List of Excipients in Branded Drug SACUBITRIL AND VALSARTAN

Generic Drugs Containing SACUBITRIL AND VALSARTAN

Company	Ingredient	NDC	Excipient
Major Pharmaceuticals	sacubitril and valsartan	0904-7580	CELLULOSE, MICROCRYSTALLINE
Major Pharmaceuticals	sacubitril and valsartan	0904-7580	FERRIC OXIDE RED
Major Pharmaceuticals	sacubitril and valsartan	0904-7580	FERRIC OXIDE YELLOW
Major Pharmaceuticals	sacubitril and valsartan	0904-7580	FERROSOFERRIC OXIDE
Major Pharmaceuticals	sacubitril and valsartan	0904-7580	HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED

What are the Most Frequently-Used Excipients in SACUBITRIL AND VALSARTAN?

# Of NDCs	Excipient
1	AMMONIA
1	CALCIUM CARBONATE
24	CELLULOSE, MICROCRYSTALLINE
6	CROSCARMELLOSE SODIUM
32	CROSPOVIDONE

Sacubitril and Valsartan Excipient Strategy, Patent Protection, and Commercial Opportunities

Last updated: August 25, 2026

Sacubitril/valsartan is a high-value fixed-dose combination marketed by Novartis as Entresto. Its commercial opportunity is shifting from the originator tablet toward lower-cost generics, pediatric dosage forms, sprinkle products, oral suspensions, orally disintegrating tablets, and differentiated formulations. The core excipient platform is conventional and manufacturable at scale, but meaningful value remains in excipient systems that improve aqueous stability, taste, dose flexibility, pediatric administration, dissolution, and supply-chain resilience.

What is the commercial status of sacubitril/valsartan?

Sacubitril/valsartan combines the neprilysin inhibitor sacubitril with the angiotensin II receptor blocker valsartan. The active pharmaceutical ingredient is supplied as a complex containing sacubitril and valsartan in a 1:1 molar ratio. The product is approved for heart failure with reduced ejection fraction and for selected pediatric heart-failure patients.

Entresto is marketed in three adult tablet strengths:

Marketed strength	Sacubitril component	Valsartan component	Approximate total active content
24/26 mg	24 mg	26 mg	50 mg
49/51 mg	49 mg	51 mg	100 mg
97/103 mg	97 mg	103 mg	200 mg

The product is administered twice daily. The 24/26 mg and 49/51 mg strengths are commonly used during initiation and titration, while 97/103 mg twice daily is the target adult dose for many patients.

Novartis reported approximately $6 billion in global Entresto sales in 2023, making it one of the company’s largest products. The product’s commercial scale creates demand for lower-cost excipients, dual-source supply, improved tablet compression, and differentiated dosage forms. [1]

What excipients are used in Entresto tablets?

The Entresto tablet core uses standard direct-compression and dry-granulation excipients. FDA labeling identifies the core excipients as microcrystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, magnesium stearate, talc, and colloidal silicon dioxide. The film coating contains hypromellose, titanium dioxide, macrogol 4000, and colorants that vary by strength. [2]

Functional role	Entresto excipient platform	Commercial purpose
Diluent and compression aid	Microcrystalline cellulose	Tablet mass, compactability, content uniformity
Disintegrant and binder	Low-substituted hydroxypropylcellulose	Tablet breakup and mechanical strength
Superdisintegrant	Crospovidone	Rapid disintegration and dissolution
Lubricant	Magnesium stearate	Ejection from tablet tooling
Glidant	Colloidal silicon dioxide	Powder flow and blend uniformity
Anti-adherent or coating aid	Talc	Processing and film-coat performance
Film former	Hypromellose	Mechanical protection and appearance
Plasticizer	Macrogol 4000	Coating flexibility
Opacifier	Titanium dioxide	Appearance and light protection
Colorants	Iron oxides and related pigments	Strength identification

The formulation does not depend on a novel excipient. That lowers development and regulatory risk for generic manufacturers. The main technical barriers are active-ingredient solid form, blend uniformity, dissolution matching, tablet robustness, impurity control, and compliance with the reference product’s quality attributes.

Why is the excipient platform technically important?

Sacubitril/valsartan presents several formulation issues:

• It is a dual-active fixed-dose product with a defined stoichiometric relationship.
• The active complex has solid-form and hydration-state considerations.
• The tablets require reliable performance across three strengths.
• The product must support twice-daily dosing and dose titration.
• Pediatric use requires dosage flexibility that conventional adult tablets do not provide.
• Taste can become a major issue when the tablet is dispersed, crushed, or converted into a liquid or sprinkle format.

A generic tablet can use the same excipient classes without using the same suppliers or exact quantitative composition. Excipients remain commercially important because changes in grade, particle size, moisture, density, lubrication, and compaction can alter dissolution and stability.

What excipient strategies are available for generic sacubitril/valsartan?

The most attractive generic strategy is a conventional immediate-release tablet using a robust, globally available excipient system. The priority is regulatory equivalence rather than formulation novelty.

Direct compression

Direct compression can reduce manufacturing steps and improve operating cost. A practical system would typically combine microcrystalline cellulose or silicified microcrystalline cellulose with crospovidone, low-substituted hydroxypropylcellulose, colloidal silicon dioxide, and magnesium stearate.

Key development variables include:

• Active-to-excipient particle-size ratio
• Blend segregation during hopper transfer
• Lubrication time
• Tablet tensile strength
• Disintegration time
• Dissolution at multiple pH conditions
• Moisture exposure during storage

Silicified microcrystalline cellulose can improve flow and compactability, but it may change tablet porosity and dissolution relative to conventional microcrystalline cellulose. Any substitution requires comparative dissolution and stability work.

Dry granulation

Roller compaction can improve content uniformity and flow when the active complex has poor flow or compressibility. It can also support high-throughput manufacturing at lower water exposure than wet granulation.

The principal risks are over-compaction, slower tablet disintegration, and dissolution changes caused by reduced porosity. Crospovidone loading and granule porosity become important optimization variables.

Wet granulation

Wet granulation can improve blend uniformity across low-dose strengths, particularly the 24/26 mg tablet. It also enables controlled particle-size engineering. The disadvantage is additional process complexity and potential moisture-related solid-form or impurity risk.

Aqueous binders should be assessed carefully. The development program should monitor:

• Solid-state conversion
• Assay and content uniformity
• Related substances
• Water activity
• Tablet dissolution after accelerated storage

Film coating

Film coating is a relatively low-value differentiation area for standard generics but can improve brand recognition and swallowability. A conventional hypromellose-based coating is likely to provide a cost-effective platform.

Commercial opportunities include:

• Lower-cost ready-to-use coating systems
• Titanium-dioxide-free coatings for markets with formulation preferences
• Moisture-barrier coatings
• Color systems that reduce reliance on supply-constrained pigments
• Coatings designed for pediatric identification and strength differentiation

A coating change is unlikely to create meaningful patent protection by itself unless it produces a specific technical result and is claimed in combination with the active formulation.

What formulation opportunities exist beyond the standard tablet?

The strongest commercial opportunities are in pediatric and administration-flexibility products.

Sprinkle and oral-pellet formulations

Pediatric patients may have difficulty swallowing adult tablets. An oral-pellet or sprinkle formulation can permit administration with soft food or liquid, improve dose flexibility, and reduce off-label tablet manipulation.

A successful sprinkle product must control:

• Taste and mouthfeel
• Pellet size
• Dose uniformity
• Release after mixing with food
• Moisture sensitivity
• Packaging protection
• Compatibility with feeding tubes, if claimed

The excipient strategy may include neutral or polymeric taste-masking coatings, inert pellet cores, plasticizers, anti-tacking agents, and protective overcoats. The coating must prevent premature release in the mouth without delaying gastrointestinal dissolution.

Novartis received FDA approval for Entresto Sprinkle, expanding the product into pediatric administration and dosage flexibility. [3] This creates a commercial benchmark for generic or licensed alternatives, but the regulatory pathway may require more than a conventional ANDA depending on the product’s dosage form and reference-product status.

Oral suspension and extemporaneous liquid formulations

An oral suspension could address pediatric patients, dysphagia, and feeding-tube administration. The central technical problem is aqueous stability. A liquid system must control hydrolysis, precipitation, pH drift, microbial growth, sedimentation, and redispersibility.

Potential excipient categories include:

• Suspending agents such as xanthan gum or cellulose derivatives
• Wetting agents
• Buffer systems
• Chelating agents
• Preservatives
• Sweeteners and flavors
• Antifoaming agents
• Taste-masking polymers

The development team must avoid excipients that destabilize the sacubitril/valsartan complex or alter absorption. A powder-for-reconstitution presentation may provide a better stability profile than a ready-to-use liquid.

Orally disintegrating tablets

An orally disintegrating tablet could target patients with dysphagia and improve convenience. The formulation would require a high-performance superdisintegrant, porous tablet structure, low friability, and taste masking.

Commercial constraints include:

• Large active dose in the highest strength
• Potentially strong bitterness
• Sensitivity to moisture
• Packaging cost
• Difficulty maintaining mechanical strength at rapid-disintegration performance

A three-strength ODT platform may be less efficient than a lower-strength ODT used for titration or a multiparticulate product that permits flexible dosing.

Modified-release products

Modified release is a lower-probability opportunity because sacubitril/valsartan is already dosed twice daily and the fixed-dose combination has a substantial active load. A once-daily product could have commercial value, but it would require clinical bridging and may fall outside a simple generic strategy.

Potential technologies include hydrophilic matrix tablets, coated multiparticulates, and osmotic systems. Each would face formulation and regulatory requirements beyond those for an immediate-release tablet.

What patents protect sacubitril/valsartan?

The historic core patent estate included patents covering the combination of sacubitril and valsartan and related pharmaceutical compositions. US Patent No. 8,283,842 was one of the principal U.S. patents associated with Entresto and had an Orange Book-listed expiration in 2023, subject to applicable pediatric exclusivity. [4]

Later patents and applications have addressed solid forms, pharmaceutical compositions, dosage forms, and related formulation features. Patent scope and enforceability must be assessed claim by claim because a generic may avoid a composition claim while encountering a solid-form, manufacturing, or dosage-form patent.

Protection category	Typical claim subject	Risk to a generic
Combination composition	Sacubitril plus valsartan in specified ratios or forms	High for early products using the claimed active form
Solid form	Crystalline, amorphous, hydrate, or salt characteristics	High if the commercial API falls within the claims
Tablet formulation	Excipients, ratios, dissolution, or stability limitations	Moderate to high depending on claim breadth
Pediatric dosage form	Pellets, granules, sprinkle administration, or dose flexibility	High for competing pediatric products
Manufacturing process	Crystallization, isolation, drying, or impurity-control steps	Moderate; depends on API supplier and process
Method of treatment	Heart-failure treatment and dosing regimens	Relevant to Paragraph IV and labeling strategy
Device or packaging	Administration systems or moisture-protective packaging	Usually lower for standard tablets

The excipient formulation itself can be patentable when it produces a defined technical benefit. A broad claim to “sacubitril/valsartan with a disintegrant” is vulnerable to prior art and obviousness challenges. Stronger claims typically require measurable limitations such as dissolution performance, stability thresholds, particle-size distribution, solid-state identity, or pediatric administration characteristics.

When does sacubitril/valsartan lose exclusivity?

The main small-molecule composition patent expired in the United States in 2023, with pediatric exclusivity potentially extending protection into 2024. Generic entry timing has also depended on patent settlements, regulatory approvals, and later patents. [4,5]

The relevant exclusivity analysis is:

Exclusivity or barrier	Practical significance
New chemical entity exclusivity	Expired; Entresto was approved in 2015
Core composition patent	Expired in 2023, subject to pediatric extension
Later solid-form and formulation patents	May delay or limit commercial entry
Pediatric exclusivity	Added six months to eligible listed patent or exclusivity periods
ANDA approval	Does not necessarily equal immediate commercial launch
Paragraph IV settlement	May establish a negotiated launch date
Orphan-drug exclusivity	Not the principal barrier for the adult Entresto market

Entresto is listed in the FDA Orange Book under NDA 207620. [4] A generic applicant must evaluate every relevant listed patent and determine whether it will file a Paragraph III certification, Paragraph IV certification, or another legally permitted certification.

Which companies are challenging the Entresto patent estate?

Generic competition has involved major and specialty generic manufacturers filing abbreviated applications for sacubitril/valsartan tablets. Public litigation and settlement records should be reviewed for each applicant because entry dates, licensed launch rights, and patent challenges can differ by company.

The highest-risk challengers generally have:

• Commercial-scale API access
• A validated solid-form position
• Multiple tablet strengths
• A Paragraph IV litigation budget
• Experience with complex fixed-dose combinations
• A launch plan that can support rapid substitution

The most important competitive distinction is not simply FDA approval. It is the ability to launch without infringing surviving solid-form or formulation claims and to supply all three strengths consistently.

What is the FDA regulatory status of sacubitril/valsartan?

The reference product is approved under NDA 207620. Generic tablets are generally pursued through ANDAs referencing Entresto, while materially different dosage forms may require a different regulatory strategy.

Standard generic tablet

A conventional immediate-release tablet is the most straightforward regulatory opportunity. The development package should establish:

• Pharmaceutical equivalence
• Bioequivalence
• Comparative dissolution
• Strength equivalence or waiver rationale
• Impurity and degradation-product control
• Stability through the proposed shelf life
• Compliance with labeling and inactive-ingredient requirements

The inactive ingredients do not need to be identical to Entresto’s ingredients, but they must be acceptable for the route, dose, population, and dosage form.

Pediatric product

A sprinkle, pellet, or liquid product may require additional studies addressing administration with food, mixing vehicles, feeding tubes, dose recovery, and stability after opening or dispersion. Pediatric excipient selection also requires attention to age-specific exposure limits and tolerability.

How strong is the sacubitril/valsartan formulation patent estate?

The estate is strongest where formulation claims are tied to a defined solid form, a clinically relevant dosage form, or a measurable performance profile. It is weaker for broad claims relying on conventional excipients without a demonstrated technical effect.

Stronger patent positions

• Defined crystalline or hydrated active form
• Solid-state properties linked to stability or manufacturability
• Pediatric multiparticulate products
• Specific taste-masking architectures
• Administration methods involving a protected dosage form
• Formulations with narrow dissolution or stability limitations

Weaker patent positions

• Generic use of microcrystalline cellulose
• Conventional hypromellose film coating
• Routine substitution of crospovidone for another disintegrant
• Broad claims to immediate-release tablets
• Excipients selected solely from standard formulation practice

A generic manufacturer should separate freedom-to-operate analysis for the API, tablet, coating, packaging, manufacturing process, and method-of-use labeling. A non-infringing tablet can still face risk through the API solid form or an unlicensed manufacturing process.

What commercial opportunities exist for excipient suppliers?

Excipient suppliers can capture value in five areas.

1. High-performance direct-compression systems

A co-processed excipient that improves flow, compaction, and disintegration can reduce manufacturing complexity. The strongest commercial case is a platform that supports all three tablet strengths with limited process adjustment.

2. Moisture-control systems

Moisture-barrier excipients, desiccant-compatible packaging, and low-moisture coating systems can reduce degradation and extend shelf life. These products are particularly relevant for global markets with high heat and humidity.

3. Pediatric taste masking

Taste-masking polymers and multiparticulate coating systems have the clearest differentiated value. Suppliers that can provide reproducible coating thickness, low agglomeration, and rapid post-gastric release are positioned for licensing and contract-development opportunities.

4. Liquid and reconstitution systems

A stable powder-for-reconstitution system could support pediatric and dysphagia markets. Commercial value depends on room-temperature stability, preservative strategy, bottle compatibility, and acceptable taste.

5. Global regulatory support

Suppliers with multiple compendial grades and regional regulatory files can reduce qualification time. Generic manufacturers will favor excipient vendors that offer consistent particle-size specifications, DMF support where relevant, and dual manufacturing sites.

How does sacubitril/valsartan compare with competing heart-failure products?

Sacubitril/valsartan competes with generic valsartan, ACE inhibitors, beta blockers, mineralocorticoid antagonists, and newer heart-failure therapies such as dapagliflozin and empagliflozin.

Product class	Excipient opportunity	Competitive position
Sacubitril/valsartan	Pediatric, sprinkle, liquid, ODT, generic tablet	High-value fixed-dose combination
Valsartan alone	Low-cost conventional tablets and liquids	Mature generic market
ACE inhibitors	Standard tablets and liquids	Established, lower differentiation
SGLT2 inhibitors	Tablets, taste-neutral coating, high-volume generic opportunity later	Expanding heart-failure use
Mineralocorticoid antagonists	Tablets and oral suspensions	Lower active-dose burden
Beta blockers	Extended-release and pediatric liquid systems	Strong formulation diversity

Sacubitril/valsartan has greater formulation complexity than valsartan alone but also more opportunities for product differentiation. Its clinical value and twice-daily fixed-dose structure support premium pricing before full generic erosion.

What generic launch scenarios exist?

Three launch scenarios are commercially plausible.

Early authorized or licensed entry

A generic or authorized generic enters under a settlement or license before full patent exhaustion. The originator may preserve market share through branding, contracting, pediatric products, and supply agreements.

Multi-player generic entry

Several manufacturers enter after core patent expiry or settlement dates. Prices decline rapidly, especially for the 49/51 mg and 97/103 mg strengths. Manufacturing reliability and pharmacy-channel contracting become more important than formulation differentiation.

Differentiated dosage-form entry

A company launches a sprinkle, oral suspension, or ODT product aimed at pediatric or dysphagia populations. The addressable market is smaller than the adult tablet market, but pricing and switching barriers can be higher.

What licensing deals and partnership opportunities are relevant?

The most attractive licensing targets are not basic tablet formulations. They are:

• Pediatric sprinkle or pellet technology
• Stable oral suspension technology
• Taste-masking systems
• Novel solid forms with freedom-to-operate value
• Global generic rights by territory
• Authorized-generic supply agreements
• Excipient and contract-manufacturing packages

A licensing transaction should allocate rights by dosage form and geography. A company may have a strong U.S. tablet position but limited pediatric or emerging-market capability. The commercial value of a formulation license depends on patent term, regulatory exclusivity, manufacturing scale, and whether the product can be substituted through normal pharmacy channels.

What manufacturing and IP barriers affect commercial entry?

The principal manufacturing barriers are API solid-form control, content uniformity at the lowest strength, dissolution matching, moisture management, and reliable scale-up across multiple tablet sizes.

The principal IP barriers are:

1. Surviving solid-form claims.
2. Formulation patents covering specific performance characteristics.
3. Pediatric dosage-form claims.
4. Manufacturing-process claims.
5. Method-of-use claims that affect ANDA labeling.
6. Settlement restrictions on launch timing.

The most defensible commercial position combines a non-infringing API source, a documented solid-state characterization package, a simple immediate-release tablet, and a separate differentiated pediatric platform.

Key Takeaways

• Sacubitril/valsartan is a major fixed-dose heart-failure product with a multibillion-dollar originator market.
• Entresto uses a conventional excipient system based on microcrystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, magnesium stearate, talc, colloidal silicon dioxide, and a hypromellose film coat.
• The standard generic tablet is technically accessible, but API solid form, dissolution, content uniformity, and patent clearance remain important.
• Pediatric sprinkle, pellet, oral suspension, and orally disintegrating products offer the strongest differentiated excipient opportunities.
• The historic core composition patent expired in 2023, subject to pediatric exclusivity, while later formulation and solid-form rights may affect entry.
• Excipient patents are strongest when tied to measurable stability, dissolution, taste masking, or pediatric-administration results.
• Suppliers can create value through direct-compression platforms, moisture-control systems, pediatric taste masking, reconstitution technologies, and global regulatory support.
• Generic launch economics will depend on settlement dates, the number of approved competitors, substitution rules, and the ability to supply all three adult strengths.

FAQs

Can sacubitril/valsartan be formulated as an oral liquid?

Yes. An oral liquid or powder for reconstitution is technically feasible, but development must address aqueous stability, precipitation, taste, microbial control, dose uniformity, and compatibility with feeding tubes.

Which excipient is most important for a sacubitril/valsartan generic tablet?

No single excipient controls performance. The interaction between microcrystalline cellulose, crospovidone, low-substituted hydroxypropylcellulose, lubricant level, compression force, and API particle size is more important than any individual ingredient.

Is a sacubitril/valsartan pediatric product commercially attractive?

Yes. Pediatric products can support higher pricing and lower direct substitution than standard adult tablets. Sprinkle and multiparticulate formulations have the clearest opportunity because they address swallowing and dose-flexibility limitations.

Can a generic manufacturer use different excipients from Entresto?

Yes. FDA generic products generally do not need identical inactive ingredients, provided the formulation is acceptable for the dosage form and demonstrates pharmaceutical equivalence, bioequivalence, quality, and safety.

What is the largest intellectual-property risk for a sacubitril/valsartan generic?

The largest risk is usually the active-ingredient solid form and any later patent covering the specific API form, formulation, manufacturing process, or differentiated pediatric dosage form.

References

1. Novartis AG. (2024). Annual report 2023. Novartis.

2. U.S. Food and Drug Administration. (2024). Entresto (sacubitril and valsartan) prescribing information. FDA.

3. Novartis AG. (2024). FDA approves Entresto Sprinkle for pediatric heart failure patients. Novartis.

4. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book, NDA 207620. FDA.

5. U.S. Patent and Trademark Office. (2012). U.S. Patent No. 8,283,842: Pharmaceutical compositions comprising valsartan and sacubitril. USPTO.