Derivative works — US Patent 9549918

Defensive Disclosure: Derivatives and Novel Applications of Stabilized Macrolide Solid Dispersions

Publication Date: May 1, 2026
Reference Patent: US 9549918 B2

This document discloses novel and non-obvious extensions, variations, and applications derived from the core teachings of US patent 9,549,918. The purpose of this disclosure is to place these concepts into the public domain, thereby establishing them as prior art for any future patent applications. The following descriptions are enabling for a person having ordinary skill in the art (PHOSITA) of pharmaceutical formulation.

Axis 1: Material & Component Substitution

1.1. Stabilizer Substitution: Non-Acidic Metal Ion Chelator System

Enabling Description: A solid dispersion of tacrolimus is prepared using a hot-melt extrusion process with a vehicle of polyethylene glycol 8000 (PEG 8000) and Poloxamer 407 (70:30 w/w ratio). Instead of an organic acid, stability against C8-epimerization is achieved by incorporating 0.2% w/w of ethylenediaminetetraacetic acid (EDTA) and 1.5% w/w of a beta-cyclodextrin derivative, such as hydroxypropyl-β-cyclodextrin (HP-β-CD). The EDTA actively chelates divalent metal ions (e.g., Mg²⁺, Ca²⁺) that catalyze the epimerization reaction, while the HP-β-CD encapsulates a portion of the tacrolimus molecule, sterically hindering the degradation pathway without altering bulk pH.

Mermaid Diagram:

graph TD
    A[Tacrolimus] --> C{Melt Extruder @ 90°C};
    B[PEG 8000 / Poloxamer 407] --> C;
    D[EDTA + HP-β-CD] --> C;
    C --> E[Extruded Filament];
    E --> F[Pelletization];
    F --> G[Compression into Tablet];
    subgraph "Stabilization Mechanism"
        D1(EDTA) -- Chelates --> M(Metal Ions);
        D2(HP-β-CD) -- Encapsulates --> A;
    end

1.2. Stabilizer Substitution: Mixed Organic Acid System

Enabling Description: A stable, sustained-release tacrolimus tablet is formulated using a solid dispersion wherein the stabilizing agent is a synergistic combination of two organic acids. The formulation contains 0.15% w/w L-tartaric acid and 0.25% w/w succinic acid within a PEG 6000/Poloxamer 188 vehicle. The tartaric acid provides strong chelation and initial pH reduction, while the succinic acid acts as a secondary buffer, maintaining the acidic microenvironment more effectively over a prolonged period as the tablet matrix hydrates and dissolves in the gastrointestinal tract. This dual-acid system provides superior long-term stability (>12 months) compared to tartaric acid alone.

Mermaid Diagram:

stateDiagram-v2
    [*] --> Unstabilized: Formulation Prepared
    Unstabilized --> Stabilized: Add Tartaric + Succinic Acid
    state Stabilized {
        direction LR
        [*] --> pH_Lowered: Tartaric Acid acts
        pH_Lowered --> pH_Maintained: Succinic Acid buffers
        pH_Maintained --> [*]
    }

1.3. Vehicle Substitution: Biodegradable Polymer Matrix

Enabling Description: The PEG/poloxamer vehicle is replaced with a biodegradable matrix of poly(lactic-co-glycolic acid) (PLGA 75:25) and a plasticizer, triethyl citrate. Tacrolimus and 0.5% w/w tartaric acid are dissolved in a solvent system (acetone/dichloromethane) with the PLGA. This solution is then used to create microspheres via an oil-in-water emulsion-solvent evaporation technique. The resulting tartaric acid-infused microspheres provide sustained release of tacrolimus over 72 hours and are fully biodegradable. This formulation is intended for targeted delivery or implantable depots.

Mermaid Diagram:

flowchart LR
    subgraph "Aqueous Phase"
        B[Polyvinyl Alcohol Solution]
    end
    subgraph "Organic Phase"
        A[Tacrolimus + Tartaric Acid + PLGA in Acetone/DCM]
    end
    A -- Emulsification --> C{Homogenizer};
    B --> C;
    C -- Solvent Evaporation --> D[PLGA Microspheres];
    D -- Lyophilization --> E[Dry Powder for Injection/Implant];

1.4. Active Ingredient Substitution: Sirolimus (Rapamycin) Formulation

Enabling Description: The principles of the '918 patent are applied to stabilize sirolimus, another macrolide lactone known for its instability. A solid solution of sirolimus is prepared in a vehicle of Gelucire 50/13, a polyglycolized glyceride, via a melt-granulation process. The formulation is stabilized by the inclusion of 0.3% w/w citric acid, which prevents oxidative degradation and hydrolysis by maintaining an acidic microenvironment (pH 3.5-4.0). The resulting granules can be filled into hard capsules for oral administration.

Mermaid Diagram:

classDiagram
    class SirolimusFormulation {
        +active_ingredient: Sirolimus
        +vehicle: Gelucire_50_13
        +stabilizer: Citric_Acid
        +dosage_form: Hard_Capsule
        +stabilization_pH: 3.5
    }
    Sirolimus --|> MacrolideLactone
    Tacrolimus --|> MacrolideLactone
    SirolimusFormulation ..> Sirolimus : contains

Axis 2: Operational Parameter Expansion

2.1. Manufacturing Parameter: Cryogenic Spray-Congealing

Enabling Description: A molten mixture of tacrolimus, PEG 10000, Poloxamer 338, and 0.2% w/w tartaric acid at 100°C is atomized through a heated nozzle into a cryogenic chamber filled with liquid nitrogen vapor at -120°C. The rapid solidification (congealing) traps the tacrolimus and tartaric acid in a highly uniform, amorphous solid dispersion. This process minimizes thermal exposure time, reducing the formation of initial degradation products to below 0.01% w/w at t=0 and yielding microparticles suitable for direct compression or filling into sachets for pediatric use.

Mermaid Diagram:

sequenceDiagram
    participant MoltenSlurry as "Molten Slurry (100°C)"
    participant Atomizer
    participant CryoChamber as "Cryo Chamber (-120°C)"
    participant Collector
    MoltenSlurry->>Atomizer: Feed molten mixture
    Atomizer->>CryoChamber: Spray fine droplets
    CryoChamber->>Collector: Rapidly congeal droplets into microparticles
    Collector-->>MoltenSlurry: Particles < 0.01% degradants

2.2. Environmental Parameter: High-Altitude/Aerospace Formulation

Enabling Description: For use by astronauts in low-gravity and high-radiation environments, the stabilized tacrolimus tablet is further enhanced. The solid dispersion is prepared as claimed but is then coated with a dual-layer system. The inner layer is hydroxypropyl methylcellulose (HPMC) containing 1% w/w butylated hydroxytoluene (BHT) as an antioxidant to mitigate degradation from ionizing radiation. The outer layer is a UV-blocking enteric coating (e.g., Eudragit L100-55 with embedded titanium dioxide) to protect against light-induced degradation and ensure release in the small intestine.

Mermaid Diagram:

graph TD
    A(Core Tablet: Tacrolimus + Tartaric Acid in PEG/Poloxamer) --> B{Inner Coating};
    B -- Contains --> B1(HPMC + BHT for Radiation Shielding);
    B --> C{Outer Coating};
    C -- Contains --> C1(Eudragit + TiO2 for UV Shielding);
    C --> D[Final Aerospace-Ready Tablet];

Axis 3: Cross-Domain Application

3.1. AgTech Application: Controlled-Release Fungicide

Enabling Description: A solid dispersion of the pH-sensitive fungicide Azoxystrobin is prepared in a biodegradable vehicle of polylactic acid (PLA) and a surfactant. The formulation is stabilized against hydrolysis in alkaline soils by incorporating 2% w/w of oxalic acid. The mixture is extruded into pellets, which are coated with a water-permeable membrane. When applied to soil, moisture slowly penetrates the pellet, dissolving the oxalic acid and creating an acidic micro-environment that stabilizes the Azoxystrobin as it is slowly released over a 90-day period.

Mermaid Diagram:

stateDiagram-v2
    [*] --> InPellet: Fungicide Stable (Acidic)
    InPellet --> Releasing: Soil moisture ingress
    Releasing --> InSoil: Active fungicide released
    InSoil --> Degraded: Hydrolysis in alkaline soil
    note right of InPellet
        Oxalic acid maintains low pH
        inside the pellet, protecting
        the active ingredient.
    end note

3.2. Food Science Application: Stabilized Probiotic Delivery

Enabling Description: Live probiotic bacteria (e.g., Lactobacillus rhamnosus) are lyophilized with a cryoprotectant mixture containing lactose and 0.5% w/w malic acid. This powder is then incorporated into a solid dispersion vehicle of PEG 4000 and Poloxamer 188 using a low-temperature melt granulation process (<45°C). The malic acid creates an acidic micro-environment that keeps the bacteria in a state of suspended animation and protects them from premature activation by ambient humidity. The final granules are enteric-coated to bypass stomach acid and release the viable probiotics in the intestine.

Mermaid Diagram:

flowchart TD
    A[Probiotics + Cryoprotectant + Malic Acid] --> B(Lyophilization);
    B --> C[Stabilized Powder];
    D[Melted PEG 4000/Poloxamer < 45°C] --> E{Low-Shear Granulator};
    C --> E;
    E --> F[Granules with Dormant Probiotics];
    F --> G(Enteric Coating);
    G --> H[Final Oral Capsule];

Axis 4: Integration with Emerging Tech

4.1. AI-Driven Process Analytical Technology (PAT)

Enabling Description: During the hot-melt extrusion of the tacrolimus/tartaric acid/PEG/poloxamer formulation, a near-infrared (NIR) and a Raman spectroscopy probe are fitted to the extruder die. These sensors provide real-time data on the crystallinity, uniformity of dispersion, and concentration of both tacrolimus and 8-epitacrolimus. A trained machine learning model interprets the spectral data and dynamically adjusts process parameters (screw speed, temperature profile, feed rate) to maintain the concentration of 8-epitacrolimus in the final extrudate below a target threshold of 0.1% w/w, ensuring batch-to-batch consistency.

Mermaid Diagram:

sequenceDiagram
    participant Extruder
    participant Sensors as "NIR/Raman Probes"
    participant AI_Model as "AI Control Model"
    loop Real-time Process Control
        Extruder->>Sensors: Provides material for analysis
        Sensors->>AI_Model: Sends spectral data
        AI_Model->>Extruder: Adjusts parameters (temp, speed)
    end
    Note right of AI_Model: Goal: Minimize 8-epitacrolimus < 0.1%

4.2. IoT-Enabled Adherence and Stability Monitoring

Enabling Description: The stabilized tacrolimus formulation is packaged in a "smart" blister pack equipped with NFC (Near-Field Communication) technology and a small temperature/humidity logger. Each time a patient pushes a tablet through the foil, a circuit is broken, and the event is logged. The patient can scan the pack with their smartphone to upload adherence data. The logger continuously monitors storage conditions. If the pack is exposed to temperatures exceeding 30°C for a cumulative period of 72 hours, an alert is sent to the patient and pharmacist, warning of potential accelerated degradation and compromised stability.

Mermaid Diagram:

graph TD
    subgraph SmartBlisterPack
        A[Tablet Cavity] -- Push-through --> B(Conductive Trace Break);
        C[Temp/Humidity Logger] -- Logs --> D(Storage Data);
        E[NFC Chip] -- Stores --> B & D;
    end
    F(Patient Smartphone) -- Scans --> E;
    E -- Transmits Data --> F;
    F --> G{Cloud Platform};
    G -- Adherence Log --> H(Provider Portal);
    G -- Stability Alert? --> F;

Axis 5: The "Inverse" or Failure Mode

5.1. Intentional Inactivation for Safe Disposal

Enabling Description: A tacrolimus solid dispersion is formulated with tartaric acid as in the primary invention. However, it also incorporates 5% w/w of sodium bicarbonate, physically separated from the acidic solid dispersion by a pH-sensitive coating of Eudragit E 100. The coating is stable in the acidic core but dissolves rapidly at pH > 5. For disposal, the user dissolves the tablet in a provided "Disposal Solution" containing a mild phosphate buffer at pH 8. The Eudragit E 100 dissolves, allowing the sodium bicarbonate to react with the tartaric acid, raising the internal pH of the dissolving matrix to > 8, which rapidly accelerates the degradation of tacrolimus into inactive epimers and hydrolysis products.

Mermaid Diagram:

flowchart TD
    A[Core: Tacrolimus + Tartaric Acid] --> B{Coating: Eudragit E 100};
    B --> C{Outer Layer: Sodium Bicarbonate};
    C --> D[Final Tablet];
    subgraph "Disposal Process"
        D -- Add to --> E[Disposal Solution pH 8];
        E -- Dissolves --> B;
        A -- Reacts with --> C;
        F{pH shifts to > 8};
        F --> G[Tacrolimus Rapidly Degrades];
    end

Combination Prior Art Scenarios

Combination with Open-Source 3D-Printed Polypill: The stabilized tacrolimus/tartaric acid/PEG/poloxamer granules, produced via melt-granulation, are used as a feedstock material for a Fused Deposition Modeling (FDM) 3D printer. The printer uses an open-source design file (e.g., from the Open-Source Pharma initiative) to print a "polypill" containing metformin, lisinopril, and the tacrolimus formulation in separate, defined compartments. This allows for a single, personalized, once-daily tablet for diabetic transplant patients, with the tacrolimus component protected from chemical interaction with the other APIs.
Combination with OMOP Common Data Model: Data from an IoT-enabled "smart pill" containing the stabilized tacrolimus formulation is collected. This data includes in-vivo pH measurements, transit time, and patient-reported outcomes. The data is then structured and mapped according to the open-source Observational Medical Outcomes Partnership (OMOP) Common Data Model. This allows for large-scale, federated analysis by researchers to correlate the formulation's in-vivo behavior (i.e., maintenance of the acidic micro-environment) with clinical outcomes like rejection rates and trough level variability across diverse patient populations.
Combination with OpenMTA for Research Tools: The exact formulation and manufacturing protocol for a non-commercial, research-grade version of the stabilized tacrolimus composition is made available to academic researchers under the OpenMTA (Open Material Transfer Agreement) framework. This allows academic labs to easily obtain, replicate, and improve upon the formulation for non-commercial research into macrolide stability, GI tract absorption models, or new analytical methods for detecting degradation products, without the legal friction of traditional MTAs.