List of Excipients in Branded Drug RYZOLT

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Company	Tradename	Ingredient	NDC	Excipient	Potential Generic Entry
Stat Rx USA	RYZOLT	tramadol hydrochloride	16590-244	MAGNESIUM STEARATE
Stat Rx USA	RYZOLT	tramadol hydrochloride	16590-244	POVIDONE
Stat Rx USA	RYZOLT	tramadol hydrochloride	16590-244	SILICON DIOXIDE
Stat Rx USA	RYZOLT	tramadol hydrochloride	16590-244	SODIUM LAURYL SULFATE
Stat Rx USA	RYZOLT	tramadol hydrochloride	16590-244	XANTHAN GUM

RYZOLT Excipient Strategy, Patent Position, and Commercial Opportunities

Last updated: August 26, 2026

RYZOLT was a once-daily extended-release tramadol hydrochloride tablet approved by the FDA under NDA 021676. Its commercial opportunity is now primarily generic and reformulation-driven because the branded product is no longer marketed and the core active ingredient, tramadol, is long generic. The most attractive excipient opportunities involve hydrophilic matrix release, robust dissolution control, alcohol-resistant performance, and lower-cost manufacturing rather than recovery of the original brand.

What was RYZOLT and how was it formulated?

RYZOLT contained tramadol hydrochloride in 100 mg, 200 mg, and 300 mg extended-release tablets. The product was designed for once-daily administration, in contrast with immediate-release tramadol products that generally require multiple daily doses. The FDA approved RYZOLT in 2008 under NDA 021676. [1]

The formulation used a controlled-release tablet architecture based on a hydrophilic polymer matrix. In this design, gastrointestinal fluid penetrates the tablet, hydrates the polymer, and forms a gel layer that controls drug diffusion and matrix erosion.

RYZOLT product profile

Attribute	RYZOLT profile
Active ingredient	Tramadol hydrochloride
Dosage form	Extended-release tablet
Strengths	100 mg, 200 mg, 300 mg
Administration	Once daily
FDA application	NDA 021676
Therapeutic area	Moderate to moderately severe chronic pain
Controlled-substance status	Schedule IV opioid in the United States
Branded commercial status	Discontinued from marketing
Primary successor opportunity	Generic tramadol extended-release or differentiated once-daily formulations

The product label identified conventional pharmaceutical excipients associated with matrix-tablet manufacture and film coating, including hypromellose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, and coating components. Exact excipient composition should be taken from the approved product labeling and historical regulatory records because inactive-ingredient listings can differ by strength or manufacturing site. [1, 2]

What excipients are strategically important for a RYZOLT-type product?

The highest-value excipient category is controlled-release hypromellose. Polymer viscosity, particle size, substitution type, and concentration determine gel formation, release rate, tablet robustness, and sensitivity to agitation.

Core excipient categories

Excipient category	Function in the dosage form	Commercial relevance
Hypromellose	Hydrophilic matrix and release control	Core technology input; multiple viscosity grades may be evaluated
Microcrystalline cellulose	Diluent, compression aid, structural support	Supports direct compression and cost control
Lactose or other soluble filler	Dilution and matrix porosity	Can accelerate hydration and release
Colloidal silicon dioxide	Flow aid and moisture-control aid	Important for blend uniformity
Magnesium stearate	Lubrication	Excessive use can slow hydration and impair dissolution
Povidone or crospovidone	Binder or disintegration modifier	Useful in process optimization but may alter release
Film-coating polymers	Appearance, protection, swallowability	Opportunity for aqueous coating systems
Plasticizers and pigments	Coating flexibility and identification	Limited differentiation unless tied to stability or branding

Excipient selection must be treated as a release-design problem. A higher-viscosity hypromellose grade can reduce the need for complex manufacturing but may increase tablet size, compression sensitivity, and residual drug release. Lower-viscosity grades can improve manufacturability but may require higher polymer loading or additional matrix modifiers.

What formulation patents protected RYZOLT?

The relevant historic protection centered on controlled-release tramadol compositions and dosage forms rather than on a novel tramadol molecule. Tramadol itself is off-patent, so any surviving protection would have been directed to formulation architecture, release characteristics, manufacturing processes, or specific therapeutic uses.

The principal freedom-to-operate questions for a RYZOLT-type development are:

1. Whether any listed or unlisted formulation patent remained enforceable during the proposed launch period.
2. Whether the proposed tablet reproduces a claimed polymer matrix or release profile.
3. Whether a generic applicant can design around the original matrix composition.
4. Whether any method-of-use claims cover chronic pain treatment or once-daily dosing.
5. Whether the proposed product would rely on the RYZOLT reference listed drug through an ANDA or require a different regulatory route.

The FDA Orange Book should be used to confirm historic patent listings associated with NDA 021676 and the current status of any listed patents. The absence of a current marketed brand does not, by itself, eliminate patent or regulatory obligations. [3]

When did RYZOLT lose exclusivity and when could generics enter?

RYZOLT’s commercial exclusivity was primarily a historical issue. The active ingredient had already been marketed in immediate-release products for years before RYZOLT approval. Any new-drug exclusivity attached to the extended-release product would have run from FDA approval, while patent protection would have depended on formulation and use patents.

Exclusivity timeline

Event	Timing
Tramadol immediate-release products established	Before RYZOLT
RYZOLT FDA approval	2008
New-drug exclusivity period	Historical; linked to the 2008 approval
Branded product discontinuation	Historical
Generic opportunity	Available through ANDA or other applicable pathway, subject to current Orange Book and regulatory requirements
Current commercial position	No meaningful branded protection is expected to block development solely because of RYZOLT branding

A generic sponsor would normally evaluate a 505(j) ANDA using the RYZOLT product, if FDA records identify it as the appropriate reference listed drug. The applicant would need to address extended-release bioequivalence, food effects, dose proportionality, alcohol interaction, and discriminatory dissolution testing. [4]

What Paragraph IV challenges affected RYZOLT?

A Paragraph IV challenge is relevant only where an ANDA applicant certifies that a listed patent is invalid, unenforceable, or will not be infringed. Historic RYZOLT litigation should be confirmed through FDA patent records, PACER, and commercial patent databases before being used in a launch model.

There is no basis to treat RYZOLT as an active, high-value litigation franchise today. The product’s commercial discontinuation and the age of its approval reduce the likelihood that historic formulation patents would support a durable branded defense. The greater present risk is technical rather than litigation-based: a generic formulation may fail extended-release bioequivalence or dissolution requirements.

Key Paragraph IV issues

• Matrix release claims may be vulnerable to invalidity arguments based on prior controlled-release tramadol technology.
• A design-around using a different polymer grade, excipient ratio, granulation process, or release mechanism may reduce infringement risk.
• Method-of-use patents have less commercial value where chronic pain treatment and tramadol use are already well established.
• Patent-term calculations must account for patent-term adjustment, terminal disclaimers, and any post-grant proceedings.
• Historic settlement agreements, if any, require review for launch dates, authorized-generic rights, and restrictions on formulation changes.

What is the Orange Book status of RYZOLT?

The Orange Book is the controlling source for current reference-product designation, patent listings, exclusivity codes, and discontinued-product status. FDA records identify RYZOLT as a discontinued product rather than a currently marketed branded growth asset. [3]

A discontinued product can still have regulatory significance if FDA maintains it as a reference listed drug or if the product remains suitable for ANDA reliance. The commercial value of RYZOLT therefore depends on whether an applicant can establish a workable reference-product and bioequivalence strategy, not on the former brand’s sales alone.

FDA regulatory considerations

A RYZOLT-type generic must address:

• Extended-release in vivo bioequivalence.
• Fed and fasting conditions.
• Dose strength selection and proportionality.
• Alcohol-induced release acceleration.
• In vitro dissolution across multiple pH conditions.
• Manufacturing scale effects.
• Tablet splitting or crushing risks.
• Tramadol’s opioid and serotonergic safety profile.
• Controlled-substance registration and distribution controls.

FDA guidance for extended-release and long-acting opioid products places particular emphasis on abuse-related risks, food effects, and unintended rapid release. [5]

What commercial opportunities exist for excipient suppliers?

The strongest opportunity is not the supply of a single commodity excipient. It is a formulation platform that reduces development time and improves regulatory reproducibility.

1. High-viscosity hypromellose platforms

Suppliers can offer grade-selection packages for 100 mg, 200 mg, and 300 mg strengths. The commercial proposition includes:

• Controlled hydration.
• Consistent viscosity after processing.
• Reduced sensitivity to lubricant concentration.
• Comparable dissolution across scale-up batches.
• Availability from more than one qualified manufacturing site.

A supplier that can demonstrate equivalent performance across polymer grades may help a generic manufacturer avoid dependence on one source.

2. Direct-compression excipient systems

A co-processed filler or flow-enhancing system could reduce wet granulation requirements and improve manufacturing economics. The value proposition is strongest where the high drug load creates poor flow, weak tablets, or segregation risk.

3. Alcohol-resistant release systems

A formulation that maintains controlled release in ethanol-containing media can reduce dose-dumping concerns. Potential approaches include:

• Higher-viscosity polymer matrices.
• Polymer combinations with stronger gel integrity.
• Insoluble matrix modifiers.
• Coatings that reduce surface erosion.
• Multiparticulate systems with controlled membrane release.

Any such claim must be supported by comparative dissolution and safety data. An excipient supplier should avoid marketing a product as abuse-deterrent without evidence that meets applicable FDA standards.

4. Taste, swallowability, and patient-compliance improvements

Large once-daily opioid tablets can create swallowing problems. Film coatings, tablet-shape optimization, and lower-density matrices may reduce tablet burden. These changes can have commercial value even when they do not create independent patent protection.

5. Manufacturing risk reduction

The most practical excipient opportunity may involve process robustness:

• Lower sensitivity to magnesium stearate mixing time.
• Improved ejection force.
• Reduced sticking and picking.
• Better content uniformity.
• Stable release after accelerated storage.
• Reduced tablet weight variability.

These benefits are valuable to generic manufacturers because extended-release products can fail during scale-up even when laboratory dissolution is acceptable.

How strong is the patent estate for a RYZOLT-type formulation?

The patent estate is likely weak as a barrier to a conventional generic but can remain relevant for specific release architectures. A basic hydrophilic matrix using widely known excipients is difficult to protect broadly. Narrow claims may still cover particular polymer ratios, dissolution profiles, manufacturing steps, or combinations of excipients.

Patent-strength assessment

Claim area	Likely barrier strength	Commercial assessment
Tramadol active ingredient	Very low	Generic and widely available
Basic hypromellose matrix	Low	Prior art is extensive
Specific polymer ratio	Low to moderate	Depends on claim scope and prosecution history
Defined dissolution profile	Moderate	May create bioequivalence and infringement issues
Alcohol-resistant release	Moderate	More defensible if supported by unexpected results
Manufacturing process	Low to moderate	Relevant if process is difficult to design around
Method of use	Low	Crowded chronic-pain field
Novel multiparticulate or abuse-deterrent system	Moderate to high	Depends on technical evidence and claim drafting

A new excipient combination may offer better commercial protection than a simple product-by-process claim. The strongest filing strategy would link composition, manufacturing parameters, dissolution behavior, and clinical performance while preserving multiple design-around positions.

How does RYZOLT compare with competing tramadol products?

Product type	Dosing	Formulation opportunity	Competitive position
Immediate-release tramadol	Multiple daily doses	Conventional tablet or capsule	Low cost, extensive generic competition
RYZOLT-type extended release	Once daily	Hydrophilic matrix or other controlled-release system	Differentiated adherence and release profile
Other extended-release tramadol products	Once daily	Matrix, multiparticulate, or dual-release designs	Compete on bioequivalence, price, and supply
Combination analgesics	Variable	Immediate or modified release	Compete through efficacy, tolerability, and prescribing restrictions

The commercial advantage of once-daily tramadol is limited by the maturity of the opioid market, generic pricing pressure, and tightening prescribing controls. A new product needs a clear benefit in adherence, tolerability, abuse-risk management, or manufacturing cost.

What generic launch scenarios exist?

Conventional ANDA launch

This is the lowest-cost pathway if RYZOLT remains a usable reference product and no blocking patent remains. The principal risks are extended-release bioequivalence, dissolution failure, and limited market size.

Paragraph IV launch

A Paragraph IV launch could create earlier market entry where listed formulation patents remain. The economics depend on whether the expected market supports litigation costs. For a discontinued branded product, litigation value may be limited unless the product has a substitute market or a strategically important authorized-generic position.

505(b)(2) reformulation

A 505(b)(2) strategy may be appropriate for a new dosage form, altered release mechanism, lower abuse potential, or a clinically differentiated regimen. This pathway generally carries greater development cost than an ANDA but can support formulation-specific intellectual property.

Non-opioid or abuse-risk differentiated product

A reformulation that reduces rapid release, simplifies dosing, or improves adherence could target controlled-substance prescribers and institutional buyers. The product would still face the underlying limitations of tramadol’s opioid and serotonergic pharmacology.

What revenue exposure does RYZOLT create today?

RYZOLT should not be modeled as a significant branded-revenue asset without current sales evidence. Its value is better assessed through addressable generic tramadol extended-release volume, expected reimbursement, manufacturing cost, and the probability of regulatory approval.

A commercial model should include:

• Prescription volume for extended-release tramadol.
• Average selling price after generic entry.
• Number of approved competitors.
• API and excipient cost per tablet.
• Cost of controlled-substance compliance.
• Bioequivalence and clinical development expense.
• Probability and timing of launch.
• Substitution from immediate-release tramadol.
• Payer restrictions and opioid-prescribing trends.

Key Takeaways

• RYZOLT was a once-daily extended-release tramadol hydrochloride tablet approved in 2008 under NDA 021676.
• Its formulation strategy relied on controlled release rather than a novel active ingredient.
• The main excipient opportunity is a robust hydrophilic matrix platform based on hypromellose and compression-support excipients.
• Current commercial value is generic and reformulation-driven because the branded product is discontinued.
• The likely patent barrier is low for a conventional matrix tablet but may be higher for alcohol-resistant, multiparticulate, or technically differentiated systems.
• Generic developers must focus on extended-release bioequivalence, dissolution, food effects, alcohol interaction, and manufacturing scale-up.
• Excipient suppliers can compete through polymer-grade consistency, co-processed direct-compression systems, and manufacturing-risk reduction.
• Revenue exposure should be modeled from current extended-release tramadol demand, not historic RYZOLT brand sales.

FAQs About RYZOLT Excipient and Commercial Strategy

What is the most important excipient in a RYZOLT generic?

Hypromellose is the most important release-controlling excipient in a conventional RYZOLT-type hydrophilic matrix tablet. Its viscosity grade, concentration, and processing conditions can materially change the dissolution profile.

Can a generic manufacturer use a different polymer from the original RYZOLT formulation?

Yes, a different polymer or polymer combination may be used if the product meets FDA bioequivalence and quality requirements and does not infringe enforceable formulation claims.

Is RYZOLT an abuse-deterrent opioid?

RYZOLT was an extended-release tramadol product, but extended release alone does not establish FDA abuse-deterrent labeling. Abuse-deterrent status requires a formulation and regulatory determination supported by applicable evidence.

Does RYZOLT have biosimilar risk?

No. Tramadol is a small-molecule drug, not a biologic. The relevant competition is from generic ANDA products and potentially 505(b)(2) reformulations, not biosimilars.

Which geographic markets are most relevant for a RYZOLT-type product?

The United States is the most relevant market for Orange Book, ANDA, controlled-substance, and Paragraph IV analysis. Europe and other markets require separate review of national or regional reference products, formulation patents, regulatory classifications, and opioid controls.

References

1. U.S. Food and Drug Administration. (2008). RYZOLT (tramadol hydrochloride) extended-release tablets: Prescribing information. NDA 021676.

2. National Library of Medicine. (n.d.). DailyMed: RYZOLT tramadol hydrochloride extended-release tablet labeling. U.S. National Library of Medicine.

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

4. U.S. Food and Drug Administration. (2009). Guidance for industry: Bioequivalence recommendations for specific products. Center for Drug Evaluation and Research.

5. U.S. Food and Drug Administration. (2015). Guidance for industry: Abuse-deterrent opioids: Evaluation and labeling. Center for Drug Evaluation and Research.