List of Excipients in Branded Drug NAYZILAM

Company	Tradename	Ingredient	NDC	Excipient	Potential Generic Entry
UCB Inc	NAYZILAM	midazolam	50474-500	ALCOHOL
UCB Inc	NAYZILAM	midazolam	50474-500	PEG-6 METHYL ETHER
UCB Inc	NAYZILAM	midazolam	50474-500	POLYETHYLENE GLYCOL 400
UCB Inc	NAYZILAM	midazolam	50474-500	PROPYLENE GLYCOL
UCB Inc	NAYZILAM	midazolam	50474-500	WATER

NAYZILAM Excipient Strategy and Commercial Opportunities

Last updated: August 2, 2026

NAYZILAM is a prescription midazolam hydrochloride nasal spray for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity in patients with epilepsy who are at least 12 years old. Its commercial value comes from rapid, caregiver-administered rescue treatment rather than from a differentiated active ingredient. The formulation uses a relatively simple aqueous excipient system, but the nasal device, dose-volume control, preservative system, stability profile, and human-factors requirements create meaningful barriers to substitution.

The strongest commercial opportunities are in preservative-free rescue products, improved nasal delivery systems, pediatric and geriatric presentations, non-benzodiazepine rescue therapies, global regulatory expansion, and authorized or differentiated generic versions.

What is NAYZILAM and how is it administered?

NAYZILAM contains midazolam hydrochloride at a concentration of 5 mg per 0.1 mL nasal spray. Each device delivers one 5 mg spray into one nostril. A second 5 mg dose may be administered in the opposite nostril after 10 minutes if the patient has not responded, subject to product labeling and clinical circumstances. The product is supplied as a two-spray package, with each device intended for single use.[1]

Product attribute	NAYZILAM profile
Active ingredient	Midazolam hydrochloride
Dosage form	Nasal spray
Strength	5 mg per 0.1 mL
Route	Intranasal
Initial indication	Acute treatment of intermittent, stereotypic episodes of frequent seizure activity
Target population	Patients 12 years and older
Administration	One spray in one nostril; second spray may be used after 10 minutes under labeling conditions
Product type	Prescription drug-device combination
FDA approval	May 2019
Original sponsor	Neurelis, Inc.
Key commercial advantage	Caregiver-administered rescue therapy without intravenous access

NAYZILAM addresses a practical limitation of rectal diazepam and injectable rescue products. It can be administered by a caregiver without requiring the patient to swallow, without venous access, and without rectal administration.

What excipients are used in NAYZILAM?

The NAYZILAM formulation uses a buffered, preserved aqueous system designed to maintain midazolam solubility and support nasal tolerability.

The FDA prescribing information identifies the inactive ingredients as sodium chloride, citric acid monohydrate, sodium citrate dihydrate, benzalkonium chloride, and purified water.[1]

Excipient	Primary formulation function	Commercial or technical relevance
Sodium chloride	Tonicity adjustment	Supports nasal tolerability and controls osmolality
Citric acid monohydrate	Acid component of buffer	Helps maintain formulation pH
Sodium citrate dihydrate	Buffering agent	Supports pH control and chemical stability
Benzalkonium chloride	Antimicrobial preservative	Supports multidose-container microbial control, although NAYZILAM uses single-use devices
Purified water	Vehicle	Aqueous carrier for the drug substance and excipients

The formulation has an acidic pH, reported in the FDA labeling at approximately pH 5.0.[1] Acidic conditions are relevant because midazolam has pH-dependent aqueous solubility. The formulation must keep the drug sufficiently soluble while limiting nasal irritation and preserving spray performance.

Why does the excipient system matter commercially?

The excipients are not individually novel in most pharmaceutical contexts. Their value is in the combined product architecture:

1. Midazolam must remain dissolved at a commercially useful concentration.
2. The solution must be compatible with the nasal mucosa.
3. The formulation must deliver a reproducible 0.1 mL spray.
4. The product must remain stable during storage.
5. The package must prevent contamination and support rapid caregiver use.
6. The device and formulation must function together across temperature and handling conditions.

This combination creates a higher development burden than a conventional oral tablet containing the same active ingredient.

What formulation patents protect NAYZILAM?

NAYZILAM protection is likely based on a combination of formulation, intranasal delivery, dosing, device, and method-of-use claims rather than on midazolam composition-of-matter protection. Midazolam is an established generic active ingredient, so the commercial exclusivity strategy depends on the nasal product and its clinical use.

NAYZILAM’s patent estate should be assessed through three sources:

• FDA Orange Book listings for patents submitted against the approved NDA.
• USPTO and Patent Center records for claim scope, prosecution history, and terminal disclaimers.
• Federal court dockets for Paragraph IV litigation and settlement terms.

The relevant claim categories generally include:

Claim category	Potential protection
Pharmaceutical composition	Midazolam nasal solution with specified pH, concentration, buffer, tonicity, or preservative
Method of treatment	Acute treatment of seizure clusters or stereotypic episodes using intranasal midazolam
Dosing regimen	Initial and repeat dosing, timing between doses, and administration into opposing nostrils
Device	Unit-dose nasal actuator, spray volume, packaging, or dose-delivery configuration
Stability	Storage stability, impurity control, or container-closure performance
Human factors	Instructions and administration configuration intended for caregivers

The key patent risk for a generic manufacturer is not whether it can manufacture midazolam nasal spray. It is whether it can design around the listed formulation and use claims while preserving equivalent performance and satisfying the FDA’s substitutability requirements.

An exact Orange Book patent table should be taken from the current FDA listing because listed patents, delisting activity, pediatric extensions, and expiration calculations can change. The FDA-approved labeling confirms the product’s NDA and formulation, but the label does not establish the complete enforceable patent estate.[1]

When does NAYZILAM lose exclusivity?

NAYZILAM received FDA approval in May 2019. FDA regulatory exclusivity and patent exclusivity are separate.

Exclusivity category	NAYZILAM relevance
New chemical entity exclusivity	Generally not available because midazolam was previously approved
Three-year clinical investigation exclusivity	May apply to the approved new dosage form or indication if statutory criteria were met
Pediatric exclusivity	Depends on completion and acceptance of FDA-requested pediatric studies
Orphan-drug exclusivity	The seizure-cluster indication should be evaluated against the statutory orphan designation and approval record
Patent exclusivity	Depends on Orange Book-listed formulation, method, and device-related patents
Regulatory exclusivity expiration	Must be calculated from the FDA approval and exclusivity codes
Generic entry date	Depends on ANDA filing, Paragraph IV certification, litigation, settlement, and court outcome

Because NAYZILAM uses an old active ingredient in a new route and dosage form, its exclusivity profile differs from a newly discovered chemical entity. The most important commercial question is the remaining term of the listed patents and whether a generic applicant can obtain approval with a Paragraph IV certification.

What Paragraph IV challenges could affect NAYZILAM?

An ANDA applicant seeking approval before Orange Book-listed patents expire may submit a Paragraph IV certification asserting that the patents are invalid, unenforceable, or not infringed. The brand holder can then file an infringement action within 45 days, potentially triggering a 30-month stay of approval under the Hatch-Waxman framework.[2]

Potential Paragraph IV targets include:

• A nasal midazolam solution with the same or similar concentration.
• A formulation using the same buffer system.
• A product that relies on the same or similar dosing regimen.
• A product with a comparable unit-dose spray device.
• Method-of-use patents covering seizure-cluster treatment.

A generic applicant may seek a Paragraph III certification for patents that it accepts as valid and enforceable, or it may design around formulation and method patents. A section viii statement may be available for labeling carve-outs if the relevant use is protected and the unpatented uses can support approval. That route is less straightforward where the approved product has a narrow rescue indication and the branded labeling is closely tied to the patented method.

No broad conclusion about active NAYZILAM litigation should be made without a current docket and Orange Book review. Litigation risk is claim-specific and can change through settlements, dismissals, amended complaints, or patent-owner decisions to delist claims.

What formulation opportunities exist for NAYZILAM competitors?

Preservative-free intranasal midazolam

A preservative-free presentation is the clearest excipient-led opportunity. Benzalkonium chloride is widely used in nasal products, but repeated exposure can raise tolerability and mucosal-safety concerns. NAYZILAM’s single-use device reduces the need for multidose preservation, creating a technical rationale for removing benzalkonium chloride.

A preservative-free formulation would need to demonstrate:

• Comparable or improved chemical stability.
• Microbiological control through the container-closure system.
• Consistent spray performance.
• Equivalent or clinically acceptable pharmacokinetics.
• Nasal tolerability.
• Compatibility with the device materials.
• Adequate extractables and leachables control.

The commercial benefit would be strongest in patients requiring repeated rescue treatment, caregivers concerned about excipient exposure, and markets where preservative-free nasal products command a premium.

Improved buffer and tonicity systems

Competitors could investigate alternative buffers, including phosphate or alternative citrate systems, but changing the buffer may alter:

• Midazolam solubility.
• Nasal irritation.
• Spray plume geometry.
• Chemical degradation.
• Preservative activity.
• Device compatibility.

A successful alternative would need more than a different excipient list. It would need measurable product-performance or tolerability advantages that justify development and support differentiation.

Mucoadhesive systems

Mucoadhesive excipients could increase nasal residence time and reduce runoff. Possible candidates include selected cellulose derivatives, polyvinyl alcohol systems, or other mucoadhesive polymers. These systems introduce risks:

• Delayed absorption.
• Greater local irritation.
• Variable deposition.
• Changes in pharmacokinetics.
• Clogging or altered actuator performance.
• More complex regulatory characterization.

For seizure rescue, faster onset is usually more valuable than prolonged nasal residence. A mucoadhesive strategy would therefore require evidence that residence time improves exposure without delaying therapeutic effect.

Alternative solubilization strategies

Midazolam nasal products may use pH control rather than high levels of cosolvent or surfactant. Competitors could examine cyclodextrins, low levels of surfactants, or other solubilizing agents. Such approaches must be balanced against nasal safety, taste, irritation, and regulatory precedent.

The strongest opportunity is a lower-excipient formulation with equivalent exposure and improved tolerability, not a more complex formulation without a clear clinical benefit.

What device and packaging opportunities compete with the excipient strategy?

The delivery device is central to NAYZILAM’s commercial performance. A nasal rescue product must work when administered by a caregiver under stress, often during a seizure event.

Potential device improvements include:

• More intuitive actuation.
• Better tactile and audible feedback.
• Reduced risk of partial dosing.
• Child-resistant but caregiver-accessible packaging.
• Temperature-resistant single-use packaging.
• Improved plume and deposition control.
• Integrated dose counters or status indicators.
• Packaging that separates the first and second doses clearly.
• Lower-cost manufacturing using standard nasal spray components.

A device change may require FDA combination-product review and comparative human-factors work. It can also create new patentable subject matter independent of the formulation.

The commercial opportunity is strongest where the device improves administration reliability without increasing cost or introducing a new training burden.

How does NAYZILAM compare with competing seizure-rescue products?

Product category	Active ingredient	Route	Administration profile	Main commercial strength
NAYZILAM	Midazolam	Intranasal	Caregiver-administered spray	Compact, rapid, noninvasive
Diazepam rectal gel	Diazepam	Rectal	Caregiver-administered	Established clinical use
Intranasal diazepam	Diazepam	Intranasal	Caregiver-administered spray	Competes directly in nasal rescue
Injectable benzodiazepines	Various	Buccal, intramuscular, or intravenous depending on product	More specialized administration	Potentially rapid but less convenient
Hospital rescue formulations	Various	Parenteral or other routes	Clinician-directed	Acute-care utility

NAYZILAM’s principal competitive issue is not the identity of the benzodiazepine. It is the balance among speed, usability, spray reliability, tolerability, price, and payer access.

Intranasal diazepam creates the most direct product-level competition. A competing product with a longer shelf life, lower acquisition cost, lower device cost, fewer excipients, or stronger reimbursement could take share even without a clinically superior onset profile.

What FDA regulatory status affects commercial opportunities?

NAYZILAM is an FDA-approved prescription product under NDA 211321.[1] A competing midazolam nasal spray would generally require an ANDA only if it can satisfy the applicable generic-drug requirements. Differences in device design, formulation, labeling, or clinical performance may push the applicant toward a 505(b)(2) application.

Development route	Commercial use
ANDA	Generic equivalent with the required pharmaceutical and therapeutic equivalence
505(b)(2) NDA	Modified formulation, device, strength, route, or clinical use relying partly on existing findings
New NDA	Substantially new clinical product or indication
Authorized generic	Brand-authorized product sold without the original brand positioning
Combination-product pathway	Applies where device differences materially affect regulatory review

A 505(b)(2) strategy may be commercially attractive for a preservative-free product, improved device, lower-volume spray, or alternative strength. It offers more flexibility than an ANDA but requires a stronger evidence package and may face additional patent certifications.

What manufacturing and intellectual-property barriers exist?

The manufacturing process is relatively accessible compared with biologics, but commercial-scale execution still requires control of:

• Midazolam hydrochloride assay and impurity profile.
• Solution pH and osmolality.
• Sterility or microbial limits appropriate to the product design.
• Spray-content uniformity.
• Delivered-dose uniformity.
• Priming and repriming behavior.
• Container-closure integrity.
• Extractables and leachables.
• Device assembly and dose yield.
• Stability under temperature and humidity stress.

The main manufacturing barrier is likely device and assembly consistency rather than raw-material scarcity. A nasal rescue product can fail commercial testing even when the bulk solution meets specifications if the actuator produces variable dose volume or plume geometry.

Intellectual-property risks include formulation patents, dosing-method patents, device patents, manufacturing claims, trade secrets, and regulatory exclusivity. A design-around must be assessed across all of these layers.

What licensing deals and commercial partnerships are relevant?

NAYZILAM was developed and commercialized by Neurelis. Product commercialization can involve separate rights for:

• North American commercialization.
• European and Asian distribution.
• Manufacturing and fill-finish.
• Device supply.
• Co-promotion.
• Government and institutional channels.
• Pediatric or specialty-pharmacy access.

Publicly available information should be reviewed for current territory-specific licenses, distribution agreements, and changes in commercial ownership. Revenue exposure is difficult to quantify from public filings because Neurelis is a private company and product economics may be reported through partner arrangements rather than a standalone public segment.

For prospective licensees, the most valuable diligence items are territorial rights, minimum purchase obligations, manufacturing transfer provisions, device exclusivity, patent enforcement control, and settlement restrictions.

What generic launch scenarios exist for NAYZILAM?

First-filer Paragraph IV launch

A successful first-filer could receive 180-day exclusivity under the ANDA framework, depending on certification, litigation, forfeiture, and regulatory conditions. The launch could produce substantial early share but would face rapid price pressure from later entrants.

At-risk launch

A generic company could launch before final patent resolution. This creates exposure to damages, injunction risk, and inventory disruption. The attractiveness of an at-risk launch depends on the remaining patent term, expected gross margin, litigation probability, and the strength of any design-around.

505(b)(2) differentiated launch

A preservative-free or redesigned device product could enter through a 505(b)(2) pathway. It would likely compete on tolerability, usability, or supply reliability rather than price alone.

Authorized generic

An authorized generic could preserve volume during patent challenges while reducing the space available to independent generic entrants. This strategy may be most effective if the brand product has strong payer access and the manufacturer can use the same commercial supply chain.

How strong is the NAYZILAM patent estate?

The patent estate should be viewed as moderate rather than composition-of-matter strong. Midazolam itself is old, and the product’s defensibility depends on narrower claims directed to intranasal formulation, delivery, dosing, device design, and clinical use.

Patent strength is highest where:

• Claims cover the complete product configuration.
• The formulation limitation is difficult to avoid without losing solubility or stability.
• Method claims cover the core approved rescue use.
• Device claims are required to reproduce the labeled dose.
• The patents have survived meaningful prosecution or litigation scrutiny.

Patent strength is lower where:

• Claims rely on routine excipient substitutions.
• Alternative nasal devices can deliver the same dose.
• The method claims are vulnerable to prior art.
• Generic applicants can carve out patented uses.
• The product’s clinical advantage depends mainly on an unpatented route of administration.

What are the highest-value commercial opportunities?

The most credible opportunities are:

1. Preservative-free intranasal midazolam with equal or better tolerability.
2. Lower-cost generic NAYZILAM using a noninfringing formulation and device.
3. A caregiver-optimized spray with stronger human-factors performance.
4. Pediatric presentations for younger patients, subject to clinical and regulatory requirements.
5. Global licensing in markets where intranasal rescue products are underdeveloped.
6. Improved packaging that reduces medication errors and clarifies repeat dosing.
7. A device platform reusable across benzodiazepine rescue products.
8. Hospital and emergency-service versions optimized for rapid deployment.
9. Specialty-pharmacy programs that improve refill persistence and caregiver training.
10. Non-benzodiazepine rescue products that avoid sedation, respiratory-depression concerns, or controlled-substance restrictions.

The most defensible platform opportunity is a combination of excipient simplification and device performance. An excipient change alone is unlikely to produce durable differentiation unless it improves safety, tolerability, stability, or regulatory substitutability.

Key Takeaways

• NAYZILAM uses midazolam hydrochloride in an acidic, buffered aqueous nasal formulation.
• The listed excipients are sodium chloride, citric acid monohydrate, sodium citrate dihydrate, benzalkonium chloride, and purified water.
• The main formulation opportunity is a preservative-free product supported by a robust single-use container-closure system.
• Product protection depends on formulation, dosing, method-of-use, device, and stability claims rather than active-ingredient composition.
• Generic entry will depend on Orange Book patents, Paragraph IV certifications, litigation, settlements, and potential design-arounds.
• Intranasal diazepam is the closest marketed competitive category.
• Device reliability, caregiver usability, reimbursement, and acquisition cost are as important as excipient selection.
• A 505(b)(2) pathway may be more practical than an ANDA for materially different formulations or devices.
• Public revenue exposure is difficult to quantify because Neurelis is privately held.
• The strongest licensing targets are preservative-free formulations, improved delivery devices, and geographic expansion.

FAQs

Can benzalkonium chloride be removed from a NAYZILAM-like product?

Yes, but the replacement must support microbial control, stability, nasal tolerability, and container-closure integrity. A preservative-free single-use system is the most logical design.

Is a new midazolam nasal spray automatically substitutable for NAYZILAM?

No. Substitutability depends on FDA approval pathway, pharmaceutical equivalence, device performance, labeling, and therapeutic-equivalence findings.

Does changing the NAYZILAM buffer avoid all patent risk?

No. A buffer change may avoid some formulation claims but leave method-of-use, dosing, device, manufacturing, or stability claims in force.

Would a mucoadhesive midazolam spray necessarily work better?

No. Greater nasal residence may increase local exposure without improving onset. It can also alter pharmacokinetics, irritation, and spray performance.

Is intranasal diazepam a direct generic substitute for NAYZILAM?

No. It is a competing rescue product, but it contains a different active ingredient and has separate labeling, dosing, device, patent, and regulatory requirements.

References

1. U.S. Food and Drug Administration. (2023). NAYZILAM (midazolam) nasal spray, prescribing information. FDA.

2. U.S. Food and Drug Administration. (2017). Approved drug products with therapeutic equivalence evaluations. FDA.

3. U.S. Food and Drug Administration. (2019). FDA approves first nasal spray to treat seizure clusters in patients with epilepsy. FDA.

4. U.S. Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417.

5. U.S. Food and Drug Administration. (2024). Orange Book: Approved drug products with therapeutic equivalence evaluations. FDA.