List of Excipients in Branded Drug NITROMIST

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Company	Tradename	Ingredient	NDC	Excipient	Potential Generic Entry
Evus Pharmaceuticals LLC	NITROMIST	nitroglycerin	73262-430	BUTANE
Evus Pharmaceuticals LLC	NITROMIST	nitroglycerin	73262-430	CAPRYLIC/CAPRIC/SUCCINIC TRIGLYCERIDE
Evus Pharmaceuticals LLC	NITROMIST	nitroglycerin	73262-430	MENTHOL
Evus Pharmaceuticals LLC	NITROMIST	nitroglycerin	73262-430	PEPPERMINT OIL

NITROMIST Excipient Strategy and Commercial Opportunities

Last updated: October 3, 2026

NITROMIST is a nitroglycerin lingual aerosol delivering 0.4 mg per metered spray for acute relief of angina pectoris. Its commercial value is tied less to the active ingredient, which is an established generic nitrate, than to the combination of solvent system, taste-masking profile, metered-dose pump, dose uniformity, packaging, and regulatory substitutability. The strongest opportunities are authorized or branded-generic versions, improved stability systems, low-cost device platforms, and differentiated rescue products for patients who cannot use sublingual tablets reliably.

What is NITROMIST and how does its formulation work?

NITROMIST is a transmucosal nitroglycerin product administered as a spray onto or under the tongue. Each actuation delivers 0.4 mg of nitroglycerin. The product is intended for rapid treatment of an acute angina attack and for prophylaxis before activities known to precipitate angina.[1]

The formulation relies on a volatile, alcohol-containing liquid system. The main technical objectives are:

• Rapid dissolution of nitroglycerin.
• Uniform delivery from each actuation.
• Fast evaporation after oral administration.
• Acceptable peppermint flavor.
• Protection from light, heat, and formulation loss.
• Consistent pump performance through the labeled spray count.

Nitroglycerin is chemically sensitive and can migrate into or interact with packaging components. The container, pump, actuator, gasket, and closure are therefore part of the product performance system rather than simple secondary packaging.

What excipients are used in NITROMIST?

Public product information identifies alcohol and peppermint oil among the inactive ingredients. The commercial formulation is designed around an alcoholic vehicle and flavor system rather than an aqueous oral spray.[1,2]

Formulation element	Likely function	Commercial significance
Ethanol or alcohol vehicle	Solubilizes nitroglycerin and promotes rapid evaporation	Affects spray plume, evaporation, flammability, and patient tolerability
Peppermint oil or flavor	Masks the sharp taste of the solvent and nitrate	Influences patient acceptance and potential flavor differentiation
Nitroglycerin	Vasodilating active ingredient	Requires dose uniformity and chemical stability
Metered pump	Controls delivered dose	Creates device and combination-product regulatory risk
Container and closure system	Limits light exposure, leakage, sorption, and evaporation	Can determine shelf life and manufacturing cost

The precise excipient composition should be established from the current approved labeling, regulatory filings, and product quality documentation before a development or licensing decision. Public labels are not always sufficient to reconstruct quantitative formulation composition.

What excipient strategies can improve NITROMIST or a generic nitroglycerin spray?

The most commercially relevant strategies involve stability, patient acceptance, and device compatibility.

Can the alcohol system be optimized?

Yes. Alcohol concentration can be adjusted within a validated formulation space to balance nitroglycerin solubility, spray characteristics, evaporation rate, and mucosal tolerability. A lower alcohol content could reduce burning or dryness, but it may require a co-solvent or a different solvent architecture.

Potential co-solvent candidates include:

• Propylene glycol.
• Polyethylene glycol of suitable molecular weight.
• Certain pharmaceutical-grade glycols or compatible nonaqueous solvents.

Each alternative introduces development issues. Higher-viscosity co-solvents can alter pump metering and spray plume geometry. Hygroscopic excipients may increase water uptake during storage. Aqueous systems may reduce nitroglycerin stability or require pH and preservative controls.

Can taste and mouthfeel be improved?

Peppermint is a practical flavor because it is associated with oral freshness and can mask the solvent. Commercial differentiation could come from:

• Lower-intensity peppermint.
• Cooling flavor systems.
• Neutral or unflavored versions for patients with flavor sensitivity.
• Reduced-burn formulations.
• Flavor systems designed for geriatric patients with altered taste perception.

Flavor changes are not automatically low-risk. Essential oils can affect solubility, container compatibility, extractables, and delivered dose. Any new flavor system would require comparative stability and performance studies.

Can the formulation reduce mucosal irritation?

A lower-irritancy formulation could have commercial value, particularly for repeated use. The main design variables are alcohol level, solvent selection, flavor oil concentration, spray droplet size, and dose deposition pattern.

A formulation that reduces irritation while preserving rapid onset could support a differentiated product claim, but the claim would require clinical or human-factors support. A purely formulation-based change would generally face a regulatory burden if it alters pharmacokinetics, local tolerability, or dose delivery.

Can an aqueous nitroglycerin spray compete with NITROMIST?

An aqueous system would be technically more difficult. Nitroglycerin has limited water compatibility and the product needs a high degree of dose uniformity at a small volume. A water-based formulation could require solubilizers, pH control, preservatives, or complex emulsification.

The opportunity is real but narrow. An aqueous or low-alcohol product could target patients who dislike the current sensory profile. The development risk is higher than for an ethanol-based formulation because the sponsor would need to establish chemical stability, microbial control, container compatibility, and bioequivalence.

What formulation patents protect nitroglycerin lingual sprays?

Nitroglycerin lingual sprays have historically been protected through a combination of formulation, delivery-device, packaging, and method-of-use claims. The relevant patent categories include:

Patent category	Typical claim scope	Commercial effect
Formulation	Nitroglycerin dissolved in a specified nonaqueous vehicle with flavoring agents	Can delay direct formulation copying
Metered delivery	Pump dose, actuation volume, spray geometry, or dose uniformity	Can protect the product-device combination
Container system	Light protection, low-sorption materials, closure integrity	May create manufacturing barriers
Stability	Shelf life, impurity control, or packaging configuration	Can support regulatory differentiation
Method of use	Administration before exertion or during acute angina	Usually narrower once the active ingredient is generic
Patient-use instructions	Number and timing of sprays, positioning, and repeat dosing	Often difficult to enforce as a commercial barrier

Historically, some NITROMIST-related patent protection has expired or become less significant as the product matured. The key current question is not whether a historical patent once covered the product, but whether any unexpired patent is listed in the FDA Orange Book for the specific NITROMIST NDA and whether that patent can block an ANDA applicant.

What is the FDA regulatory status of NITROMIST?

NITROMIST is an FDA-approved prescription drug product delivered through a metered lingual aerosol. It is regulated as a drug-device combination because the pump and actuator determine dose delivery.[1]

The principal regulatory routes are:

505(b)(2) route

A sponsor developing a materially different formulation, device, flavor system, or administration system could consider a 505(b)(2) application. This route may be appropriate where the product relies partly on NITROMIST or another approved nitroglycerin product but contains changes requiring new clinical or pharmacology support.

ANDA route

A conventional generic sponsor would seek approval through an ANDA if it can demonstrate pharmaceutical equivalence and bioequivalence. The product must match the reference product in relevant characteristics, including:

• Strength.
• Dosage form.
• Route of administration.
• Delivered dose.
• Spray performance.
• Labeling, subject to permitted generic differences.
• Stability and container-closure performance.

For a spray product, in vitro equivalence is particularly important. The FDA may evaluate delivered volume, dose uniformity, droplet or particle characteristics, spray pattern, plume geometry, priming, repriming, tail-off, and performance across the container life.

What is the Orange Book status of NITROMIST?

The Orange Book is the controlling source for current listed patents, therapeutic equivalence codes, and reference-product status. NITROMIST should be reviewed by NDA number rather than by product name alone because nitroglycerin spray products can have different sponsors, strengths, labels, and reference designations.[3]

The relevant Orange Book review should identify:

1. The current reference listed drug.
2. Any patents listed against the NITROMIST NDA.
3. Patent-use codes.
4. The drug’s therapeutic equivalence status.
5. Whether the product has an active exclusivity period.
6. Whether the listing is associated with the formulation, device, or method of use.

A historical patent does not necessarily create a current filing barrier. The practical exposure depends on active Orange Book listings, the scope of the claims, and whether a proposed ANDA requires a Paragraph IV certification.

When does NITROMIST lose exclusivity?

NITROMIST’s basic active-ingredient exclusivity is not the principal commercial barrier. Nitroglycerin has been used for decades and is available in multiple dosage forms, including sublingual tablets, ointments, transdermal systems, and sprays.

The relevant loss-of-exclusivity questions are:

Exclusivity issue	Relevance to NITROMIST
New chemical entity exclusivity	Not relevant to long-established nitroglycerin
Orphan exclusivity	Not applicable to standard angina treatment
Pediatric exclusivity	Must be checked against the specific NDA record
Formulation patent term	Depends on any surviving claims
Device patent term	May affect a particular pump or actuator
Regulatory exclusivity	Depends on the NDA history and any later approvals
Orange Book listing	Determines the ANDA certification pathway

A generic competitor can potentially enter after approval even if a method-of-use patent remains, provided the ANDA label uses a permitted carve-out and the remaining patent does not cover the proposed use.

How many patents cover NITROMIST?

The answer depends on whether the analysis includes:

• Patents assigned to the original sponsor.
• Patents covering the formulation.
• Patents covering the pump or actuator.
• Packaging patents.
• Expired patents.
• Continuations and divisionals.
• Foreign equivalents.
• Patents listed in the Orange Book.

For commercial clearance, the relevant number is the count of unexpired, enforceable claims that read on the proposed product. Patent-family counting and Orange Book counting can produce different results. A large historical patent family does not necessarily indicate meaningful current protection.

What Paragraph IV challenges and generic entry risks exist?

A direct generic challenge would likely focus on three issues:

Pharmaceutical equivalence

The applicant would need to match the reference strength, route, dosage form, and delivery performance. A nonidentical formulation can create equivalence risk if the excipient system changes spray behavior or dose delivery.

Device equivalence

The pump and actuator must deliver a reproducible dose. Differences in actuation force, priming requirements, plume geometry, or end-of-container performance may require additional comparative evidence.

Patent certification

If the Orange Book identifies an unexpired patent, an ANDA applicant could file a Paragraph IV certification alleging that the patent is invalid, unenforceable, or not infringed. The NDA holder could then initiate litigation within the statutory period, potentially creating a 30-month stay of approval under the Hatch-Waxman framework.[4]

A method-of-use patent may be less damaging if the generic label can omit the patented indication or instruction without undermining safe use of the remaining label.

What manufacturing and intellectual-property barriers matter most?

The main barriers are process and device controls rather than complex synthesis of nitroglycerin.

Manufacturing barriers

• Safe handling of an explosive organic nitrate.
• Control of nitroglycerin concentration and impurity profile.
• Prevention of solvent loss during filling.
• Consistent crimping and pump assembly.
• Low-sorption contact materials.
• Light-protective packaging.
• In-process controls for spray weight and actuation performance.
• Stability testing under long-term and accelerated conditions.

Intellectual-property barriers

• Pump and metering mechanisms.
• Actuator geometry.
• Container-closure systems.
• Low-loss or low-sorption materials.
• Formulation systems that improve stability.
• Human-factors features that reduce administration errors.

The device platform may be a more durable commercial barrier than the excipient list. A sponsor with an established metered-spray manufacturing line can have a cost advantage even where formulation claims are weak.

What commercial opportunities exist for NITROMIST excipients and competitors?

1. Authorized generic or branded generic

The lowest-risk opportunity is a product that closely follows the reference formulation and uses an established metered pump. Competitive advantage would come from lower acquisition cost, payer contracting, pharmacy distribution, and reliable supply.

2. Improved-sensory nitroglycerin spray

A lower-burn or reduced-flavor product could target patients who discontinue or avoid nitroglycerin spray because of taste or oral irritation. The commercial proposition would require evidence that the product preserves rapid relief and dose consistency.

3. Lower-alcohol formulation

A lower-alcohol system could create a differentiated product, but the sponsor would need to solve solubility, stability, evaporation, and device-performance issues. This is a moderate-risk 505(b)(2) opportunity rather than a simple generic opportunity.

4. Device-led differentiation

A pump with fewer priming steps, better dose tracking, improved cap design, or easier actuation could address adherence and administration errors. Device changes may support product differentiation even when the active ingredient and indication remain conventional.

5. Unit-dose or travel packaging

Portable packaging, dose counters, improved leak resistance, and temperature-stable configurations could appeal to patients who carry rescue medication routinely. Packaging changes would need to preserve dose integrity and meet child-resistant and transport requirements where applicable.

6. Combination rescue platforms

Combining nitroglycerin delivery with digital adherence tracking or emergency-use instructions could create a specialty product, although the regulatory pathway would become more complex. The commercial value would depend on reimbursement and clinical utility rather than excipient innovation alone.

How does NITROMIST compare with other nitroglycerin products?

Product type	Main advantage	Main limitation	Excipient opportunity
Lingual aerosol	Rapid, needle-free delivery; no tablet dissolution requirement	Device dependence and solvent taste	Lower-irritancy vehicle, improved flavor, dose counter
Sublingual tablet	Low cost and familiar use	Requires tablet placement and dissolution	Fast-disintegrating or taste-masked tablet
Transdermal patch	Extended delivery	Not intended for immediate rescue	Adhesive, skin tolerability, controlled release
Topical ointment	Flexible dosing	Messy administration and slower use	Improved spreadability and dosing measurement
Buccal or film product	Potentially discreet and portable	Film adhesion and dose uniformity	Mucoadhesive polymers and taste masking

NITROMIST has its strongest position in rapid rescue where a patient wants a spray rather than a tablet. Its weakest points are device complexity, solvent sensation, and the need for correct administration technique.

What revenue exposure and competitive dynamics should investors assess?

Nitroglycerin spray is a mature, niche pharmaceutical market. Revenue exposure is therefore sensitive to:

• Generic entry.
• Reimbursement tier placement.
• Cardiovascular prescribing trends.
• Product shortages.
• Pump-component supply.
• Contract manufacturing cost.
• Hospital and retail channel mix.
• Patient preference for tablets versus spray.
• Brand retention among patients with established rescue routines.

The largest value risk is usually loss of exclusivity through a substitutable generic spray, not substitution by an unrelated active ingredient. The largest upside is a differentiated product that combines equivalent pharmacology with improved usability and stable manufacturing economics.

What is the overall patent strength of NITROMIST?

NITROMIST has a relatively weak active-ingredient position because nitroglycerin is old and broadly available. Its defensibility depends on product-specific features:

Asset	Relative strength
Nitroglycerin molecule	Very weak
Standard angina indication	Weak
Basic alcohol solution	Weak to moderate
Specific flavor system	Moderate if narrowly claimed
Metered pump and actuator	Moderate
Packaging and stability system	Moderate
Manufacturing process	Moderate, often difficult to enforce
Human-factors or integrated device features	Potentially stronger for a new product

The best commercial strategy is to treat excipients as part of a broader formulation-device package. An excipient-only patent is unlikely to sustain a premium unless it produces measurable stability, tolerability, or delivery benefits.

Key Takeaways

• NITROMIST is a 0.4 mg-per-spray nitroglycerin lingual aerosol for acute angina relief.
• Its formulation is built around an alcohol-containing vehicle and peppermint flavor system.
• The most valuable technical targets are solvent tolerability, flavor, stability, pump compatibility, and dose uniformity.
• A close-copy ANDA is the lowest-risk entry route; a materially improved product may require a 505(b)(2) application.
• Device and packaging patents may be more commercially relevant than basic excipient claims.
• Generic entry risk depends on current Orange Book listings, patent-use codes, and the ability to carve out protected methods of use.
• The strongest commercial opportunities are branded generics, authorized generics, lower-irritancy formulations, improved pumps, dose counters, and portable packaging.
• Nitroglycerin’s mature active-ingredient status limits molecule-level exclusivity. Product differentiation must come from delivery, usability, stability, or manufacturing economics.

FAQs

Can propylene glycol replace ethanol in a nitroglycerin lingual spray?

It may be technically possible, but the change would affect solubility, viscosity, evaporation, spray pattern, mucosal tolerability, and pump performance. It would require a full formulation and device comparability program.

Is peppermint oil essential to NITROMIST performance?

Peppermint oil is primarily a sensory excipient. It is not the therapeutic component, but changing or removing it can affect patient acceptance, solubility, stability, and regulatory comparability.

Is a generic nitroglycerin spray automatically substitutable for NITROMIST?

No. Substitution depends on FDA therapeutic-equivalence determinations, product-specific labeling, dosage form, delivery system, and pharmacy-substitution rules.

Can a new pump create patent protection for a nitroglycerin spray?

Yes. A novel pump, actuator, dose counter, or container-closure system may support device or combination-product claims. Patent strength depends on novelty, nonobviousness, claim breadth, and freedom-to-operate analysis.

Does a new flavor require a new clinical trial?

Not necessarily. A flavor change may be handled through an ANDA or supplemental pathway if it does not alter critical product performance. A new clinical or pharmacology package may be required if the change affects exposure, local tolerability, or therapeutic performance.

References

1. Food and Drug Administration. (n.d.). NITROMIST (nitroglycerin) lingual aerosol, metered: Prescribing information. DailyMed.

2. National Library of Medicine. (n.d.). Nitromist drug label. DailyMed.

3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. FDA, Center for Drug Evaluation and Research.

4. U.S. Code, 21 U.S.C. § 355(j). Abbreviated applications for new drugs.