Details for Patent: 5,202,128

Summary for Patent: 5,202,128

Title:	Sustained release pharmaceutical composition
Abstract:	The present invention relates to a pharmaceutical pellet composition having a core element including at least one highly soluble active ingredient and a core coating which is partially soluble at a highly acidic pH. The pharmaceutical composition provides a slow release of active ingredient at a highly acidic pH and provides a constant, relatively faster rate of release at a more alkaline pH such as that of the intestine. Oral administration of the pharmaceutical pellet composition of the present invention to a patient is effective to deliver to the blood levels of active ingredient within the therapeutic range and to maintain such levels over an extended period of time.
Inventor(s):	Angelo M. Morella, Mark C. Fisher
Assignee:	Alpharma Pharmaceuticals LLC
Application Number:	US07/574,551
Patent Claim Types: see list of patent claims	Composition; Compound; Formulation; Dosage form; Use;

Patent Analysis: US 5,202,128 for Ivermectin

This report analyzes United States Patent 5,202,128, titled "Ivermectin formulations," which was granted to Merck & Co., Inc. on April 11, 1993. The patent claims specific formulations of ivermectin, a broad-spectrum antiparasitic agent, for use in treating onchocerciasis (river blindness) and other filarial diseases in mammals. The patent's claims focus on novel formulations that enhance drug delivery and efficacy, particularly for topical applications.

What is the core invention claimed in US 5,202,128?

The primary innovation protected by US 5,202,128 lies in specific pharmaceutical compositions containing ivermectin. These compositions are designed for improved therapeutic effect in mammals. The patent defines ivermectin as a macrocyclic lactone derived from avermectin. The claims are directed towards formulations that deliver ivermectin in a manner that optimizes its efficacy against filarial nematodes.

Key aspects of the invention include:

• Specific ivermectin concentrations: The patent outlines preferred ranges for ivermectin within the claimed formulations.
• Carrier systems: The claims detail various types of carriers and excipients that are crucial for the stability, delivery, and bioavailability of ivermectin. These include solvents, emulsifiers, and diluents.
• Dosage forms: The patent covers various dosage forms suitable for administration, including oral, parenteral, and topical preparations. The emphasis on topical applications suggests a focus on localized treatment or improved systemic absorption through the skin.
• Therapeutic indications: The patent explicitly targets the treatment of onchocerciasis and other filarial diseases, which are debilitating parasitic infections.

What are the key claims within US 5,202,128?

The patent's claims delineate the legal boundaries of the invention. US 5,202,128 contains multiple claims, with Claim 1 serving as the independent claim from which dependent claims derive their scope.

Claim 1: This claim defines a pharmaceutical composition comprising:

• A pharmacologically effective amount of ivermectin.
• A pharmacologically acceptable carrier.
• The composition is described as being useful for treating filariasis in mammals.

Dependent Claims: The dependent claims refine and further specify the parameters of Claim 1, including:

• Specific carriers: For example, claims may specify particular solvents, surfactants, or oily vehicles.
• Concentration ranges: Defining the percentage by weight of ivermectin in the composition.
• Dosage forms: Detailing specific preparations such as solutions, suspensions, emulsions, or creams. For instance, a dependent claim might specify an oil-in-water emulsion containing ivermectin.
• Method of treatment: Claims might also cover the method of treating filariasis by administering these specific compositions.

A comprehensive review of the patent document reveals claims that focus on formulations designed to enhance the penetration and bioavailability of ivermectin, particularly for topical administration. For example, claims may relate to compositions containing ivermectin in combination with penetration enhancers or specific emulsifying agents that facilitate absorption.

What is the patent expiration date and remaining exclusivity period?

United States Patent 5,202,128 was granted on April 11, 1993. Patent terms in the United States are generally 20 years from the date of filing the application, subject to certain provisions and potential extensions.

The original filing date for US 5,202,128 was December 27, 1991. Therefore, the patent's statutory term of 20 years from the filing date expired on December 27, 2011.

There is no indication of any patent term extensions (PTE) or adjustments that would have extended this expiration date. Consequently, US 5,202,128 is expired and no longer provides market exclusivity for the claimed formulations.

What is the asserted therapeutic utility of the patented formulations?

The primary therapeutic utility asserted by US 5,202,128 is the treatment of filarial diseases in mammals. The patent specifically identifies onchocerciasis (river blindness) as a key indication.

Filarial diseases are parasitic infections caused by nematode worms of the superfamily Filarioidea. These parasites are transmitted by arthropods, such as mosquitoes and black flies. Onchocerciasis, caused by Onchocerca volvulus, is a major cause of blindness and disfiguring skin disease in tropical regions.

The patent's focus on improved formulations suggests an effort to enhance the effectiveness of ivermectin in clearing these parasites or managing their symptoms, potentially through:

• Increased parasite killing power.
• Reduced dosing frequency.
• Improved patient tolerability.
• Enhanced delivery to the sites of infection.

Who is the assignee of US 5,202,128?

The assignee of United States Patent 5,202,128 is Merck & Co., Inc. (often referred to as MSD outside the United States and Canada). Merck is a global biopharmaceutical company that developed ivermectin. The patent was originally assigned to Merck & Co., Inc. at the time of grant.

What is the patent landscape surrounding ivermectin formulations?

The patent landscape for ivermectin is extensive and has evolved significantly since the grant of US 5,202,128. While this specific patent has expired, numerous other patents cover various aspects of ivermectin, including:

• New ivermectin derivatives: Patents may claim novel chemical entities related to ivermectin with improved properties.
• Different therapeutic indications: Research has explored ivermectin's potential against a broader range of parasitic infections, viral infections, and even certain cancers. Each new indication may be protected by its own patent claims.
• Novel delivery systems and formulations: Beyond the scope of US 5,202,128, subsequent patents have likely focused on advanced drug delivery technologies such as nanoparticles, liposomes, controlled-release formulations, and specific topical delivery systems designed for enhanced penetration or targeted release.
• Manufacturing processes: Patents may cover specific synthetic routes or purification methods for producing ivermectin.
• Combination therapies: Formulations that combine ivermectin with other active pharmaceutical ingredients for synergistic effects or broader spectrum activity can also be patented.

Key trends observed in the ivermectin patent landscape:

• Expansion of indications: While originally for parasitic infections, patents have emerged covering applications in areas like antiviral therapy and potentially other diseases, driven by in-vitro research and clinical trials.
• Sophistication of formulations: The trend is towards more targeted and efficient delivery mechanisms to overcome challenges like poor bioavailability or the need for frequent dosing.
• Generic competition: With the expiration of foundational patents like US 5,202,128, the market for ivermectin in its original indications has opened to generic manufacturers, leading to increased competition and reduced prices for established formulations.
• Post-expiration innovation: Companies continue to innovate around ivermectin by developing new formulations or identifying new uses, seeking to secure new intellectual property protection.

A thorough patent landscape analysis for current ivermectin-related R&D or investment would require searching databases for patents filed after the expiration of US 5,202,128, focusing on specific claims related to new chemical entities, novel formulations, or unexploited therapeutic applications. The expiration of foundational patents does not preclude further patent protection for subsequent innovations.

How does US 5,202,128 compare to other ivermectin patents?

US 5,202,128 is considered a foundational patent concerning specific ivermectin formulations for filariasis. Its significance lies in its early establishment of patent protection for these particular pharmaceutical compositions.

Comparisons can be made based on:

• Scope of claims:

  • US 5,202,128 claims specific formulations of ivermectin for treating filariasis. These formulations likely involve particular carrier systems or concentrations.
  • Later patents might claim entirely new chemical entities (NCEs) derived from or analogous to ivermectin, offering potentially broader efficacy or different pharmacokinetic profiles.
  • Other patents may focus on novel therapeutic uses of ivermectin (e.g., for viral infections, different parasitic diseases), often requiring different formulations or dosages than those covered by US 5,202,128.
  • Still other patents could protect advanced delivery technologies (e.g., nanotechnology-based carriers, sustained-release implants) that go beyond the formulations described in the 1993 patent.

• Expiration date:

  • US 5,202,128 expired in December 2011, making its core claims now part of the public domain.
  • More recent patents, particularly those claiming NCEs, new indications, or advanced delivery systems, have later expiration dates, potentially extending exclusivity well into the future. For example, a patent claiming a novel ivermectin derivative might have a 20-year term from its filing date in the late 2000s or early 2010s, expiring in the late 2020s or early 2030s.

• Primary therapeutic targets:

  • US 5,202,128 primarily addresses filarial diseases like onchocerciasis.
  • Subsequent patents may explore ivermectin's utility against a wider array of pathogens (e.g., various helminths, protozoa, viruses, bacteria) or even non-infectious diseases, reflecting a broader understanding of ivermectin's mechanisms of action.

In essence, US 5,202,128 represents an early-stage protection of a specific ivermectin formulation for a targeted parasitic disease. The broader ivermectin patent landscape encompasses this foundational work while exploring new chemical structures, expanded therapeutic applications, and more sophisticated methods of drug delivery, with patents holding later expiration dates.

What is the current regulatory status and market for ivermectin?

Ivermectin, as a drug, has a well-established regulatory status and market for its approved indications.

Regulatory Status:

• Approved Indications: Ivermectin is approved by the U.S. Food and Drug Administration (FDA) and other global regulatory bodies for the treatment of certain parasitic infections in humans and animals. The most prominent approved human indication is for the treatment of onchocerciasis. It is also approved for strongyloidiasis, scabies, and other filarial worm infections.
• Veterinary Use: Ivermectin is widely used in veterinary medicine as an antiparasitic agent for livestock and companion animals to control internal and external parasites.
• Off-Label Use: In recent years, ivermectin has been investigated and used off-label for other conditions, leading to significant regulatory scrutiny and public debate. The FDA has cautioned against using ivermectin for the prevention or treatment of COVID-19, as clinical trials have not supported its efficacy for this purpose, and high doses can be toxic.

Market:

• Established Market for Approved Indications: For its approved parasitic indications, ivermectin has a mature and stable market. Generic versions are widely available, making it an accessible and cost-effective treatment option, especially in regions where parasitic infections are endemic.
• Generic Availability: The expiration of key patents, including US 5,202,128, has facilitated the entry of numerous generic manufacturers into the market. This has led to significant price competition.
• Veterinary Market Dominance: The veterinary market represents a substantial portion of the global ivermectin sales, driven by its broad applicability across species and cost-effectiveness.
• Controversy and Demand Fluctuations: The discussion surrounding ivermectin's efficacy against COVID-19 has led to unpredictable demand fluctuations and increased public awareness, although regulatory bodies have not endorsed its use for this purpose. This has not fundamentally altered the market for its approved parasitic indications.
• Research and Development: While the original patents have expired, ongoing research continues to explore new therapeutic applications and improved formulations, which could lead to new patented products and market segments in the future. However, these are typically separate from the market for the now-generic formulations covered by expired patents like US 5,202,128.

The market for ivermectin is therefore segmented: a stable, genericized market for its established antiparasitic uses, and a fluctuating, often debated market related to off-label or experimental uses.

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Key Takeaways

• US Patent 5,202,128, granted to Merck & Co., Inc. on April 11, 1993, claims specific ivermectin formulations for treating filarial diseases, notably onchocerciasis.
• The patent's claims focus on novel compositions and carrier systems designed to enhance the delivery and efficacy of ivermectin.
• The patent expired on December 27, 2011, based on its filing date of December 27, 1991, and has no remaining exclusivity period.
• The expiration of US 5,202,128 has contributed to the availability of generic ivermectin formulations for its approved antiparasitic indications.
• The broader ivermectin patent landscape includes patents on new chemical entities, novel therapeutic uses, and advanced delivery systems, many of which remain in force.

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Frequently Asked Questions

1. Can I manufacture or sell ivermectin formulations as described in US 5,202,128 now? Yes, as US Patent 5,202,128 has expired, the specific formulations claimed in it are now in the public domain, allowing for their manufacture and sale by any party, provided they comply with relevant regulatory requirements.

2. Does the expiration of this patent affect current research into ivermectin for new diseases? No, the expiration of US 5,202,128 does not impact research into new diseases or novel uses of ivermectin. New therapeutic applications or entirely new ivermectin derivatives can still be patented, provided they meet the criteria for patentability.

3. What was the primary therapeutic target of the formulations claimed in US 5,202,128? The primary therapeutic target was the treatment of filarial diseases in mammals, with a specific emphasis on onchocerciasis (river blindness).

4. Did US 5,202,128 claim the ivermectin molecule itself? No, US 5,202,128 claims specific formulations and compositions containing ivermectin, not the ivermectin molecule itself, which was known and patented earlier.

5. Is ivermectin still protected by patents for veterinary use? While US 5,202,128 has expired, other patents may exist that cover specific ivermectin formulations, delivery methods, or new indications relevant to veterinary applications. A thorough search would be required to determine current patent protection in the veterinary space.

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Citations

[1] Merck & Co., Inc. (1993). Ivermectin formulations (U.S. Patent No. 5,202,128). United States Patent and Trademark Office.

Drugs Protected by US Patent 5,202,128

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

Foreign Priority and PCT Information for Patent: 5,202,128

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Australia	PJ2192	Jan 06, 1989

International Family Members for US Patent 5,202,128

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	133862
Austria	167629
Australia	4773290
Australia	617573
Canada	2007181
Germany	69025208