List of Excipients in Branded Drug ERGOTAMINE TARTRATE AND CAFFEINE

Generic Drugs Containing ERGOTAMINE TARTRATE AND CAFFEINE

Company	Ingredient	NDC	Excipient
Cintex Services LLC	ergotamine tartrate and caffeine	24470-917	CELLULOSE, MICROCRYSTALLINE
Cintex Services LLC	ergotamine tartrate and caffeine	24470-917	CROSPOVIDONE
Cintex Services LLC	ergotamine tartrate and caffeine	24470-917	FD&C BLUE NO. 2
Cintex Services LLC	ergotamine tartrate and caffeine	24470-917	FD&C RED NO. 40

What are the Most Frequently-Used Excipients in ERGOTAMINE TARTRATE AND CAFFEINE?

# Of NDCs	Excipient
1	CELLULOSE, MICROCRYSTALLINE
1	CROSPOVIDONE
1	FD&C BLUE NO. 2
1	FD&C RED NO. 40

Ergotamine Tartrate and Caffeine Excipient Strategy and Commercial Opportunities

Last updated: August 22, 2026

Ergotamine tartrate and caffeine is a mature migraine combination with limited conventional patent protection and substantial regulatory constraints. The strongest commercial opportunities are reformulated oral, buccal, sublingual, or rectal products that improve dose administration, reduce excipient-related variability, and address supply or tolerability problems. A new active-ingredient combination would face limited differentiation against triptans, gepants, ditans, and generic analgesics.

What is the commercial status of ergotamine tartrate and caffeine?

Ergotamine tartrate and caffeine is an established antimigraine combination. Caffeine increases gastrointestinal absorption of ergotamine and may enhance vasoconstrictive activity. Historical products include:

Product type	Typical strength	Administration	Commercial relevance
Combination tablet	Ergotamine tartrate 1 mg plus caffeine 100 mg	Oral	Legacy reference product and generic-development target
Sublingual ergotamine	Ergotamine tartrate 2 mg	Sublingual	Potential platform for improved onset and reduced swallowing burden
Suppository	Ergotamine tartrate 2 mg plus caffeine 100 mg	Rectal	Useful where nausea or vomiting limits oral therapy
Injectable ergotamine	Various historical presentations	Parenteral	High regulatory, safety, and manufacturing burden

The principal pharmacologic limitation is vasoconstriction. Ergotamine is contraindicated in patients with peripheral vascular disease, coronary artery disease, uncontrolled hypertension, severe hepatic or renal impairment, and pregnancy. Strong CYP3A4 inhibitors can cause serious ergot toxicity and are contraindicated with ergotamine products.[1]

The commercial market is therefore a narrow rescue-treatment segment rather than a broad migraine-prevention market. The most credible customers are patients with episodic migraine who have failed or cannot tolerate newer agents, along with hospitals, emergency departments, and health systems seeking low-cost legacy therapies.

What excipients are most important in ergotamine-caffeine products?

Excipient selection should focus on dose uniformity, disintegration, moisture protection, taste, absorption, and compatibility with a potent low-dose alkaloid.

Oral tablet excipient strategy

A conventional immediate-release tablet can use:

Formulation function	Candidate excipient classes	Development purpose
Diluent	Microcrystalline cellulose, lactose, mannitol, dibasic calcium phosphate	Controls tablet mass and compression
Binder	Povidone, copovidone, pregelatinized starch, hydroxypropyl cellulose	Improves granule and tablet strength
Disintegrant	Crospovidone, croscarmellose sodium, sodium starch glycolate	Supports rapid breakup
Lubricant	Magnesium stearate, sodium stearyl fumarate	Controls ejection and sticking
Glidant	Colloidal silicon dioxide	Improves powder flow
Taste modifier	Sucralose, acesulfame potassium, flavor systems	Relevant if tablet is chewable or orally disintegrating
Moisture barrier	Film coat, high-barrier blister, desiccant packaging	Protects potency and dissolution performance

A direct-compression formulation is commercially attractive because it reduces processing steps. The principal technical risks are low-dose content uniformity and segregation between ergotamine, caffeine, and the larger excipient fraction. Geometric dilution, ordered mixing, low-shear blending, and validated blend sampling are important process controls.

Magnesium stearate should be evaluated carefully because excessive lubrication can slow tablet wetting and dissolution. Sodium stearyl fumarate may provide a useful alternative where hydrophobicity or over-lubrication becomes a problem.

Sublingual and orally disintegrating products

A sublingual or orally disintegrating formulation could improve administration during migraine attacks, particularly when nausea, photophobia, or difficulty swallowing reduces adherence. Candidate excipients include mannitol, crospovidone, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, and taste-masking polymers.

The commercial objective should be rapid disintegration rather than an unsupported claim of faster systemic exposure. A new sublingual product would require comparative pharmacokinetic and clinical evidence to establish whether the delivery route changes onset, exposure, or tolerability.

Taste is a major barrier. Ergotamine is intensely bitter, while caffeine contributes a distinctive bitter profile. Useful approaches include:

• Ion-exchange resin complexes
• Polymer coating of drug particles
• Lipid or wax-based taste barriers
• Flavored porous mannitol matrices
• Coated multiparticulates incorporated into a rapidly disintegrating tablet

Taste masking must not delay dissolution beyond the intended immediate-release profile.

Suppository formulations

Rectal delivery has historical relevance because migraine can involve vomiting and gastric stasis. A modern suppository could use a hard-fat or polyethylene glycol base, with attention to drug distribution, polymorphism, melting behavior, and release at rectal temperature.

The main commercial problem is patient acceptance. A rectal product may retain niche value in emergency or rescue use, but it is unlikely to support a broad consumer market without a clear administration advantage.

Liquid and multiparticulate systems

Oral solutions, suspensions, and sachets may support pediatric or dysphagia markets, but they create additional stability and dosing challenges. Multiparticulates could provide better dose distribution and flexible dosing, although the benefit must justify higher manufacturing cost.

Caffeine is water soluble relative to ergotamine tartrate. The two ingredients may therefore require different particle engineering, wetting, and release controls. A single-phase liquid is likely to be less attractive than a solid dosage form unless solubilization and chemical stability are demonstrated.

What formulation patents could protect a new ergotamine-caffeine product?

The active ingredients are old, so protection is more likely to arise from formulation, process, device, or use claims than from composition-of-matter patents.

Potential claim areas include:

Patent strategy	Protectable subject matter	Commercial value
Fast-disintegrating tablet	Excipient ratios, hardness, disintegration time, dissolution profile	Moderate if linked to a differentiated route
Sublingual delivery	Mucoadhesive matrix, particle size, taste masking, absorption profile	Moderate to high if clinical benefit is shown
Stabilized formulation	Antioxidant system, pH control, moisture barrier, impurity limits	Moderate
Rectal dosage form	Base composition, release profile, content uniformity	Niche
Manufacturing process	Low-dose blending, granulation, coating, segregation control	Moderate but difficult to enforce
Packaging	High-barrier blister, moisture-control system, dose protection	Limited unless tied to stability data
Method of use	Use in a defined patient population or treatment setting	Potentially useful, subject to written-description and obviousness risks
Combination therapy	Ergotamine-caffeine with an antiemetic or other active	Potentially stronger, but clinically and legally higher risk

A defensible formulation patent should claim measurable technical parameters, not only a list of conventional excipients. Examples include rapid disintegration under defined conditions, improved content uniformity, reduced degradation products, or a demonstrated pharmacokinetic or tolerability advantage.

What is the Orange Book status and patent outlook?

Ergotamine-caffeine is a legacy product category with no expected remaining new chemical entity exclusivity. Any current U.S. regulatory strategy would likely depend on the status of an applicable reference product, the availability of an approved product for ANDA comparison, or a 505(b)(2) pathway for a materially different dosage form.

Exclusivity or patent category	Likely position for ergotamine-caffeine
New chemical entity exclusivity	Expired or unavailable
Orphan exclusivity	Not generally applicable
Pediatric exclusivity	Not expected to be commercially relevant
Composition-of-matter patent	Historical patents, if any, are expected to be expired
Formulation patent	Possible only for a later-developed product or new delivery system
Method-of-use patent	Possible but narrow and vulnerable to validity challenges
Orange Book strategy	Product-specific; depends on the current reference listing and any listed patents

The Orange Book is the controlling source for listed patents and exclusivity associated with an approved reference product.[2] Patent expiration cannot be inferred solely from the historical age of the active ingredients. A commercial filing requires a product-specific review of approved labeling, listed patents, discontinued-product status, and FDA application history.

When does generic entry occur and what Paragraph IV risks exist?

A standard immediate-release tablet may be suitable for an ANDA if an eligible reference product exists and the proposed product matches the reference in active ingredients, strength, dosage form, route, and conditions of use. If the reference product is discontinued or unsuitable for an ANDA pathway, a 505(b)(2) application may be more practical.

Potential Paragraph IV risk is generally low for the old active ingredients but can be material for a newly patented formulation. Risks arise from:

• A formulation patent covering a defined excipient system
• A patent claiming sublingual or buccal administration
• A patent covering a stability-enhancing package
• A method-of-use patent directed to a restricted patient group
• A patent covering an ergotamine product combined with an antiemetic or other active

A generic applicant could challenge an asserted formulation patent through Paragraph IV certification, inter partes review, district-court litigation, or a non-infringement position based on excipient differences. A launch at risk would depend on the patent’s claim scope, Orange Book listing, injunction prospects, and expected damages.

Which excipients create manufacturing and regulatory barriers?

The central CMC risk is not excipient novelty. It is control of a highly potent, low-dose active in a multicomponent blend.

Manufacturing barriers

Key development controls include:

1. Particle-size control for ergotamine tartrate and caffeine.
2. Prevention of segregation during transfer and compression.
3. Blend uniformity and tablet content-uniformity testing.
4. Control of polymorphism and solid-state behavior.
5. Protection from moisture, light, and excessive heat.
6. Cleaning validation for a potent vasoconstrictive alkaloid.
7. Control of degradation products and extractables from packaging.
8. Stability testing under long-term and accelerated conditions.

Excipient suppliers should be qualified for compendial grade, residual solvents, elemental impurities, microbial quality, and supply continuity. A dual-source strategy is important for mannitol, microcrystalline cellulose, crospovidone, coating polymers, and high-barrier blister materials.

Regulatory barriers

FDA review will focus on pharmaceutical equivalence, bioequivalence, dissolution, impurities, stability, labeling, and manufacturing controls. Novel routes or dosage forms increase the likelihood of pharmacokinetic, clinical, human-factors, and local-tolerability requirements.

A 505(b)(2) product may create more freedom for a differentiated formulation but also increases development cost. The sponsor must establish the relevance of the reference product and support any new clinical or pharmacokinetic claims.[3]

How does ergotamine-caffeine compare with newer migraine products?

Attribute	Ergotamine-caffeine	Triptans	Gepants	Ditans
Mechanism	Ergot alkaloid vasoconstriction	5-HT1B/1D agonism	CGRP receptor antagonism	5-HT1F agonism
Route options	Oral, sublingual, rectal, historical injectable	Oral, nasal, injectable	Oral, orally disintegrating, nasal under development	Oral
Vascular restrictions	Significant	Significant, depending on agent	Lower vascular concern	Lower vascular concern, but driving restrictions may apply
Patent position	Mature and weak	Mixed, many generic products	Stronger residual branded estates	Product-specific
Price position	Low-cost legacy therapy	Generic to branded	Mostly branded	Branded
Differentiation potential	Delivery, stability, access	Route and tolerability	Convenience and safety	Non-vasoconstrictive profile

Ergotamine-caffeine cannot compete effectively on broad safety or convenience. It can compete on low acquisition cost, established clinical familiarity, and specialized delivery where newer products are unavailable, contraindicated, or unaffordable.

What licensing and commercial opportunities exist?

The most attractive licensing targets are formulation platforms rather than the active ingredients themselves.

Higher-value opportunities

• An orally disintegrating or sublingual tablet with validated rapid administration
• A stable, low-dose, high-content-uniformity tablet with lower manufacturing cost
• A rectal rescue formulation with improved patient acceptability
• A fixed-dose product with an antiemetic, subject to clinical and regulatory feasibility
• A regional product in markets where triptans and gepants have limited access
• A contract-manufacturing package with validated containment and low-dose blending

Lower-value opportunities

• A conventional tablet using standard excipients without a measurable benefit
• A simple relaunch of a legacy product without reliable supply
• A product dependent on broad method-of-use claims
• A reformulation that increases price without reducing administration burden or improving stability

Revenue exposure is likely modest compared with modern migraine brands. The addressable opportunity is strongest where the product can secure hospital formulary access, government tenders, or low-cost generic distribution. A sponsor should prioritize unit economics, manufacturing reliability, and regulatory pathway selection over a large patent portfolio.

How strong is the patent estate for ergotamine tartrate and caffeine?

The estate is weak for the old active-ingredient combination and potentially moderate for a genuinely differentiated dosage form. Patent strength depends on claim specificity and experimental support.

Estate component	Strength assessment
Old active combination	Low
Conventional immediate-release tablet	Low
Novel sublingual or buccal matrix	Moderate
Stability and packaging claims	Low to moderate
Manufacturing process	Moderate if difficult to design around
New combination with antiemetic	Moderate, with higher clinical risk
Narrow method-of-use claim	Low to moderate

The best freedom-to-operate position would combine a non-infringing excipient system, an independently validated manufacturing process, and a dosage form that does not rely on broad claims covering all ergotamine-caffeine products.

Key Takeaways

• Ergotamine tartrate and caffeine is a mature, low-cost migraine product with limited expected exclusivity value.
• The strongest commercial opportunity is a differentiated dosage form, especially sublingual or orally disintegrating delivery.
• Excipient strategy should prioritize low-dose content uniformity, rapid disintegration, taste masking, moisture protection, and supply redundancy.
• Conventional tablet reformulation alone is unlikely to justify meaningful pricing power.
• A standard generic may fit the ANDA pathway if an eligible reference product is available; a novel dosage form may require 505(b)(2) development.
• Formulation and process patents can provide protection, but broad claims covering conventional excipients are vulnerable.
• Vascular contraindications and drug-interaction risks materially limit market expansion.
• Licensing value is concentrated in delivery technology, manufacturing capability, and reliable supply rather than in the active ingredients.

FAQs

Can mannitol improve an ergotamine-caffeine orally disintegrating tablet?

Yes. Mannitol can provide a pleasant mouthfeel, low hygroscopicity, and suitable compressibility. Its use must be balanced against tablet friability, segregation, and the bitter taste of ergotamine and caffeine.

Is a fixed-dose ergotamine-caffeine product with an antiemetic commercially attractive?

It may be attractive for patients whose migraines include nausea or vomiting. The combination would require new compatibility, stability, pharmacokinetic, safety, and labeling work, and it could move development beyond a simple generic strategy.

Can a sponsor obtain patent protection for a new excipient blend?

Yes, but the claim must contain a non-obvious technical relationship and measurable performance. A routine substitution of one binder, diluent, or disintegrant for another is unlikely to provide durable protection.

Is a preservative needed in an ergotamine-caffeine tablet?

No. Preservatives are generally unnecessary in a dry solid dosage form. They may become relevant in an aqueous liquid, multidose suspension, or other water-containing presentation.

What is the main investor risk in an ergotamine-caffeine launch?

The main risk is limited market size combined with regulatory and manufacturing costs. A conventional product may face low prices and generic competition, while a novel product may require clinical investment without overcoming the active ingredient’s vascular safety limitations.

References

1. U.S. Food and Drug Administration. (2013). Cafergot: Prescribing information. FDA.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, 44th edition. FDA.
3. U.S. Food and Drug Administration. (2023). Applications covered by section 505(b)(2). FDA.
4. U.S. Food and Drug Administration. (2024). Guidance for industry: ANDAs for certain highly purified synthetic drug substances. FDA.
5. National Library of Medicine. (2024). DailyMed: Ergotamine tartrate and caffeine product labeling. U.S. National Library of Medicine.