SGL — 001 / Formulation

The design space

What was compared, what was chosen, and what the choice costs. 2 higher-scoring benchmarks sit in the comparison and were not adopted. 6 of 15 excipients under consideration have no intranasal precedent — marked in amber.

§ 01 — Actives

Four axes, each scored to 5, ranked by total. The declared focus is not the highest scorer; the benchmarks that outscore it are kept in view rather than dropped. Expand a candidate for the note behind its score.

Intranasal insulin

20/20

Mechanism 5 of 5, Evidence 5 of 5, Manufacturability 5 of 5, Regulatory 5 of 5. Total 20 of 20. benchmark.

Intranasal oxytocin

17/20

Mechanism 5 of 5, Evidence 3 of 5, Manufacturability 5 of 5, Regulatory 4 of 5. Total 17 of 20. benchmark.

NAD⁺ precursors (NMN, nicotinamide riboside)

12/20

Mechanism 3 of 5, Evidence 2 of 5, Manufacturability 5 of 5, Regulatory 2 of 5. Total 12 of 20. excluded.

MSC secretome / conditioned medium (cell-free)

8/20

Mechanism 2 of 5, Evidence 2 of 5, Manufacturability 2 of 5, Regulatory 2 of 5. Total 8 of 20. focus.

Naive/unmodified MSC- or adipose-derived exosomes (EVs)

7/20

Mechanism 1 of 5, Evidence 2 of 5, Manufacturability 2 of 5, Regulatory 2 of 5. Total 7 of 20. excluded.

Engineered or cargo-loaded EVs (e.g. miRNA-, BDNF-, or drug-loaded exosomes)

4/20

Mechanism 2 of 5, Evidence 0 of 5, Manufacturability 1 of 5, Regulatory 1 of 5. Total 4 of 20. excluded.

excludedfocusbenchmark
Naive/unmodified MSC- or adipose-derived exosomes (EVs)exosomeexcluded7/20MechanismEvidenceManufacturabilityRegulatory

A purified/isolated exosome preparation is mechanistically the cleanest option but cost-prohibitive to purify at nasal-spray scale. The secretome retains this fraction without the purification cost.

Engineered or cargo-loaded EVs (e.g. miRNA-, BDNF-, or drug-loaded exosomes)exosomeexcluded4/20MechanismEvidenceManufacturabilityRegulatory

Excluded for now — zero human intranasal precedent, rodent/in vitro models only. Inherits naive EVs' undefined delivery mechanism plus an unvalidated loading step, with no regulatory precedent for the combination-product question.

MSC secretome / conditioned medium (cell-free)secretomefocus8/20MechanismEvidenceManufacturabilityRegulatory

Intended active is the exosome fraction of the secretome. Full exosome purification is cost-prohibitive at consumer nasal-spray scale, so the product is unpurified MSC secretome that retains the exosome fraction rather than a purified isolate. Remaining secretome components (soluble growth factors and cytokines) may contribute additively; this is not established and is not relied on for the core mechanism.

Intranasal insulinpeptidebenchmark20/20MechanismEvidenceManufacturabilityRegulatory

Highest four-axis score of any candidate compared — tracked as a benchmark, not adopted. Not a regenerative/tissue-repair active; would not support the focus candidate's mechanistic framing. SNIFF (NCT01767909), n≈240, RCT, 12 months, in the target population (MCI/Alzheimer's).

Intranasal oxytocinpeptidebenchmark17/20MechanismEvidenceManufacturabilityRegulatory

Exceeds the focus candidate on mechanism, manufacturability, and regulatory tractability — tracked as a benchmark, not adopted. Evidence is the most genuinely mixed in the comparison: a well-run RCT (NEJM 2021) found no significant cognitive/social effect.

NAD⁺ precursors (NMN, nicotinamide riboside)small-moleculeexcluded12/20MechanismEvidenceManufacturabilityRegulatory

Excluded — its one strong axis (manufacturability, as an unregulated supplement) evaporates once a cognitive-function disease claim forces reclassification as a drug. No intranasal human trial of any kind was found; oral cognitive evidence is itself weak or null.

§ 02 — Excipient map

Select a function to isolate the candidates for that role; entries with no nasal-route precedent carry the regulatory risk. Expand an entry for its precedent and tradeoff.

00112233nasal-route precedent →EV-stability evidence →Monobasic potassium phosphate / dibasic sodium phosphate — precedent 3, EV-stability 2Monobasic potassium phosphate / dibasic sodium phosphateSodium chloride — precedent 3, EV-stability 1Sodium chlorideTrehalose (25 mM) — precedent 0, EV-stability 3Trehalose (25 mM)Mannitol — precedent 2, EV-stability 1MannitolHuman serum albumin (0.2%) — precedent 0, EV-stability 2Human serum albumin (0.2%)HEPES (25 mM) — precedent 0, EV-stability 2HEPES (25 mM)Sucrose (5%) — precedent 0, EV-stability 3Sucrose (5%)Poloxamer 188 (0.02%) — precedent 0, EV-stability 3Poloxamer 188 (0.02%)Polysorbate 80 (0.01% w/v) — precedent 2, EV-stability 1Polysorbate 80 (0.01% w/v)Hypromellose 2910 (5 mPa·s) — precedent 3, EV-stability 1Hypromellose 2910 (5 mPa·s)n-Dodecyl β-D-maltoside (DDM / Intravail) — precedent 3, EV-stability 0n-Dodecyl β-D-maltoside (DDM / Intravail)Chitosan — precedent 0, EV-stability 1ChitosanBenzalkonium chloride (BAC) — precedent 3, EV-stability 0Benzalkonium chloride (BAC)Plain PBS (as vehicle) — precedent 2, EV-stability 0Plain PBS (as vehicle)Citrate buffer — precedent 3, EV-stability 0Citrate buffer
chosencandidateruled-outno intranasal precedent

15 of 15

Monobasic potassium phosphate / dibasic sodium phosphatebufferchosen
Precedent
IID nasal MONOBASIC POTASSIUM PHOSPHATE; TOSYMRA (NDA 210884); SPRIX (NDA 022382)
Tradeoff
10 mM stays well below the ~0.13 M threshold where a buffer starts overriding nasal pH (Washington et al. 2000), but the molarity itself is transferred from a lyophilisate study, not derived for this product.
Sodium chloridetonicitychosen
Precedent
IID nasal SOLUTION 330 mg / LIQUID 7.4 mg/mL; TOSYMRA; calcitonin-salmon nasal spray
Tradeoff
Level is open pending the stabilizer decision, since the stabilizer itself contributes osmolality; counter-ion identity (Na⁺ vs K⁺) may matter more to vesicle stability than a tonicity calculation captures.
Trehalose (25 mM)stabilizercandidate! no intranasal precedent
Precedent
no precedent — regulatory risk (IID: intradermal, subcutaneous only; no nasal-route entry)
Tradeoff
Deepest EV-specific stabilization evidence of any excipient considered (Bosch 2016, Görgens 2022, Charoenviriyakul 2018), but would need a nasal-route safety qualification package.
Mannitolstabilizercandidate
Precedent
IID nasal SPRAY, 41.5 mg
Tradeoff
Only sugar/polyol with nasal precedent and a stated max potency, but a crystallizing bulking agent — a weaker lyoprotectant for a membrane particle than an amorphous disaccharide; no EV-specific data found.
Human serum albumin (0.2%)stabilizercandidate! no intranasal precedent
Precedent
no precedent — regulatory risk (IID: intravenous, oral only; no nasal-route entry)
Tradeoff
Suppresses the plastic-surface EV adsorption loss Görgens (2022) measured within minutes, but carries no nasal-route precedent at all.
HEPES (25 mM)buffercandidate! no intranasal precedent
Precedent
no precedent — regulatory risk (absent from the IID entirely, by any route)
Tradeoff
Buffer base of PBS-HAT, the lead published EV-stabilization buffer (Görgens 2022), but has no US excipient precedent whatsoever.
Sucrose (5%)stabilizercandidate! no intranasal precedent
Precedent
no precedent — regulatory risk (IID: 10 other routes incl. IV, ophthalmic, oral; no nasal-route entry)
Tradeoff
Improves EV colloidal stability on freeze-thaw and supports a lyophilisate stable 6 months at 40°C (Trenkenschuh 2022), but zero nasal-route precedent.
Poloxamer 188 (0.02%)stabilizercandidate! no intranasal precedent
Precedent
no precedent — regulatory risk (IID: 7 other routes incl. IV, ophthalmic, intratympanic; no nasal-route entry)
Tradeoff
The single most effective published EV colloidal-stability agent (Trenkenschuh 2022), but zero nasal-route precedent.
Polysorbate 80 (0.01% w/v)stabilizercandidate
Precedent
IID nasal SPRAY, METERED, 0.1 mg/1 mL
Tradeoff
The nasal-precedented stand-in for poloxamer 188, but its CMC is in the low micromolar range — even 0.01% sits above it, the same surfactant-above-CMC property that disqualified DDM, unmeasured against these vesicles.
Hypromellose 2910 (5 mPa·s)mucoadhesivecandidate
Precedent
IID nasal SPRAY/SPRAY METERED, 1 mg/1 mL; seen in azelastine ANDAs
Tradeoff
Deliberately deferred, not chosen: added viscosity coarsens the plume and risks the <4.6% olfactory deposition fraction the product depends on; cellulose-polymer/EV adsorption compatibility is untested.
n-Dodecyl β-D-maltoside (DDM / Intravail)permeationruled-out
Precedent
IID nasal SPRAY; TOSYMRA (NDA 210884) at 0.2% w/v
Tradeoff
~23× its own CMC and roughly 500 mol detergent per mol lipid at this product's target particle concentration — would be expected to dissolve the vesicle active.
Chitosanpermeationruled-out! no intranasal precedent
Precedent
no precedent — regulatory risk (absent from the nasal IID and from all 694 nasal labels)
Tradeoff
Frequently proposed in the delivery literature as a nasal permeation enhancer, but its cationic, membrane-interacting mode of action raises the same vesicle-disruption question as every other enhancer here.
Benzalkonium chloride (BAC)preservativeruled-out
Precedent
the dominant nasal preservative, 535 of 694 nasal labels
Tradeoff
Ciliotoxic at nasal use concentrations (Riechelmann et al. 2004, p<0.0001); a cationic surfactant in continuous contact with a vesicle active for the whole in-use life of the bottle.
Plain PBS (as vehicle)bufferruled-out
Precedent
sodium chloride and sodium phosphate both have nasal precedent
Tradeoff
Severe EV recovery loss within days on storage and within minutes on dilution (Görgens et al. 2022); ranked below potassium phosphate for EV stability (Trenkenschuh et al. 2022).
Citrate bufferbufferruled-out
Precedent
IID nasal citrate entries; TOSYMRA uses citric acid monohydrate
Tradeoff
Good nasal precedent, but buffers to pH 5–6 — the acidic region associated with EV aggregation and vesicle fusion (Trenkenschuh et al. 2022). Precedent for the wrong pH.

§ 03 — Presentation

The format decision, compared on what it costs the manufacturer and the person holding the bottle.

liquid

unsupported
Shelf life
unpublished by Signal; site meta description claims "shelf-stable" but no storage temperature or duration appears anywhere on the page (fetched 2026-09-03)
Cold chain
none specified as currently marketed
User steps
single actuation from a 10 mL multi-dose metered spray, no reconstitution
Full verdict

unsupported as currently specified — EVs in aqueous buffer without a nasal-precedented stabilizer lose recoverable particles within minutes to days (Görgens et al. 2022); the "shelf-stable" claim has no formulation or storage-condition evidence behind it.

Shelf life — full
unpublished by Signal; site meta description claims "shelf-stable" but no storage temperature or duration appears anywhere on the page (fetched 2026-09-03)
Cold chain — full
none specified as currently marketed
User steps — full
single actuation from a 10 mL multi-dose metered spray, no reconstitution

lyophilized

best-evidenced
Shelf life
6 months at 40°C for particle size and concentration (Trenkenschuh et al. 2022) — the only published route to anything resembling "shelf-stable" for this active; not tested for this specific formulation
Cold chain
not required for storage per the cited lyophilisate data; unconfirmed for this product
User steps
reconstitute the lyophilized cake with diluent before use, then spray — an added step versus the currently marketed single-actuation format
Full verdict

best-evidenced route to a genuine stability claim, but presentation-and-device.md (device, fill, reconstitution spec) does not exist yet, and it changes the stabilizer decision from a cryoprotectant-in-solution to a lyophilisate cake.

Shelf life — full
6 months at 40°C for particle size and concentration (Trenkenschuh et al. 2022) — the only published route to anything resembling "shelf-stable" for this active; not tested for this specific formulation
Cold chain — full
not required for storage per the cited lyophilisate data; unconfirmed for this product
User steps — full
reconstitute the lyophilized cake with diluent before use, then spray — an added step versus the currently marketed single-actuation format

frozen

ruled out
Shelf life
consensus long-term storage condition for EV preparations at −80°C (Ahmadian et al. 2024, cited via sgl-001-spec.md); one freeze-thaw cycle costs 23–36% of particles
Cold chain
required — an unbroken −80°C freezer chain from manufacture through point of use
User steps
thaw before each use; repeated freeze-thaw is destructive, so single-use aliquots would be needed rather than a multi-dose bottle
Full verdict

ruled out for a consumer multi-dose product — the cold-chain requirement and per-cycle particle loss are incompatible with a bottle used over multiple days and with the site's own "shelf-stable" framing.

Shelf life — full
consensus long-term storage condition for EV preparations at −80°C (Ahmadian et al. 2024, cited via sgl-001-spec.md); one freeze-thaw cycle costs 23–36% of particles
Cold chain — full
required — an unbroken −80°C freezer chain from manufacture through point of use
User steps — full
thaw before each use; repeated freeze-thaw is destructive, so single-use aliquots would be needed rather than a multi-dose bottle