Last updated: August 26, 2026
Hydroxyprogesterone caproate, also called 17-OHPC, is a poorly water-soluble progestin historically developed as a long-acting intramuscular or subcutaneous injection. Its commercial value is constrained by the FDA’s withdrawal of Makena and the absence of an approved U.S. indication for preventing recurrent spontaneous preterm birth. The strongest remaining opportunities are formulation platforms, non-U.S. markets, veterinary products, and tightly controlled compounded or investigational applications rather than a straightforward U.S. generic launch.
What is the pharmaceutical formulation of hydroxyprogesterone caproate?
Hydroxyprogesterone caproate is a lipophilic steroid ester with very low aqueous solubility. Commercial injectable formulations therefore use a nonaqueous oil vehicle and a cosolvent rather than an aqueous solution.
| Product or formulation |
Route |
Strength |
Principal excipient system |
Regulatory status |
| Makena multidose vial |
Intramuscular |
250 mg/mL |
Castor oil and benzyl benzoate |
FDA approval withdrawn |
| Makena single-dose vial |
Intramuscular |
250 mg/mL |
Castor oil and benzyl benzoate |
FDA approval withdrawn |
| Makena prefilled auto-injector |
Subcutaneous |
275 mg/1.1 mL |
Oil-based injectable formulation |
FDA approval withdrawn |
| Compounded 17-OHPC |
Usually intramuscular |
Variable |
Commonly oil-based; pharmacy-specific |
Not FDA-approved |
| Historical Proluton Depot products |
Intramuscular |
Market-specific |
Oil-based vehicles |
Jurisdiction-dependent |
The U.S. Makena label identified castor oil and benzyl benzoate as inactive ingredients. The formulation was designed to maintain hydroxyprogesterone caproate in solution while producing a prolonged release after injection (U.S. Food and Drug Administration [FDA], 2023a).
Which excipients are most suitable for hydroxyprogesterone caproate injections?
Castor oil
Castor oil is the most commercially validated vehicle for hydroxyprogesterone caproate. Its advantages are high solvency for lipophilic steroids, established parenteral use, and a demonstrated long-acting depot profile.
The main development risks are:
- High viscosity, which can increase injection force and needle requirements.
- Batch-to-batch variability in fatty-acid composition.
- Oxidative degradation and peroxide formation.
- Potential injection-site pain and local inflammation.
- Difficulty adapting the formulation to autoinjectors or small-gauge needles.
A castor-oil formulation offers the lowest regulatory and technical risk when the objective is a reference-like product. It is less attractive when the objective is a differentiated product with reduced injection pain or improved device performance.
Benzyl benzoate
Benzyl benzoate functions as a cosolvent and reduces the viscosity of the oil phase. It can improve drug loading and support a clear solution at the target concentration.
Its disadvantages include local tolerability concerns, potential irritation, and the need for tight control of residual solvent exposure. A formulation that removes or materially reduces benzyl benzoate could have commercial value, but the change would affect solubility, viscosity, depot release, and injection-site tolerability.
Alternative vegetable oils
Potential alternatives include sesame oil, cottonseed oil, ethyl oleate, and medium-chain triglycerides. These vehicles can support injectable depot formulations, but each creates a different regulatory and technical profile.
| Vehicle |
Solubility potential |
Viscosity profile |
Differentiation value |
Principal development issue |
| Castor oil |
High |
High |
Low |
Injection force and tolerability |
| Sesame oil |
Moderate to high |
Moderate |
Moderate |
Allergenicity and source variability |
| Cottonseed oil |
Moderate |
Moderate |
Moderate |
Refining and impurity controls |
| Ethyl oleate |
High for lipophilic compounds |
Lower |
High |
Oxidation and depot-performance validation |
| Medium-chain triglycerides |
Moderate |
Low to moderate |
High |
Drug solubility and release duration |
| Benzyl benzoate-containing blend |
High |
Adjustable |
Moderate |
Local tolerability and exposure |
| Polymeric injectable depot |
Formulation-dependent |
Variable |
Very high |
Complex CMC and clinical bridging |
Ethyl oleate and medium-chain triglycerides are the most commercially relevant alternatives where the business objective is to reduce viscosity or support a smaller injection volume. They require full assessment of chemical stability, container compatibility, particulate formation, sterilization compatibility, and pharmacokinetic comparability.
How should an excipient development program be structured?
The formulation program should begin with a reference-like castor-oil formulation and then evaluate differentiated vehicles in parallel.
Recommended screening sequence
- Measure equilibrium solubility of hydroxyprogesterone caproate in each candidate vehicle.
- Assess crystallization during refrigerated, room-temperature, and accelerated storage.
- Measure viscosity across the intended temperature range.
- Test syringeability through the target needle and device.
- Evaluate assay, related substances, water content, peroxide value, and visible and subvisible particles.
- Conduct container-closure compatibility studies.
- Compare in vitro release with the reference product where a reference product is legally and commercially available.
- Conduct local tolerance and pharmacokinetic studies.
The critical formulation failure mode is delayed precipitation after administration. A product can appear clear during release testing and still produce drug crystallization after dilution by tissue fluid. The development package therefore needs depot-release and local-tolerance work, not only standard solution stability.
What formulation patents protect hydroxyprogesterone caproate products?
The active pharmaceutical ingredient is an old steroid ester, so composition-of-matter exclusivity is generally not the main barrier. Commercial protection is more likely to arise from:
- Specific oil and cosolvent ratios.
- Concentrated injectable solutions.
- Subcutaneous delivery systems.
- Prefilled syringes and autoinjectors.
- Controlled-release microspheres or implants.
- Manufacturing methods that control polymorph, particle size, or residual impurities.
- Specific methods of treating pregnancy-related conditions.
Patent value depends on claim scope and enforceability rather than on the presence of a hydroxyprogesterone caproate claim alone. A formulation patent that covers only a narrow castor-oil and benzyl-benzoate ratio may be vulnerable to design-around through a different oil, concentration, or route.
Orange Book status and patent listings
Makena was approved under NDA 021945. The NDA’s U.S. market status changed after the FDA ordered withdrawal of approval in 2023. Orange Book relevance is therefore limited for future U.S. development because:
- There is no currently marketed FDA-approved Makena product.
- Any historical listed patents must be checked against their expiration, listing status, and enforceability.
- A future ANDA strategy would depend on a currently referenceable listed product and FDA acceptance of the applicable regulatory pathway.
- A new formulation with different excipients, route, or delivery technology would more likely require a 505(b)(2) application than a conventional ANDA.
The strongest defensible IP strategy would focus on a technically meaningful formulation or delivery improvement, supported by claims covering composition, manufacturing, device, and method of use.
When does hydroxyprogesterone caproate lose exclusivity?
The product’s central commercial exclusivity has already been disrupted in the United States. FDA approved Makena in 2011 under the accelerated approval pathway. The required confirmatory PROLONG trial did not verify clinical benefit, and the FDA subsequently ordered withdrawal after administrative proceedings. Covis Pharma discontinued Makena sales in the United States in 2023 (FDA, 2023b).
| Event |
Date |
Commercial implication |
| Makena approved under accelerated approval |
2011 |
U.S. commercial launch |
| Confirmatory PROLONG study reported |
2019 |
Failed to confirm benefit |
| FDA proposed withdrawal |
2020 |
Regulatory risk increased |
| FDA withdrawal order |
April 2023 |
Approval removed |
| U.S. commercial discontinuation |
2023 |
Reference product no longer marketed |
The withdrawal is more important than ordinary patent expiry. Even if formulation or method patents remain relevant in a historical sense, the absence of an approved marketed reference product weakens the conventional generic opportunity.
What is the FDA regulatory status of hydroxyprogesterone caproate?
The FDA withdrew Makena’s approval because the confirmatory trial failed to demonstrate benefit for reducing the risk of recurrent spontaneous preterm birth. The agency stated that hydroxyprogesterone caproate should no longer be used for that indication and that compounded versions are not FDA-approved alternatives to Makena (FDA, 2023b).
ACOG subsequently updated its clinical guidance, stating that intramuscular 17-OHPC is not recommended for the primary prevention of preterm birth in patients with a history of spontaneous preterm birth (American College of Obstetricians and Gynecologists [ACOG], 2023).
This regulatory history creates a major barrier for a U.S. product positioned around the former Makena indication. A new product would require a credible clinical and regulatory strategy, not merely an equivalent excipient profile.
What commercial opportunities remain for hydroxyprogesterone caproate?
1. Reformulated long-acting injectable
A lower-viscosity formulation could target:
- Smaller needles.
- Lower injection force.
- Prefilled syringe or autoinjector compatibility.
- Reduced injection-site pain.
- Improved cold-chain or room-temperature stability.
- Lower benzyl benzoate exposure.
This is the most credible formulation opportunity, but it would require a new regulatory package if marketed for a new or previously withdrawn indication.
2. Non-U.S. markets
Hydroxyprogesterone caproate has had historical use in multiple countries under different product names and indications. Market access is jurisdiction-specific. A company would need to establish:
- Whether the product remains approved locally.
- Whether the jurisdiction accepts the historic clinical evidence.
- Whether local guidelines still support use.
- Whether a new formulation requires bridging studies.
- Whether the excipient system is permitted for parenteral use under local standards.
The international opportunity is therefore fragmented rather than global by default.
3. Specialty and compounded supply
Compounding pharmacies may continue to receive prescriptions in limited circumstances, but compounded products are not FDA-approved and do not carry the same assurance of quality, sterility, potency, or clinical evidence as an approved product. A commercial supplier could pursue pharmaceutical-grade API, validated sterile manufacturing, or contract manufacturing services, subject to applicable law.
4. Veterinary applications
Veterinary reproductive medicine may provide a separate opportunity. The commercial case would depend on species-specific pharmacology, residue requirements, veterinary labeling, and demand for progestin-based reproductive management. Human drug data would not automatically establish veterinary approval.
5. Drug-delivery platform licensing
A polymeric depot, implant, or microparticle system could have licensing value if it demonstrates a meaningful improvement in dosing interval, tolerability, or adherence. The platform would need composition and process patents that are difficult to design around.
Which companies are challenging hydroxyprogesterone caproate products?
The principal U.S. market event was not a conventional Paragraph IV generic challenge. The dominant competitive issue was FDA withdrawal of Makena after the failed confirmatory study. Generic and compounded products existed or were discussed in the market, but the commercial structure differs from a typical branded drug facing multiple ANDA filers.
A Paragraph IV strategy would be difficult to evaluate without a currently marketed reference product and verified Orange Book listings. A company pursuing a U.S. launch would likely examine a 505(b)(2) pathway, a new clinical indication, or a non-U.S. strategy rather than rely solely on abbreviated generic substitution.
What manufacturing and IP barriers affect commercialization?
The main manufacturing barriers are:
- Sterile processing of a high-dose oil solution.
- Control of viscosity and fill accuracy.
- Prevention of precipitation and crystallization.
- Control of oxidation in vegetable oils.
- Compatibility with elastomeric closures and syringe components.
- Device performance at refrigerated and room temperatures.
- Reproducible depot release after injection.
The main IP barriers are narrower:
- Historical product and formulation patents.
- Device patents covering autoinjectors or prefilled systems.
- Process patents for sterile manufacture and impurity control.
- Method-of-use claims tied to pregnancy-related indications.
- Potential freedom-to-operate issues in individual jurisdictions.
How strong is the hydroxyprogesterone caproate commercial opportunity?
The opportunity is weak for a direct U.S. generic but moderate for differentiated formulation technology.
| Opportunity |
Commercial attractiveness |
Regulatory risk |
Technical risk |
| Reference-like IM injectable |
Low |
High |
Moderate |
| Lower-viscosity injectable |
Moderate |
High |
High |
| Autoinjector-compatible product |
Moderate |
High |
High |
| New approved indication |
Potentially high |
Very high |
High |
| Non-U.S. product |
Moderate |
Market-specific |
Moderate |
| Compounding supply |
Low to moderate |
High compliance burden |
Moderate |
| Veterinary product |
Moderate |
Species-specific |
Moderate |
| Depot or implant platform |
Potentially high |
Very high |
Very high |
Revenue exposure to the former U.S. Makena market has materially declined because the approved product was withdrawn. Any investment case should value hydroxyprogesterone caproate as a development asset or platform component, not as an established U.S. branded franchise.
Key Takeaways
- Hydroxyprogesterone caproate is best suited to nonaqueous long-acting formulations.
- Castor oil and benzyl benzoate are the established reference excipients for Makena-type injections.
- Ethyl oleate and medium-chain triglycerides offer the clearest routes to lower viscosity and device compatibility.
- The FDA withdrew Makena approval in 2023 after the confirmatory trial failed to verify clinical benefit.
- A conventional U.S. generic opportunity is weak because the reference product is no longer marketed.
- Commercially meaningful differentiation would require improved tolerability, delivery technology, a new indication, or a non-U.S. regulatory strategy.
- Formulation, device, manufacturing, and depot-release patents are more relevant than old composition-of-matter rights.
- Compounded products are not substitutes for FDA-approved products from a regulatory or quality standpoint.
FAQs
Can hydroxyprogesterone caproate be formulated as an aqueous injection?
Not readily. Its low aqueous solubility makes an oil-based solution, suspension, cosolvent system, or advanced delivery technology more practical than a conventional aqueous injection.
What excipient could replace benzyl benzoate in hydroxyprogesterone caproate?
Ethyl oleate, sesame oil, cottonseed oil, and medium-chain triglycerides are candidates. The replacement must be evaluated for solubility, precipitation, viscosity, local tolerance, stability, and pharmacokinetic comparability.
Is compounded 17-OHPC the same as Makena?
No. Compounded 17-OHPC is not FDA-approved and may differ in excipients, concentration, sterility controls, manufacturing conditions, and quality testing.
Could a new hydroxyprogesterone caproate formulation receive FDA approval?
Yes, but a new formulation would require a viable clinical indication and an appropriate regulatory pathway. A formulation-only change would not resolve the failed efficacy evidence for the former recurrent preterm birth indication.
Does hydroxyprogesterone caproate have biosimilar risk?
No. Hydroxyprogesterone caproate is a small-molecule steroid ester, not a biologic. Competitive products would be evaluated as generics, 505(b)(2) products, or new drug applications rather than biosimilars.
References
-
American College of Obstetricians and Gynecologists. (2023). Practice advisory: Updated guidance on the use of progestogen supplementation for prevention of recurrent preterm birth. https://www.acog.org
-
DailyMed. (2023). Makena: Hydroxyprogesterone caproate injection, solution. U.S. National Library of Medicine. https://dailymed.nlm.nih.gov
-
U.S. Food and Drug Administration. (2023a). Makena prescribing information. https://www.accessdata.fda.gov
-
U.S. Food and Drug Administration. (2023b). FDA Commissioner and Chief Scientist announce decision to withdraw approval of Makena. https://www.fda.gov
-
Blackwell, S. C., Gyamfi-Bannerman, C., Biggio, J. R., et al. (2020). 17-OHPC to prevent recurrent preterm birth in singleton gestations: A systematic review and meta-analysis. American Journal of Obstetrics and Gynecology, 223(4), 538-549. https://doi.org/10.1016/j.ajog.2020.04.011
