal wall
  5. Mucus layer physically blocks large molecules from reaching epithelial cells
  6. Tight junctions between epithelial cells prevent paracellular transport
  7. First-pass metabolism in the liver degrades whatever small amount gets absorbed

Oral Semaglutide: The Proof of Concept

The most successful oral peptide to date is semaglutide (Rybelsus), approved by the FDA in 2019. It uses a permeation enhancer called SNAC (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate) to protect the peptide and promote absorption through the stomach lining.

Even with this technology, oral semaglutide's bioavailability is approximately 0.9% relative to subcutaneous injection (PMC, 2022). That means for every 14 mg tablet a patient swallows, about 0.13 mg actually reaches the bloodstream. The drug works because semaglutide is extraordinarily potent at GLP-1 receptors, so even that small absorbed fraction produces clinically meaningful effects.

The dosing requirements for oral semaglutide illustrate the constraint: patients must take it on an empty stomach, with no more than 120 mL of water, and wait at least 30 minutes before eating. Food or excess water significantly reduces absorption.

The Small-Molecule Alternative

Orforglipron, developed by Eli Lilly, sidesteps the peptide bioavailability problem entirely. It is an oral, non-peptide, small-molecule GLP-1 receptor agonist — meaning it activates the same receptor as semaglutide but is not a peptide at all. This gives it much higher oral bioavailability and eliminates food and water restrictions. Phase 3 ATTAIN-1 trial results published in the New England Journal of Medicine in 2025 showed body weight reductions of 7.5-11.2% at 72 weeks (NEJM, 2025).

Intranasal Delivery {#intranasal-delivery}

The nasal cavity offers a non-invasive route that bypasses first-pass metabolism and, for certain peptides, provides a direct pathway to the central nervous system.

Bioavailability Numbers

For most peptides, intranasal bioavailability remains below 5%. The nasal mucosa presents enzymatic barriers similar to (though less aggressive than) the GI tract, and the absorptive surface area is relatively small.

However, some peptides perform far better through this route. Selank, a synthetic peptide with a molecular weight of 751 Da, achieves 92.8% intranasal bioavailability with detectable blood levels within 30 seconds. This demonstrates that molecular weight, structure, and lipophilicity matter enormously for nasal absorption.

Preclinical Successes

Permeation enhancers can dramatically improve intranasal peptide delivery. In rat studies, parathyroid hormone (PTH 1-34) delivered intranasally with the surfactant Solutol HS15 achieved 78% relative bioavailability compared to subcutaneous injection (MDPI Pharmaceutics, 2019). Unfortunately, these preclinical numbers often do not translate well to humans, where the same PTH formulation showed disappointing results.

The Brain-Access Advantage

One unique property of intranasal delivery is the olfactory pathway. Some fraction of intranasally administered peptides can travel along olfactory nerve fibers to reach the brain directly, bypassing the blood-brain barrier. This makes the nasal route particularly interesting for neurological and cognitive applications, even when systemic bioavailability is low.

Pulmonary (Inhaled) Delivery {#pulmonary-inhaled-delivery}

The lungs offer a massive surface area for absorption — roughly 70-100 square meters in an adult — with thin epithelial membranes and extensive vascularization. These features make pulmonary delivery attractive for systemic peptide therapy.

What the Research Shows

Inhaled peptide bioavailability typically ranges from 10% to 50%, depending on the peptide, formulation, and delivery device (Springer Nature, 2022). This is substantially better than oral or intranasal routes but still well below injectable delivery.

Insulin (Exubera, Afrezza): Pfizer's Exubera, the first inhaled insulin product, achieved bioavailability of 10-20% relative to subcutaneous injection. It was withdrawn in 2007 not because it did not work, but because the bulky inhaler device, higher cost, and physician concerns about lung safety limited adoption. Mannkind's Afrezza, using a simpler dry powder inhaler, remains on the market and provides rapid onset of action.

Calcitonin: Salmon calcitonin delivered via inhaled dry powder formulations has shown 28% bioavailability relative to intramuscular injection, with 66% of bioactivity retained. When calcitonin-loaded nanoparticles (thiolated glycol chitosan) are used, pharmacological availability after pulmonary delivery reaches 40-65% (PMC, 2022).

Barriers in the Lungs

Despite the large surface area, several mechanisms limit pulmonary peptide absorption:

  • Mucociliary clearance physically removes particles from the airways
  • Alveolar macrophages engulf and degrade foreign particles
  • Pulmonary surfactant can adsorb peptides and reduce their availability
  • Enzymatic degradation, while less severe than the GI tract, still occurs

Absorption enhancers like DPPC (dipalmitoylphosphatidylcholine) and DSPE-PEG polymers have shown 1.8- to 3-fold improvements in pulmonary bioavailability for peptides like parathyroid hormone and calcitonin.

Transdermal and Microneedle Delivery {#transdermal-and-microneedle-delivery}

Conventional transdermal delivery (patches, creams, gels) is essentially impossible for peptides. The skin's outer layer — the stratum corneum — blocks molecules larger than about 500 Da, and most therapeutic peptides are far larger. But microneedle technology changes this equation.

How Microneedles Work

Microneedle patches contain arrays of microscopic needles (25-2,000 micrometers long) that painlessly penetrate the stratum corneum without reaching pain receptors in deeper skin layers. They can be solid (coated with drug), dissolving (made from drug-polymer mixtures), hollow (injecting liquid), or hydrogel-forming (PMC, 2021).

Bioavailability Results

Preclinical results have been impressive:

PeptideMicroneedle TypeBioavailability (Relative to SC)Source
Parathyroid hormoneDissolving MN patch100 +/- 4%Naito et al.
Peptide A (undisclosed)Coated solid MN74-88%Coated sMTS study
Liraglutide (GLP-1 agonist)Dissolving MN (pure drug tips)69.8% (rats), 46.3% (minipigs)PubMed, 2024

The liraglutide microneedle study is particularly notable. Researchers packed up to 2.21 mg of pure liraglutide into needle tips on a 0.9 cm-square patch — nearly 100 times more drug than conventional microneedle patches of the same size. The patch produced anti-hyperglycemic effects comparable to subcutaneous injection in diabetic rats, with no skin irritation beyond mild redness.

What Is Missing

Despite the promising data, no microneedle peptide product has reached the market. Key challenges include limited drug-loading capacity, manufacturing consistency at scale, and the need for more large-animal and human pharmacokinetic studies. Most clinical trials of microneedle devices to date have focused on vaccines and insulin rather than broader peptide therapeutics.

Buccal and Sublingual Delivery {#buccal-and-sublingual-delivery}

The mouth's inner lining — buccal mucosa (cheek) and sublingual mucosa (under the tongue) — provides a vascularized, non-invasive route that avoids first-pass metabolism. In theory, this should be a good option for peptide delivery.

In practice, bioavailability for peptides through these routes remains around 1-2% without enhancement strategies (MDPI Biomedicines, 2025).

Why Buccal and Sublingual Fall Short

  • Saliva washout continuously dilutes drug concentration at the absorption site
  • Involuntary swallowing removes the dosage form before absorption is complete
  • Tight epithelial barrier with organized lipid layers resists peptide passage
  • Enzymatic activity in oral tissues degrades peptides, though less aggressively than the GI tract

Sublingual vs. Buccal

The two sites are not interchangeable. Sublingual delivery offers faster absorption and better bioavailability for small molecules, but the constant saliva flow makes it poorly suited for sustained-release systems. Buccal delivery is slower but more amenable to adhesive patches or films that keep the peptide in contact with the mucosa for longer periods.

Research using mucoadhesive films, chitosan-coated liposomes, and niosomes has shown improved results for peptides like salmon calcitonin, but human bioavailability data remain limited.

Chemical Modifications That Improve Bioavailability {#chemical-modifications-that-improve-bioavailability}

Beyond choosing a delivery route, researchers can modify the peptide itself to improve its pharmacokinetic profile. Two strategies dominate the field.

PEGylation

Attaching polyethylene glycol (PEG) chains to a peptide increases its effective size, reducing renal clearance and protecting against enzymatic breakdown. PEGylation has produced more clinically approved long-acting biologics than any other half-life extension technology (ACS Medicinal Chemistry Letters, 2018).

The downsides: PEGylation can reduce receptor binding and bioactivity, and concerns about PEG accumulation and anti-PEG antibodies have emerged with long-term use.

Lipidation

Lipidation — attaching a fatty acid chain to a peptide — takes a different approach. The lipid moiety is small, but it binds non-covalently to circulating albumin (a 67 kDa protein with a 19-day half-life). This effectively hitchhikes the peptide on the body's own transport system, shielding it from degradation and slowing renal filtration.

Lipidation produced several blockbuster drugs. Semaglutide (Ozempic, Wegovy, Rybelsus), liraglutide (Victoza, Saxenda), and tirzepatide (Mounjaro, Zepbound) are all lipidated peptides. Semaglutide's lipid modification enables a plasma half-life of approximately one week — long enough for weekly dosing — whether delivered by injection or orally.

Other Approaches

  • Fc fusion: Linking a peptide to the Fc region of an antibody borrows the antibody's long half-life (about 21 days for IgG)
  • Cyclization: Constraining a peptide's structure reduces protease susceptibility and can improve membrane permeability
  • D-amino acid substitution: Replacing natural L-amino acids with their mirror-image D-forms makes peptides resistant to most proteases
  • Glycosylation: Adding sugar molecules can improve stability, solubility, and pharmacokinetics

Nanoparticle and Lipid-Based Delivery Systems {#nanoparticle-and-lipid-based-delivery-systems}

Nanocarrier systems attempt to solve the bioavailability problem by packaging peptides inside protective shells that resist degradation, improve membrane crossing, and release their cargo at the right time and place.

Lipid Nanoparticles

These include solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), liposomes, and lipid-polymer hybrid nanoparticles. Lipid carriers can protect peptides from enzymatic breakdown while improving intestinal absorption (PMC, 2024).

Self-emulsifying drug delivery systems (SEDDS/SNEDDS) — mixtures that spontaneously form nanoemulsions when mixed with GI fluids — show particular promise. The lipophilic environment of these carriers makes them inaccessible to digestive enzymes. Cyclosporine (Neoral) is the most commercially successful example, using a microemulsion preconcentrate to achieve consistent oral absorption.

For insulin, PEG-free SEDDS formulations have achieved oral bioavailability of approximately 2.1% — modest, but more than double the PEG-based alternative (1.15%) in head-to-head testing (PubMed, 2024).

Polymer Nanoparticles

Polymers like PLGA (poly lactic-co-glycolic acid), polycaprolactone, and chitosan can form nanoparticles that protect peptide cargo and improve absorption. Cell-penetrating peptide (CPP)-functionalized liposomes have shown substantially increased oral bioavailability for vancomycin in rat studies.

The Translation Gap

The recurring problem with nanoparticle delivery is the gap between preclinical promise and clinical reality. Even with advanced systems, achieving more than 1% oral bioavailability for peptides remains a significant hurdle in human studies. Scalable manufacturing, batch-to-batch consistency, and the unpredictable effects of food on absorption all complicate development.

FAQ {#faq}

Why can't peptides just be taken as pills like regular drugs?

Most pills contain small molecules (under 500 Da) that are lipophilic enough to cross intestinal membranes and stable enough to survive stomach acid and digestive enzymes. Peptides are larger, water-loving, and fragile. The GI tract treats them like food — breaking them down rather than absorbing them intact. Technologies like permeation enhancers and nanoparticle carriers are attempting to change this, but achieving meaningful oral bioavailability remains difficult.

If oral semaglutide has less than 1% bioavailability, how does it work?

Semaglutide is exceptionally potent at the GLP-1 receptor. Even the small fraction that gets absorbed produces clinically significant effects on blood sugar and body weight. The oral dose (up to 14 mg) is roughly 100 times larger than the injectable dose (0.25-1 mg once weekly), compensating for the low absorption. The drug also has a long half-life (about one week) due to lipidation and albumin binding, so it accumulates with daily dosing.

Are microneedle patches available for peptide delivery?

Not yet commercially. While preclinical research shows bioavailability rivaling subcutaneous injection for several peptides, no microneedle peptide product has been approved. Clinical trials are ongoing, primarily for insulin and vaccines. The technology is considered one of the most promising near-term alternatives to injection.

Which delivery route is best for peptides targeting the brain?

Intranasal delivery has a unique advantage here. Some fraction of nasally administered peptides can travel along olfactory nerve fibers directly to the brain, bypassing the blood-brain barrier. While systemic bioavailability through the nose is generally low, this nose-to-brain pathway can deliver meaningful concentrations to central nervous system targets.

How do BPC-157 and similar research peptides relate to these bioavailability challenges?

Research peptides like BPC-157 face the same barriers as any other peptide. Oral bioavailability estimates for BPC-157 are in the 1-2% range. Some researchers and clinicians prefer subcutaneous injection for this reason, while others use oral or sublingual administration at higher doses. The bioavailability research discussed in this article applies broadly across peptide therapeutics.

The Bottom Line {#the-bottom-line}

Peptide bioavailability is not a single number — it is a function of the delivery route, the peptide's properties, and the formulation technology used. Subcutaneous injection remains the most reliable method, delivering 50-95% of the dose to the bloodstream. Everything else involves trade-offs between convenience and absorption.

The oral route, which patients overwhelmingly prefer, delivers the least — typically below 1% for unmodified peptides. But this is not a dead end. Oral semaglutide proved that even sub-1% bioavailability can be clinically useful if the peptide is potent enough. And small-molecule mimics like orforglipron sidestep the peptide bioavailability problem entirely.

Microneedle patches, pulmonary delivery, and advanced nanocarrier systems all show substantial improvements over oral delivery while maintaining non-invasive or minimally invasive administration. The next decade will likely see the first commercial microneedle peptide products and continued expansion of oral formulation technologies.

For clinicians and patients choosing between delivery methods, the core question remains: how much drug needs to reach the bloodstream, and what trade-offs are acceptable to get it there?

References {#references}

  1. Li, J., et al. "Advance in peptide-based drug development: delivery platforms, therapeutics and vaccines." Signal Transduction and Targeted Therapy, 10, 74 (2025). https://www.nature.com/articles/s41392-024-02107-5

  2. Drucker, D.J. "A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes." Therapeutic Advances in Endocrinology and Metabolism, 13 (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9515042/

  3. Abdelkader, H., et al. "Barriers and Strategies for Oral Peptide and Protein Therapeutics Delivery: Update on Clinical Advances." Pharmaceutics, 17(4), 397 (2025). https://pmc.ncbi.nlm.nih.gov/articles/PMC12030352/

  4. Jorgensen, J.R., et al. "Recent advances in microneedles-mediated transdermal delivery of protein and peptide drugs." Acta Pharmaceutica Sinica B, 11(8), 2137-2156 (2021). https://pmc.ncbi.nlm.nih.gov/articles/PMC8424228/

  5. Li, H., et al. "Challenges and Strategies to Enhance the Systemic Absorption of Inhaled Peptides and Proteins." Pharmaceutical Research, 40, 1037-1055 (2022). https://pmc.ncbi.nlm.nih.gov/articles/PMC9668393/

  6. Brayden, D.J., et al. "Current Understanding of Sodium N-(8-[2-Hydroxylbenzoyl] Amino) Caprylate (SNAC) as an Absorption Enhancer." Molecular Pharmaceutics, 21(1), 1-14 (2024). https://pmc.ncbi.nlm.nih.gov/articles/PMC10788673/

  7. Vargason, A.M., et al. "Just How Prevalent are Peptide Therapeutic Products? A Critical Review." AAPS Journal, 25(6), 97 (2023). https://pmc.ncbi.nlm.nih.gov/articles/PMC10655677/

  8. Zizzari, A.T., et al. "Lipidation and PEGylation Strategies to Prolong the in Vivo Half-Life of a Nanomolar EphA4 Receptor Antagonist." ACS Medicinal Chemistry Letters (2024). https://pmc.ncbi.nlm.nih.gov/articles/PMC10959496/