Derivative works — US Patent 12290598

Defensive Disclosure and Prior Art Generation for Technology Related to US 12,290,598

Publication Date: May 13, 2026
Subject: Novel variations and applications of orally administered pharmaceutical compositions for localized gastrointestinal delivery. This document is intended to enter the public domain to serve as prior art for future patent applications.

Part 1: Derivatives of Orally Disintegrating Tablet (ODT) Compositions (Ref: Claim 1)

1.1 Material & Component Substitution: Thiolated Mucoadhesive Polymers

Enabling Description: This variation substitutes the standard film-forming binder (e.g., PVP, HPMC) in the corticosteroid-containing granules with a thiolated polymer, such as thiolated chitosan or thiolated polyacrylic acid. Upon disintegration of the ODT in the oral cavity, the resulting suspension contains microgranules with surface thiol groups. These groups form covalent disulfide bonds with cysteine-rich subdomains of mucus glycoproteins lining the esophagus. This covalent bonding significantly increases the residence time and local concentration of the corticosteroid at the inflamed mucosa, providing a more targeted and prolonged therapeutic effect compared to non-specific adhesion. The granules are prepared by granulating the corticosteroid with a solution of the thiolated polymer, followed by drying.

Mermaid Diagram:

graph TD
    A[ODT Ingestion] --> B{Disintegration in Saliva};
    B --> C[Suspension of Microgranules];
    C --> D{Granule Transport to Esophagus};
    D --> E[Thiolated Polymer Granules];
    E -- Covalent Bonding --> F(Mucus Glycoproteins);
    F -- Forms --> G[Localized Bioadhesive Corticosteroid Layer];
    C --> H[Rapidly Dispersing Granules Dissolve];

1.2 Material & Component Substitution: Metal-Organic Framework (MOF) Carrier

Enabling Description: The corticosteroid is not present as free crystals but is instead encapsulated within a biocompatible Metal-Organic Framework (MOF), such as ZIF-8 (Zeolitic Imidazolate Framework-8). The corticosteroid-loaded MOF particles are then granulated with a film-forming binder. The ODT disintegrates, releasing the MOF particles. The MOF's porous structure protects the corticosteroid and provides a secondary, pH-triggered release mechanism. The ZIF-8 structure is stable in the near-neutral pH of the mouth and esophagus but begins to decompose and release the drug in the slightly more acidic microenvironment of inflamed esophageal tissue, leading to highly targeted drug delivery.

Mermaid Diagram:

classDiagram
    class ODT {
        +disintegrate()
    }
    class CorticosteroidGranule {
        <<MOF-based>>
    }
    class RapidDispersingGranule
    class MOF_ZIF8 {
        -corticosteroidPayload
        +releaseOnAcidicPH()
    }
    ODT "1" *-- "many" CorticosteroidGranule
    ODT "1" *-- "many" RapidDispersingGranule
    CorticosteroidGranule "1" *-- "many" MOF_ZIF8

1.3 Operational Parameter Expansion: Cryogenic/Lyophilized ODT

Enabling Description: This variation utilizes a lyophilization (freeze-drying) process to create the ODT. The corticosteroid granules and rapidly dispersing microgranules are suspended in an aqueous solution containing a matrix-forming agent like gelatin or mannitol. This suspension is filled into blister packs and then freeze-dried. The resulting ODT is a highly porous, wafer-like structure that disintegrates in under 5 seconds. This formulation is particularly suited for pediatric or severely dysphagic patients who cannot tolerate any granular texture. The extreme porosity is achieved by sublimating the ice crystals under vacuum, leaving a delicate but intact matrix.

Mermaid Diagram:

flowchart LR
    subgraph Preparation
        A[Suspend Granules in Aqueous Matrix] --> B[Pour into Blister Molds];
    end
    subgraph Lyophilization Process
        C[Freeze at -40°C] --> D{Primary Drying (Sublimation under Vacuum)};
        D --> E{Secondary Drying (Desorption)};
    end
    subgraph Result
        F[Highly Porous ODT Wafer] --> G[Disintegration < 5s];
    end
    B --> C;
    E --> F;

1.4 Cross-Domain Application: Veterinary Deworming ODT

Enabling Description: The ODT platform is adapted for veterinary use, specifically for administering antihelminthic agents (e.g., Ivermectin, Praziquantel) to companion animals (canine, feline). The corticosteroid is replaced with the powdered antihelminthic drug, which is known to be unpalatable. The drug is co-granulated with a veterinary-approved binder. The rapidly dispersing microgranules are formulated with animal-friendly flavors (e.g., liver, tuna) and xylitol is strictly avoided (as it's toxic to canines). The ODT format allows for easy administration by the owner, as it disintegrates instantly in the animal's mouth, preventing the animal from spitting out a conventional pill.

Mermaid Diagram:

sequenceDiagram
    participant Owner
    participant Animal
    participant ODT
    Owner->>Animal: Places ODT in mouth
    ODT->>ODT: Disintegrates on contact with saliva
    ODT-->>Animal: Releases antihelminthic microgranules
    Note right of Animal: Palatable flavorant<br/>ensures swallowing
    Animal->>Animal: Swallows suspension

1.5 Cross-Domain Application: Bioremediation Tablet for Water Treatment

Enabling Description: The technology is applied to environmental science for bioremediation. The corticosteroid is replaced with a lyophilized consortium of hydrocarbon-degrading bacteria (e.g., Pseudomonas putida). The "corticosteroid-containing granule" is now a bacteria-containing granule, protected by a water-soluble binder like polyethylene glycol (PEG). The rapidly dispersing microgranules are composed of a non-toxic disintegrant (e.g., sodium starch glycolate) and a nutrient source (e.g., lactose) for the bacteria. When thrown into a body of water contaminated with an oil spill, the tablet rapidly disintegrates, dispersing the dormant bacteria and the initial nutrient package over a wide surface area, kickstarting the bioremediation process.

Mermaid Diagram:

graph TD
    A[Tablet Deployed in Contaminated Water] --> B{Rapid Disintegration};
    B --> C[Dispersal of Bacteria Granules];
    B --> D[Dissolution of Nutrient Granules];
    C & D --> E{Activation & Proliferation of Bacteria};
    E --> F[Metabolism of Hydrocarbons];
    F --> G[Clean Water + Byproducts];

1.6 The "Inverse" / Failure Mode: Taste-Masking Challenge Tablet

Enabling Description: A variation is designed for Quality Assurance in pharmaceutical manufacturing. The ODT is manufactured with taste-masked placebo granules containing an intensely bitter but safe compound (e.g., denatonium benzoate) instead of a corticosteroid. These "challenge tablets" are used by a sensory panel to test the integrity and efficacy of the taste-masking layer (e.g., ethylcellulose coating). If the panelist detects a bitter taste upon disintegration, it signifies a failure in the coating process (e.g., insufficient thickness, fractures). This provides a quantifiable method for validating the taste-masking unit operation.

Mermaid Diagram:

stateDiagram-v2
    [*] --> Ingested
    Ingested --> Disintegrating: Rapid
    state Disintegrating {
        state "Taste-masking Intact" as Intact
        state "Taste-masking Failed" as Failed
        [*] --> Intact
        [*] --> Failed
        Intact --> No_Bitter_Taste
        Failed --> Bitter_Taste
    }
    No_Bitter_Taste --> QC_Pass
    Bitter_Taste --> QC_Fail
    QC_Pass --> [*]
    QC_Fail --> [*]

Part 2: Derivatives of Liquid Pharmaceutical Compositions (Ref: Claim 20)

2.1 Material & Component Substitution: Shear-Thinning Biopolymer Gel

Enabling Description: This liquid formulation replaces the specified bio-gelling polymer with a shear-thinning, mucoadhesive biopolymer such as gellan gum or a high-viscosity grade of hyaluronic acid. The corticosteroid is suspended in this non-aqueous, viscous liquid. At rest, the formulation is a thick gel, preventing the drug particles from settling. When administered (e.g., sprayed), the high shear forces in the pump nozzle cause the viscosity to drop dramatically (shear-thinning), allowing for easy atomization and delivery. Upon contact with the esophageal mucosa, the shear force is removed, and the formulation instantly returns to its high-viscosity state, forming a uniform, adhesive coating. This provides excellent mucosal adhesion without relying on a phase change.

Mermaid Diagram:

xychart-beta
    title Viscosity vs. Shear Rate
    x-axis "Shear Rate (s^-1)"
    y-axis "Viscosity (Pa·s)"
    line [
        { "x": 0, "y": 10},
        { "x": 50, "y": 9},
        { "x": 100, "y": 7},
        { "x": 500, "y": 2},
        { "x": 1000, "y": 0.5}
    ]
    annotation "High Viscosity at Rest" (10, 8.5)
    annotation "Low Viscosity during Spraying" (900, 2)

2.2 Integration with Emerging Tech: AI-Dosed Smart Nebulizer

Enabling Description: The liquid corticosteroid composition is packaged in a cartridge for use in a "smart nebulizer" or "smart spray" device. The device contains an IoT sensor suite (flow meter, temperature sensor). The patient logs symptoms (e.g., dysphagia score) into a connected mobile app. A cloud-based AI model analyzes the patient-reported outcomes (PROs) and historical dosing data to recommend an optimized spray duration and frequency, which is then programmed into the device. The device delivers the precise dose of the bio-gelling liquid and records the event on a HIPAA-compliant server, providing the clinician with high-fidelity adherence and response data.

Mermaid Diagram:

sequenceDiagram
    participant Patient
    participant MobileApp
    participant Cloud_AI
    participant SmartNebulizer
    Patient->>MobileApp: Logs symptoms (dysphagia score)
    MobileApp->>Cloud_AI: Sends symptom data
    Cloud_AI->>Cloud_AI: Analyzes data, calculates optimal dose
    Cloud_AI->>MobileApp: Sends new dosing regimen
    MobileApp->>SmartNebulizer: Updates device via Bluetooth
    Patient->>SmartNebulizer: Activates device
    SmartNebulizer->>SmartNebulizer: Delivers precise dose of bio-gelling liquid
    SmartNebulizer->>MobileApp: Confirms dose delivery (adherence)

2.3 Cross-Domain Application: Aerospace Sealant/Coating

Enabling Description: The principle of a non-aqueous liquid that gels on contact with a trigger is applied to aerospace engineering. The composition is a two-part system. Part A is the corticosteroid-analog (a corrosion inhibitor or self-healing monomer) suspended in a non-aqueous, non-volatile solvent (e.g., a silicone oil). Part B is the "bio-gelling polymer" analog (a cross-linking catalyst). The two parts are stored separately and mixed during application. The mixture is sprayed onto a surface (e.g., a difficult-to-reach internal fuselage component). The trigger for gelation is not water, but atmospheric humidity or a slight temperature change, which activates the catalyst, causing the liquid to rapidly cure into a solid, protective, or sealing layer in situ.

Mermaid Diagram:

flowchart TD
    A[Part A: Inhibitor in Silicone Oil] --> M;
    B[Part B: Crosslinking Catalyst] --> M;
    M{Mixing Chamber in Applicator};
    M --> S[Spraying onto Aerospace Component];
    S --> T{Trigger: Atmospheric Humidity};
    T --> G[In-Situ Curing/Gelation];
    G --> F[Protective Solid Coating Formed];

Part 3: Derivatives of Manufacturing Methods (Ref: Claim 15)

3.1 Operational Parameter Expansion: Continuous Manufacturing Process

Enabling Description: The batch-based method of making ODTs is converted into a continuous manufacturing process. This involves: 1) Continuous feeding of corticosteroid and binder into a twin-screw extruder for wet granulation (Step a). 2) Simultaneous continuous granulation of the disintegrant/sugar alcohol in a separate granulator (Step b). 3) The outputs of both granulators are fed into a continuous blender. 4) The blended powder flows directly into a rotary tablet press equipped with the external lubrication system (Step d). Process Analytical Technology (PAT) sensors (e.g., Near-Infrared spectroscopy) are used at each stage to monitor blend uniformity and granule properties in real-time, allowing for automated control and adjustment of the process parameters.

Mermaid Diagram:

graph TD
    subgraph Line 1
        A1[API Feeder] --> B[Twin-Screw Granulator];
        A2[Binder Feeder] --> B;
    end
    subgraph Line 2
        C1[Disintegrant Feeder] --> D[Continuous Granulator];
        C2[Sugar Alcohol Feeder] --> D;
    end
    B --> E[Continuous Blender];
    D --> E;
    E --> F[Rotary Tablet Press];
    F -- External Lubrication --> F;
    F --> G[Finished ODTs];

    subgraph PAT Control Loop
        P1[NIR Sensor] -- monitors --> E;
        P1 --> P2[Control System];
        P2 -- adjusts --> A1;
        P2 -- adjusts --> C1;
    end

3.2 Integration with Emerging Tech: Blockchain for Supply Chain Verification

Enabling Description: The manufacturing method is integrated with a blockchain-based supply chain ledger. Each raw material batch (corticosteroid, excipients) is assigned a unique cryptographic hash and its certificate of analysis is recorded on the blockchain. As the materials move through the manufacturing steps (granulation, blending, compression), the process parameters (e.g., temperatures, speeds, press force) from the PAT sensors are added as new transactions to the block corresponding to that specific batch of ODTs. The external lubrication system's lot number and usage data are also recorded. This creates an immutable, auditable, end-to-end record of the tablet's provenance, which can be verified by regulators or patients by scanning a QR code on the final packaging.

Mermaid Diagram:

erDiagram
    RAW_MATERIAL ||--o{ BATCH : has
    RAW_MATERIAL {
        string LotNumber
        string Supplier
        string CertificateHash
    }
    BATCH ||--o{ MANUFACTURING_STEP : undergoes
    BATCH {
        string BatchID
        string ProductID
        string FinalQRCode
    }
    MANUFACTURING_STEP {
        string StepName
        string Timestamp
        string PAT_DataHash
    }

Part 4: Combination with Open-Source Standards

4.1 Combination Prior Art: ODT Dispensing and FHIR-based Adherence Tracking

Enabling Description: The orally disintegrating tablets of US 12,290,598 are packaged in a "smart" blister pack that uses conductive traces to detect when a tablet is removed. This smart package incorporates a microcontroller running an open-source real-time operating system (e.g., Zephyr RTOS) with a Bluetooth Low Energy (BLE) stack. Upon tablet removal, the device creates a digital record of the event. This event data is formatted as a FHIR (Fast Healthcare Interoperability Resources) R4 MedicationAdministration resource. The resource, containing patient ID, medication details, and timestamp, is transmitted via a patient's smartphone to their provider's Electronic Health Record (EHR) system. This provides a standardized, interoperable method for tracking patient adherence to the prescribed therapy.

4.2 Combination Prior Art: Manufacturing QC with OpenCV

Enabling Description: The method of making the tablets (Ref: Claim 15) is enhanced with an in-line quality control (QC) system built on open-source technology. After compression, tablets are passed under a high-resolution camera connected to a single-board computer (e.g., Raspberry Pi). The computer runs a Python script utilizing the OpenCV (Open Source Computer Vision Library). The script performs real-time analysis of each tablet's image to check for defects such as capping, lamination, and incorrect debossing. The OpenCV findContours and matchTemplate functions are used to verify tablet shape and markings against a digital golden template. Any tablet identified as defective is removed from the line by a pneumatic actuator, ensuring 100% visual inspection without proprietary hardware.

4.3 Combination Prior Art: Process Control with OPC-UA

Enabling Description: The manufacturing process, particularly the blending and compression steps, is automated using the OPC-UA (Open Platform Communications Unified Architecture) open-source standard for industrial M2M communication. The rotary tablet press, the continuous blender, and the external lubrication system are all designed to function as OPC-UA servers. A central SCADA system, acting as an OPC-UA client, communicates with each piece of equipment to set parameters and monitor status (e.g., compression force, blend uniformity from PAT, lubricant flow rate). This use of an open, platform-independent standard allows for the creation of a "plug-and-play" manufacturing line using equipment from different vendors without the need for custom drivers or proprietary gateways.