Simulaite Report

This report compares the oral bioavailability of CBD and CBN across 7 delivery formulations — buccal strips, sublingual strips, sublingual tincture, oral tincture, and gummies — at 25 mg dose per compound, using the Simulaite

PBPK engine on a virtual population of n=100 American individuals under both fasted and fed conditions. The simulation reveals dramatic differences between delivery routes — from <2% for swallowed formats (oral tincture, gummy) to >79% for ideal-patient buccal strips — driven by first-pass metabolism bypass, mucosal absorption kinetics, and food effects.

• Buccal strips achieve 22-78% CBD bioavailability (depending on patient swallowing) — significantly higher than oral formats

Key Takeaways

(gummy, tincture) which deliver <2% when administered non-sublingually and while fasted

• For transmucosal routes (buccal/sublingual), CBN outperforms CBD by 8-16% — but for swallowed routes, CBD actually does better than CBN (e.g., 1.3% vs 0.3% for gummy)
• Patients should minimize swallowing during strip dissolution — natural swallowing drops bioavailability about 4× (from 78% to 22%) as drug is lost to GI tract before full mucosal absorption
• Sublingual underperforms buccal by ~32-47% (depending on patient swallowing) — smaller surface area (10 vs 14 cm²) and higher salivary flow
• Food intake dramatically boosts oral formats: 4.8× improvement for tincture (1.1% to 5.5% CBD) and 3.4× for gummy (1.3% to 4.3% CBD) — lipids stimulate lymphatic transport and slow GI transit
• Fed vs fasted makes little difference for transmucosal routes — absorption happens before swallowing, so first-pass bypass is already achieved

CBD and CBN are highly lipophilic phytocannabinoids derived from cannabis. Both compounds are significantly metabolized by CYP and UGT enzymes warranting transmucosal delivery to bypass first-pass metabolism. Their lipophilicity enables lymphatic transport with specialized delivery systems and/or having a fat-heavy meal while taking them. We use our suite of graph neural networks to predict relevant molecular properties and interactions with liver enzymes, plasma proteins, and the gut wall to inform the simulations.

1. Buccal Strip

Delivery Type

Oral Fast-Dissolving Strip

Route

Buccal (cheek)

Surface Area

3.5 × 4 cm (14 cm²)

Dissolve Time

~30 min

Dose per Compound

25 mg

Lipid Excipient

None (polymer matrix)

Patient Type

Standard (includes natural swallowing)

2. Sublingual Strip

Delivery Type

Oral Fast-Dissolving Strip

Route

Sublingual (under tongue)

Surface Area

2.5 × 4 cm (10 cm²)

Dissolve Time

~20 min

Dose per Compound

25 mg

Lipid Excipient

None (polymer matrix)

Patient Type

Standard (includes natural swallowing)

3. Buccal Strip — Ideal Patient

Delivery Type

Oral Fast-Dissolving Strip

Route

Buccal (cheek)

Surface Area

3.5 × 4 cm (14 cm²)

Dissolve Time

~30 min

Dose per Compound

25 mg

Lipid Excipient

None (polymer matrix)

Patient Type

Ideal (refrains from swallowing)

4. Sublingual Strip — Ideal Patient

Delivery Type

Oral Fast-Dissolving Strip

Route

Sublingual (under tongue)

Surface Area

2.5 × 4 cm (10 cm²)

Dissolve Time

~20 min

Dose per Compound

25 mg

Lipid Excipient

None (polymer matrix)

Patient Type

Ideal (refrains from swallowing)

5. Oral MCT Tincture

Delivery Type

Liquid Tincture

Route

Oral (swallowed)

Volume

1 mL

Dose per Compound

25 mg

Lipid Excipient

MCT Oil

Administration

Swallowed immediately

6. Sublingual MCT Tincture

Delivery Type

Liquid Tincture

Route

Sublingual hold then swallow

Volume

1 mL

Dose per Compound

25 mg

Lipid Excipient

MCT Oil

Hold Time

1.5 min (90 sec)

7. MCT + Lecithin Gummy

Delivery Type

Solid Gummy

Route

Oral (swallowed)

Weight

~3 g

Dose per Compound

25 mg

Lipid Excipient

MCT Oil + Lecithin

Release Profile

Gradual release over ~45 min

A virtual population of 100 American individuals was generated using population physiology from pharmaceutical databases. Each individual has unique organ volumes, blood flows, and enzyme expression levels derived from clinical datasets, capturing inter-individual variability in absorption, distribution, and clearance. Both fasted and fed states were simulated to assess the impact of food on bioavailability.

Bioavailability (F%) Comparison

Absolute bioavailability (F%) for each formulation under fasted and fed conditions, computed as: F% = AUC(oral or transmucosal) / AUC(IV bolus)

× 100. The IV bolus serves as the 100% reference — it bypasses all absorption barriers and delivers drug directly to systemic circulation.

AUC (ng/mL·h) — Fasted State

AUC captures the clinically relevant inter-individual variability — driven by differences in clearance, volume of distribution, and (for oral routes) GI

absorption. CV% reflects real patient-to-patient exposure differences.

Absorption Pathway Breakdown — Transmucosal Formulations (Fasted)

In standard patients, natural swallowing during strip dissolution significantly increases the swallowed fraction (drug lost to GI tract before full mucosal absorption). In ideal patients, only passive salivary flow contributes to swallowing, resulting in minimal loss.

Absorbed = drug reaching systemic circulation via oral mucosa (bypasses first-pass). Swallowed = drug lost to GI tract before mucosal absorption.

Plasma Concentration–Time Profiles

Median plasma concentration–time profiles (P5–P95 shaded), fasted (solid) and fed (dashed), n=100.

CYP and UGT enzyme contributions to total intrinsic clearance, plus P-glycoprotein efflux substrate status. Values are compound properties derived from GNN predictions and integrated into the PBPK simulation. Substrate and inhibition magnitude is applied during simulation (not shown).

Substrate Profile — Enzymes & Transporters

Intrinsic clearance (CLint) fractions per compound. Bold teal = dominant clearance enzyme.

Metabolic Insights

• UGT1A1 glucuronidation is the dominant clearance pathway for both CBD (41.4%) and CBN (43.6%) — consistent with extensive Phase II conjugation of cannabinoids.
• CYP3A4 is the dominant CYP pathway for both (CBD: 28.3%, CBN: 26.8%). CYP2D6 is a consistent secondary pathway

(CBD: 18.8%, CBN: 17.2%).

• SULT1A1 contribution is 0% for both compounds — sulfation is not a significant pathway for cannabinoids at these doses.

GNN predictions for enzyme inhibition. Inhibition magnitude is also predicted by our GNN suite and applied during simulation (not shown). CBD inhibits CYP3A4 and CYP2C9; CBN inhibits a broader panel including CYP1A2, CYP3A4, CYP2D6, CYP2C9, and CYP2C19. MCT Oil (excipient in tincture/gummy formulations) provides additional CYP3A4 inhibition at gut-wall concentrations.

Inhibition Profile — Enzymes & Transporters

Both CBD and CBN inhibit CYP3A4 and CYP2C9 — clinically relevant for co-administration with statins, warfarin, immunosuppressants, and other CYP3A4/2C9 substrates. CBN additionally inhibits CYP1A2, CYP2D6, and CYP2C19 with high probability, giving it a broader DDI risk profile.

Our simulation results are contextualized against published clinical studies examining CBD bioavailability across different delivery routes and prandial states.

1. CURE Pharmaceutical OTF Study (2022)

Source: CURE Pharmaceutical OTF Study — worldpharmatoday.com/news/cure-pharmaceutical-cbd-oral-thin-film- pharmacokinetic-study-shows-improved-bioavailability-compared-to-cbd-soft-gel/. CBD Oral Thin Film (OTF) pharmacokinetic study. CUREform™ delivery platform (solubilization + encapsulation). 25 mg CBD OTF vs 25 mg CBD soft gel in 14 healthy adults.

Relevance

Our buccal/sublingual strip delivery is mechanistically similar to OTF (oral transmucosal). Both show improved bioavailability

vs swallowed formulations. The CURE study confirms that transmucosal delivery of CBD achieves significantly higher Cmax and faster Tmax than soft gel — consistent with our simulation showing 21.5% F for buccal strip vs 1.1% for oral tincture.

2. Della Rocca et al. (2022) — Oral vs OTM in Dogs

Source: Della Rocca et al. (2022) — https://doi.org/10.3389/fvets.2022.1104152 CBD 1 mg/kg oral vs oral transmucosal (OTM) in 12 dogs. Result: Cmax ~207 ng/mL (oral) vs ~200 ng/mL (OTM), Tmax ~2.2h vs ~1.9h — no significant difference.

Relevance to Our Simulation

• The dog study found no OTM benefit — consistent with our simulation showing that when swallowing is not controlled, sublingual bioavailability approaches oral levels.

3. Saals et al. (2025) — High-Fat Meal Effect

Source: Saals et al. (2025) — https://doi.org/10.1038/s41598-025-87621-4 Single oral dose CBD-rich extract (70 mg CBD equivalent). High-fat meal vs fasting in 11 healthy participants. Fed/Fasted Cmax ratio: 17.4× (90% CI 12.4–24.2). Fed/Fasted

AUC ratio: 9.7× (90% CI 7.7–12.3).

Comparison to Our Simulation

• Our PBPK simulation shows a 4.8× fed/fasted ratio for CBD oral tincture and 3.4× for gummy — similar magnitude to the 9.7× AUC increase observed clinically (capsule format).
• The clinical study used a high-fat meal (55-65g fat) while our simulation uses 30g fat. Despite this difference, both show substantial fed-state enhancement, demonstrating the powerful effect of fat on cannabinoid bioavailability.
• The fed-state enhancement is driven by lymphatic transport and increased bile salt solubilization — mechanisms captured in our PBPK model.