List of Excipients in Branded Drug ANNOVERA

Company	Tradename	Ingredient	NDC	Excipient	Potential Generic Entry
TherapeuticsMD Inc	ANNOVERA	segesterone acetate and ethinyl estradiol	50261-313	DIBUTYLTIN DILAURATE	2039-06-21
TherapeuticsMD Inc	ANNOVERA	segesterone acetate and ethinyl estradiol	50261-313	TITANIUM DIOXIDE	2039-06-21
Mayne Pharma	ANNOVERA	segesterone acetate and ethinyl estradiol	68308-752	DIBUTYLTIN DILAURATE	2039-06-21
Mayne Pharma	ANNOVERA	segesterone acetate and ethinyl estradiol	68308-752	TITANIUM DIOXIDE	2039-06-21

ANNOVERA Excipient Strategy and Commercial Opportunities

Last updated: September 9, 2026

ANNOVERA is a reusable, year-long vaginal contraceptive system containing segesterone acetate and ethinyl estradiol in a silicone elastomer ring. Its commercial differentiation depends less on conventional excipients than on the silicone matrix, drug-loading architecture, controlled release, biocompatibility, and repeat-use performance. The strongest opportunities are in material qualification, manufacturing efficiency, lifecycle formulations, device improvements, and generic or alternative-system development.

What is ANNOVERA and how does its formulation work?

ANNOVERA is an FDA-approved vaginal contraceptive system for the prevention of pregnancy in females of reproductive potential. The system is used for 21 days followed by seven days out of the vagina, repeated for 13 cycles, or one year.[1]

Attribute	ANNOVERA
Active ingredients	Segesterone acetate and ethinyl estradiol
Dosage form	Reusable vaginal ring
Segesterone acetate content	103 mg
Ethinyl estradiol content	17.4 mg
Approximate daily release	0.15 mg segesterone acetate and 0.013 mg ethinyl estradiol
Route	Vaginal
Use period	Up to 13 cycles or one year
FDA approval	August 10, 2018
NDA	209627
Primary formulation material	Silicone elastomer
Product category	Drug-device combination product

ANNOVERA is not a conventional tablet or disposable vaginal ring. The ring is designed to retain the active ingredients while releasing them gradually through a silicone elastomer matrix. The formulation must maintain drug release after repeated insertion, removal, washing, storage, and exposure to vaginal fluids.

The silicone material functions as the drug-release matrix and as the physical delivery system. It should therefore be evaluated as a critical formulation component rather than as an incidental inactive ingredient.

What excipients and formulation materials are used in ANNOVERA?

The FDA prescribing information identifies silicone elastomer as the principal inactive formulation material.[1] The product contains the two active pharmaceutical ingredients within a flexible silicone vaginal system.

Silicone elastomer

Silicone elastomer provides:

• Drug containment
• Controlled diffusion
• Mechanical flexibility
• Vaginal biocompatibility
• Resistance to repeated handling
• Structural integrity during one year of use

The commercial value of the silicone formulation is tied to polymer grade, curing chemistry, crosslink density, drug dispersion, surface characteristics, and manufacturing conditions. Small changes in these parameters can alter release rates, residual monomer levels, extractables, flexibility, and dimensional stability.

Drug-loading architecture

ANNOVERA’s release profile depends on the interaction between:

• Segesterone acetate solubility in the silicone matrix
• Ethinyl estradiol solubility in the matrix
• Drug particle size and distribution
• Polymer crosslinking
• Ring dimensions
• Surface area-to-volume ratio
• Manufacturing temperature and cure time
• Storage conditions

Because the two hormones have different physicochemical properties, a single polymer matrix must provide an acceptable release profile for both compounds. This creates a formulation-control challenge that is more complex than loading a single active ingredient into a silicone ring.

What is not commercially interchangeable?

A substitute polymer is not automatically equivalent to the silicone elastomer used in ANNOVERA. A different silicone grade, thermoplastic elastomer, polyurethane, or ethylene-vinyl acetate system could change:

• Initial burst release
• Steady-state hormone delivery
• Residual drug content
• Ring flexibility
• Mucosal compatibility
• Extractable and leachable profile
• Shelf life
• Cleaning and reuse performance

A reformulated system would likely require extensive comparative dissolution, mechanical, biocompatibility, stability, and clinical or bridging evidence.

How strong is the ANNOVERA excipient strategy?

The formulation strategy is commercially defensible because the polymer is integral to product performance. The key protection is not the mere use of silicone. It is the combination of:

1. Two specific steroid hormones.
2. A reusable vaginal ring.
3. Controlled release over repeated cycles.
4. Defined physical and chemical properties.
5. A manufacturing process that produces consistent drug distribution.
6. Compatibility with vaginal use and repeated handling.

Silicone itself is a widely used medical material. Its broad availability limits the value of a generic polymer claim. The stronger technical barrier is achieving the same release profile and product performance with a reproducible manufacturing process.

Excipient-related strength assessment

Formulation element	Barrier strength	Commercial significance
General silicone elastomer use	Moderate to low	Multiple suppliers and grades exist
Specific silicone grade and cure system	Moderate	Can create qualification and process barriers
Dual-hormone drug dispersion	Moderate to high	Requires control of two release profiles
One-year reusable release profile	High	Requires long-duration performance data
Ring geometry and manufacturing process	Moderate to high	May support device and process claims
Extractables and leachables package	Moderate	Important for regulatory approval and supplier qualification
User-cleaning and reuse performance	Moderate to high	Creates product-specific usability and stability requirements

What regulatory requirements apply to ANNOVERA excipients?

The FDA treats ANNOVERA as a combination product because it combines drug and delivery-system characteristics. The sponsor must control the silicone elastomer as a critical material and demonstrate that the finished system remains safe and effective throughout its intended use period.

Critical quality attributes

Important quality attributes include:

• Active content uniformity
• Drug distribution within the ring
• In vitro release rate
• Ring dimensions
• Tensile strength and elongation
• Compression and recovery
• Surface defects
• Residual solvents and volatile compounds
• Extractables and leachables
• Microbial quality
• Stability after repeated use
• Packaging compatibility

The FDA’s combination-product framework and ICH quality guidelines support a risk-based control strategy for formulation materials, manufacturing parameters, and drug-device interactions.[2][3]

Extractables and leachables

Silicone elastomers can contain low-molecular-weight siloxanes, catalysts, processing aids, pigments, and other residual substances. A commercially viable ANNOVERA-like product would require:

• Supplier-specific material characterization
• Controlled curing conditions
• A toxicological assessment of extractables
• Leachables testing under physiologically relevant conditions
• Evaluation after repeated insertion and removal
• Assessment of storage in the supplied packaging

USP chapters <1663> and <1664> provide a recognized framework for extractables and leachables assessment.[4][5]

The relevant exposure profile is unusual because the system remains in contact with vaginal tissue for repeated 21-day periods over one year. Standard short-term medical-device testing may not adequately represent the full exposure pattern.

What formulation patents protect ANNOVERA?

ANNOVERA’s patent protection is expected to focus on the drug-delivery system, hormone combination, ring construction, controlled release, and methods of contraception rather than on silicone as a generic material.

The Orange Book should be reviewed for the current patent and regulatory-exclusivity entries associated with NDA 209627.[6] FDA approval records establish the product’s approval date, but the approval record alone does not define the complete scope of privately held patent rights.

Potential claim categories include:

• Vaginal systems containing segesterone acetate and ethinyl estradiol
• Controlled release of the two hormones from a silicone ring
• Reusable contraceptive rings
• Specific drug loading and release ranges
• Ring dimensions and structural configurations
• Methods of preventing pregnancy
• Manufacturing methods for drug-loaded silicone systems
• Use of the system over repeated cycles

Patent strength depends on claim breadth and validity, not on the number of listed patents. Claims directed only to a broad combination of known hormones and a known vaginal ring may face prior-art pressure. Claims that capture the specific release profile, one-year reuse, loading architecture, or manufacturing controls are more difficult to design around.

When does ANNOVERA lose exclusivity?

ANNOVERA does not have a single “patent expiration date” that determines all market entry risk. The practical exclusivity timeline depends on:

• Listed Orange Book patents
• Patent-term adjustment
• Patent-term extension
• Regulatory exclusivity
• Paragraph IV certifications
• Litigation outcomes
• Settlement terms
• Whether a competing product is therapeutically equivalent or uses a different delivery system

The FDA approved ANNOVERA in 2018. Any applicable new chemical entity or other regulatory exclusivity period has expired. Market-entry risk therefore turns primarily on patent rights and the regulatory pathway for a competing product.[1][6]

A competing sponsor may pursue:

• An ANDA for a therapeutically equivalent product, if FDA requirements can be met.
• A 505(b)(2) application for a modified vaginal system or formulation.
• A full NDA for a materially different product.
• A medical-device or combination-product strategy where the drug and delivery system differ substantially.

What generic entry risks exist for ANNOVERA?

Generic entry is more difficult than for a conventional oral contraceptive. A challenger would need to demonstrate more than matching the active ingredients.

Technical barriers

A potential generic or follow-on system would need to address:

• Equivalent or sufficiently comparable release rates
• Drug content uniformity
• Mechanical integrity during one year of use
• Compatibility with vaginal tissue
• Stability after repeated removal and reinsertion
• Similar user handling
• Cleaning instructions
• Packaging and storage
• Extractables and leachables
• Hormone exposure and pharmacokinetic comparability

The absence of a conventional tablet-style dissolution test may complicate ANDA development. In vitro release may be necessary but may not fully establish equivalence if device design, ring dimensions, or polymer chemistry differ.

Paragraph IV exposure

A Paragraph IV challenger could contest listed patents by asserting that the patents are invalid, unenforceable, or not infringed. The commercial value of such a challenge would depend on the number and scope of Orange Book-listed patents and the likelihood of a 30-month stay following patent litigation.

A design-around strategy may be more attractive if the challenger can develop a different polymer matrix, ring geometry, or release mechanism. That path may avoid direct infringement but could shift the product into a 505(b)(2) or NDA strategy with higher development costs.

What biosimilar risk applies to ANNOVERA?

ANNOVERA has no biosimilar risk because it is a small-molecule hormonal drug-device combination, not a biologic regulated under the biosimilar pathway.

The relevant competitors are:

• Generic combination vaginal systems
• New branded vaginal rings
• Oral contraceptives
• Transdermal contraceptive systems
• Long-acting reversible contraceptives
• Progestin-only products
• Emergency contraception and fertility-control products

A follow-on ring would compete through generic or hybrid drug pathways, not through a 351(k) biosimilar application.

What commercial opportunities exist for excipient suppliers?

The largest near-term opportunity is not a new excipient molecule. It is supply, qualification, and process support for medical-grade silicone and related manufacturing inputs.

Medical-grade silicone supply

Suppliers can compete through:

• Consistent low-extractables grades
• Tight control of volatile siloxanes
• Hormone-compatible elastomer systems
• Documented biocompatibility
• Long-term stability data
• Change-control discipline
• Dual-source qualification
• Regulatory support packages

A supplier with a validated material package can reduce sponsor risk during scale-up and post-approval changes.

Process technology

Manufacturing companies can offer:

• Precision mixing of hormones into silicone
• Improved drug dispersion
• Automated ring forming
• Low-defect molding
• Inline dimensional inspection
• Cure-process monitoring
• Improved yield
• Closed-system handling
• Serialization and traceability

The value of process improvements is high because defective rings create both product-loss and regulatory risk.

Analytical services

Specialized laboratories can support:

• Dual-analyte content testing
• Long-duration in vitro release
• Residual solvent analysis
• Siloxane profiling
• Extractables and leachables testing
• Mechanical testing after simulated use
• Stability studies
• Comparative characterization for follow-on products

A laboratory capable of linking material properties to hormone release can become a strategic development partner rather than a routine contract-testing provider.

What lifecycle opportunities exist for ANNOVERA?

Lifecycle development can improve convenience, adherence, manufacturing cost, or market segmentation.

Potential product opportunities

Opportunity	Product concept	Main development issue
Lower-cost ring	Equivalent performance with reduced material and processing cost	Must preserve release and mechanical properties
Extended-duration ring	More than one year of use	Long-term safety and stability
Smaller ring	Improved comfort or insertion	May alter release and retention
Simplified cleaning system	Improved user handling	Human-factors and infection-control evaluation
Alternative polymer matrix	Non-silicone or modified silicone system	New extractables, release, and biocompatibility package
Lower-estrogen system	Reduced ethinyl estradiol exposure	New efficacy and bleeding-profile evidence
Progestin-only ring	Segesterone acetate without estrogen	New clinical and regulatory program
Multipurpose ring	Contraception plus prevention-related function	Combination-product and clinical complexity

A lower-cost version with the same active ingredients and delivery duration would face the most direct patent and regulatory competition. A progestin-only or multipurpose ring could create greater differentiation but would require a new clinical and commercial strategy.

How does ANNOVERA compare with other contraceptive delivery systems?

Product type	Reuse period	Primary commercial advantage	Excipient or formulation barrier
ANNOVERA	One year	User-controlled, reusable, non-daily contraception	Long-duration dual-hormone silicone release
Disposable monthly vaginal ring	One month	Familiar monthly use	Lower material and durability burden
Oral contraceptive	Daily	Broad generic availability	Low formulation barrier
Transdermal patch	Weekly	Simple administration	Adhesive, skin permeation, and irritation
Hormonal IUD	Several years	Long duration and high efficacy	Device placement and localized release
Implant	Several years	Long-acting contraception	Implant insertion and removal
Injection	Several months	Infrequent dosing	Adherence to clinical visits

ANNOVERA’s differentiation is strongest against daily oral products and monthly disposable rings. Its principal weakness is that the user must manage insertion, removal, cleaning, storage, and reuse. Excipient and device improvements that reduce handling burden could have direct commercial value.

What licensing and partnership opportunities exist?

The most valuable licensing targets are likely to involve technology platforms rather than a single commodity excipient.

Potential deal structures include:

• Silicone-material supply agreements
• Exclusive access to low-extractables elastomer grades
• Contract manufacturing of drug-loaded rings
• Regional commercialization licenses
• Co-development of next-generation vaginal systems
• Licensing of release-control or molding technology
• Analytical and regulatory support partnerships
• Acquisition of follow-on vaginal-ring assets

For a sponsor, the most important diligence issues are ownership of formulation patents, freedom to operate around ring geometry and release specifications, supplier-change obligations, and the extent to which manufacturing know-how is documented in the regulatory file.

What manufacturing and IP barriers affect commercial entry?

The main manufacturing barrier is reproducibly achieving two hormone release profiles from a reusable silicone device. The main IP barrier is avoiding claims that cover the combination of active ingredients, ring configuration, controlled release, and contraceptive use.

A credible entry plan should include:

1. A complete Orange Book review for NDA 209627.
2. Patent-family mapping by claim type and jurisdiction.
3. Material and supplier freedom-to-operate analysis.
4. Comparative release testing.
5. Extractables and leachables assessment.
6. Mechanical testing after simulated repeated use.
7. Regulatory pathway selection between ANDA, 505(b)(2), and NDA.
8. Paragraph IV and litigation scenario analysis.
9. Manufacturing scale-up and yield modeling.
10. Commercial forecasting against oral, ring, patch, implant, and IUD competitors.

Key Takeaways

• ANNOVERA uses segesterone acetate and ethinyl estradiol in a reusable silicone elastomer vaginal ring.
• Silicone is the principal inactive formulation material and functions as the drug-release matrix.
• The strongest formulation barrier is the combined control of dual-hormone release, flexibility, durability, biocompatibility, and one-year reuse.
• Conventional biosimilar competition does not apply.
• Generic entry would likely require complex comparative release, device, stability, and biocompatibility evidence.
• The best excipient opportunities involve medical-grade silicone supply, process control, extractables testing, and manufacturing automation.
• Lifecycle opportunities include lower-cost systems, smaller rings, extended-use designs, progestin-only products, and improved cleaning or storage systems.
• Current exclusivity analysis should rely on the Orange Book and the underlying patent families, not on FDA approval date alone.

FAQs

Can ANNOVERA use a different silicone supplier?

Potentially, but a supplier change would require material comparability, manufacturing validation, stability data, and regulatory change assessment. Differences in cure chemistry, volatile content, drug sorption, or release performance could make the change significant.

Is silicone an excipient or a medical-device component in ANNOVERA?

It performs both functions. Silicone is the physical ring and the matrix that controls hormone release. Regulatory assessment must therefore address pharmaceutical excipient attributes and medical-device performance.

Could a generic ANNOVERA use polyurethane instead of silicone?

A polyurethane system could be developed, but it would likely require a different regulatory and patent strategy. Polymer substitution can change release, mechanical behavior, extractables, and mucosal exposure.

Does ANNOVERA qualify for a conventional ANDA?

That depends on FDA determinations regarding reference-product equivalence, delivery-system comparability, listed patents, and the evidence required for a follow-on ring. A materially different ring may be better suited to a 505(b)(2) or NDA pathway.

What is the most attractive commercial opportunity around ANNOVERA?

The most actionable opportunity is a validated, low-extractables silicone and manufacturing platform that can deliver consistent dual-hormone release while reducing production cost and supporting a follow-on or lifecycle vaginal-ring product.

References

1. U.S. Food and Drug Administration. (2018). ANNOVERA (segesterone acetate and ethinyl estradiol vaginal system) prescribing information. FDA.

2. U.S. Food and Drug Administration. (2019). Drug-device combination products: Guidance for industry and FDA staff. FDA.

3. International Council for Harmonisation. (2009). ICH Q8(R2): Pharmaceutical development. ICH.

4. United States Pharmacopeia. (2022). General chapter <1663>: Assessment of extractables associated with pharmaceutical packaging/delivery systems. USP.

5. United States Pharmacopeia. (2022). General chapter <1664>: Assessment of drug product leachables associated with pharmaceutical packaging/delivery systems. USP.

6. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book. FDA.