List of Excipients in Branded Drug PROMETRIUM

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Company	Tradename	Ingredient	NDC	Excipient	Potential Generic Entry
Physicians Total Care Inc	PROMETRIUM	progesterone	54868-4250	D&C YELLOW NO. 10
Physicians Total Care Inc	PROMETRIUM	progesterone	54868-4250	FD&C RED NO. 40
Physicians Total Care Inc	PROMETRIUM	progesterone	54868-4250	GELATIN
Physicians Total Care Inc	PROMETRIUM	progesterone	54868-4250	GLYCERIN

PROMETRIUM Excipient Strategy and Commercial Opportunities

Last updated: September 24, 2026

PROMETRIUM is an oral micronized progesterone product whose principal commercial vulnerability is the excipient system, particularly peanut oil. The active ingredient is no longer protected by meaningful composition-of-matter exclusivity in the United States, and generic progesterone capsules are widely available. The strongest commercial opportunities are therefore in peanut-free delivery, improved dissolution and absorption, vaginal-or-oral flexibility, patient adherence, and differentiated packaging rather than in conventional generic substitution alone.

What is PROMETRIUM and how is it formulated?

PROMETRIUM contains micronized progesterone in soft gelatin capsules. The product was approved by the FDA for secondary amenorrhea and for prevention of endometrial hyperplasia in postmenopausal women receiving conjugated estrogens. Commercial strengths include 100 mg and 200 mg capsules.[1]

The original formulation uses an oil-based fill and a gelatin shell. The labeled inactive ingredients include peanut oil, gelatin, glycerin, lecithin, mineral oil, titanium dioxide, and color additives, depending on capsule strength and presentation.[1,2]

Attribute	PROMETRIUM
Active ingredient	Micronized progesterone
Dosage form	Soft gelatin oral capsule
Commercial strengths	100 mg and 200 mg
Original sponsor	Solvay Pharmaceuticals
U.S. regulatory pathway	NDA
Main indications	Secondary amenorrhea; prevention of endometrial hyperplasia
Principal excipient issue	Peanut oil
Pharmacokinetic characteristic	Low oral bioavailability relative to parenteral administration; food increases exposure
Current competitive category	Generic progesterone capsules and compounded progesterone products

Micronization increases surface area and improves dissolution of progesterone, which is poorly water-soluble. The formulation remains sensitive to the choice of oil vehicle, surfactant system, capsule shell, storage conditions, and administration with food.[1,3]

What excipients are used in PROMETRIUM?

The most commercially relevant excipient is peanut oil. Its presence creates labeling, prescribing, pharmacy, and patient-screening issues for individuals with peanut allergy. The product label states that PROMETRIUM should not be used in patients with known or suspected hypersensitivity to peanuts.[1]

Other formulation components have functional roles:

Excipient or excipient class	Function	Commercial relevance
Peanut oil	Lipophilic vehicle for micronized progesterone	Allergy concern; creates demand for alternative oils
Lecithin	Emulsifier and wetting aid	Supports dispersion and dissolution
Gelatin	Softgel shell former	Affects shell integrity, stability, and animal-origin positioning
Glycerin	Plasticizer and humectant	Controls shell flexibility
Mineral oil	Processing or fill-phase component	May influence viscosity and product consistency
Titanium dioxide and colorants	Opacification and identification	Relevant to colorant-free and clean-label positioning

The exact excipient composition can vary by strength, manufacturer, and generic supplier. FDA-approved labeling and the applicable product-specific prescribing information control the composition of each marketed product.[1,2]

Why is peanut-free progesterone the clearest excipient opportunity?

Peanut oil is a direct source of product differentiation. A generic progesterone capsule that replaces peanut oil with a non-allergenic lipid vehicle can address a clinically visible limitation without changing the active ingredient or route of administration.

Potential replacement vehicles include:

• Medium-chain triglycerides
• Coconut-derived triglycerides
• Soybean oil
• Sesame oil
• Corn oil
• Olive-derived lipid systems
• Synthetic triglycerides
• Mixed lipid and surfactant systems

Each alternative introduces its own regulatory and commercial constraints. Soy and sesame oils can create separate allergy concerns. Coconut-derived excipients may be acceptable for many patients but still require precise labeling. Synthetic or highly purified lipid systems may offer a stronger differentiation profile but can increase manufacturing cost.

The commercial objective is not simply to remove peanut oil. The replacement system must maintain:

1. Progesterone solubilization.
2. Capsule-fill uniformity.
3. Dissolution performance.
4. Stability throughout shelf life.
5. Bioequivalence or clinically acceptable exposure.
6. Compatibility with the gelatin shell.
7. Scalable encapsulation and supply security.

A peanut-free product can be positioned for patients with peanut allergy, patients avoiding animal-derived or specific agricultural oils, and prescribers who prefer to eliminate an avoidable excipient concern.

What formulations are protected by PROMETRIUM patents?

The historical PROMETRIUM product was protected primarily through formulation, process, and regulatory exclusivity rather than a continuing active ingredient patent. Micronized progesterone itself is an established active pharmaceutical ingredient, and the basic concept of oral micronized progesterone is not commercially exclusive.

A current commercial diligence review should distinguish among:

Protection category	PROMETRIUM position
Progesterone composition of matter	Expired or commercially non-exclusive
Micronization technology	Broadly developed and not specific to one sponsor
Original oral softgel formulation	Historical protection; generic competition exists
Peanut-oil vehicle	Not a durable exclusivity platform
New peanut-free vehicle	Potentially protectable through formulation and process claims
Modified-release formulation	Potential opportunity for new patents
Vaginal delivery system	Potentially protectable depending on formulation and device
Method of treatment	Possible protection for selected dosing or patient populations
Manufacturing process	May support trade secrets and limited patent coverage
Packaging and dose administration	Usually weak as a standalone patent strategy

No active patent position should be assumed solely from the PROMETRIUM brand name. Patent status must be checked by jurisdiction, patent family, claim scope, terminal disclaimers, maintenance fees, and Orange Book listing history. The FDA Orange Book remains the principal U.S. source for listed patents associated with approved drug products.[4]

When does PROMETRIUM lose exclusivity?

PROMETRIUM has already lost practical U.S. market exclusivity. FDA-approved generic progesterone capsules are available, and the drug is no longer dependent on a single branded supplier for ordinary oral progesterone treatment.

Exclusivity element	Commercial status
New chemical entity exclusivity	Expired
Original NDA exclusivity	Expired
Generic competition	Established
Paragraph IV launch risk	Primarily historical for the original product
Current barrier to entry	Formulation quality, bioequivalence, manufacturing scale, and channel access
Brand-specific switching barrier	Limited for oral capsules
Regulatory differentiation opportunity	High for improved excipients and delivery systems

For a new product, the relevant question is not whether PROMETRIUM remains exclusive. It is whether a differentiated progesterone formulation can obtain independent patents, FDA approval, or market exclusivity.

What is the Orange Book status of PROMETRIUM?

PROMETRIUM was approved under an NDA, while generic progesterone capsules were approved through ANDAs referencing the relevant reference product. Orange Book listings can change as products are discontinued, transferred, or updated, and listed patents may expire or be removed.

The commercially important point is that an applicant developing a conventional immediate-release progesterone softgel faces an established generic reference framework. A new product is more likely to require a differentiated formulation, dosage form, delivery route, or indication to support a separate commercial position.[4]

A generic applicant using the same basic oral dosage form may face ordinary ANDA requirements, including:

• Pharmaceutical equivalence
• Bioequivalence
• Assay and content uniformity
• Dissolution testing
• Impurity control
• Stability data
• Softgel manufacturing validation
• Inactive ingredient justification
• Labeling consistency

A material change in excipient composition can affect the regulatory strategy if it changes absorption, tolerability, dissolution, or safety. A peanut-free generic may still qualify for an ANDA, but the formulation must satisfy FDA requirements for inactive ingredients and demonstrate equivalence to the reference product.

Are Paragraph IV challenges still relevant to PROMETRIUM?

Paragraph IV litigation was most relevant during the initial generic-entry period for progesterone capsules. A new applicant challenging an active patent listed for the reference product could submit a Paragraph IV certification and trigger potential litigation under the Hatch-Waxman framework.

For current commercial planning, the larger issue is whether a new formulation creates its own patent estate. A company cannot rely on the absence of PROMETRIUM exclusivity to avoid litigation risk. A new peanut-free or modified-release formulation could generate patents covering:

• Specific lipid vehicles
• Defined progesterone-to-excipient ratios
• Particle-size distributions
• Surfactant combinations
• Dissolution profiles
• Softgel shell compositions
• Manufacturing temperatures and mixing conditions
• Storage-stability characteristics
• Patient populations with excipient intolerance

A follow-on product should be designed around claims that are difficult to design around without sacrificing pharmacokinetic or manufacturing performance.

How strong is the patent estate for a new progesterone excipient platform?

A new excipient strategy can support a moderate patent estate if it produces a measurable technical effect. Weak claims generally cover the presence of a common oil or a broad list of conventional excipients. Stronger claims define a narrow formulation architecture linked to a reproducible result.

Stronger patent claim categories

• Specific micronized progesterone particle-size ranges.
• Defined ratios of progesterone, lipid vehicle, and surfactant.
• A peanut-free formulation with a specified dissolution profile.
• Improved exposure under fed and fasted conditions.
• Reduced pharmacokinetic variability.
• Enhanced stability at controlled and accelerated conditions.
• Reduced capsule leakage or shell brittleness.
• A formulation compatible with both oral and vaginal administration.

Weaker claim categories

• Progesterone combined with any pharmaceutically acceptable oil.
• Generic substitution of one vegetable oil for another.
• Broad lists of known surfactants without demonstrated performance.
• Claims based only on patient preference.
• Color, flavor, or packaging changes without therapeutic effect.

The best patent strategy combines composition claims with process, use, and performance claims. Trade-secret protection is also relevant for oil purification, micronized progesterone dispersion, deaeration, encapsulation parameters, and shell-drying conditions.

What FDA regulatory pathways apply to improved progesterone formulations?

The pathway depends on how closely the product follows the reference product.

Product concept	Likely pathway
Same strength, route, dosage form, and therapeutic intent	ANDA
Same active ingredient with meaningful formulation or labeling changes	505(b)(2) NDA
New vaginal product or modified-release system	505(b)(2) or full NDA depending on reliance
New indication with supporting clinical evidence	505(b)(2) or supplemental NDA
Compounded progesterone	Section 503A or 503B framework, subject to applicable conditions
Combination hormone product	NDA or ANDA depending on reference and formulation

A 505(b)(2) strategy can be attractive for a peanut-free product if the sponsor seeks labeling, dosing, route, or pharmacokinetic differentiation that does not fit comfortably within an ANDA. It is also the more natural pathway for a modified-release, vaginal, buccal, or other delivery system that differs materially from the reference product.[5]

FDA review will focus on progesterone exposure, dose proportionality, food effect, dissolution, tolerability, excipient safety, and whether the alternative vehicle changes the clinical pharmacology profile.

What commercial opportunities exist beyond a standard generic?

Peanut-free oral progesterone

This is the most direct opportunity. The product can compete on excipient safety, prescriber confidence, and pharmacy substitution control. The target market includes patients with peanut allergy or documented intolerance to the reference formulation.

Improved oral bioavailability

A formulation that reduces food dependence or lowers interpatient variability could command a premium if supported by clinical pharmacology data. Progesterone exposure can be materially affected by administration with food, making a more predictable formulation commercially valuable.[1,3]

Vaginal progesterone

Vaginal delivery avoids first-pass hepatic metabolism and is already established in progesterone treatment. A product optimized for vaginal administration could compete in assisted reproductive technology, luteal support, and selected hormone-therapy applications. Opportunities include reduced leakage, lower dosing frequency, improved applicator design, and reduced patient discomfort.

Modified-release progesterone

A once-daily or less frequent formulation could address adherence problems associated with cyclic or divided dosing. The patent opportunity is stronger when the release profile produces a demonstrated clinical or pharmacokinetic benefit.

Combination hormone therapy

Progesterone can be combined commercially with estrogen products for menopausal hormone therapy. A fixed-dose combination could simplify treatment and reduce prescribing friction, but it would introduce additional formulation, dose-selection, and regulatory complexity.

Specialty and compounding channels

Compounded progesterone remains relevant where patients require nonstandard strengths, routes, or excipient exclusions. An FDA-approved product with multiple strengths and a peanut-free formulation could capture demand now served by compounding pharmacies, particularly where consistency and regulatory status influence prescribing.

Which companies are competing in the progesterone market?

Competition includes generic manufacturers, specialty hormone companies, fertility-focused suppliers, compounding pharmacies, and developers of vaginal delivery systems. The principal competitive dimensions are:

Competitive factor	Strategic implication
Low-cost generic oral capsules	Limits pricing for undifferentiated products
Peanut-free formulation	Creates a clear patient-screening advantage
Vaginal delivery	Expands beyond direct oral-generic competition
Fertility-market relationships	Provides specialist distribution and prescribing access
Multiple strengths	Improves dose flexibility
Reliable supply	Matters because hormone products are vulnerable to shortages and channel disruption
Brand recognition	Still relevant in menopause and fertility practices
Formulation patents	Can protect premium pricing if claims are technically narrow and enforceable

A company entering this market needs a defined channel strategy. Retail pharmacy generics prioritize acquisition cost and substitution economics. Fertility products prioritize specialist adoption and adherence. Menopause products require patient education, payer access, and differentiation from low-cost generics.

What manufacturing and supply-chain barriers affect excipient strategy?

Softgel manufacturing is a meaningful operational barrier. A new lipid vehicle can alter fill viscosity, encapsulation speed, seam quality, oxygen exposure, and shell compatibility. Progesterone is also sensitive to content uniformity because the dose is low relative to the total capsule fill.

Key manufacturing controls include:

• Micronized API particle-size distribution.
• Uniform dispersion in the lipid vehicle.
• Temperature control during blending.
• Oxygen and light exposure.
• Capsule-shell moisture.
• Seam integrity.
• Fill-weight control.
• Dissolution consistency.
• Stability under accelerated conditions.
• Supplier qualification for oils and surfactants.

The commercial risk is concentrated in scale-up. A formulation that performs in laboratory softgels may show leakage, sedimentation, or dissolution drift during commercial production. A robust program should establish critical material attributes and critical process parameters before patent filing and pivotal bioequivalence batches.

What licensing opportunities exist for PROMETRIUM-related technology?

Licensing opportunities are more likely to involve platform technology than the PROMETRIUM brand itself. Potential transactions include:

• A lipid-based delivery platform for poorly water-soluble hormones.
• A peanut-free progesterone formulation.
• A vaginal softgel or insert.
• A modified-release capsule.
• A manufacturing process for high-content-uniformity micronized API.
• A fertility-focused distribution agreement.
• A co-development deal with a specialty hormone company.
• A contract manufacturing arrangement with a softgel producer.

The most valuable deal asset would combine composition claims, bioequivalence data, scalable manufacturing, and a defined commercial indication. A formulation patent without clinical differentiation is less attractive because conventional oral progesterone is already commoditized.

What generic launch scenarios exist?

Low-cost conventional generic

This approach competes on price and supply reliability. It has the lowest development risk and the weakest pricing power.

Peanut-free generic

This approach preserves the familiar oral softgel while addressing the reference product’s most visible excipient limitation. It has stronger commercial positioning but must demonstrate formulation equivalence and excipient safety.

Premium 505(b)(2) product

This approach uses a new vehicle, modified-release profile, or alternative route. It has higher development cost but offers greater patent and pricing potential.

Vaginal progesterone product

This approach competes in fertility and hormone-support markets rather than relying only on retail substitution. Device, administration, and patient-use features become important.

Compounded-product replacement

This approach targets patients who require nonstandard excipients or strengths. FDA approval, manufacturing consistency, and prescriber trust are the principal advantages.

Key Takeaways

• PROMETRIUM is an oral micronized progesterone softgel historically formulated with peanut oil.
• U.S. market exclusivity has expired, and generic progesterone capsules are established.
• Peanut oil is the clearest excipient-based commercial weakness.
• A peanut-free formulation can differentiate without changing the active ingredient.
• Stronger patent opportunities involve defined lipid systems, dissolution performance, pharmacokinetic control, and manufacturing parameters.
• A conventional generic is likely to face intense price competition.
• A 505(b)(2) product may offer better protection for modified-release, vaginal, or pharmacokinetically differentiated formulations.
• Softgel scale-up, content uniformity, shell compatibility, and excipient supply are material manufacturing risks.
• The most attractive commercial strategy combines a non-allergenic vehicle, reliable exposure, specialist positioning, and an independent formulation patent estate.

FAQs

Is PROMETRIUM safe for patients with peanut allergy?

The FDA labeling identifies peanut oil as an inactive ingredient and contraindicates use in patients with known or suspected peanut hypersensitivity.[1]

Can progesterone capsules be made without peanut oil?

Yes. Alternative lipid vehicles can be used, but the sponsor must establish excipient safety, pharmaceutical performance, stability, and bioequivalence or other applicable regulatory requirements.

Is micronized progesterone still patent protected?

The basic active ingredient and conventional oral micronized progesterone concept are not commercially exclusive in the U.S. New formulation, delivery, process, or method claims may still be patentable if they satisfy novelty, non-obviousness, and written-description requirements.

Is vaginal progesterone a substitute for oral PROMETRIUM?

Vaginal progesterone has different pharmacokinetic and clinical-use characteristics. It may be appropriate for specific indications, but route substitution requires clinical and regulatory support.

What is the best commercial strategy for a new PROMETRIUM competitor?

The strongest strategy is a peanut-free, scalable softgel or vaginal formulation supported by bioequivalence or clinical pharmacology data, differentiated labeling, and patents covering the formulation and manufacturing process.

References

1. U.S. Food and Drug Administration. (2022). PROMETRIUM (progesterone) capsules, prescribing information.
2. National Library of Medicine. (n.d.). DailyMed: Progesterone capsule product labeling.
3. U.S. Food and Drug Administration. (2003). Clinical pharmacology and biopharmaceutics review for micronized progesterone products.
4. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
5. U.S. Food and Drug Administration. (2023). Applications covered by Section 505(b)(2).