List of Excipients in Branded Drug RAMELTEON

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Generic Drugs Containing RAMELTEON

Company	Ingredient	NDC	Excipient
Actavis Pharma Inc	ramelteon	0591-2191	FD&C YELLOW NO. 6
Actavis Pharma Inc	ramelteon	0591-2191	HYDROXYPROPYL CELLULOSE
Actavis Pharma Inc	ramelteon	0591-2191	HYPROMELLOSES
Actavis Pharma Inc	ramelteon	0591-2191	LACTOSE MONOHYDRATE
Actavis Pharma Inc	ramelteon	0591-2191	MAGNESIUM STEARATE

What are the Most Frequently-Used Excipients in RAMELTEON?

# Of NDCs	Excipient
7	ANHYDROUS LACTOSE
2	COPOVIDONE
11	COPOVIDONE K25-31
10	CROSCARMELLOSE SODIUM
9	CROSPOVIDONE

Ramelteon Excipient Strategy and Commercial Opportunities

Last updated: August 22, 2026

Ramelteon is a low-dose, immediate-release melatonin MT1/MT2 receptor agonist with an established generic market and limited remaining protection for the original tablet. The strongest excipient-driven opportunities are orally disintegrating tablets, taste-masked pediatric or geriatric products, and bioavailability-enhanced formulations. A conventional 8 mg tablet remains the lowest-risk commercial product, but price competition is substantial. New products must create measurable clinical, administration, adherence, or pharmacokinetic value rather than rely on routine excipient substitution.

What is the FDA status of ramelteon?

Ramelteon was approved by the FDA as Rozerem 8 mg tablets in 2005 for insomnia characterized by difficulty with sleep onset.[1] It is a prescription drug, not a controlled substance, and its mechanism differs from benzodiazepine receptor agonists and dual orexin receptor antagonists.

Attribute	Ramelteon
Active ingredient	Ramelteon
Original brand	Rozerem
Original sponsor	Takeda Pharmaceuticals
Dosage form	Immediate-release oral tablet
Strength	8 mg
FDA approval	2005
Therapeutic category	Insomnia treatment, melatonin receptor agonist
Controlled-substance status	Not scheduled federally
Main administration issue	Oral tablet swallowing and adherence
Main formulation issue	Poor aqueous solubility and low-dose content uniformity

The approved label instructs patients to take ramelteon within 30 minutes of bedtime and not with or immediately after a high-fat meal.[2] The product is not intended for administration with alcohol. Ramelteon is metabolized primarily by CYP1A2, and strong CYP1A2 inhibitors such as fluvoxamine are clinically relevant interaction risks.[2]

Generic ramelteon tablets have entered the U.S. market. The original five-year new chemical entity exclusivity expired years ago, and the commercial market is no longer protected by the original brand exclusivity period.[3] Current patent and approval status should be checked against the FDA Orange Book and Drugs@FDA before a launch or licensing decision.[4,5]

What excipients are used in the original Rozerem tablet?

The original Rozerem tablet uses a conventional immediate-release excipient platform. Public product information identifies lactose monohydrate, starch, hydroxypropyl cellulose, and magnesium stearate in the tablet core, with film-coating components listed in product labeling.[2]

The formulation strategy is commercially conservative:

• Lactose provides bulk for the 8 mg dose.
• Starch supports tablet structure and disintegration.
• Hydroxypropyl cellulose functions as a binder.
• Magnesium stearate provides lubrication.
• Film coating improves handling, appearance, and swallowability.

This platform is easy to manufacture with direct compression or a wet-granulation process, depending on the selected grades and material flow properties. It does not appear to depend on an unusually complex delivery system. That reduces formulation barriers for generic manufacturers but also limits differentiation based solely on excipient selection.

What are the key physicochemical formulation constraints?

Ramelteon has a low oral dose but limited aqueous solubility. The low dose reduces the quantity of active ingredient needed per tablet, while the solubility profile can still affect dissolution, absorption, and formulation robustness. The principal development objectives are rapid disintegration, reproducible dissolution, chemical stability, and uniform distribution of the active ingredient.

Solubility and dissolution

Potential approaches include:

• Micronized or nanomilled ramelteon.
• Amorphous solid dispersions.
• Surfactant-assisted wetting.
• Cyclodextrin complexation.
• Lipid-based or self-emulsifying systems.
• Co-processed excipient systems that improve powder dispersion.

For an 8 mg immediate-release product, a full lipid system or complex amorphous dispersion may be commercially excessive unless it produces a clear improvement in food-effect performance, onset, or dose flexibility. A simpler approach using particle-size control, a superdisintegrant, and a hydrophilic wetting system is more likely to offer an attractive cost-to-benefit ratio.

Content uniformity

Because ramelteon is a low-dose drug, blend uniformity and segregation control are important. A high-dilution formulation increases the risk of content-uniformity failures if particle size, density, or surface properties differ materially between ramelteon and the excipients.

Useful controls include:

• Geometric dilution or ordered blending.
• Low-segregation excipient grades.
• Granulation where direct blending is unreliable.
• In-process near-infrared monitoring.
• Tight control of ramelteon particle size and morphology.

A formulation patent based only on replacing lactose with microcrystalline cellulose is likely to have limited defensibility. A stronger patent position would connect excipient selection to a defined dissolution profile, stability result, bioavailability outcome, or manufacturing advantage.

Which excipient platforms offer the best commercial opportunities?

Orally disintegrating tablets

An orally disintegrating tablet is the clearest differentiated opportunity. The target populations include older adults with dysphagia, patients who resist conventional tablets, and users seeking administration without water.

A practical ODT platform could use:

• Mannitol for mouthfeel and compactability.
• Crospovidone or croscarmellose sodium for rapid disintegration.
• Low-substituted hydroxypropyl cellulose for swelling and wicking.
• Colloidal silicon dioxide for flow control.
• Sucralose or another permitted sweetener for taste management.
• A flavor system selected after sensory testing.
• A low level of lubricant to avoid slowing disintegration.

Ramelteon has a bitter or otherwise unfavorable oral sensory profile risk typical of low-dose active pharmaceutical ingredients. Taste masking may require polymer coating, ion-complexation, a lipid barrier, or a multiparticulate approach. The commercial value of an ODT depends on whether the product has acceptable taste, disintegrates rapidly, and maintains bioequivalence or a clinically justified exposure profile.

Sublingual or buccal products

Sublingual and buccal ramelteon products could target rapid sleep-onset treatment. The opportunity is technically plausible but commercially more difficult. The approved product is already used at bedtime, and faster onset must translate into a meaningful patient or prescriber benefit.

Key risks include:

• Variable residence time in the mouth.
• Swallowed dose variability.
• Irritation or unpleasant taste.
• Higher sensitivity to formulation-driven exposure changes.
• Need for a new drug application or 505(b)(2) regulatory strategy rather than a conventional ANDA if the dosage form differs materially from the reference product.

A sublingual product should not be positioned solely as a faster version of the tablet unless pharmacokinetic and clinical data establish the benefit.

Oral liquid or granules

An oral solution, suspension, or reconstitutable granule could support patients who cannot swallow tablets and could open pediatric or institutional channels. Ramelteon’s low solubility makes a simple aqueous solution less attractive. A suspension or multiparticulate system may be more practical.

Candidate excipient functions include:

• Suspending agents such as xanthan gum or microcrystalline cellulose-carboxymethylcellulose systems.
• Wetting agents to prevent floating and clumping.
• Buffer systems for chemical stability.
• Preservatives if supplied as a multidose liquid.
• Flavor and sweetener systems.
• Antioxidants only where justified by degradation data.

A liquid formulation creates packaging, microbial-control, dosing-device, and stability costs. It is more likely to succeed in a defined dysphagia, long-term-care, or pediatric market than as a broad replacement for an inexpensive tablet.

Multiparticulates and sprinkle formulations

Coated granules or pellets in a capsule or sachet could provide administration flexibility. The formulation could be designed for sprinkling on soft food while preserving immediate release.

This platform may protect:

• Polymer-coated ramelteon particles.
• A defined release profile.
• A multiparticulate size distribution.
• A food-compatible administration method.
• A manufacturing process that limits dose segregation.

Sprinkle products require careful evaluation of dose recovery, stability after opening, adhesion to food, and whether chewing changes exposure.

How should excipients be selected for a generic ramelteon tablet?

A generic manufacturer should prioritize bioequivalence, manufacturing yield, and cost rather than pursue unnecessary formulation complexity.

Development objective	Preferred excipient strategy	Main risk
Rapid dissolution	Superdisintegrant plus controlled particle size	Excessive lubricant or hydrophobic coating can slow release
Content uniformity	Ordered blending or controlled granulation	Segregation during compression and transfer
Tablet robustness	Lactose, starch, microcrystalline cellulose, or co-processed filler	Hardness may delay disintegration
Flow	Colloidal silicon dioxide or engineered excipient grade	Overuse can impair compactability
Swallowability	Thin film coat and optimized tablet geometry	Coating can add dissolution variability
Low-cost manufacturing	Direct compression where blend properties permit	Ramelteon dilution and segregation
Lactose-free positioning	Microcrystalline cellulose, mannitol, or dibasic calcium phosphate	Different dissolution and compaction behavior
ODT development	Mannitol, crospovidone, flavor, sweetener	Taste masking and friability

A lactose-free tablet could have commercial relevance for institutional purchasing or patients with lactose sensitivity, but lactose in a conventional tablet is generally present at an amount far below dietary exposure levels. The claim must be commercially validated rather than assumed.

What patents protect ramelteon formulations?

The original ramelteon patent estate included composition-of-matter and drug-related patent filings associated with Takeda. The principal U.S. composition patent commonly associated with ramelteon is U.S. Patent No. 6,034,239.[6] The original patent term and any patent-term adjustment or extension should be confirmed through the USPTO Patent Center and FDA Orange Book records.

The strategic position is now different from the launch period:

1. Core molecule protection is historical rather than a current barrier in the U.S. generic market.
2. Routine tablet excipients are unlikely to provide durable exclusivity.
3. New opportunities depend on formulation, dosage form, manufacturing, or method-of-use claims.
4. Method-of-use claims must address written-description, enablement, obviousness, and infringement risks.
5. A new dosage form may require a 505(b)(2) application rather than an ANDA.

Potentially protectable subject matter includes:

• Specific amorphous or crystalline ramelteon forms.
• Particle-size distributions tied to dissolution or exposure.
• Taste-masked particles.
• ODT compositions with defined disintegration and dissolution limits.
• Oral liquids or suspensions with stability and preservative systems.
• Multiparticulate sprinkle formulations.
• Manufacturing processes that improve content uniformity.
• Formulations designed to reduce food-effect variability.

A patent claiming a broad list of conventional excipients is vulnerable to invalidity and design-around arguments. Commercially stronger claims should connect the excipient system to a measurable technical result.

When does ramelteon lose exclusivity, and what generic entry risks exist?

Ramelteon’s original U.S. exclusivity has expired. Generic entry risk is therefore high for standard 8 mg immediate-release tablets. The main competitive factors are manufacturing cost, supply reliability, wholesaler access, payer contracting, and the number of approved suppliers.

Risk area	Assessment
Conventional 8 mg tablet	High generic competition
ODT	Moderate development and regulatory risk
Oral liquid	Higher technical and commercial risk
Sublingual product	High clinical and regulatory differentiation burden
Novel controlled release	Limited rationale given ramelteon’s sleep-onset positioning
Biosimilar risk	Not applicable; ramelteon is a small molecule
Paragraph IV risk	Relevant only to unexpired listed patents for a particular product or formulation
Formulation patent risk	Product-specific and dependent on claim scope
Supply-chain risk	Active pharmaceutical ingredient qualification and low-volume demand can matter more than patent barriers

A Paragraph IV challenge remains relevant when an Orange Book-listed patent covers the reference product or a later-added formulation. For an old immediate-release product, the larger practical concern is often ordinary price erosion rather than patent litigation.

What FDA pathways apply to new ramelteon products?

A conventional 8 mg tablet that references Rozerem can generally pursue an ANDA if it meets sameness, bioequivalence, quality, and labeling requirements.[7] A materially different dosage form or route may require a 505(b)(2) application.

Product concept	Likely pathway	Evidence burden
Conventional 8 mg tablet	ANDA	Pharmaceutical equivalence and bioequivalence
Lactose-free tablet	ANDA if equivalent and appropriately supported	Bioequivalence and quality comparability
ODT	Often 505(b)(2), depending on reference and formulation	PK, clinical bridge, usability, and quality data
Oral suspension	505(b)(2) likely	PK, stability, dosing accuracy, microbial control
Sublingual tablet	505(b)(2) likely	PK and clinical justification
Pediatric product	505(b)(2) or supplemental development	Pediatric safety, dosing, palatability, and efficacy support

FDA guidance for 505(b)(2) applications allows reliance in part on FDA findings for an approved product while requiring support for the product’s differences.[8] An excipient change alone does not guarantee regulatory exclusivity. Any commercial strategy should align formulation claims with a defensible clinical or administration benefit.

Which companies are competing in the ramelteon market?

The market includes Takeda’s branded Rozerem and generic manufacturers supplying ramelteon tablets. Generic suppliers can compete through:

• Low manufacturing cost.
• Multiple package sizes.
• Reliable wholesaler supply.
• Authorized-generic or brand-equivalent arrangements.
• Contract manufacturing.
• State Medicaid and managed-care access.

The competitive landscape is broader than ramelteon. Insomnia products include generic zolpidem, eszopiclone, zaleplon, doxepin, suvorexant, lemborexant, daridorexant, and over-the-counter melatonin. Ramelteon’s commercial differentiation is its melatonin-receptor mechanism and noncontrolled status, while its limitations include narrow positioning around sleep onset and lack of a strong formulation franchise.

What licensing and partnership opportunities exist?

Licensing opportunities are more credible for a differentiated dosage form than for a standard tablet. Potential partners include:

• Specialty pharmaceutical companies focused on sleep medicine.
• Generic companies with 505(b)(2) development capabilities.
• Pediatric and geriatric formulation specialists.
• Contract development and manufacturing organizations.
• Companies with ODT, taste-masking, or multiparticulate platforms.

The most licensable assets would include a patent family, reproducible manufacturing process, comparative pharmacokinetic data, and a defined target population. A formulation that only reduces tablet cost is more likely to support a supply or contract-manufacturing agreement than a high-value royalty license.

How strong is the ramelteon patent estate?

The legacy estate is weak as a barrier to standard U.S. generic tablets because the product has been marketed for nearly two decades and generic competition exists. New formulation patents could still have value, but their strength depends on claim specificity and demonstrated performance.

Patent category	Current strategic value
Composition of matter	Low for U.S. exclusivity after historical expiration
Conventional immediate-release tablet	Low unless a narrow unexpired claim exists
ODT and taste masking	Moderate if supported by strong data
Oral liquid or suspension	Moderate, with higher regulatory costs
Sublingual delivery	Moderate to high legal risk and evidence burden
Manufacturing process	Moderate if it creates a difficult-to-replicate quality advantage
Method of use	Variable and vulnerable to labeling and enforceability issues
International formulation rights	Potentially valuable where generic penetration is lower

Geographic strategy should distinguish the United States from Europe, Japan, and emerging markets. Patent status, regulatory exclusivity, reference-product requirements, and reimbursement conditions differ by country. A global license should not assume that U.S. patent expiration determines freedom to operate elsewhere.

What is the commercial outlook for ramelteon excipient innovation?

The best near-term opportunity is a differentiated oral product that solves a concrete administration problem without materially increasing cost. An ODT with acceptable taste and reliable bioequivalence has the strongest balance of technical feasibility and market differentiation.

The weakest opportunity is a complex controlled-release product. Ramelteon is used for sleep onset, and the original immediate-release dosage form already fits that use. Extending exposure could increase development cost without improving the core therapeutic proposition.

A practical development sequence is:

1. Optimize an immediate-release generic tablet for cost and supply reliability.
2. Screen ODT platforms using mannitol, superdisintegrants, and taste-masking technologies.
3. Evaluate a sprinkle or multiparticulate format for dysphagia populations.
4. Develop an oral liquid only if a defined institutional or pediatric market justifies the added controls.
5. Reserve sublingual development for a program with demonstrated onset or adherence advantages.

Key Takeaways

• Ramelteon is an established, noncontrolled insomnia drug with generic competition.
• The original Rozerem formulation uses a conventional tablet excipient system.
• Standard 8 mg tablets have limited differentiation and high price pressure.
• ODT, taste-masked, sprinkle, and oral-liquid products offer the clearest excipient-driven opportunities.
• Low-dose content uniformity, poor solubility, dissolution, taste, and food-effect performance are the main formulation variables.
• Ramelteon is a small molecule, so biosimilar risk is not applicable.
• New commercial value will depend on measurable administration or pharmacokinetic benefits.
• A conventional generic can use the ANDA pathway; materially different dosage forms will generally require a 505(b)(2) strategy.
• Formulation patents should claim a defined technical effect, not merely a broad list of conventional excipients.
• The strongest partnership asset would combine formulation IP, bioequivalence or PK data, and a focused patient segment.

FAQs

Can ramelteon be formulated as an orally disintegrating tablet?

Yes. An ODT can use mannitol, crospovidone or croscarmellose sodium, a taste-masking system, and a low level of lubricant. The main development risks are bitterness, friability, dissolution, and exposure comparability.

Is a ramelteon extended-release formulation commercially attractive?

Usually not. Ramelteon is positioned for sleep onset, and its immediate-release profile aligns with that use. Extended release would need to show a clear clinical benefit to justify added formulation and regulatory costs.

Can excipients eliminate ramelteon’s food effect?

Excipients may reduce formulation sensitivity to food, but they cannot be assumed to eliminate the clinically observed effect. A new product would need comparative pharmacokinetic studies under fed and fasted conditions.

Is ramelteon suitable for a pediatric liquid product?

It is technically suitable for liquid or multiparticulate development, but pediatric use would require appropriate dosing, palatability, stability, administration-device, and clinical support. The original adult tablet approval does not by itself establish pediatric use.

What is the most defensible patent strategy for a new ramelteon product?

The strongest strategy would combine a specific dosage form or excipient system with measured improvements in dissolution, taste masking, stability, food-effect control, dose uniformity, or patient administration. Broad claims covering routine excipient substitutions are less defensible.

References

1. U.S. Food and Drug Administration. (2005). Rozerem approval letter and prescribing information. FDA.

2. U.S. Food and Drug Administration. (2023). Rozerem (ramelteon) prescribing information. FDA/DailyMed.

3. U.S. Food and Drug Administration. (2024). New chemical entity exclusivity and generic drug approval resources. FDA.

4. U.S. Food and Drug Administration. (2025). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.

5. U.S. Food and Drug Administration. (2025). Drugs@FDA: FDA-approved drugs database. FDA.

6. U.S. Patent No. 6,034,239. (2000). Melatonin receptor agonist. United States Patent and Trademark Office.

7. U.S. Food and Drug Administration. (2024). Abbreviated new drug application submissions: Generic drug development guidance. FDA.

8. U.S. Food and Drug Administration. (2024). Applications covered by section 505(b)(2): Guidance for industry. FDA.