List of Excipients in Branded Drug GLIPIZIDE AND METFORMIN HYDROCHLORIDE

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Generic Drugs Containing GLIPIZIDE AND METFORMIN HYDROCHLORIDE

Company	Ingredient	NDC	Excipient
Teva Pharmaceuticals USA Inc	glipizide and metformin hydrochloride	0093-7455	CELLULOSE, MICROCRYSTALLINE
Teva Pharmaceuticals USA Inc	glipizide and metformin hydrochloride	0093-7455	CROSCARMELLOSE SODIUM
Teva Pharmaceuticals USA Inc	glipizide and metformin hydrochloride	0093-7455	FERRIC OXIDE RED
Teva Pharmaceuticals USA Inc	glipizide and metformin hydrochloride	0093-7455	FERRIC OXIDE YELLOW
Teva Pharmaceuticals USA Inc	glipizide and metformin hydrochloride	0093-7455	FERROSOFERRIC OXIDE
Teva Pharmaceuticals USA Inc	glipizide and metformin hydrochloride	0093-7455	MAGNESIUM STEARATE

What are the Most Frequently-Used Excipients in GLIPIZIDE AND METFORMIN HYDROCHLORIDE?

# Of NDCs	Excipient
11	CELLULOSE, MICROCRYSTALLINE
1	CI 77891
11	CROSCARMELLOSE SODIUM
7	FERRIC OXIDE RED
4	FERRIC OXIDE YELLOW
4	FERROSOFERRIC OXIDE

Glipizide and Metformin Hydrochloride: Excipient Strategy, Patent Status, and Commercial Opportunities

Last updated: September 25, 2026

Glipizide/metformin hydrochloride is an established immediate-release fixed-dose combination for type 2 diabetes. Its commercial value is primarily in low-cost generic manufacturing, differentiated tablet performance, and geographic expansion rather than in residual compound or formulation patent protection. The main formulation challenge is combining a low-dose, poorly soluble sulfonylurea with a high-dose, highly soluble biguanide while controlling content uniformity, tablet size, dissolution, and gastrointestinal tolerability.

What is the regulatory and commercial status of glipizide/metformin hydrochloride?

The original U.S. product was marketed as Metaglip, a fixed-dose tablet containing glipizide and metformin hydrochloride. FDA approved the product under NDA 021431 in 2002. Approved strengths included:

Strength	Glipizide	Metformin hydrochloride	Dosage form
Low strength	2.5 mg	250 mg	Immediate-release tablet
Intermediate strength	2.5 mg	500 mg	Immediate-release tablet
High strength	5 mg	500 mg	Immediate-release tablet

The product is indicated as an adjunct to diet and exercise for adults with type 2 diabetes when treatment with both components is appropriate. The label identifies the pharmacologic roles of the two active ingredients: glipizide stimulates pancreatic insulin release, while metformin reduces hepatic glucose production and improves insulin sensitivity.[1]

Generic versions are marketed under the active-ingredient name. The product is a small-molecule combination, so it does not face biosimilar competition. Competition arises through abbreviated new drug applications, generally supported by pharmaceutical equivalence and bioequivalence rather than by full clinical development.

What are the main commercial demand drivers?

Demand is supported by several factors:

• Continued use of metformin as foundational type 2 diabetes therapy.
• Use of sulfonylureas where cost and access are more important than newer drug-class benefits.
• Demand for low-cost fixed-dose combinations.
• Distribution through public health systems, cash-pay markets, and low-income countries.
• Use in markets where GLP-1 receptor agonists, SGLT2 inhibitors, and DPP-4 inhibitors remain less accessible.

The commercial limitation is therapeutic substitution. Newer products offer cardiovascular, renal, weight, or hypoglycemia advantages that glipizide/metformin generally does not provide. U.S. products therefore compete mainly on price, availability, tablet quality, and payer coverage.

What excipient strategy is appropriate for the combination tablet?

The most practical strategy is a robust immediate-release formulation based on separate granulation or staged processing of the two active ingredients. A single direct-compression blend may be possible, but it creates higher risk of segregation because glipizide is present at a much lower mass than metformin hydrochloride.

How do the active ingredients affect formulation design?

Attribute	Glipizide	Metformin hydrochloride	Formulation consequence
Typical dose in combination	2.5 or 5 mg	250 or 500 mg	Large dose asymmetry
Solubility	Low aqueous solubility	High aqueous solubility	Different dissolution controls
Dose uniformity risk	High because of low dose	Lower on a mass basis	Requires ordered mixing or granulation
Gastrointestinal profile	Hypoglycemia risk is pharmacologic	GI upset is common	Avoid unnecessary release acceleration
Compression behavior	Low-dose component can segregate	High-dose component drives tablet size	Optimize granule density and flow
Release target	Immediate release	Immediate release	Avoid excessive hydrophobic lubrication

A suitable excipient platform may include:

• Microcrystalline cellulose for compactability and tablet strength.
• Povidone or copovidone as a binder.
• Crospovidone or croscarmellose sodium as a superdisintegrant.
• Colloidal silicon dioxide to improve flow.
• Magnesium stearate at controlled concentration and mixing time.
• Lactose monohydrate, mannitol, or another diluent depending on compatibility and target tablet size.
• Hypromellose-based film coating for identification, swallowability, and moisture protection.

These excipients are conventional and generally compatible with an ANDA strategy. The commercial advantage will not come from using a novel excipient. It will come from process control, tablet size, dissolution consistency, and manufacturing cost.

Should the formulation use wet granulation or direct compression?

Wet granulation is usually the stronger development option for the higher metformin strengths because it improves flow, reduces segregation, and supports uniform distribution of low-dose glipizide. It can also reduce compression variability in large tablets.

Direct compression may provide lower manufacturing cost and fewer unit operations. It is more attractive when:

• Both active ingredients have suitable particle-size distributions.
• Glipizide is pre-diluted or incorporated through an ordered-mixing process.
• Blend uniformity remains acceptable at commercial scale.
• The resulting tablet is not excessively large or friable.

A practical development program should compare at least three architectures:

1. A common granulation containing both active ingredients.
2. Separate granulation of glipizide followed by blending with metformin granules.
3. Direct compression with engineered particle-size and density control.

The second approach can provide the best balance when glipizide segregation is the principal risk. Separate processing also permits tighter control of glipizide distribution without subjecting the entire metformin load to the same granulation conditions.

What excipients can differentiate a generic glipizide/metformin product?

Excipient differentiation is commercially relevant when it improves tolerability, manufacturability, or patient use without changing the immediate-release performance.

Low-hygroscopicity and moisture-control platform

Metformin hydrochloride is highly soluble and can create processing and stability challenges under high humidity. A formulation using low-moisture excipients, controlled packaging, and a robust film coat may reduce sticking, softening, and dissolution drift.

Commercial options include:

• High-density microcrystalline cellulose.
• Mannitol in place of some lactose.
• Low-moisture grades of disintegrant.
• Aluminum-aluminum blister packaging for humid markets.
• High-barrier HDPE bottles with desiccant for lower-cost distribution.

Smaller-tablet platform

The 500 mg metformin hydrochloride strength drives tablet mass. A smaller tablet can improve adherence, particularly for patients who already take multiple medicines. Size reduction may require:

• Higher-density granules.
• Optimized roller compaction or wet granulation.
• More efficient superdisintegrant placement.
• A thinner, stronger film coat.
• Careful control of lubricant concentration.

A smaller tablet is commercially useful, but excessive compression can delay metformin dissolution. The product must remain within the immediate-release dissolution profile expected for the reference product.

Reduced-excipient and low-sugar platform

A product marketed for patients concerned about excipient load can use a short, conventional excipient list and avoid sucrose-containing coatings. The claim must remain factual. “Sugar-free” or “sucrose-free” may have value in selected markets, but it is not a substitute for bioequivalence and stability performance.

Patient-friendly identification

Color, debossing, and packaging can reduce dispensing errors among multiple strengths. Because glipizide/metformin tablets are available in several dose ratios, clear strength differentiation is commercially important. A manufacturer can use:

• Distinct tablet color by strength.
• Strength-specific imprinting.
• Unit-dose packaging.
• QR-linked patient information where permitted.
• Blister cards organized by morning and evening dosing.

What formulations are protected by patents?

The original fixed-dose combination does not have a meaningful remaining U.S. compound-patent barrier. Glipizide and metformin hydrochloride are mature active ingredients, and the original Metaglip exclusivity period has expired.

The key intellectual-property categories are:

IP category	Current commercial relevance
Glipizide compound patents	Expired
Metformin compound patents	Expired
Original fixed-dose combination protection	Expired
Immediate-release formulation patents	No material barrier identified for ordinary generic entry
Modified-release formulation patents	Potentially relevant only to a new product design
Manufacturing-process patents	May affect a specific supplier or process, but do not generally block conventional entry
Trade dress and trademarks	Brand and packaging rights may remain separate from drug patent rights

The Orange Book status for the original product should be distinguished from the status of any individual generic application. A generic applicant must evaluate current Orange Book listings, ANDA-specific litigation exposure, and any applicable pediatric or regulatory exclusivity. The core product, however, is not commercially protected by a live compound patent.

Are there method-of-use patents?

The principal use is treatment of type 2 diabetes. That use is longstanding and does not provide a practical exclusivity barrier for ordinary generic development. Any method-of-use claim would need to be evaluated for scope, enforceability, and listing status. A generic label can also use a “skinny label” approach where a patented indication is carved out, subject to applicable FDA and litigation requirements.

When does glipizide/metformin lose exclusivity?

The meaningful U.S. exclusivity periods ended years ago.

Milestone	Timing
Original fixed-dose product approval	2002
New chemical entity exclusivity	Not applicable to the combination in the current commercial period
Five-year NCE protection	Not available for a combination of previously known active ingredients
Three-year clinical-investigation exclusivity	Expired
Pediatric exclusivity	No current barrier
Compound-patent exclusivity	Expired
Current market position	Generic, price-competitive category

The product’s commercial life is therefore governed by manufacturing economics and market access rather than by a protected exclusivity window.

Which companies are challenging the reference product?

Generic competition is established, and products are marketed by multiple generic manufacturers in the United States and international markets. The market is not dependent on a single challenger.

Because the active ingredients and original combination are mature, Paragraph IV litigation is less likely to determine market entry than it would for a recently approved product. A new generic applicant could still file a Paragraph IV certification against any listed patent, but the probability that an old combination patent blocks the category is low.

What is the Paragraph IV risk?

For a conventional immediate-release generic, the main risk areas are:

• A newly listed formulation patent.
• A patent directed to a specific excipient system.
• A process patent covering a commercially important manufacturing route.
• A dispute over the scope of the reference product’s labeling.
• Failure to design around a patent on a modified-release or multilayer formulation.

The risk is materially higher for a new extended-release, once-daily, orally disintegrating, or multiparticulate product than for a standard immediate-release tablet.

What is the FDA regulatory pathway?

A conventional generic product would generally use an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act. The development package typically requires:

• Pharmaceutical equivalence to the reference product.
• Comparative dissolution.
• Assay and content-uniformity data.
• Impurity and degradation-product control.
• Stability data.
• Bioequivalence under the applicable FDA product-specific guidance.
• Demonstration that inactive ingredients do not create safety or performance concerns.

A novel formulation with a different release profile, new route, or material clinical distinction may require a 505(b)(2) application instead. That pathway can support lifecycle innovation but carries higher development cost and greater regulatory risk.

What generic launch scenarios exist?

Scenario 1: Conventional immediate-release generic

This is the lowest-risk commercial program. The product uses the established strengths and matches the reference product’s release characteristics.

Commercial requirements are:

• Low tablet cost.
• Reliable supply of both APIs.
• Strong blend-uniformity control.
• Competitive packaging.
• Efficient scale-up.

Scenario 2: Smaller, easier-to-swallow tablet

This targets adherence and pharmacy substitution. It may require a denser formulation and additional comparative dissolution work. The product remains an immediate-release generic if it meets the applicable requirements.

Scenario 3: Extended-release fixed-dose combination

A once-daily product could compete for adherence and reduce dosing frequency. It would face more substantial development requirements because glipizide and metformin have different pharmacokinetic and release-control needs. The product may require clinical pharmacology studies and could raise patent questions if it overlaps with protected delivery systems.

Scenario 4: Market-specific low-cost formulation

Manufacturers can target Latin America, South Asia, Africa, and other price-sensitive markets with:

• High-volume bottle packaging.
• Moisture-resistant blister packs where humidity is high.
• Limited strength portfolios.
• Local API sourcing.
• Simplified coating and imprinting.
• Government-tender pricing.

This strategy depends on local registration, supply reliability, and country-specific procurement rules rather than U.S. patent rights.

How strong is the patent estate?

The patent estate is weak for a standard immediate-release generic and potentially stronger for differentiated delivery.

Factor	Assessment
Active-ingredient patents	Weak or expired
Original combination protection	Expired
Ordinary IR tablet	Low patent barrier
Extended-release product	Moderate potential barrier
Novel excipient system	Case-specific
Manufacturing process	Supplier- and route-specific
Regulatory exclusivity	No meaningful current barrier
Litigation exposure	Low for conventional generic entry
Commercial differentiation	More important than patent protection

The most defensible assets for a new entrant are likely to be process know-how, scale-up data, low-cost manufacturing, packaging performance, and regulatory execution. These assets may not create blocking rights, but they can reduce failure rates and protect margins.

What manufacturing and intellectual-property barriers matter?

Manufacturing barriers

The main technical barriers are:

• Uniform distribution of 2.5 mg or 5 mg glipizide through a high-dose metformin matrix.
• Control of tablet weight and hardness.
• Prevention of sticking during compression.
• Consistent disintegration despite high tablet density.
• Moisture control during granulation and storage.
• API particle-size consistency.
• Scale-up of a process that passes blend-uniformity testing.

IP barriers

A manufacturer should screen for:

• Patents on modified-release matrices.
• Patents on multilayer or bilayer tablets.
• Patents on taste-masked or orally disintegrating systems.
• Patents on specific granulation sequences.
• Patents covering combination products with other antidiabetic agents.
• Country-specific rights outside the United States.

For standard immediate-release tablets, freedom-to-operate analysis is generally more important for process patents and formulation improvements than for the active ingredients.

How does glipizide/metformin compare with newer diabetes combinations?

Product class	Main advantage	Main limitation versus glipizide/metformin
Glipizide/metformin	Low cost and familiar therapy	Hypoglycemia and limited weight benefit
DPP-4 inhibitor/metformin	Low hypoglycemia risk	Higher price; less glucose-lowering potency in some patients
SGLT2 inhibitor/metformin	Cardiovascular and renal benefits for some agents	Higher cost and infection-related adverse effects
GLP-1 receptor agonist plus metformin	Weight reduction and strong glucose lowering	Injection or high oral cost; access constraints
Sulfonylurea/metformin	Established low-cost option	Less favorable durability and hypoglycemia profile

The combination remains commercially viable where price and availability dominate prescribing decisions. Its competitive position is weaker in insured markets that favor agents with demonstrated cardiovascular or renal outcomes.

What licensing deals and partnerships are commercially relevant?

There is no strategic licensing requirement to commercialize a conventional generic glipizide/metformin tablet. The relevant partnership models are:

• API supply agreements for glipizide and metformin hydrochloride.
• Contract development and manufacturing arrangements.
• Regional licensing for registrations and distribution.
• Government-tender partnerships.
• Co-packaging or portfolio agreements with other diabetes products.

A licensing deal is more defensible for a differentiated formulation, such as a once-daily modified-release product, a high-humidity stability platform, or a compact tablet with validated adherence benefits. A plain immediate-release generic is more likely to be developed through supply and distribution contracts than through royalty-bearing patent licenses.

What is the revenue exposure and commercial opportunity?

The product has low unit economics but potentially high volume. Revenue exposure depends on:

• Number of approved strengths.
• Access to major wholesalers and pharmacy chains.
• Tender participation.
• API cost and yield.
• Tablet size and packaging cost.
• Geographic concentration.
• Ability to avoid manufacturing interruptions.

A portfolio approach is stronger than launching one strength. The 2.5/500 mg and 5/500 mg strengths are likely to address the largest metformin-dose segment, while the 2.5/250 mg strength can support titration and lower-dose patients. The optimal portfolio depends on local prescribing and substitution rules.

Key Takeaways

• Glipizide/metformin hydrochloride is a mature, generic immediate-release combination.
• The original U.S. product, Metaglip, was approved in 2002 under NDA 021431.
• Compound, combination, and original exclusivity barriers have expired.
• The central formulation problem is low-dose glipizide uniformity within a high-dose metformin tablet.
• Wet granulation or separate glipizide pre-granulation is generally more robust than an uncontrolled direct-compression blend.
• Commercial differentiation can come from tablet size, moisture stability, packaging, strength identification, and manufacturing cost.
• Biosimilar risk is not relevant because both active ingredients are small molecules.
• Paragraph IV risk is low for a conventional immediate-release product but can increase for modified-release or novel delivery systems.
• The strongest commercial opportunity is a reliable, low-cost, multi-strength generic supported by regional registration and efficient supply.
• The strongest potential IP opportunity is a differentiated release or manufacturing platform, not the conventional combination itself.

FAQs

Is glipizide/metformin hydrochloride still patent protected?

The original active ingredients and fixed-dose combination are mature products with expired core patent protection. New patents could still affect a specific modified-release, process, or delivery system.

Can glipizide and metformin be formulated as an extended-release tablet?

Yes, but the development burden is higher than for an immediate-release generic because the two drugs have different dose loads, solubility characteristics, and release-control requirements.

Which excipient is most important for glipizide content uniformity?

The binder and granulation architecture are more important than any single excipient. Povidone or copovidone combined with controlled granulation can improve distribution of the low-dose glipizide component.

Is a glipizide/metformin product eligible for biosimilar approval?

No. Glipizide and metformin hydrochloride are small-molecule active ingredients. A conventional copy product would generally use the generic drug pathway, not the biosimilar pathway.

What is the best commercial differentiation strategy?

For a standard generic, the strongest strategy is a compact, stable, multi-strength tablet with reliable dissolution, clear strength identification, low manufacturing cost, and packaging suited to the target climate and distribution channel.

References

1. U.S. Food and Drug Administration. (2002). Metaglip (glipizide and metformin hydrochloride) tablets, NDA 021431: Prescribing information.
2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, 44th edition.
3. U.S. Food and Drug Administration. (2024). Orange Book: Approved drug products with therapeutic equivalence evaluations.
4. U.S. Food and Drug Administration. (2024). Metformin hydrochloride and glipizide: Product-specific guidance for generic drug development.
5. U.S. Food and Drug Administration. (2024). Inactive ingredient database.
6. DailyMed. (2024). Glipizide and metformin hydrochloride tablets: Labeling and product information. National Library of Medicine.