List of Excipients in Branded Drug MAKENA

Company	Tradename	Ingredient	NDC	Excipient	Potential Generic Entry
AMAG Pharmaceuticals Inc	MAKENA	hydroxyprogesterone caproate	64011-243	BENZYL ALCOHOL
AMAG Pharmaceuticals Inc	MAKENA	hydroxyprogesterone caproate	64011-243	BENZYL BENZOATE
AMAG Pharmaceuticals Inc	MAKENA	hydroxyprogesterone caproate	64011-243	CASTOR OIL

Makena Excipient Strategy and Commercial Opportunities After FDA Withdrawal

Last updated: August 24, 2026

Makena, the brand name for hydroxyprogesterone caproate, was a sterile injectable progestin supplied as a 250 mg/mL intramuscular oil solution and a 275 mg/1.1 mL subcutaneous auto-injector. Its commercial position changed materially after the FDA withdrew approval in 2023 following failure of the required confirmatory trial. The strongest remaining commercial opportunities are in formulation technology, sterile manufacturing, device-enabled delivery, and regulated international markets, not in a conventional U.S. branded-drug relaunch.

Makena’s excipient platform is relatively simple: castor oil and benzyl benzoate in an oil-based depot injection. That simplicity creates formulation opportunities, but the clinical and regulatory status of hydroxyprogesterone caproate is the principal commercial constraint.[1][2]

What is Makena and how was it formulated?

Makena contains hydroxyprogesterone caproate, also known as 17-OHPC. The product was developed to reduce the risk of recurrent spontaneous preterm birth in pregnant women with a singleton pregnancy and a history of spontaneous preterm birth.

Makena dosage forms and excipients

Product	Strength	Route	Presentation	Key inactive ingredients
Makena injection	250 mg/mL	Intramuscular	Single-dose vial and multidose vial	Castor oil, benzyl benzoate
Makena auto-injector	275 mg/1.1 mL	Subcutaneous	Single-use auto-injector	Castor oil, benzyl benzoate

The formulation uses a nonaqueous oil vehicle to solubilize hydroxyprogesterone caproate and create a depot after injection. Benzyl benzoate functions as a cosolvent and formulation aid. Castor oil is the primary vehicle.[1]

Makena’s labeling identifies benzyl benzoate as an excipient of clinical relevance because benzyl benzoate exposure can be relevant in pregnancy and in patients with hypersensitivity concerns. The oil-based formulation also creates practical issues involving injection volume, viscosity, needle gauge, injection-site pain, and cold-temperature handling.

What is the FDA regulatory status of Makena?

The FDA approved Makena in 2011 under the accelerated approval pathway. The approval relied on an earlier study showing a reduction in recurrent preterm birth, with a required confirmatory trial to verify clinical benefit.[2]

The confirmatory PROLONG trial did not demonstrate the required benefit on preterm birth or neonatal outcomes. Following extensive regulatory proceedings, the FDA issued a final decision withdrawing approval. The withdrawal became effective June 12, 2023.[3]

Makena FDA timeline

Date	Regulatory event
February 2011	FDA grants accelerated approval to Makena
2019	PROLONG confirmatory trial fails to verify clinical benefit
October 2020	FDA advisory committee recommends withdrawal
2021-2022	Administrative hearing and FDA review continue
April 2023	FDA announces final withdrawal decision
June 12, 2023	Makena approval withdrawal becomes effective

The FDA’s withdrawal was based on failure to confirm efficacy, not on an excipient defect. The agency’s action therefore does not establish that castor oil, benzyl benzoate, or the oil-depot platform is unsuitable for injectable drug development.

When did Makena lose exclusivity and commercial protection?

Makena’s market protection was weakened by both patent timing and the withdrawal of the approved indication.

Makena received orphan-drug exclusivity only if the approved indication qualified under the applicable orphan-drug framework. The principal commercial protection came from the product’s approval status, patent rights, market adoption, and reimbursement position rather than from a durable composition-of-matter patent on hydroxyprogesterone caproate.

Public patent records identify U.S. Patent No. 7,851,468 as a key use patent associated with hydroxyprogesterone caproate for reducing the risk of preterm birth.[4] The patent was directed to method-of-use claims rather than ownership of the active pharmaceutical ingredient itself. Hydroxyprogesterone caproate is an established progestin, and the commercial estate did not depend on a new-molecule composition patent.

What patents protect Makena?

The relevant patent categories include:

1. Method-of-use patents covering administration of 17-OHPC to pregnant women with a prior spontaneous preterm birth.
2. Formulation patents, if any claims cover concentration, solvent ratios, impurity controls, or depot performance.
3. Device patents covering an auto-injector, needle system, or dose-delivery configuration.
4. Manufacturing and process patents covering purification, crystallization, residual solvent control, or sterile filling.

The method-of-use estate was more commercially relevant than the excipient estate. A castor-oil and benzyl-benzoate formulation is difficult to protect broadly unless the applicant demonstrates a specific technical effect, such as improved solubility, reduced injection pain, enhanced stability, lower impurity formation, or superior depot release.

Because Makena approval was withdrawn, an Orange Book patent listing does not by itself create a viable U.S. commercial pathway. Any future applicant would need an approvable indication and a regulatory route independent of the withdrawn NDA.

What is the Orange Book status of Makena?

Makena was listed in FDA’s Orange Book under NDA 021945 while approved. After withdrawal, the product’s Orange Book relevance became limited because the NDA is no longer an approved basis for commercial distribution.

An Orange Book listing can identify patents and use codes associated with an approved drug. It does not validate the underlying clinical benefit after FDA withdrawal, and it does not create an automatic pathway for a generic applicant where the reference product is no longer approved for marketing.

How would a generic applicant challenge Makena?

A conventional ANDA strategy would face substantial obstacles:

• The reference product is no longer approved for marketing in the United States.
• Hydroxyprogesterone caproate products would need a legally supportable reference product and an approved labeling framework.
• A Paragraph IV certification would have limited commercial value if the branded reference product has been withdrawn.
• A formulation that differs materially in excipients, route, concentration, or delivery device could require a separate regulatory strategy.
• A product intended for a new indication would likely require an NDA rather than a simple ANDA.

The absence of a current approved U.S. reference product reduces the attractiveness of a standard generic launch. The regulatory opportunity is more likely to involve a new drug application, a reformulated product tied to new clinical evidence, or a non-U.S. development program.

What excipients are used in Makena?

Makena uses castor oil and benzyl benzoate. The formulation strategy is based on solubilization of a lipophilic steroid and controlled persistence after injection.

Castor oil

Castor oil provides the principal nonaqueous vehicle. Its advantages include strong solvent capacity for lipophilic compounds and established use in injectable products. Its limitations include:

• High viscosity relative to aqueous injection vehicles
• Injection-force requirements
• Potential injection-site discomfort
• Lot-to-lot control requirements
• Oxidative stability considerations
• Dependence on robust supplier qualification

A reformulated product could evaluate medium-chain triglycerides, sesame oil, cottonseed oil, ethyl oleate, or other pharmaceutically acceptable lipid vehicles. Any substitution would require new studies for solubility, precipitation risk, degradation, local tolerance, extractables, container closure compatibility, and release kinetics.

Benzyl benzoate

Benzyl benzoate improves solubilization and can reduce the viscosity or precipitation risk of an oil formulation. It can also affect the local tolerability profile and the amount of active drug that remains dissolved during storage.

Potential alternatives include benzyl alcohol-containing systems, ethanol-containing systems, ethyl oleate, propylene glycol derivatives, or mixed lipid/cosolvent systems. These alternatives create pregnancy-specific toxicology and tolerability requirements. A lower-benzyl-benzoate or benzyl-benzoate-free formulation could have commercial value if it improves tolerability without changing exposure or depot performance.

What formulation patents could protect a reformulated hydroxyprogesterone caproate product?

The strongest formulation patent opportunities would require measurable technical advantages. Broad claims covering hydroxyprogesterone caproate in oil are likely vulnerable because the active ingredient and oil-injection concept are established.

High-value formulation claim areas

Claim area	Potential commercial value	Technical evidence needed
Reduced-viscosity injection	Easier administration and smaller needle requirements	Rheology, injection-force, usability data
Lower injection-site pain	Better adherence and patient acceptance	Controlled local-tolerability studies
Benzyl-benzoate-free formulation	Differentiation for pregnancy use	Solubility, stability, safety, exposure data
Smaller injection volume	More convenient administration	Dose uniformity and pharmacokinetic comparability
Improved cold stability	Wider distribution and storage flexibility	Accelerated and real-time stability
Reduced impurities	Better shelf life and quality control	Degradation pathway and specification data
Sustained-release depot	Potentially less frequent dosing	Pharmacokinetic and clinical outcome data
Device-compatible formulation	Patient or provider administration advantage	Human-factors, container closure, device studies

A patent filing should focus on defined excipient ranges and demonstrated performance. Claims limited to a specific oil, cosolvent ratio, active concentration, viscosity range, or impurity threshold are more defensible than broad claims directed to any injectable hydroxyprogesterone caproate formulation.

What commercial opportunities exist for Makena excipients?

The commercial opportunity is primarily a platform opportunity rather than a direct continuation of the former Makena brand.

1. Reformulated sterile injectable platform

A contract development and manufacturing organization could develop a hydroxyprogesterone caproate formulation with:

• Lower viscosity
• Smaller injection volume
• Reduced injection pain
• Improved syringeability
• Better stability
• Compatibility with an autoinjector or prefilled syringe

The product would need a clinically supportable indication. Formulation improvements alone would not resolve the efficacy issue that led to withdrawal.

2. Excipient supply and qualification

Suppliers of pharmaceutical-grade castor oil, benzyl benzoate, alternative lipid vehicles, antioxidants, and specialty cosolvents could target developers working on long-acting steroid injections.

The most valuable supply attributes include:

• Consistent fatty-acid and hydroxyl-value profiles
• Low peroxide and aldehyde levels
• Tight microbial and endotoxin controls
• Reliable global availability
• Documentation suitable for pregnancy-related products
• Compatibility with sterile filtration or aseptic processing

Supplier differentiation would come from quality systems, regulatory documentation, and reliable batch consistency rather than from the identity of the excipient alone.

3. Device-enabled administration

Makena’s subcutaneous auto-injector demonstrated a commercial preference for reducing dependence on intramuscular administration. A future product could combine a lower-viscosity formulation with:

• A prefilled syringe
• An autoinjector
• A hidden-needle system
• A dose-confirmation mechanism
• A low-force delivery system

Device patents may provide stronger differentiation than excipient patents when the formulation composition is conventional.

4. International and non-U.S. markets

Regulatory conditions differ by jurisdiction, but the clinical controversy surrounding 17-OHPC is global. In 2024, the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee recommended suspension of hydroxyprogesterone caproate medicines in the European Union because available evidence did not show benefit and raised potential cancer concerns in offspring exposed in utero.[5]

That action reduces the attractiveness of a Europe-first strategy. Other markets may maintain products or evaluate them under different standards, but the commercial case depends on country-specific regulatory status, treatment guidelines, reimbursement, and supply requirements.

5. Compounding and hospital supply

Compounded 17-OHPC may remain a niche source of demand in some jurisdictions. In the United States, compounded products are not FDA-approved and do not have the same premarket review for safety, effectiveness, or manufacturing quality as approved drugs.[6]

A 503B outsourcing facility or specialty compounder could have a supply opportunity only within applicable federal and state requirements. This is a regulated service market, not an equivalent substitute for an approved Makena product.

How strong is the Makena patent estate?

The estate is weak for broad excipient-based exclusivity and stronger for narrow, evidence-backed improvements.

Estate assessment

Estate component	Strength	Commercial assessment
Active-ingredient composition	Low	Hydroxyprogesterone caproate is established
Broad oil formulation	Low to moderate	Prior-art exposure is substantial
Specific excipient ratio	Moderate	Patentability depends on unexpected performance
Reduced-pain formulation	Moderate to high	Requires credible comparative data
Auto-injector configuration	Moderate to high	Device claims may create separate protection
Manufacturing controls	Moderate	Useful for quality and process differentiation
Original method of use	Limited	Clinical benefit and regulatory status undermine value
New indication	Potentially high	Requires new clinical evidence and regulatory approval

The patent strategy should combine composition claims with process, device, and use claims. Patent term should be managed against the time required for clinical development, regulatory review, and commercial launch. A formulation patent with only a few years of remaining life has limited value unless the product can reach the market rapidly.

Which companies are challenging or replacing Makena?

The U.S. commercial landscape changed after Covis Pharma discontinued Makena. Generic or compounded hydroxyprogesterone caproate products may exist in certain markets or settings, but no FDA-approved U.S. generic has replaced Makena as an approved product for the withdrawn indication.

The main competitive alternatives in the preterm-birth market are not direct hydroxyprogesterone caproate substitutes. They include:

• Vaginal progesterone in selected patient populations
• Cervical-length surveillance
• Cerclage in clinically appropriate cases
• Obstetric risk-management protocols
• Products and services aimed at preterm-birth prediction and prevention

The FDA withdrawal does not establish that all progesterone therapies are ineffective. It removes Makena’s approved U.S. indication and reflects the evidence specific to hydroxyprogesterone caproate and the required confirmatory trial.[3]

What generic launch risks exist for hydroxyprogesterone caproate?

A future U.S. launch would face five principal risks.

First, the absence of an approved reference product complicates the ANDA route. Second, new evidence may be required to establish a clinically supportable indication. Third, obstetric guidelines have moved away from routine use of 17-OHPC. Fourth, payers may resist reimbursement for a product associated with the withdrawn indication. Fifth, excipient and delivery changes could trigger additional bridging work.

The most plausible launch scenarios are:

Scenario	Regulatory route	Commercial probability
Conventional U.S. generic to Makena	ANDA	Low after withdrawal
Reformulated product with same historical indication	NDA or other FDA-supported pathway	Low without new efficacy evidence
New indication for hydroxyprogesterone caproate	NDA	Dependent on new clinical data
International product in a permissive jurisdiction	Local pathway	Country-specific
Compounded product	Applicable compounding framework	Limited and regulated
Excipient or device platform licensed to another developer	Partnership or CMO model	More practical than a branded relaunch

What licensing deals could support a Makena-related strategy?

A licensing transaction would be more attractive around technology than around the withdrawn brand.

Potential deal structures include:

• Exclusive rights to a low-viscosity oil formulation
• Regional rights for a hydroxyprogesterone caproate product
• Device licensing for subcutaneous depot injections
• Supply agreements for qualified castor oil or alternative lipid vehicles
• Co-development of a new indication
• CMO partnerships covering aseptic filling and device assembly

A buyer would likely discount the value of legacy Makena trademarks, historical sales, and withdrawn-use patents. It may place greater value on formulation data, device human-factors work, scalable sterile manufacturing, and rights that apply to other long-acting steroid products.

What revenue exposure did Makena create?

Makena generated substantial historical revenue before withdrawal, but prior sales are not a reliable forecast for a future hydroxyprogesterone caproate product. Revenue depended on accelerated approval, reimbursement, limited competition, and clinical adoption of the preterm-birth indication.

After withdrawal, revenue exposure shifted from branded product sales to:

• Residual international sales where permitted
• Compounded-product demand
• Contract manufacturing
• Excipient supply
• Device technology
• Licensing of formulation know-how
• Development of other long-acting injectable products

The commercial value of a Makena-related asset should therefore be assessed on forward regulatory viability and transferable technology, not historical peak sales.

Key Takeaways

• Makena used a castor-oil and benzyl-benzoate injectable formulation.
• The FDA withdrew approval effective June 12, 2023, after the PROLONG trial failed to confirm clinical benefit.
• Makena is not a biologic, so biosimilar analysis does not apply. Any future generic pathway would involve small-molecule regulatory rules.
• Broad excipient patents are likely weak because hydroxyprogesterone caproate and oil-based injection systems are established.
• Stronger patent opportunities involve reduced viscosity, lower injection-site pain, improved stability, smaller dose volume, device compatibility, and defined excipient ratios.
• A conventional U.S. ANDA launch is commercially unattractive while no approved reference product supports the withdrawn indication.
• The most credible commercial opportunities are reformulation technology, sterile manufacturing, device licensing, excipient supply, and country-specific development.
• EU regulatory action in 2024 further reduced the value of a broad international 17-OHPC strategy.

FAQs

Can a company launch a new castor-oil formulation of hydroxyprogesterone caproate?

Yes, but a new formulation would still require a viable regulatory pathway and clinical justification. Excipient changes do not restore Makena’s withdrawn approval.

Is benzyl benzoate the main patent opportunity in a Makena reformulation?

No. Benzyl benzoate removal or reduction could support patent claims only if the formulation demonstrates a specific technical benefit, such as improved tolerability or stability.

Does Makena have biosimilar competition?

No. Hydroxyprogesterone caproate is a small-molecule drug, not a biologic. The relevant competition would involve generics, new drug products, compounded products, or alternative therapies.

Could an auto-injector create new exclusivity for a hydroxyprogesterone caproate product?

Potentially. A device-enabled product could obtain patent protection for the injector, dose-control system, needle configuration, or formulation-device combination. Regulatory approval would remain necessary.

Are Makena’s historical sales a reliable basis for valuing a reformulation?

No. Historical sales reflected a specific accelerated approval and reimbursement environment. Current valuation should focus on clinical evidence, regulatory feasibility, patent term, manufacturing economics, and market access.

References

1. U.S. Food and Drug Administration. (2023). Makena (hydroxyprogesterone caproate injection) prescribing information. FDA.

2. U.S. Food and Drug Administration. (2011). FDA approves Makena to reduce risk of preterm birth. FDA.

3. U.S. Food and Drug Administration. (2023). FDA Commissioner and Chief Scientist announce decision to withdraw approval of Makena. FDA.

4. United States Patent and Trademark Office. (2010). U.S. Patent No. 7,851,468, methods of preventing preterm delivery. USPTO.

5. European Medicines Agency. (2024). Hydroxyprogesterone caproate medicines recommended for suspension in the EU. EMA.

6. U.S. Food and Drug Administration. (2023). Compounding and the FDA: Questions and answers. FDA.