Routes of Administration: Subcutaneous vs Intramuscular vs Intranasal

The short version

The route of administration is the path a drug takes from outside the body to the systemic circulation. It determines how quickly the drug is absorbed, how much of the dose reaches the blood intact, and how practical the treatment is for the patient and clinician.

For peptides, the choice of route is constrained. The oral route digests most peptides before they can be absorbed. The result is that subcutaneous injection is the default delivery method for nearly all approved peptide therapeutics, from insulin to GLP-1 receptor agonists to somatostatin analogs. Intranasal delivery works for a small number of peptides. Oral delivery has been achieved for semaglutide using a specialized absorption enhancer but remains the exception rather than the rule.

Subcutaneous injection

Subcutaneous (SC) injection delivers a drug into the layer of adipose tissue directly beneath the skin. This is the most common route for therapeutic peptides because it bypasses the gastrointestinal tract, avoids hepatic first-pass metabolism (drugs absorbed subcutaneously enter the peripheral circulation, not the portal blood), and is generally well tolerated when technique is correct.^[1]

Depot formation and absorption kinetics

After SC injection, the drug forms a small depot at the injection site. Absorption into the systemic circulation occurs by diffusion through the interstitial fluid and capillary uptake, and is slower than intramuscular or intravenous administration. This slower absorption smooths the peak concentration and contributes to a less pronounced Cmax compared with IM injection of the same dose.

For most approved peptide therapeutics, SC bioavailability ranges from 50% to 90%. Semaglutide achieves approximately 89% SC bioavailability, largely because its albumin binding via the fatty diacid chain protects it from local proteases and extends its residence at the injection site before systemic uptake.^[3]Tirzepatide achieves approximately 80% SC bioavailability through analogous mechanisms.^[4]

Injection sites

Common SC injection sites for peptide therapeutics are:

• Abdomen (preferred for most peptides, typically 2-3 cm from the navel)
• Upper outer thigh
• Outer upper arm
• Upper buttock (less common)

Rotating injection sites prevents lipohypertrophy, a localized buildup of adipose tissue from repeated injections in the same spot that can alter absorption unpredictably. Blood flow to the injection site affects absorption rate: exercise increases blood flow and can accelerate absorption, as can warm environments.

Technique and patient preference

Modern auto-injector pens and prefilled syringes have simplified SC self-administration. Pen devices for GLP-1 receptor agonists (for example, the Ozempic and Victoza pens) use very fine needles (typically 4-8 mm, 29-32 gauge) and are widely accepted by patients. Injection-site reactions (local redness, swelling, bruising) are common but usually transient and mild. A small proportion of patients experience persistent injection-site discomfort that influences adherence.

Intramuscular injection

Intramuscular (IM) injection delivers the drug into skeletal muscle. Muscle tissue is more vascular than subcutaneous fat, and the rich capillary network allows faster absorption and a higher Cmax for many drugs.^[2]For peptides, IM injection produces faster absorption onset than SC but is not commonly used as the standard delivery route for therapeutic peptides.

Common IM injection sites are the deltoid (upper arm), vastus lateralis (outer thigh), and gluteal muscles. Needles are longer (typically 16-38 mm) and larger gauge than SC needles, which makes the injection more uncomfortable. IM injections also carry a small risk of inadvertent intravascular injection if vein or artery is entered.

Among approved peptide therapeutics, IM injection is used for certain depot formulations (for example, long-acting octreotide LAR, the depot somatostatin analog) where the drug is embedded in a microsphere formulation that releases slowly from the injection site over weeks. In these cases, the IM route provides a stable injection site in well-perfused muscle; the dose is absorbed from the depot rather than acutely from the injection.

Intranasal delivery

The nasal mucosa is highly vascularized and lacks the acid/protease environment of the stomach, making it an attractive alternative route for small peptides. Drugs absorbed through the nasal mucosa enter the systemic circulation directly (via nasal veins draining to the systemic venous system), bypassing hepatic first-pass metabolism.^[6]

The limitations of intranasal delivery are significant:

• Molecular weight limit. The nasal epithelium is more permeable than the intestinal epithelium, but permeability still falls sharply above approximately 1,000 Da. This restricts intranasal delivery to relatively small peptides. Most GLP-1 receptor agonists (semaglutide is approximately 4,114 Da; liraglutide approximately 3,751 Da) are too large for practical intranasal absorption without absorption enhancers.
• Mucociliary clearance. The nasal mucosa is continuously swept clean by the mucociliary apparatus, moving deposited material toward the nasopharynx and eventual swallowing. The contact time between a nasal spray and the absorption surface is short (typically 15-30 minutes), which limits the dose that can be absorbed.
• Volume limitation. Nasal sprays typically deliver 50-200 microliters per nostril. This limits the dose that can be given and makes the route unsuitable for compounds requiring large doses.
• Variable bioavailability. Intranasal bioavailability for therapeutic peptides is typically 5-20%, but varies substantially with nasal congestion, formulation, technique, and individual anatomy.^[6]

Approved examples

Two approved peptide therapeutics illustrate the scope of intranasal delivery:

• Calcitonin nasal spray (Miacalcin). Salmon calcitonin is a 32-amino acid peptide (approximately 3,432 Da) used for postmenopausal osteoporosis. It is available as a nasal spray at 200 IU per actuation. Intranasal bioavailability is approximately 3-5% relative to SC administration, but calcitonin has a wide therapeutic margin and the intranasal route is adequate for the modest doses needed.^[7]
• Desmopressin nasal spray (DDAVP). Desmopressin is a synthetic analog of arginine vasopressin, a 9-amino acid peptide used for central diabetes insipidus and nocturnal enuresis. It is available as both intranasal solution and nasal spray. Intranasal bioavailability is approximately 10-20%, and the route is effective because very small doses (micrograms) are pharmacologically active.^[8]

Both examples share a feature: the peptide is small (fewer than 35 residues) and is active at very low plasma concentrations, making the modest bioavailability of intranasal delivery acceptable.

Oral delivery

Oral delivery is the preferred route for most drugs because it is convenient, painless, and compatible with self-administration. For peptides, it is the most technically challenging route because the gastrointestinal tract is designed to digest peptides.

The barriers to oral peptide absorption are gastric acid and pepsin in the stomach, pancreatic and brush-border proteases in the small intestine, and the relatively impermeable intestinal epithelium. Native peptides typically achieve oral bioavailability below 1-2%.^[1]

The most clinically significant exception is oral semaglutide (Rybelsus). The SNAC absorption enhancer co-formulated with semaglutide creates a localized alkaline microenvironment in the stomach that suppresses pepsin and transiently increases gastric mucosal permeability, enabling transcellular absorption. The resulting absolute bioavailability is approximately 1%. While this sounds low, it is sufficient because the oral doses (3-14 mg) are calibrated to this low F, producing plasma exposures comparable to the subcutaneous formulation at its therapeutic doses.^[5]

Oral semaglutide requires specific dosing conditions: empty stomach, limited water (120 mL), upright position, 30-minute wait before eating. These requirements reflect the sensitivity of the SNAC mechanism to gastric contents. A meal or even a larger volume of water dilutes SNAC and reduces the local pH effect, substantially reducing absorption.

Inhaled and transdermal delivery

Inhaled

Inhalation delivers drug to the pulmonary alveoli, which have an enormous surface area (~100 m² in adults), thin epithelium, and high blood flow. In principle, this should make inhalation an effective route for peptide absorption. In practice, only one approved peptide therapeutic uses the inhaled route: Afrezza, an inhaled insulin product (technosphere insulin) approved by the FDA in 2014.

Afrezza uses a dry-powder formulation that deposits insulin in the deep lung, achieving a very rapid onset of action (peak insulin levels within 12-15 minutes vs 50-90 minutes for SC rapid-acting insulin analogs). Bioavailability is approximately 21-26% relative to SC insulin. The route requires specialized inhalation devices, patient training, and pulmonary function monitoring.

Pulmonary delivery of other peptides has been studied but has not produced additional approved products. Challenges include variability in deposition (affected by breathing technique, disease state, and device characteristics) and the potential for local pulmonary effects with chronic use.

Transdermal

The skin is designed to exclude foreign molecules. The stratum corneum (the outermost epidermal layer) is a highly effective barrier. Small, lipophilic molecules can cross it (nicotine patches, fentanyl patches), but peptides are too large and too hydrophilic for passive transdermal diffusion.

Enhancement strategies including microneedles (arrays of microscopic needles that pierce the stratum corneum without reaching nerve endings), iontophoresis (electrical current to drive charged molecules across the skin), and sonophoresis (ultrasound to disrupt the skin barrier) have been studied for peptide delivery but none has reached broad clinical use for systemic peptide delivery. Transdermal delivery remains niche for peptides.

How route choice influences clinical use and patient preference

Route of administration is not purely a pharmacokinetic decision. Patient acceptance, adherence, and practical feasibility all matter.

• Needle aversion. A meaningful fraction of patients have needle aversion or anxiety. For long-term treatments such as GLP-1 receptor agonists, this can affect whether patients start therapy, adhere to it, or prefer an oral formulation despite the dosing restrictions it requires.
• Dosing frequency. Routes that support longer dosing intervals (once weekly SC, once monthly IM depot) improve adherence for chronic conditions compared with daily or twice-daily dosing.
• Training and error rates. SC injections are straightforward to learn, but errors in technique (injecting into muscle instead of subcutaneous tissue, not rotating sites, poor storage of temperature-sensitive peptides) alter absorption and can produce unexpected results.
• Pharmacokinetic consequences of route error. A dose intended subcutaneously that inadvertently enters muscle can absorb faster and produce a higher Cmax than expected, potentially intensifying side effects. This is particularly relevant for insulin, where timing of peak exposure relative to meals is critical.
• Storage and handling. Most peptide injectables require refrigeration (2-8 degrees C) until first use. This limits accessibility in resource-limited settings and complicates travel. Thermostable formulations and oral alternatives reduce this barrier.

Summary

Subcutaneous injection is the most common route for peptide therapeutics because it avoids gastrointestinal degradation, bypasses first-pass metabolism, achieves bioavailability of 50-89% for most engineered peptides, and supports self-administration with modern auto-injector devices. Intramuscular injection is faster-absorbing but less comfortable, and is mainly used for depot formulations of longer-acting peptides.

Intranasal delivery is practical only for small peptides active at very low doses; calcitonin and desmopressin are the clearest approved examples. Oral delivery for native peptides is blocked by gastrointestinal digestion, but the SNAC-enabled formulation of oral semaglutide demonstrates that engineered solutions can achieve clinically meaningful absorption at approximately 1% bioavailability when doses are calibrated accordingly. Inhaled delivery works for insulin, and transdermal delivery for peptides remains in early development.

Route choice is determined by the interplay of pharmacokinetics (bioavailability, absorption rate, dose requirements), practical factors (patient preference, dosing frequency, storage), and clinical context (whether rapid onset matters, whether self-administration is feasible, whether injection-site effects are acceptable).