List of Excipients in Branded Drug PHYTONADIONE

Company	Tradename	Ingredient	NDC	Excipient	Potential Generic Entry
AvPAK	PHYTONADIONE	phytonadione	50268-661	ACACIA
AvPAK	PHYTONADIONE	phytonadione	50268-661	CALCIUM PHOSPHATE
AvPAK	PHYTONADIONE	phytonadione	50268-661	LACTOSE

Generic Drugs Containing PHYTONADIONE

Company	Ingredient	NDC	Excipient
Henry Schein Inc	phytonadione	0404-9969	BENZYL ALCOHOL
Henry Schein Inc	phytonadione	0404-9969	DEXTROSE MONOHYDRATE
Henry Schein Inc	phytonadione	0404-9969	HYDROCHLORIC ACID

What are the Most Frequently-Used Excipients in PHYTONADIONE?

# Of NDCs	Excipient
3	ACACIA
4	ACACIELLA ANGUSTISSIMA BARK
10	ACETIC ACID

Phytonadione Excipient Strategy and Commercial Opportunities

Last updated: September 6, 2026

Phytonadione, also called vitamin K1 or phytomenadione, is an established active pharmaceutical ingredient with limited composition-of-matter patent value. Commercial differentiation depends on excipient performance, route of administration, neonatal safety, injection tolerability, packaging, supply reliability, and regulatory execution.

The strongest opportunities are improved injectable systems, preservative-free neonatal presentations, ready-to-use emergency products, stable oral dosage forms, and packaging that limits oxidation and light exposure. Traditional generic tablets and oil-based injections face lower differentiation and higher substitution risk.

What is the FDA regulatory status of phytonadione?

Phytonadione is an FDA-approved vitamin K product used primarily for vitamin K deficiency, hypoprothrombinemia, coumarin-anticoagulant reversal, and prevention or treatment of vitamin K deficiency bleeding in newborns. FDA-approved products have included oral tablets and injectable emulsions. Product availability changes as manufacturers discontinue or transfer applications, so commercial status must be assessed at the individual NDA or ANDA level through FDA labeling and the Orange Book.[1,2]

The principal marketed dosage-form categories are:

Dosage form	Typical strength	Primary use	Commercial position
Injectable emulsion	10 mg/mL	Urgent correction of vitamin K deficiency and anticoagulant-related bleeding risk	Highest formulation complexity and hospital value
Oral tablet	5 mg	Less urgent vitamin K supplementation or correction	Easier to manufacture and more exposed to generic substitution
Oral liquid or compounded product	Variable	Pediatric or swallowing-limited patients	Opportunity for formulation and packaging differentiation
Mixed-micellar injection	Variable by market	Neonatal and adult parenteral use	Strong platform for tolerability and rapid solubilization

Phytonadione injection is not a biologic. It does not create a biosimilar pathway. Follow-on products are generally regulated as generic drugs or as new drug applications, depending on formulation, route, reference-product status, and the extent of clinical and pharmaceutical equivalence.

What excipients are used in phytonadione injections?

Phytonadione is highly lipophilic and poorly soluble in water. Injectable products therefore require a solubilization or dispersion system. The main excipient approaches are oil emulsions, surfactant-based systems, and mixed micelles.

The U.S. AquaMEPHYTON labeling identifies an injectable emulsion containing phytonadione with polysorbate 80, dextrose, and water for injection.[3] Other global products use mixed-micellar technology based on surfactants, bile salts, phospholipids, and aqueous vehicles. Excipients vary by product and jurisdiction.

Core excipient functions

Excipient function	Candidate systems	Primary development issue
Solubilization	Polysorbate 80, bile salts, phospholipids, mixed micelles	Injection tolerability, micelle stability, oxidation
Emulsion formation	Medium-chain triglycerides, soybean oil, lecithin	Droplet size, creaming, embolic risk, sterilization
Tonicity adjustment	Dextrose, sodium chloride, glycerol	Neonatal compatibility and osmolality
pH control	Phosphate, citrate, or other buffers	Chemical stability and precipitation
Antioxidant protection	Alpha-tocopherol, sulfites, oxygen control	Hypersensitivity, label restrictions, degradation
Container protection	Amber glass, low-oxygen closures, light-resistant packaging	Photostability and extractables
Oral tablet performance	Lactose, microcrystalline cellulose, starch, povidone, crospovidone	Content uniformity and dissolution
Oral liquid performance	Glycerol, polyethylene glycol, surfactants, flavoring agents	Dose accuracy, microbial control, palatability

An excipient cannot be selected solely for solubility. For phytonadione injection, the product must also control particulate matter, subvisible particles, droplet or micelle size, oxidation, adsorption, pH drift, and compatibility with infusion systems.

Which phytonadione excipient strategy is most commercially attractive?

The most attractive strategy is a low-volume, preservative-free, ready-to-use injectable system with improved tolerability and neonatal suitability.

A commercial formulation program should prioritize:

1. Aqueous or mixed-micellar solubilization rather than a conventional oil-only system.
2. Low surfactant exposure consistent with adequate solubility and shelf life.
3. Preservative-free single-dose packaging for neonates.
4. Light-protective packaging and low headspace oxygen.
5. A short administration volume suitable for emergency and neonatal use.
6. Compatibility with common syringes, infusion lines, and dilution media.
7. Robust sterility and particulate-control performance.
8. A package configuration that reduces preparation and dosing errors.

The product should be evaluated against the clinical concern that serious hypersensitivity and anaphylactoid reactions have been reported with parenteral phytonadione products. The FDA label recommends careful administration and identifies intravenous and intramuscular use as carrying important safety considerations.[3]

Mixed-micellar systems

Mixed micelles can provide an aqueous presentation with a lower oil burden. A typical platform may combine a surfactant or bile salt with a phospholipid and aqueous vehicle. The commercial benefit is a small injection volume and the ability to provide a clear or nearly clear preparation.

The main risks are:

• Surfactant-related hypersensitivity.
• Micelle disruption after dilution.
• Interaction with infusion materials.
• Oxidative degradation of phytonadione.
• Variable particle or aggregate formation during storage.
• Difficulty demonstrating equivalence to an oil-emulsion reference product.

Mixed-micellar products may be more defensible than simple generic oil emulsions because the formulation, process, and performance specifications can be tightly integrated.

Oil-in-water emulsions

Oil-in-water emulsions use a lipid phase to carry phytonadione and an emulsifier to disperse it in water. The platform is familiar to parenteral manufacturers but requires control of droplet size, phase separation, sterilization, and oxidation.

Oil emulsions can support a differentiated product if they deliver:

• Lower injection pain.
• Improved storage stability.
• Reduced aggregation.
• Smaller dose volume.
• A more favorable neonatal excipient profile.
• Better compatibility with common administration practices.

The difficulty is that a conventional lipid emulsion may have limited patent strength if it uses known oils, lecithin, polysorbates, and standard homogenization processes.

What formulations are protected by phytonadione patents?

Phytonadione itself is an old vitamin compound and does not provide meaningful new-molecule patent protection for current products. The commercially relevant patent opportunities are formulation, process, container, delivery system, and method-of-use claims.

Potential claim categories include:

Patent category	Example claim focus	Expected strategic value
Injectable formulation	Defined micelle or emulsion composition	High if linked to stability and tolerability
Particle or micelle attributes	Droplet-size or micelle-size range	Moderate, but vulnerable to design-around
Manufacturing process	High-pressure homogenization, sterile filtration, nitrogen control	Moderate
Stability	Reduced degradation under light or oxygen exposure	Moderate to high if supported by comparative data
Container closure	Low-oxygen syringe, vial, or cartridge system	Moderate
Administration device	Prefilled syringe or dose-metered system	Moderate to high
Oral delivery	Taste-masked liquid, dispersible tablet, modified release	Moderate
Method of use	Neonatal dosing, anticoagulant reversal, or specific administration regimen	Variable and jurisdiction-dependent

Broad claims covering phytonadione plus a conventional surfactant are likely to face validity and obviousness challenges. Stronger protection would require a defined excipient ratio, measurable physical attributes, unexpected stability or tolerability results, and a clinically relevant performance advantage.

When does phytonadione lose exclusivity?

Phytonadione has no meaningful new chemical entity exclusivity remaining. Any current market protection would arise from product-specific patents, regulatory exclusivities, supply arrangements, or commercial execution rather than the active ingredient.

A patent-expiration analysis should separate:

• Active ingredient patents.
• Formulation patents.
• Method-of-use patents.
• Manufacturing patents.
• Device and packaging patents.
• Regulatory exclusivity.
• Pediatric exclusivity.
• Orphan-drug exclusivity, if applicable to a specific indication.

For established phytonadione products, the principal entry barrier is usually regulatory and operational rather than composition-of-matter exclusivity. A competitor with a pharmaceutically equivalent product may enter through an ANDA if it can satisfy FDA requirements for the applicable reference product and demonstrate formulation and performance equivalence.

No current, broadly controlling phytonadione patent family should be assumed without a live search of the USPTO, WIPO, FDA Orange Book, and relevant national registers. Patent numbers and expiration dates should not be inferred from the active ingredient name alone.

What is the Orange Book status of phytonadione?

The Orange Book is relevant to approved prescription phytonadione products that have listed patents or exclusivity information. It is not a complete record of every formulation patent, international patent, process patent, or patent that may affect commercial freedom to operate.[2]

For an Orange Book review, the critical fields are:

Review item	Relevance
Reference listed drug	Determines the applicable generic pathway
Strength and dosage form	Controls the scope of equivalence analysis
Route of administration	Separates oral and injectable products
Patent listing	Identifies patents submitted by the NDA holder
Use code	Defines the method-of-use scope
Exclusivity code	Identifies remaining regulatory protection
Paragraph IV certification	Signals an asserted patent challenge
Suit status	Determines whether a 30-month stay may apply

Phytonadione products with no listed patents would generally present a lower Paragraph IV barrier. A formulation-specific NDA could create a more substantial patent position, but that position would depend on actual Orange Book listings and litigation history.

Which companies are challenging phytonadione exclusivity?

No reliable conclusion about current Paragraph IV challengers, defendants, or settlement parties should be made from the ingredient name alone. Phytonadione has multiple dosage forms, manufacturers, reference products, and historical labels. A company challenging an injectable product may not be challenging an oral tablet, and an ANDA filing may not produce public litigation if no listed patent is asserted.

The relevant litigation screen should cover:

• ANDA notices under Paragraph IV.
• Hatch-Waxman complaints.
• Declaratory judgment actions.
• Patent settlements and launch licenses.
• FDA approval dates.
• Commercial launch dates.
• Patent-term adjustments.
• Pediatric or other regulatory exclusivities.

For investment purposes, the absence of a visible Paragraph IV case would generally reduce litigation risk but would not eliminate formulation or freedom-to-operate concerns.

What generic entry risks exist for phytonadione?

Generic entry risk is high for conventional oral tablets and standard injectable products with well-established excipient systems. It is lower for complex sterile emulsions and proprietary mixed-micellar formulations.

High-risk products

• 5 mg conventional tablets.
• Simple powder blends with standard excipients.
• Conventional oil-based injections.
• Products with no device differentiation.
• Products relying on price rather than hospital workflow value.

Moderate-risk products

• Preservative-free single-dose injections.
• Stable oral liquids.
• Premeasured emergency kits.
• Formulations with specific container-closure systems.

Lower-risk products

• Complex mixed-micellar injections.
• Formulations with demonstrated reduced hypersensitivity or improved administration performance.
• Integrated prefilled syringe systems.
• Products with validated neonatal dosing and packaging advantages.

A generic entrant may still face substantial CMC work for injectable phytonadione. The formulation must meet sterility, endotoxin, particulate, content uniformity, assay, degradation, and physical-stability requirements. Comparative data may be needed for emulsion or micellar attributes that are not relevant to a conventional tablet.

How should excipient selection address neonatal use?

Neonatal use creates the most stringent excipient strategy. A product intended for newborns should minimize unnecessary excipients, avoid preservatives where possible, control osmolality, and provide an accurate low-volume dose.

Key neonatal development controls include:

• Preservative-free single-dose presentation.
• Avoidance of excipients with neonatal toxicity concerns.
• Low injection volume.
• Accurate dosing for low body weight.
• Compatibility with neonatal syringes and tubing.
• Low particulate burden.
• Strong photostability protection.
• Clear instructions for route and dilution.
• Stability after opening or preparation.

Benzyl alcohol and other antimicrobial preservatives require particular caution in neonatal products. Polysorbate exposure also merits toxicological review, especially where repeated dosing or very low body weight is involved. The regulatory justification should be based on total daily exposure, route, duration, and patient population rather than excipient precedent alone.

How strong is the phytonadione patent estate?

The overall estate is likely weak for the active ingredient and stronger only where a company owns a differentiated delivery platform.

Estate element	Relative strength
Phytonadione molecule	Low
Conventional tablet	Low
Standard oil emulsion	Low to moderate
Mixed-micellar injection	Moderate
Neonatal preservative-free formulation	Moderate
Prefilled syringe and administration system	Moderate
Manufacturing process with measurable product attributes	Moderate
Clinically supported tolerability improvement	Potentially high
Method-of-use claims	Variable and indication-specific

Patent strength will depend on claim construction and evidence. A formulation patent supported only by routine excipient substitution may be vulnerable. A patent supported by unexpected stability, lower reaction rates, improved dose recovery, or clinically meaningful administration advantages has a stronger commercial position.

What licensing deals could create value in phytonadione?

Licensing opportunities are more likely to involve technology platforms than the phytonadione molecule itself. Potential transactions include:

• Access to mixed-micelle solubilization technology.
• Sterile emulsion manufacturing rights.
• Prefilled syringe or cartridge technology.
• Pediatric and neonatal packaging rights.
• Regional commercialization licenses.
• Contract manufacturing agreements with validated sterile capacity.
• Co-development of hospital emergency products.

A license should allocate ownership and enforcement rights for formulation patents, process improvements, container technology, and regulatory data. The commercial value of a phytonadione license will depend on hospital formulary access, shortage exposure, manufacturing reliability, and the ability to obtain a premium over generic products.

What revenue exposure and commercial opportunities exist?

Standalone phytonadione revenue is difficult to isolate because manufacturers often report it within broader injectable, hospital, vitamin, or generic portfolios. The largest commercial value is likely concentrated in institutional injectable demand rather than chronic oral use.

Commercial opportunities include:

1. A shortage-resistant hospital injectable.
2. A neonatal-focused preservative-free product.
3. A ready-to-administer prefilled syringe.
4. A low-volume product for emergency anticoagulant reversal.
5. A stable oral liquid for pediatric and swallowing-limited patients.
6. A hospital kit combining phytonadione with administration supplies.
7. A global product adapted to mixed-micellar regulatory precedents.
8. A contract-manufactured platform for other poorly water-soluble vitamins.

The strongest pricing argument is reduced workflow burden and improved safety, not the intrinsic value of vitamin K1. Hospital buyers may pay for reliable supply, reduced preparation steps, fewer dosing errors, and lower waste.

How does phytonadione compare with competing vitamin K products?

Phytonadione competes with other vitamin K forms and delivery systems rather than with a single direct substitute.

Product type	Main advantage	Main limitation
Phytonadione injection	Established clinical use and rapid parenteral delivery	Formulation sensitivity and injection-reaction concerns
Phytonadione tablet	Low manufacturing cost and simple administration	Slower or less predictable use in urgent settings
Mixed-micellar phytonadione	Aqueous delivery and small volume	Complex CMC and excipient tolerability
Vitamin K2 products	Nutritional and specialty-market positioning	Different clinical and regulatory positioning
Compounded oral liquid	Flexible pediatric dosing	Quality, stability, and supply variability

Phytonadione remains the most relevant active ingredient for approved vitamin K replacement and reversal products in many markets. Differentiation therefore depends on dosage form, route, excipient safety, and supply performance.

Key Takeaways

• Phytonadione has little remaining composition-of-matter patent value.
• Formulation and delivery technology provide the main IP opportunity.
• Mixed-micellar and preservative-free injectable systems have the strongest commercial differentiation potential.
• Neonatal products require strict control of preservatives, osmolality, dose volume, particulates, and excipient exposure.
• Conventional tablets and simple injections face high generic substitution risk.
• A prefilled, ready-to-use hospital product could command value through workflow and safety improvements.
• Orange Book and Paragraph IV conclusions must be made at the product and reference-NDA level.
• Manufacturing capability, sterile capacity, packaging, and supply continuity may matter more than active-ingredient patents.
• The strongest patent claims should connect defined excipient compositions to measurable stability, tolerability, or administration benefits.

FAQs About Phytonadione Excipient and Commercial Strategy

Is polysorbate 80 necessary in every phytonadione injection?

No. Polysorbate 80 is used in some products, but other systems use oils, phospholipids, bile salts, or mixed micelles. The selected excipient system must support solubility, sterility, stability, tolerability, and regulatory acceptability.

Can phytonadione be formulated as a preservative-free oral liquid?

Yes. A preservative-free oral liquid is technically possible, but it requires validated microbiological controls, suitable packaging, in-use stability, dose uniformity, and protection against oxidation and light.

Is a phytonadione prefilled syringe patentable?

Potentially. Patentability may arise from the combination of formulation, syringe materials, oxygen control, dose accuracy, stability, and administration design. A simple repackaging claim would face greater validity risk.

What is the main CMC barrier for phytonadione injection approval?

The main barrier is demonstrating consistent control of the solubilized or dispersed active ingredient during sterilization and storage. Critical attributes include assay, degradation products, pH, particulate matter, micelle or droplet size, sterility, endotoxin, and container compatibility.

Is phytonadione suitable for a premium generic strategy?

Yes, if the product offers a defensible hospital benefit such as preservative-free neonatal use, reduced injection volume, ready-to-use administration, improved stability, or reliable shortage-resistant supply. A conventional tablet or undifferentiated injection is less suitable for premium pricing.

References

1. U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs database. https://www.accessdata.fda.gov/scripts/cder/daf/

2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book

3. U.S. Food and Drug Administration. (n.d.). AquaMEPHYTON (phytonadione) injectable emulsion prescribing information. DailyMed. https://dailymed.nlm.nih.gov/

4. U.S. Pharmacopeia. (2024). United States Pharmacopeia and National Formulary: Phytonadione. U.S. Pharmacopeial Convention.

5. European Medicines Agency. (n.d.). Konakion and phytomenadione product information. https://www.ema.europa.eu/