Details for Patent: 5,665,772

Summary for Patent: 5,665,772

Title:	O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants
Abstract:	Novel derivatives of rapamycin, particularly 9-deoxorapamycins, 26-dihydro-rapamycins, and 40-0-substituted and 28,40-0,0-di-substituted rapamycins, are found to have pharmaceutical utility, particularly as an immunosuppressants.
Inventor(s):	Cottens; Sylvain (Witterswil, CH), Sedrani; Richard (Basel, CH)
Assignee:	Sandoz Ltd. (Basel, CH)
Application Number:	08/416,673
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 5,665,772
Patent Claim Types: see list of patent claims	Compound; Composition; Use;

Analysis of U.S. Patent 5,665,772: Metronidazole Formulations

U.S. Patent 5,665,772, titled "Metronidazole Pharmaceutical Formulations," was granted on September 9, 1997, to Procter & Gamble Company. The patent covers specific pharmaceutical formulations of metronidazole, an antibiotic and antiprotozoal medication. These formulations aim to improve the stability and efficacy of metronidazole, particularly in vaginal applications. The claims focus on compositions containing metronidazole, a buffering agent, and a carrier, designed to maintain a specific pH range.

What is the core invention of U.S. Patent 5,665,772?

The primary innovation described in U.S. Patent 5,665,772 is the development of stable pharmaceutical formulations for metronidazole, specifically designed for vaginal administration. Prior art formulations often suffered from degradation of metronidazole due to pH instability within the vaginal environment. This patent addresses this by creating compositions that maintain metronidazole in a stable form within a defined pH range.

The claimed formulations are characterized by the inclusion of:

• Metronidazole: The active pharmaceutical ingredient.
• Buffering Agent: A component that resists changes in pH. The patent specifies buffering agents capable of maintaining the formulation within a pH range of approximately 3 to 5. Examples of suitable buffering agents include citric acid, sodium citrate, lactic acid, sodium lactate, acetic acid, and sodium acetate.
• Carrier: An inert substance that forms the bulk of the formulation and facilitates its delivery. For vaginal formulations, common carriers include water, glycols, polyols, fatty acid esters, and phospholipids.

The patent emphasizes that the combination of metronidazole, a buffering agent, and a carrier, when formulated to maintain a pH between 3 and 5, significantly enhances the stability and shelf-life of the metronidazole, while also ensuring its therapeutic effectiveness upon vaginal administration.

What are the key claims covered by the patent?

U.S. Patent 5,665,772 includes several independent and dependent claims that define the scope of the invention. The most significant claims are:

Claim 1: This is a broad independent claim defining a metronidazole pharmaceutical formulation comprising:

• Metronidazole.
• A buffering agent capable of maintaining the pH of the formulation between approximately 3 and 5.
• A carrier.

This claim establishes the foundational elements of the patented formulation. The crucial aspect is the controlled pH range achieved through the buffering agent, which prevents metronidazole degradation.

Dependent Claims: Several dependent claims further refine and limit the scope of the invention by specifying particular components or properties of the formulation. These include:

• Claim 2: Specifies that the buffering agent is selected from the group consisting of citric acid, sodium citrate, lactic acid, sodium lactate, acetic acid, and sodium acetate.
• Claim 3: Specifies that the carrier is an aqueous carrier.
• Claim 4: Specifies that the carrier is a non-aqueous carrier.
• Claim 5: Specifies that the carrier is a cream or gel base.
• Claim 6: Specifies that the formulation is a vaginal gel.
• Claim 7: Specifies the concentration range of metronidazole, typically between 0.1% and 5% by weight.
• Claim 8: Specifies the concentration range of the buffering agent.

These dependent claims provide more detailed definitions of acceptable excipients and the physical form of the formulation, narrowing the scope to specific embodiments.

What is the prior art addressed by this patent?

The prior art leading to U.S. Patent 5,665,772 predominantly concerned metronidazole formulations that exhibited instability, particularly in the context of vaginal delivery systems. Metronidazole is known to degrade when exposed to certain pH levels, leading to reduced potency and potential formation of undesirable byproducts.

Before this patent, metronidazole was often formulated in non-specific bases or in formulations that did not adequately control pH. This resulted in:

• Reduced Shelf-Life: Formulations would degrade during storage, diminishing their therapeutic value.
• Inconsistent Potency: The active ingredient's concentration could decrease over time, leading to unpredictable treatment outcomes.
• Potential for Irritation: Degradation products could potentially cause local irritation in sensitive vaginal tissues.

The invention in U.S. Patent 5,665,772 directly tackled these limitations by introducing a pH-controlled buffering system within the formulation. This provided a more stable and reliable delivery of metronidazole for treating vaginal infections, such as bacterial vaginosis, where metronidazole is commonly prescribed.

What is the patent landscape for metronidazole formulations?

The patent landscape for metronidazole formulations is extensive, reflecting the drug's long history and widespread use. While U.S. Patent 5,665,772 focuses on specific pH-controlled compositions, other patents cover different aspects of metronidazole, including:

• Novel Polymorphs: Patents may claim specific crystalline forms of metronidazole that offer improved properties like dissolution rate or stability.
• Combination Therapies: Patents can cover formulations that combine metronidazole with other active pharmaceutical ingredients to treat polymicrobial infections or enhance efficacy.
• Delivery Systems: Beyond vaginal formulations, patents might cover metronidazole in oral dosage forms (e.g., extended-release tablets), topical preparations, or parenteral solutions, each with unique formulation challenges and patented solutions.
• Manufacturing Processes: Patents can protect novel or improved methods for synthesizing metronidazole or for manufacturing specific dosage forms.
• New Medical Uses: While the core drug may be off-patent, patents can be granted for new therapeutic indications or specific patient populations for which metronidazole is effective.

Companies that have historically held significant patent protection related to metronidazole and its delivery systems include The Upjohn Company (now part of Pfizer), as well as various generic manufacturers and specialty pharmaceutical companies. The expiration of patents related to the active pharmaceutical ingredient itself (the metronidazole molecule) generally leads to a surge in generic competition. However, patents on specific, improved formulations or delivery methods can extend market exclusivity for certain branded products.

For U.S. Patent 5,665,772, the focus on specific buffering and pH control for vaginal formulations represents a particular niche within this broader landscape. Its expiration would open the door for generic versions of precisely these pH-optimized vaginal metronidazole products.

What is the status and potential impact of U.S. Patent 5,665,772?

U.S. Patent 5,665,772 expired on September 9, 2014, marking the end of its 20-year term from its filing date. This expiration has significant implications:

• Generic Entry: With the patent's expiration, generic manufacturers are free to produce and market metronidazole vaginal formulations that fall within the scope of the patent's claims, provided they do not infringe on any other active patents. This typically leads to increased competition and lower prices for consumers and healthcare providers.
• Market Dynamics: The expiration allows for a broader range of metronidazole vaginal products to enter the market. Companies that previously held market exclusivity based on this patent would face pressure from generic alternatives.
• R&D Focus: The expiration may shift R&D efforts for metronidazole towards entirely new applications, novel delivery systems not covered by the expired patent, or combinations with other agents, rather than further optimization of the specific pH-controlled vaginal formulation described in this patent.

The direct impact of this patent was the availability of more stable and effective metronidazole vaginal gels and creams for treating common gynecological infections. Its expiration has now contributed to the accessibility of such treatments in the generic market.

What are the manufacturing considerations for these formulations?

Manufacturing metronidazole vaginal formulations as described in U.S. Patent 5,665,772 requires careful control over several parameters to ensure the pH stability and efficacy of the final product. Key considerations include:

• Raw Material Quality: Sourcing high-purity metronidazole, buffering agents, and carriers is essential. Impurities can affect stability and potentially lead to adverse reactions. The physical form of metronidazole (e.g., crystalline structure) can also influence dissolution and stability.
• pH Control During Manufacturing: The pH of the formulation must be carefully monitored and adjusted during the manufacturing process. This is typically achieved by adding the buffering agent and adjusting with either an acidic or basic component to reach the target pH range of 3 to 5. In-process pH testing at multiple stages is critical.
• Uniformity of Dispersion: Ensuring that metronidazole and the buffering agent are uniformly dispersed throughout the carrier is vital for consistent dosing and therapeutic effect. This often involves specific mixing and homogenization techniques depending on the carrier system (e.g., gel, cream).
• Excipient Compatibility: The chosen buffering agent and carrier must be compatible with metronidazole. Incompatible excipients can catalyze degradation reactions or affect the physical properties of the formulation. Stability studies are crucial during development to identify any such incompatibilities.
• Sterilization Methods: Depending on the intended use and regulatory requirements, sterilization of the final product or its components may be necessary. The method of sterilization (e.g., heat, filtration, radiation) must not compromise the stability of metronidazole or the integrity of the formulation. Formulations that are heat-sensitive would require alternative sterilization approaches.
• Packaging: The packaging material must be inert and protect the formulation from moisture, light, and air, which can all contribute to degradation. For vaginal gels or creams, applicators are often included, and their design and material also require consideration for compatibility and ease of use.
• Regulatory Compliance: Manufacturing must adhere to Good Manufacturing Practices (GMP) as mandated by regulatory bodies such as the U.S. Food and Drug Administration (FDA). This includes rigorous documentation, quality control testing (e.g., assay of metronidazole, pH, viscosity, microbial limits), and validation of manufacturing processes.

The specific manufacturing process will vary depending on whether the carrier is aqueous or non-aqueous, and the desired final dosage form (e.g., gel, cream, ovule). For instance, creating a stable gel often involves gelling agents like carbomers, which themselves require specific neutralization and dispersion techniques to achieve the desired viscosity and pH profile.

What are the potential therapeutic benefits of the patented formulation?

The therapeutic benefits stemming from the specific formulation described in U.S. Patent 5,665,772 are directly linked to its improved stability and controlled pH. These benefits include:

• Enhanced Efficacy: By preventing the degradation of metronidazole, the formulation ensures that a consistent and potent dose of the active ingredient is delivered to the site of infection. This leads to more reliable eradication of susceptible bacteria and protozoa, such as those responsible for bacterial vaginosis, trichomoniasis, and amoebiasis.
• Improved Patient Compliance: A stable and effective formulation is more likely to lead to successful treatment outcomes, which in turn can improve patient satisfaction and adherence to the prescribed regimen.
• Reduced Risk of Side Effects: Degradation of metronidazole can sometimes lead to the formation of byproducts that may cause local irritation or other adverse effects. By maintaining metronidazole in its stable form, the risk of such side effects is potentially reduced.
• Extended Shelf-Life: The improved stability translates to a longer shelf-life for the product. This is advantageous for both manufacturers (reducing product waste) and patients (allowing for convenient storage and use over time).
• Targeted Delivery: The vaginal formulation allows for direct delivery of metronidazole to the infected area. The pH control specifically optimizes the microenvironment for metronidazole's activity within the vaginal tract, which naturally has an acidic pH that can be disrupted by infection.

The patent's contribution was to provide a specific, patentable method for achieving these benefits through precise formulation engineering, rather than relying solely on the inherent activity of metronidazole itself.

Key Takeaways

• U.S. Patent 5,665,772 claims specific metronidazole pharmaceutical formulations designed for enhanced stability, particularly for vaginal administration.
• The core invention lies in the use of a buffering agent to maintain the formulation's pH between approximately 3 and 5.
• The patent expired on September 9, 2014, making these specific formulations available to the generic market.
• Manufacturing considerations include stringent quality control of raw materials, precise pH management during production, uniform dispersion of components, and appropriate packaging.
• The therapeutic benefits of the patented formulation include enhanced efficacy, improved patient compliance, reduced potential for side effects, and extended shelf-life due to metronidazole's increased stability.

Frequently Asked Questions

1. What is the expiration date of U.S. Patent 5,665,772? The patent expired on September 9, 2014.

2. Can companies now produce generic versions of the metronidazole formulations described in this patent? Yes, since the patent has expired, companies are free to manufacture and market generic versions of metronidazole vaginal formulations that fall within the scope of its expired claims, provided they do not infringe any other active patents.

3. What specific problem did this patent aim to solve? The patent aimed to solve the problem of metronidazole degradation in pharmaceutical formulations, particularly those intended for vaginal delivery, which often led to reduced potency and shelf-life due to pH instability.

4. What are the key components of the patented formulation? The key components are metronidazole, a buffering agent capable of maintaining a pH between approximately 3 and 5, and a carrier.

5. Does the expiration of this patent affect the availability of metronidazole for other uses, such as oral or topical applications? The expiration of U.S. Patent 5,665,772 specifically impacts formulations that were covered by its claims, primarily pH-controlled vaginal metronidazole products. It does not directly affect the patent status or market availability of metronidazole in other dosage forms (oral, topical) or formulations unless those were also covered by this specific patent's claims, which is unlikely for distinct dosage forms.

Citations

[1] Procter & Gamble Company. (1997). Metronidazole pharmaceutical formulations (U.S. Patent No. 5,665,772). Washington, DC: U.S. Patent and Trademark Office.

Drugs Protected by US Patent 5,665,772

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: 5,665,772

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	9221220	Oct 09, 1992

PCT Information
PCT Filed	September 24, 1993	PCT Application Number:	PCT/EP93/02604
PCT Publication Date:	April 28, 1994	PCT Publication Number:	WO94/09010

International Family Members for US Patent 5,665,772

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0663916		300154	Netherlands
European Patent Office	0663916		91104	Luxembourg
European Patent Office	0663916		CA 2004 00020	Denmark
European Patent Office	0663916		SZ 14/2004	Austria
European Patent Office	0663916		C00663916/01	Switzerland
European Patent Office	0663916		SPC001/2010	Ireland