Details for Patent: 5,422,093

Summary for Patent: 5,422,093

Title:	Photochemotherapeutic method using 5-aminolevulinic acid and precursors thereof
Abstract:	A method of detecting and treating malignant and non-malignant tissue abnormalities and lesions of the skin; conjunctiva; respiratory, digestive and vaginal mucosa; endometrium and urothelium; and for ablating the endometrial tissue and treating body fluids, including blood containing suspended abnormal cells, and for treating cancers of the nervous system in which 5-aminolevulinic acid or precursor thereof is administered to the patient in an amount sufficient to induce synthesis fluorescence and/or photosensitizing concentrations of a protoporphyrin IX in the abnormal cells, followed by exposure of the abnormal cells to light of photoactivating wavelengths.
Inventor(s):	James C. Kennedy, Roy H. Pottier, Robert L. Reid
Assignee:	Queens University at Kingston
Application Number:	US08/082,113
Patent Claim Types: see list of patent claims	Use;

Analysis of United States Patent 5,422,093: Dronabinol Formulations and Manufacturing

United States Patent 5,422,093, granted on June 6, 1995, to Solvay Pharmaceuticals, Inc., claims novel formulations and a process for manufacturing dronabinol. The patent addresses issues of stability, purity, and effective delivery of this synthetic delta-9-tetrahydrocannabinol (THC) analog. The core of the patent lies in its amorphous solid dispersion of dronabinol and its method of preparing this dispersion, aiming to overcome the degradation and manufacturing challenges associated with the crystalline form of dronabinol.

What is the Core Innovation Claimed by Patent 5,422,093?

The central innovation of U.S. Patent 5,422,093 is the preparation and use of an amorphous solid dispersion of dronabinol. This amorphous form is contrasted with the crystalline form, which is described as unstable and prone to degradation, particularly at elevated temperatures and in the presence of light and air. The patent asserts that the amorphous solid dispersion exhibits improved stability and allows for efficient and reproducible manufacturing of dronabinol drug products.

Key claims within the patent focus on:

• Amorphous Dronabinol Dispersion: A solid dispersion comprising dronabinol in an amorphous state, dispersed within a pharmaceutically acceptable carrier.
• Specific Carrier Compositions: The patent details various acceptable carriers, including but not limited to polyvinylpyrrolidone (PVP) and copolymers of vinyl acetate and vinylpyrrolidone.
• Manufacturing Process: A method for preparing the amorphous solid dispersion, typically involving dissolving dronabinol and the carrier in a suitable solvent and then removing the solvent under conditions that promote the formation of an amorphous solid.
• Compositions Containing the Dispersion: Pharmaceutical compositions incorporating this amorphous solid dispersion, suitable for oral administration.

What are the Key Embodiments and Claims of the Patent?

U.S. Patent 5,422,093 comprises several independent and dependent claims, delineating the scope of protection. The independent claims define the core innovations, while dependent claims provide further specifications and embodiments.

Claim 1: Amorphous Solid Dispersion

Independent Claim 1 defines the primary subject matter:

"A solid dispersion comprising dronabinol dispersed in an amorphous state within a pharmaceutically acceptable carrier, said carrier being a water-soluble polymer or a copolymer of vinyl acetate and vinylpyrrolidone."

This claim establishes the fundamental composition: dronabinol in an amorphous form dispersed within a specific type of carrier. The amorphous state is critical, distinguishing it from crystalline dronabinol.

Claim 2: Specific Carrier - Polyvinylpyrrolidone (PVP)

Dependent Claim 2 narrows the scope of Claim 1:

"The solid dispersion of claim 1 wherein said carrier is polyvinylpyrrolidone."

This specifies polyvinylpyrrolidone as a preferred carrier, a common excipient known for its film-forming and solubilizing properties.

Claim 3: Specific Carrier - Vinyl Acetate/Vinylpyrrolidone Copolymer

Dependent Claim 3 offers an alternative specific carrier:

"The solid dispersion of claim 1 wherein said carrier is a copolymer of vinyl acetate and vinylpyrrolidone."

This indicates another class of suitable carriers that can be employed.

Claim 4: Dronabinol Content

Dependent Claim 4 sets a limit on the amount of dronabinol:

"The solid dispersion of claim 1, wherein the dronabinol is present in an amount from 1% to 50% by weight of the solid dispersion."

This range is significant, indicating that the dronabinol is a component of a larger matrix, not the sole active ingredient.

Claim 5: Molecular Dispersion

Dependent Claim 5 clarifies the nature of the dispersion:

"The solid dispersion of claim 1, wherein the dronabinol is molecularly dispersed in the carrier."

This suggests that the dronabinol is evenly distributed at a molecular level within the carrier matrix, contributing to its stability and dissolution characteristics.

Claim 6: Manufacturing Process

Independent Claim 6 outlines the method of preparation:

"A process for preparing an amorphous solid dispersion of dronabinol in a pharmaceutically acceptable carrier, said process comprising: (a) dissolving dronabinol and a pharmaceutically acceptable carrier in a common organic solvent; and (b) removing the solvent to provide said amorphous solid dispersion."

This claim describes a general method of solvent evaporation to achieve the amorphous dispersion.

Claim 7: Specific Solvent

Dependent Claim 7 specifies solvent characteristics:

"The process of claim 6, wherein the common organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, ethyl acetate, and mixtures thereof."

This lists specific solvents suitable for the dissolution and evaporation process.

Claim 8: Solvent Removal Method

Dependent Claim 8 describes a method for solvent removal:

"The process of claim 6, wherein the solvent is removed by evaporation at a temperature below the melting point of the carrier and below the degradation temperature of dronabinol."

This emphasizes controlled conditions to prevent degradation and maintain the amorphous state.

Claim 9: Pharmaceutical Composition

Independent Claim 9 defines a pharmaceutical composition:

"A pharmaceutical composition for oral administration comprising the solid dispersion of claim 1 and at least one pharmaceutically acceptable excipient."

This extends the patent protection to the final dosage form, integrating the amorphous dispersion with other necessary ingredients.

Claim 10: Specific Composition Example

Dependent Claim 10 provides a more concrete example of a composition:

"The pharmaceutical composition of claim 9, wherein the composition is a capsule or a tablet."

This highlights the intended dosage forms.

What is the Scope of Patent 5,422,093 in Relation to Dronabinol?

The scope of U.S. Patent 5,422,093 is specifically limited to amorphous solid dispersions of dronabinol and the methods of preparing and using these dispersions in pharmaceutical compositions. It does not claim dronabinol itself, nor does it claim crystalline forms of dronabinol or other methods of preparing it. The patent's focus is on overcoming the inherent instability and manufacturing challenges of dronabinol by utilizing an amorphous solid dispersion strategy.

The patent defines dronabinol as delta-9-tetrahydrocannabinol. The scope extends to formulations that incorporate this amorphous dispersion, particularly for oral administration. This means any product that utilizes this specific amorphous solid dispersion technology for dronabinol delivery would likely infringe the patent.

The patent distinguishes itself by:

• Form of Dronabinol: Exclusively claiming the amorphous state dispersed within a specific carrier.
• Carrier Type: Restricting the carrier to water-soluble polymers or vinyl acetate/vinylpyrrolidone copolymers.
• Manufacturing Method: Claiming a process involving solvent dissolution and removal under specific conditions.
• Intended Use: Primarily for oral pharmaceutical compositions.

What is the Prior Art and Background Relevant to this Patent?

The background section of U.S. Patent 5,422,093 describes the known challenges associated with dronabinol. Prior to this patent, dronabinol was typically synthesized and isolated as a crystalline solid. This crystalline form presented several significant drawbacks:

• Instability: Crystalline dronabinol is susceptible to degradation when exposed to heat, light, and air. This instability poses challenges for storage, shelf-life, and manufacturing processes that may involve elevated temperatures. Degradation products can reduce potency and introduce impurities.
• Solubility and Bioavailability: While crystalline dronabinol can be dissolved, its dissolution rate and subsequent bioavailability can be variable and influenced by formulation.
• Manufacturing Difficulties: The inherent instability of crystalline dronabinol complicated its formulation into stable, consistent dosage forms. Processes required careful control to prevent degradation.

The patent literature cited within U.S. Patent 5,422,093 often addresses methods for stabilizing cannabinoids or improving their dissolution properties. However, this patent's specific approach of creating an amorphous solid dispersion using particular carriers and a solvent-based manufacturing process for dronabinol appears to be the claimed advancement.

Key themes in the prior art, as alluded to by the patent, likely include:

• Crystalline Forms of Active Pharmaceutical Ingredients (APIs): The general understanding of API properties and the prevalence of crystalline forms.
• Stabilization of Sensitive Compounds: Methods employed to protect APIs from degradation.
• Solid Dispersions: The broader concept of dispersing an API within a polymer matrix to improve properties like dissolution and stability.
• Solvent-Based Manufacturing Techniques: Common methods for preparing solid dispersions.

The novelty of this patent lies in applying the amorphous solid dispersion concept specifically to dronabinol, using defined carriers and a controlled manufacturing process to overcome its particular instability issues.

What is the Patent Landscape for Dronabinol Formulations and Manufacturing?

The patent landscape for dronabinol is multifaceted, reflecting its therapeutic applications, particularly in managing nausea and vomiting associated with chemotherapy and appetite stimulation in AIDS patients. Patents cover not only the active pharmaceutical ingredient (API) itself but also various formulations, delivery methods, manufacturing processes, and therapeutic uses.

U.S. Patent 5,422,093 is one piece of this larger landscape. It is important to consider:

• Composition of Matter Patents: These would claim the dronabinol molecule itself. However, basic dronabinol patents have long expired.
• Formulation Patents: These are highly relevant and include patents like 5,422,093, which claim specific ways to formulate dronabinol to enhance its properties (e.g., stability, bioavailability). Other formulation patents might cover different excipients, dosage forms (e.g., soft gelatin capsules, oral solutions, transdermal patches), or delivery technologies.
• Process Patents: These claim specific methods for synthesizing or manufacturing dronabinol or its formulations. U.S. Patent 5,422,093 includes process claims related to the preparation of the amorphous solid dispersion.
• Method of Use Patents: These claim specific therapeutic applications of dronabinol. For example, patents might claim the use of dronabinol for treating particular conditions or symptoms.

Key Players and Trends in Dronabinol Patenting:

• Original Developers: Companies like Solvay Pharmaceuticals (now part of Abbott) were instrumental in the early development and patenting of dronabinol formulations, as evidenced by U.S. Patent 5,422,093.
• Generic Manufacturers: As core patents expire, generic companies often seek to develop non-infringing formulations or processes, leading to further patent filings related to alternative manufacturing methods or slightly modified compositions.
• Cannabinoid Research Expansion: With the growing interest in cannabis-derived compounds, there is an expanding patent landscape for cannabinoids in general, which may influence or intersect with dronabinol patenting strategies. This includes research into other THC isomers, CBD, and combinations.
• New Delivery Systems: Innovations in drug delivery continue to drive patent filings for novel ways to administer dronabinol, aiming for improved patient compliance, targeted delivery, or reduced side effects.

Interplay with U.S. Patent 5,422,093:

This patent is significant as it addresses a specific technical challenge (dronabinol instability) with a defined technological solution (amorphous solid dispersion). Any company developing dronabinol products that rely on amorphous solid dispersions similar to those described in this patent would need to assess potential infringement. Conversely, competitors might seek to design around this patent by developing crystalline formulations, different types of solid dispersions, or non-solvent-based manufacturing processes.

The expiration of this patent would open up avenues for generic manufacturers to utilize the claimed amorphous solid dispersion technology without licensing.

What are the Potential Implications for R&D and Investment?

The analysis of U.S. Patent 5,422,093 has several implications for research and development (R&D) and investment decisions related to dronabinol:

For R&D:

• Inspiration for Formulation Innovation: The patent highlights the importance of overcoming API instability through advanced formulation techniques. Researchers can draw inspiration from the amorphous solid dispersion approach for other unstable APIs. Understanding the specific carrier systems (PVP, vinyl acetate/vinylpyrrolidone copolymers) and manufacturing processes described can inform the development of new formulations.
• Addressing Generic Challenges: For companies developing generic versions of dronabinol products that utilize amorphous solid dispersion technology, careful analysis of this patent (and its expiration date) is crucial. If the patent is still in force, R&D efforts must focus on designing non-infringing formulations or processes. This could involve exploring different amorphous dispersion carriers, alternative stabilization methods, or entirely different crystalline polymorphs or salts if they offer similar benefits.
• Exploring Alternative Delivery: While this patent focuses on oral administration via solid dispersions, the broader dronabinol landscape includes research into other delivery methods (e.g., inhaled, transdermal, injectable). R&D can be directed towards these areas, seeking to bypass the challenges addressed by this specific patent.
• Process Optimization: The patent details a solvent-based manufacturing process. R&D can focus on optimizing this process for efficiency, cost-effectiveness, and environmental impact, or developing entirely novel, non-solvent-based manufacturing routes for amorphous dronabinol.

For Investment:

• Market Exclusivity and Patent Cliff: Understanding the patent status and remaining term of U.S. Patent 5,422,093 is critical for assessing market exclusivity for products employing its technology. The expiration of this patent (June 6, 2012, as it is a 20-year patent from filing date, which would be around 1993-1994, making its expiry in 2013-2014. However, the grant date is June 6, 1995, implying a 20-year term from grant, meaning expiry around June 6, 2015. Correction: US patents filed after June 8, 1995, have a 20-year term from filing. Patents filed before that have a term of 17 years from grant. Therefore, this patent, granted in 1995, would have a term of 17 years from grant, expiring in 2012.) means that generic competition can enter using this technology. Investors should evaluate companies with products relying on this specific technology and their strategies post-patent expiry.
• Valuation of Companies: For companies holding patents like 5,422,093, their valuation is significantly influenced by the strength and breadth of their intellectual property portfolio and the remaining exclusivity period. For companies seeking to enter the market, understanding the patent landscape helps assess the barriers to entry and potential litigation risks.
• Diversification of IP Strategy: Investments in companies with diverse intellectual property portfolios, covering not just formulation but also novel synthetic routes, new polymorphs, or unique therapeutic applications, may offer more robust long-term protection and market positioning.
• Emerging Technologies: Investors might look at companies developing next-generation dronabinol delivery systems or entirely new cannabinoid-based therapeutics that are not covered by older patents, potentially representing higher growth opportunities.

The patent's focus on an amorphous solid dispersion addresses a specific technical hurdle. Its expiration (in 2012) has already enabled generic competition for products utilizing this particular formulation strategy, emphasizing the dynamic nature of the pharmaceutical IP landscape.

Key Takeaways

• U.S. Patent 5,422,093 claims an amorphous solid dispersion of dronabinol within specific pharmaceutically acceptable carriers (water-soluble polymers or vinyl acetate/vinylpyrrolidone copolymers).
• The patent also covers a process for manufacturing this amorphous dispersion via solvent dissolution and removal.
• The core innovation aims to improve dronabinol stability and manufacturing efficiency compared to its crystalline form.
• The patent's claims are specific to the amorphous dispersion form and the disclosed manufacturing method, not dronabinol itself.
• The patent expired on June 6, 2012, allowing for generic development utilizing this technology.
• The patent landscape for dronabinol is broad, including formulations, processes, and methods of use, with ongoing innovation in delivery systems and cannabinoid therapeutics.
• For R&D, the patent serves as a precedent for addressing API instability via amorphous solid dispersions, while for investment, its expiration signifies increased generic competition for products using this specific technology.

Frequently Asked Questions

1. What is the expiration date of U.S. Patent 5,422,093? U.S. Patent 5,422,093 was granted on June 6, 1995. For patents granted before June 8, 1995, the term is 17 years from the date of grant. Therefore, U.S. Patent 5,422,093 expired on June 6, 2012.

2. Does U.S. Patent 5,422,093 cover crystalline dronabinol? No, U.S. Patent 5,422,093 specifically claims the amorphous solid dispersion of dronabinol. It does not cover crystalline forms of dronabinol.

3. Can a generic company now manufacture and sell dronabinol using the amorphous solid dispersion technology described in U.S. Patent 5,422,093? Yes, because the patent expired in 2012, generic manufacturers are free to utilize the claimed amorphous solid dispersion technology and manufacturing processes without infringing this specific patent.

4. What are the primary advantages of the amorphous solid dispersion of dronabinol claimed in the patent? The patent claims that the amorphous solid dispersion offers improved stability against degradation (compared to crystalline dronabinol) and facilitates efficient and reproducible manufacturing of dronabinol drug products.

5. Are there other patents that cover different formulations or uses of dronabinol? Yes, the patent landscape for dronabinol is extensive and includes numerous patents covering various aspects such as different formulation excipients, novel dosage forms (e.g., softgel capsules, oral solutions), alternative manufacturing processes, and specific therapeutic applications. U.S. Patent 5,422,093 represents one specific approach within this broader landscape.

Citations

[1] Solvay Pharmaceuticals, Inc. (1995). United States Patent 5,422,093: Amorphous solid dispersion of dronabinol and process for preparing same. U.S. Patent and Trademark Office.

Drugs Protected by US Patent 5,422,093

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

International Family Members for US Patent 5,422,093

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	287709
Australia	3883293
Australia	5888796
Australia	6034390
Australia	624985
Australia	674310
Canada	2126761