Patent 8268847

Derivative works

Defensive disclosure: derivative variations of each claim designed to render future incremental improvements obvious or non-novel.

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Derivative works

Defensive disclosure: derivative variations of each claim designed to render future incremental improvements obvious or non-novel.

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Here is a comprehensive Defensive Disclosure document for US Patent 8268847, focusing on generating derivative variations to establish prior art for potential future incremental improvements.

Defensive Disclosure Document for US Patent 8268847

Patent Title: Therapeutic compositions comprising a specific endothelin receptor antagonist and a PDE5 inhibitor
Patent Number: US8268847B2
Current Assignee: Actelion Pharmaceuticals Ltd (acquired by Johnson & Johnson)
Inventor: Martine Clozel
Publication Date: 2012-09-18
Current Date: 2026-04-26

Objective: To establish defensive prior art against potential incremental improvements by competitors, rendering such improvements obvious or non-novel, based on the core claims of US8268847. This document describes derivative variations of the invention along specific axes, providing enabling descriptions and visual aids.

Derivatives of Independent Claim 1: Product for Therapeutic Use

Claim 1: A product containing the compound of formula (I) (N-[4-(2-bromo-4-fluorophenyl)-5-(2-methoxyethoxy)-6-methylpyrimidin-2-yl]-2-methylpropan-2-sulfamide) in free or pharmaceutically acceptable salt form, in combination with at least one compound having PDE5-inhibitory properties, in free or a pharmaceutically acceptable salt form, for therapeutic use, simultaneously, separately or over a period of time, in the treatment of a disease wherein vasoconstriction is involved.

1. Material & Component Substitution

Derivative 1.1: Prodrugs and Isotopic Labeling for Pharmacokinetic Modulation and Imaging

  • Enabling Description: The compound of formula (I) (macitentan) is prepared as a metabolically cleavable prodrug, such as an ester or amide derivative, designed to enhance oral bioavailability, extend half-life, or provide targeted release in specific tissues (e.g., lung tissue). For example, a phosphonooxymethyl prodrug of macitentan could be synthesized to improve aqueous solubility and facilitate intravenous administration, which is subsequently cleaved by endogenous phosphatases. Similarly, the PDE5 inhibitor (e.g., tadalafil) is prepared as a soft drug, designed for rapid metabolic inactivation after achieving its therapeutic effect, thereby reducing systemic side effects. Furthermore, the compounds of formula (I) or the PDE5 inhibitor are isotopically labeled with fluorine-18 or carbon-11 for Positron Emission Tomography (PET) imaging, enabling real-time assessment of drug distribution, target engagement, and metabolic fate in vivo, allowing for personalized treatment optimization based on observed tissue concentrations rather than theoretical pharmacokinetics.
graph TD
    A[Prodrug (ERA-I / PDE5i)] --> B{Administration Route};
    B -- Oral / IV --> C[Systemic Circulation];
    C --> D[Tissue-Specific Activation/Cleavage];
    D --> E[Active Drug];
    E --> F[Target Engagement (e.g., ETA/ETB receptors, PDE5 enzyme)];
    F --> G[Therapeutic Effect];
    H[Isotopically Labeled Drug] --> I{PET Imaging};
    I --> J[Real-time PK/PD Data];
    J --> K[Treatment Optimization];

Derivative 1.2: Advanced Excipients for Enhanced Stability and Bioavailability

  • Enabling Description: The product comprises the compound of formula (I) and a PDE5 inhibitor (e.g., sildenafil citrate) formulated within a solid dispersion matrix using a pH-responsive enteric polymer (e.g., hydroxypropyl methylcellulose acetate succinate, HPMCAS) and a superdisintegrant (e.g., croscarmellose sodium). This formulation enhances the dissolution rate and bioavailability, particularly for poorly soluble drug substances, by maintaining a supersaturated state in the gastrointestinal tract. Alternatively, the active principles are co-crystallized with a pharmaceutically acceptable co-former (e.g., saccharin or nicotinamide) to create a novel co-crystal form, altering physicochemical properties such as solubility, stability, and compaction characteristics, enabling improved manufacturing processes and patient compliance. The co-crystal formation is confirmed by X-ray diffraction and differential scanning calorimetry.
classDiagram
    class Product {
        +Compound_Formula_I
        +PDE5_Inhibitor
        +Solid_Dispersion_Matrix
        +pH_Responsive_Polymer
        +Superdisintegrant
        +Co_crystal_Form
        +Co_former
    }
    class Compound_Formula_I {
        +Solubility
        +Stability
    }
    class PDE5_Inhibitor {
        +Solubility
        +Stability
    }
    class Solid_Dispersion_Matrix {
        +Dissolution_Rate_Enhancement()
    }
    class Co_crystal_Form {
        +Modified_Physicochem_Props
    }
    Product --|> Compound_Formula_I
    Product --|> PDE5_Inhibitor
    Product "1" -- "1" Solid_Dispersion_Matrix : contains
    Product "1" -- "0..1" Co_crystal_Form : contains

2. Operational Parameter Expansion

Derivative 1.3: Continuous Micro-Dosing for Chronic Prophylaxis

  • Enabling Description: The product is designed for continuous, ultra-low-dose administration via a subcutaneous micro-infusion pump for chronic prophylactic treatment of early-stage pulmonary hypertension in high-risk individuals (e.g., those with connective tissue diseases, portopulmonary hypertension). The daily dose of the compound of formula (I) and tadalafil is 1/10th of the standard therapeutic dose, delivered continuously over 24 hours to maintain steady-state plasma concentrations, minimizing peak-to-trough fluctuations and associated side effects. The micro-infusion pump is programmed to deliver specific molar ratios of the active compounds (e.g., 1:1, 1:2, 2:1) based on patient-specific hemodynamic profiles. The pump system incorporates a reservoir for a sterile, stable aqueous solution of the combination, ensuring long-term stability at body temperature.
flowchart TD
    A[High-Risk Patient] --> B{Subcutaneous Micro-Infusion Pump};
    B --> C[ERA-I (Formula I) Micro-Dose];
    B --> D[PDE5i (Tadalafil) Micro-Dose];
    C & D --> E[Continuous 24h Delivery];
    E --> F[Steady-State Plasma Conc.];
    F --> G[Chronic Prophylactic Effect];
    G --> H[Monitor Hemodynamics];
    H --> B;

Derivative 1.4: Thermally-Activated Drug Release for Localized Vasodilation

  • Enabling Description: The product consists of a thermoreversible hydrogel formulation containing nanocarriers (e.g., liposomes or polymeric nanoparticles) encapsulating the compound of formula (I) and a PDE5 inhibitor (e.g., vardenafil). This formulation is injected locally into a region exhibiting localized vasoconstriction (e.g., within pulmonary arterial lesions or sites of peripheral diabetic arteriopathy). Upon application of external localized hyperthermia (e.g., via focused ultrasound or radiofrequency ablation at 40-45°C), the hydrogel undergoes a sol-gel transition, and the nanocarriers release the encapsulated drugs, providing high local drug concentrations with minimal systemic exposure. The heating parameters (temperature, duration) are precisely controlled to induce drug release while avoiding tissue damage.
sequenceDiagram
    participant P as Patient
    participant H as Healthcare Provider
    participant F as Hydrogel Formulation
    participant N as Nanocarriers (ERA-I/PDE5i)
    participant U as Localized Ultrasound/RF
    participant T as Target Tissue (Vasoconstricted)

    H->>P: Administers F (local injection)
    F->>N: Nanocarriers Disperse within F
    H->>U: Activates U (localized hyperthermia)
    U->>T: Heats Target Tissue (40-45°C)
    T-->>F: Temperature Increase
    F->>N: Hydrogel Transition & Nanocarrier Release Triggered
    N->>T: High Local Drug Concentration
    T->>P: Local Vasodilation

3. Cross-Domain Application

Derivative 1.5: Cardiovascular Support in Ex-Vivo Organ Perfusion Systems

  • Enabling Description: The combination product (macitentan and sildenafil) is incorporated into the perfusate solution for ex-vivo organ preservation and reperfusion in transplantation medicine. The solution, containing a physiologically relevant concentration of both active agents (e.g., macitentan at 100 nM, sildenafil at 1 µM), is circulated through donor organs (e.g., lungs, heart, kidneys) during cold or normothermic machine perfusion. This application aims to prevent or reverse perfusion injury-induced vasoconstriction, reduce inflammation, improve microcirculatory flow, and optimize oxygenation/nutrient delivery to the graft, thereby enhancing organ viability and post-transplant function. The perfusate is maintained at specific physiological parameters (pH 7.4, 37°C for normothermic, 4-8°C for cold).
graph LR
    A[Donor Organ] --> B{Perfusate Reservoir};
    B -- Contains ERA-I & PDE5i --> C[Perfusion Pump];
    C --> D[Oxygenator/Dialyzer];
    D --> E[Organ Vascular Bed (Ex-Vivo)];
    E -- Modulated Vasoconstriction --> F[Improved Microcirculation];
    F --> G[Enhanced Organ Viability];
    G --> B;

Derivative 1.6: Modulating Xylem Flow in Drought-Stressed Crop Plants

  • Enabling Description: The combination of a plant-compatible analog of the compound of formula (I) (e.g., a synthetic pyrimidine derivative with endothelin-like activity in plant vascular systems) and a plant-metabolizable analog of a PDE5 inhibitor (e.g., a cGMP phosphodiesterase inhibitor with structural homology to sildenafil) is developed as an agricultural agent. This agent is delivered via foliar spray or root irrigation to crop plants experiencing drought stress. The objective is to modulate xylem sap flow and stomatal conductance by mitigating stress-induced "vasoconstriction" (i.e., hydraulic impedance or cavitation within the xylem) or enhancing beneficial cGMP signaling pathways in guard cells, improving water use efficiency and drought tolerance. Concentrations are optimized for plant uptake and minimal environmental impact (e.g., 10-100 µM in irrigation water).
graph TD
    A[Drought-Stressed Crop Plant] --> B[ERA-I Analog + PDE5i Analog];
    B -- Foliar Spray / Root Irrigation --> C[Plant Uptake];
    C --> D[Xylem Vascular System / Stomata];
    D -- Modulates Hydraulic Impedance / cGMP Signaling --> E[Reduced Water Stress];
    E --> F[Improved Water Use Efficiency];
    F --> G[Enhanced Drought Tolerance];

4. Integration with Emerging Tech

Derivative 1.7: AI-Driven Personalized Dosing via Wearable Biosensors and Smart Dispensers

  • Enabling Description: The product (macitentan and tadalafil) is prescribed as part of a personalized treatment regimen managed by an AI-driven platform. Patients wear continuous physiological monitoring devices (e.g., smart patches, wristbands) that collect real-time data on blood pressure, heart rate, oxygen saturation, and cardiac output (via impedance cardiography). This data is fed into a machine learning algorithm, which dynamically adjusts the optimal dosing schedule and ratio of the two active ingredients. A smart pill dispenser, connected to the patient's EHR and the AI platform, dispenses the precise, personalized doses daily. The AI considers individual pharmacogenomic data, comorbidities, and lifestyle factors to predict drug response and minimize adverse events, thereby optimizing therapeutic outcomes for conditions like pulmonary arterial hypertension.
flowchart TD
    A[Patient] -- Wearable Biosensors --> B(Physiological Data);
    B --> C{AI Dosing Algorithm};
    C -- Pharmacogenomics, Comorbidities --> C;
    C -- Personalized Dose Rec. --> D[Smart Pill Dispenser];
    D -- Dispenses ERA-I & PDE5i --> A;
    A -- Improved Health Outcomes --> A;
    C -- Real-time Feedback Loop --> B;

Derivative 1.8: Blockchain for Authenticity and Supply Chain Integrity of Combination Products

  • Enabling Description: Each unit dose of the combination product (e.g., a co-formulated tablet containing the compound of formula (I) and sildenafil) is assigned a unique serialization code (e.g., GS1 Digital Link) at the point of manufacture. This code is recorded on a distributed ledger (blockchain) along with manufacturing batch details, expiry date, and cryptographic hash of the composition. As the product moves through the supply chain (manufacturer, wholesaler, distributor, pharmacy), each handover event is cryptographically signed and recorded on the blockchain. Patients can scan the serialization code with a smartphone app to verify the product's authenticity, track its journey, and access patient information leaflets, significantly mitigating the risk of counterfeit drugs and ensuring product integrity from production to patient.
sequenceDiagram
    participant M as Manufacturer
    participant W as Wholesaler
    participant D as Distributor
    participant P as Pharmacy
    participant C as Consumer
    participant B as Blockchain Ledger

    M->>B: Record (Serialization ID, Batch, Expiry, Composition Hash)
    M->>W: Ship Product + ID
    W->>B: Record (Receipt, Transfer to W)
    W->>D: Ship Product + ID
    D->>B: Record (Receipt, Transfer to D)
    D->>P: Ship Product + ID
    P->>B: Record (Receipt, Transfer to P)
    P->>C: Dispense Product + ID
    C->>B: Verify Product (Scan ID)
    B-->>C: Authenticity Confirmation

5. The "Inverse" or Failure Mode

Derivative 1.9: Biodegradable Implant for Controlled-Release and Programmed Degradation

  • Enabling Description: A biodegradable polymer implant (e.g., composed of poly(lactic-co-glycolic acid) (PLGA) or polycaprolactone (PCL)) containing microencapsulated compound of formula (I) and tadalafil is surgically implanted for long-term (e.g., 6-12 months) therapy. In the event of an adverse systemic reaction (e.g., severe hypotension, liver enzyme elevation), the implant is designed with a bioresorbable sacrificial layer that, upon activation by an external low-frequency ultrasound pulse or specific enzymatic injection, rapidly degrades to expose the active ingredients to an enzymatic degradation solution, leading to accelerated deactivation or controlled release into the lymphatic system for excretion, safely terminating drug exposure. The residual non-toxic degraded polymer is then naturally cleared by the body.
stateDiagram-v2
    state "Implant Intact" as Intact
    state "Drug Release (Therapeutic)" as Therapeutic
    state "Adverse Event Detected" as Adverse
    state "Deactivation Initiated" as Deactivate
    state "Accelerated Degradation" as Degradation
    state "Drug Excretion" as Excretion
    state "Residual Polymer Clearance" as Clearance

    Intact --> Therapeutic : Initial Implantation
    Therapeutic --> Adverse : Adverse Reaction
    Adverse --> Deactivate : External Trigger (Ultrasound/Enzyme)
    Deactivate --> Degradation : Sacrificial Layer Degrades
    Degradation --> Excretion : Rapid Drug Deactivation/Excretion
    Excretion --> Clearance : Natural Clearance
    Clearance --> [*]

Derivative 1.10: Self-Limiting Aerosol for Acute Respiratory Vasoconstriction with Intrinsic Safety

  • Enabling Description: An inhalable aerosol formulation containing micronized particles of the compound of formula (I) and sildenafil is developed for acute, localized treatment of severe pulmonary arterial vasoconstriction. The formulation includes a pH-sensitive matrix or a volatile excipient that ensures a rapid initial burst release into the pulmonary vasculature, providing immediate therapeutic effect. However, the active drug components within the aerosol are also co-formulated with a high proportion of an inactive, inert, rapidly metabolized precursor (e.g., a derivative with a labile ester bond). This precursor ensures that beyond the acute pulmonary exposure, systemic absorption leads to swift metabolic deactivation of any residual active compound, limiting systemic bioavailability and thus preventing prolonged systemic exposure or accumulation, providing an intrinsic self-limiting safety mechanism against excessive systemic vasodilation or other off-target effects.
graph LR
    A[Aerosol Device] --> B(Inhalation);
    B --> C[Pulmonary Vasculature (Target)];
    C -- Rapid Burst Release --> D[Acute Vasodilation];
    B --> E[Systemic Absorption (Residual)];
    E -- Inactive Precursor --> F[Rapid Metabolic Deactivation];
    F --> G[Limited Systemic Exposure];
    D & G --> H[Safety-Controlled Therapeutic Effect];

Derivatives of Independent Claim 6: Pharmaceutical Composition

Claim 6: A pharmaceutical composition containing, as active principles, the compound of formula (I) (N-[4-(2-bromo-4-fluorophenyl)-5-(2-methoxyethoxy)-6-methylpyrimidin-2-yl]-2-methylpropan-2-sulfamide) as described in claim 1, in free or pharmaceutically acceptable salt form, in combination with at least one compound having PDE5-inhibitory properties, in free or pharmaceutically acceptable salt form, as well as at least one excipient.

1. Material & Component Substitution

Derivative 6.1: Mucoadhesive Oral Films for Sublingual/Buccal Delivery

  • Enabling Description: The pharmaceutical composition comprises the compound of formula (I) and tadalafil integrated into a mucoadhesive oral film for sublingual or buccal administration. The film matrix is composed of biocompatible, water-soluble polymers such as hydroxypropyl cellulose (HPC) or carboxymethyl cellulose (CMC), blended with a plasticizer (e.g., glycerol) and a permeation enhancer (e.g., menthol or ethanol). This dosage form allows for direct absorption into the systemic circulation, bypassing first-pass metabolism, which can improve bioavailability and reduce dose for drugs with significant hepatic metabolism. The mucoadhesive properties ensure retention at the absorption site for a sufficient duration (e.g., 15-30 minutes). The film thickness is precisely controlled (e.g., 50-200 µm) for optimal handling and dissolution.
classDiagram
    class PharmaceuticalComposition {
        +Compound_Formula_I
        +PDE5_Inhibitor
        +Mucoadhesive_Polymer_Matrix
        +Plasticizer
        +Permeation_Enhancer
    }
    class Mucoadhesive_Oral_Film {
        +Sublingual_Buccal_Delivery()
        +Bypass_First_Pass()
        +Enhanced_Bioavailability()
    }
    PharmaceuticalComposition --|> Mucoadhesive_Oral_Film : is_formulated_as

Derivative 6.2: Thermally Stable Lyophilized Powder for Reconstitution

  • Enabling Description: The pharmaceutical composition is presented as a lyophilized (freeze-dried) powder containing the compound of formula (I) and sildenafil citrate, along with cryoprotectants (e.g., mannitol, trehalose) and bulking agents (e.g., dextran). This formulation is designed for superior long-term thermal stability, enabling storage and distribution without refrigeration, particularly in regions with limited cold chain infrastructure. The powder is sterile and readily reconstitutable with a sterile diluent (e.g., bacteriostatic water for injection) prior to intravenous or subcutaneous administration. The porosity and specific surface area of the lyophilized cake are controlled to ensure rapid and complete dissolution within 30 seconds.
graph TD
    A[ERA-I (Formula I)] --> B{Lyophilized Powder Composition};
    C[PDE5i (Sildenafil)] --> B;
    D[Cryoprotectants] --> B;
    E[Bulking Agents] --> B;
    B -- Enhanced Thermal Stability --> F[Ambient Storage/Distribution];
    F --> G[Reconstitution with Sterile Diluent];
    G --> H[IV / SC Administration];

2. Operational Parameter Expansion

Derivative 6.3: Ultra-Rapid Dissolving Oral Films for Acute Intervention

  • Enabling Description: The pharmaceutical composition consists of an ultra-rapid dissolving oral film containing the compound of formula (I) and tadalafil, engineered for immediate drug release (dissolution within 5-15 seconds) upon contact with saliva. This is achieved through the use of highly soluble film-forming polymers (e.g., pullulan or maltodextrin), combined with effervescent agents (e.g., sodium bicarbonate/citric acid mixture) and supersaturation enhancers (e.g., soluble cyclodextrins). This rapid onset of action is critical for acute management of sudden hypertensive crises or rapid onset angina pectoris in susceptible patients, where immediate vasodilation is required. The film is designed for ease of administration without water.
flowchart TD
    A[ERA-I (Formula I)] & B[PDE5i (Tadalafil)] --> C{Ultra-Rapid Dissolving Film};
    C -- Soluble Polymers + Effervescents + Supersaturation Enhancers --> C;
    C --> D[Contact with Saliva];
    D --> E[Rapid Dissolution (5-15s)];
    E --> F[Immediate Drug Absorption];
    F --> G[Acute Vasodilation/Therapeutic Effect];

Derivative 6.4: Biphasic Release Oral Tablets for Circadian Rhythm Management

  • Enabling Description: The pharmaceutical composition is an oral tablet engineered for biphasic drug release, specifically tailored for chronotherapeutic management of hypertension with nocturnal or early morning peaks. The tablet comprises two distinct layers or compartments. The immediate-release layer contains a portion of the compound of formula (I) and sildenafil, designed for rapid dissolution and absorption (within 30 minutes). The second layer is an extended-release matrix (e.g., using hydrophilic cellulose ethers like HPMC or hydrophobic waxes) containing the remaining doses of both active principles, programmed to release over 8-12 hours, with a delayed onset to coincide with predicted peak blood pressure elevation periods. This ensures consistent therapeutic coverage and minimizes nocturnal hypotension.
classDiagram
    class BiphasicTablet {
        +Immediate_Release_Layer
        +Extended_Release_Layer
        +ERA_I_Dose_IR
        +PDE5i_Dose_IR
        +ERA_I_Dose_ER
        +PDE5i_Dose_ER
        +Hydrophilic_Polymer_ER
        +Hydrophobic_Wax_ER
    }
    class Immediate_Release_Layer {
        +Dissolve_Rapidly()
    }
    class Extended_Release_Layer {
        +Release_Over_Time(hours)
    }
    BiphasicTablet "1" -- "1" Immediate_Release_Layer : contains
    BiphasicTablet "1" -- "1" Extended_Release_Layer : contains

3. Cross-Domain Application

Derivative 6.5: Veterinary Oral Paste for Companion Animals

  • Enabling Description: A palatable oral paste composition is developed for veterinary use in companion animals (e.g., dogs, cats) suffering from pulmonary hypertension or systemic hypertension. This composition contains the compound of formula (I) and tadalafil, formulated with veterinary-acceptable excipients such as palatable flavorings (e.g., beef, chicken flavor), suspending agents (e.g., xanthan gum), and sweeteners (e.g., sucralose). The paste format facilitates accurate and stress-free dosing for pet owners, ensuring compliance. The rheological properties of the paste are optimized for easy administration via an oral syringe, providing a consistent dose to animals of varying sizes and temperaments.
graph TD
    A[Companion Animal] --> B{Oral Paste Composition};
    B -- Contains ERA-I & PDE5i --> C[Palatable Flavoring];
    C --> D[Suspending Agent];
    D --> E[Sweetener];
    B -- Easy Administration --> F[Oral Syringe];
    F --> G[Accurate Dosing];
    G --> H[Treatment of Hypertension];

Derivative 6.6: Nutraceutical-Enhanced Topical Cream for Microcirculatory Support

  • Enabling Description: A topical dermatological cream formulation is prepared, combining microencapsulated compound of formula (I) (at a sub-systemic absorption concentration, e.g., 0.01% w/w) and a PDE5 inhibitor (e.g., sildenafil, also at a low concentration, e.g., 0.05% w/w) with nutraceutical active ingredients known for vascular health benefits (e.g., L-arginine, Ginkgo biloba extract, resveratrol). This cream is intended for cosmetic or dermatological application to improve peripheral microcirculation, reduce localized vasoconstriction in conditions like Raynaud's phenomenon affecting skin, or to enhance skin barrier function and wound healing through improved blood flow, without systemic drug exposure. The cream matrix utilizes liposomal delivery systems to enhance penetration into the dermal layers while limiting systemic diffusion.
classDiagram
    class TopicalCream {
        +Compound_Formula_I_Microencap
        +PDE5i_Microencap
        +L_Arginine
        +Ginkgo_Biloba_Extract
        +Resveratrol
        +Liposomal_Delivery_System
    }
    class Skin_Microcirculation {
        +Improved_Blood_Flow()
        +Reduced_Localized_Vasoconstriction()
        +Enhanced_Wound_Healing()
    }
    TopicalCream "1" --|> Skin_Microcirculation : supports

4. Integration with Emerging Tech

Derivative 6.7: 3D-Printed Multi-Layered Tablets for Personalized Polypharmacy

  • Enabling Description: The pharmaceutical composition is fabricated using 3D printing technology (e.g., fused deposition modeling or inkjet printing) to create multi-layered tablets. Each layer contains a precise dose of either the compound of formula (I) or tadalafil, potentially combined with other active pharmaceutical ingredients (APIs) for polypharmacy patients. The 3D printing allows for exact geometric control, enabling tailored release kinetics for each active component (e.g., immediate release for one, delayed or extended release for another) within a single tablet. This technology facilitates personalized medicine by adjusting drug content, layering, and release profiles based on individual patient needs, potentially reducing pill burden and improving adherence.
graph TD
    A[Patient-Specific Prescription] --> B{3D Printing Software};
    B --> C[3D Printer];
    C -- Layer-by-Layer Deposition --> D[Multi-Layered Tablet];
    D -- Layer 1 (ERA-I) --> E[Defined Release Profile 1];
    D -- Layer 2 (PDE5i) --> F[Defined Release Profile 2];
    D -- Optional Layer 3 (Other API) --> G[Defined Release Profile 3];
    D --> H[Personalized Dosing/Release];

Derivative 6.8: Injectable Nanobot-Mediated Targeted Delivery System

  • Enabling Description: The pharmaceutical composition comprises the compound of formula (I) and sildenafil encapsulated within biologically inspired nanobots (e.g., synthetic bacteriophage mimics or liposome-coated gold nanoparticles). These nanobots are surface-functionalized with specific ligands (e.g., antibodies to markers of vascular inflammation or specific endothelin receptor subtypes) that enable active targeting to areas of pathological vasoconstriction within the pulmonary or systemic circulation. Upon reaching the target site, the nanobots are designed for controlled release of their payload via an internal mechanism triggered by local environmental cues (e.g., low pH in ischemic tissue, specific enzymatic activity), maximizing drug concentration at the site of disease while minimizing systemic side effects.
sequenceDiagram
    participant HCP as Healthcare Provider
    participant P as Patient
    participant N as Nanobots (ERA-I/PDE5i)
    participant B as Bloodstream
    participant TT as Target Tissue (Vasoconstriction)
    
    HCP->>P: Inject N (IV)
    P->>B: N Circulate
    B->>N: N Recognize Target Ligands
    N->>TT: N Bind to TT
    TT->>N: Local Cues Trigger Release
    N->>TT: Release ERA-I & PDE5i
    TT->>P: Local Therapeutic Effect

5. The "Inverse" or Failure Mode

Derivative 6.9: Self-Neutralizing Oral Solution for Overdose Protection

  • Enabling Description: The pharmaceutical composition is an oral solution containing the compound of formula (I) and tadalafil, designed with an inherent self-neutralizing mechanism against accidental overdose. The solution includes a pH-sensitive polymeric excipient (e.g., Eudragit E PO) that, at an intentionally high, supra-therapeutic concentration of the active ingredients, undergoes a rapid precipitation or gelling transition at physiological gastric pH (1.5-3.5). This physical change significantly reduces the dissolution and absorption rates of the active principles, thereby limiting peak plasma concentrations and mitigating the severity of an overdose, while maintaining normal absorption kinetics at therapeutic doses.
stateDiagram-v2
    state "Therapeutic Dose" as Therapeutic
    state "Overdose Concentration" as Overdose
    state "Normal Absorption" as NormalAbs
    state "Rapid Precipitation/Gelling" as Precipitate
    state "Reduced Absorption" as ReducedAbs

    [*] --> Therapeutic
    [*] --> Overdose

    Therapeutic --> NormalAbs : Gastric pH (Normal Kinetics)
    Overdose --> Precipitate : Gastric pH (High Conc)
    Precipitate --> ReducedAbs : Limited Systemic Exposure
    NormalAbs --> [*]
    ReducedAbs --> [*]

Derivative 6.10: Composition with Built-in Bioavailability Switch for "Low-Power" Mode

  • Enabling Description: The pharmaceutical composition is an oral capsule containing micro-pellets of the compound of formula (I) and sildenafil. The micro-pellets are coated with a dual-layer polymer system. The inner layer is a pH-independent sustained-release coating, ensuring a baseline "low-power" therapeutic effect for mild vasoconstrictive conditions. The outer layer is a pH-sensitive, enzyme-cleavable coating (e.g., pectin or chitosan based) that, when exposed to specific dietary components (e.g., high fiber meal, specific fruit enzymes) or orally administered activating agent, rapidly degrades, allowing for an increased release rate and an augmented "full-power" therapeutic effect. This "bioavailability switch" allows patients to modulate the therapeutic intensity based on their symptoms or lifestyle without changing the prescribed dose.
flowchart TD
    A[Oral Capsule] --> B{Micro-Pellets (ERA-I/PDE5i)};
    B -- Dual-Layer Coating --> C[Inner: Sustained Release (Baseline)];
    B -- Dual-Layer Coating --> D[Outer: pH/Enzyme-Cleavable (Switch)];
    C --> E[Baseline "Low-Power" Effect];
    D -- Specific Dietary Component / Activating Agent --> F[Outer Coating Degrades];
    F --> G[Increased Release Rate];
    G --> H[Augmented "Full-Power" Effect];
    E & H --> I[Modulated Therapeutic Intensity];

Derivatives of Independent Claim 10: Method of Treatment

Claim 10: A method for the treatment of hypertension or pulmonary hypertension comprising administering to a patient in need thereof an effective amount of a compound of formula (I) (N-[4-(2-bromo-4-fluorophenyl)-5-(2-methoxyethoxy)-6-methylpyrimidin-2-yl]-2-methylpropan-2-sulfamide) as described in claim 1, in free or pharmaceutically acceptable salt form, in combination with at least one compound having PDE5-inhibitory properties, in free or pharmaceutically acceptable salt form.

1. Material & Component Substitution (Non-Pharmacological Adjuncts)

Derivative 10.1: Method with Dietary Intervention and Microbiome Modulation

  • Enabling Description: A method for treating hypertension or pulmonary hypertension involves administering the compound of formula (I) and tadalafil, in combination with a targeted dietary intervention focusing on low sodium, high potassium, and nitrate-rich foods (e.g., beetroot juice, leafy greens). Concurrently, the patient undergoes gut microbiome modulation via daily administration of specific probiotic strains (e.g., Lactobacillus plantarum, Bifidobacterium lactis) known to produce short-chain fatty acids (SCFAs) that have systemic vasodilatory and anti-inflammatory effects. This multi-pronged approach leverages synergistic physiological pathways to enhance the therapeutic efficacy of the drug combination and reduce the required drug dosage. Monitoring of gut microbiome composition and SCFAs levels provides personalized treatment adjustments.
graph TD
    A[Patient with HTN/PHN] --> B[Administer ERA-I & PDE5i];
    B --> C[Targeted Dietary Intervention];
    B --> D[Probiotic Administration];
    C --> E[Nitrate Intake / K+ / Low Na+];
    D --> F[Microbiome Modulation / SCFA Production];
    E & F --> G[Synergistic Vasodilation/Anti-inflammatory Effects];
    G --> H[Improved Therapeutic Outcome];

Derivative 10.2: Gene Therapy Co-Administration for Refractory Cases

  • Enabling Description: For patients with severe or refractory pulmonary hypertension, the method of treatment involves the systemic or localized pulmonary administration of an effective amount of the compound of formula (I) and sildenafil, co-administered with a gene therapy vector. This gene therapy vector (e.g., an adeno-associated virus, AAV) is designed to deliver a gene encoding an endothelial nitric oxide synthase (eNOS) isoform or a soluble guanylate cyclase (sGC) activator directly to the pulmonary endothelial cells. The combined pharmacological and genetic approach aims to restore endogenous nitric oxide production and cGMP signaling pathways, providing a more robust and sustained vasodilatory effect, thereby potentially reversing vascular remodeling in severe cases that are unresponsive to conventional therapy.
flowchart TD
    A[Refractory PHN Patient] --> B[Administer ERA-I & PDE5i];
    B --> C[Administer Gene Therapy Vector (e.g., AAV-eNOS)];
    C --> D[Target Pulmonary Endothelial Cells];
    D --> E[Increased eNOS Expression / sGC Activation];
    E --> F[Enhanced NO / cGMP Signaling];
    F --> G[Synergistic Vasodilation & Anti-Remodeling];
    G --> H[Long-term Disease Reversal];

2. Operational Parameter Expansion

Derivative 10.3: Chronotherapy Based on Individual Circadian Rhythm

  • Enabling Description: The method of treatment for hypertension or pulmonary hypertension involves administering the compound of formula (I) and tadalafil according to a personalized chronotherapeutic schedule. This schedule is determined by monitoring the patient's individual 24-hour blood pressure and heart rate variability patterns using ambulatory monitoring devices, identifying specific times of day when vasoconstrictive events or pressure surges are most prominent. The administration timing is adjusted (e.g., evening dosing for nocturnal hypertension, morning dosing for early-morning surges) to ensure peak drug concentrations coincide with these physiological risk windows, thereby maximizing therapeutic effect and minimizing side effects (e.g., morning hypotension). This approach uses AI algorithms to analyze long-term hemodynamic data and predict optimal dosing times.
sequenceDiagram
    participant P as Patient
    participant M as Ambulatory Monitor
    participant A as AI Algorithm
    participant HCP as Healthcare Provider

    P->>M: Wear M (24h BP/HR)
    M->>A: Transmit Data
    A->>A: Analyze Circadian Rhythms / Predict Surges
    A->>HCP: Recommend Personalized Dosing Schedule
    HCP->>P: Prescribe ERA-I & PDE5i (Chronotherapy)
    P->>P: Administer Drugs (Timed)
    P->>M: Monitor Response

Derivative 10.4: Acute Intrapulmonary Nebulized Delivery for Hypoxic Vasoconstriction

  • Enabling Description: A method for treating acute, severe pulmonary hypoxic vasoconstriction (e.g., in Acute Respiratory Distress Syndrome, ARDS, or high-altitude pulmonary edema) involves delivering an effective amount of the compound of formula (I) and sildenafil via nebulization directly into the lungs. The drugs are formulated as a stable, sterile, fine-particle aerosol for intrapulmonary deposition, ensuring high local concentrations in the pulmonary vasculature while minimizing systemic exposure and side effects. This method provides rapid onset of pulmonary vasodilation, improving ventilation-perfusion matching and oxygenation in acutely compromised patients. Dosing is guided by continuous monitoring of pulmonary artery pressure and arterial blood gases.
flowchart TD
    A[Acute Pulmonary Hypoxic Vasoconstriction] --> B{Nebulizer Device};
    B -- ERA-I & PDE5i Aerosol --> C[Intrapulmonary Deposition];
    C --> D[High Local Drug Concentration];
    D --> E[Rapid Pulmonary Vasodilation];
    E --> F[Improved V/Q Matching];
    F --> G[Enhanced Oxygenation];
    G --> H[Monitor PAP / ABG];
    H --> B;

3. Cross-Domain Application

Derivative 10.5: Cardiovascular Research in Human-on-a-Chip Systems

  • Enabling Description: A method for studying novel therapeutic combinations and vascular disease mechanisms involves treating advanced "human-on-a-chip" or "organ-on-a-chip" microfluidic platforms (e.g., lung-on-a-chip models with integrated pulmonary artery vasculature) with the compound of formula (I) and tadalafil. These microfluidic systems, engineered with living human endothelial cells, smooth muscle cells, and fibroblasts, mimic the physiological and pathological conditions of pulmonary hypertension, including vasoconstriction. The method uses the drug combination to assess its effects on vascular tone, endothelial function, and vascular remodeling at a micro-physiological scale, allowing for rapid screening of drug efficacy and toxicity, and elucidation of complex drug interactions in a controlled, high-throughput environment, reducing reliance on animal models.
graph TD
    A[Lung-on-a-Chip Model] --> B[Mimics PHN Vasculature];
    B -- Induce Vasoconstriction (e.g., Hypoxia, Cytokines) --> C[Pathological State];
    C --> D[Introduce ERA-I & PDE5i (Microfluidic Flow)];
    D --> E[Measure Vascular Tone / Endothelial Function];
    E --> F[Assess Vascular Remodeling Markers];
    F --> G[Drug Efficacy/Toxicity Data];
    G --> H[High-Throughput Screening];

Derivative 10.6: Enhancing Graft Patency in Vascular Tissue Engineering

  • Enabling Description: A method applied in vascular tissue engineering involves treating bioengineered vascular grafts or scaffold structures (e.g., synthetic arterial bypass grafts or decellularized matrix conduits) with the compound of formula (I) and sildenafil during their ex-vivo maturation phase or immediately prior to implantation. The grafts are perfused with a culture medium containing the optimal concentrations of the drug combination (e.g., macitentan at 50 nM, sildenafil at 500 nM). This treatment is intended to minimize post-implantation vasoconstriction, reduce intimal hyperplasia, improve endothelial cell alignment and function, and enhance long-term graft patency and integration by modulating intrinsic vascular tone and cellular proliferation pathways in the developing or implanted graft.
flowchart TD
    A[Bioengineered Vascular Graft] --> B{Ex-Vivo Maturation / Pre-Implantation};
    B --> C[Perfuse with Culture Medium];
    C -- Contains ERA-I & PDE5i --> D[Modulate Intrinsic Vascular Tone];
    D --> E[Reduce Intimal Hyperplasia];
    E --> F[Improve Endothelial Function];
    F --> G[Enhance Graft Patency];
    G --> H[Successful Implantation];

4. Integration with Emerging Tech

Derivative 10.7: Telemedicine-Guided Adaptive Dosing Protocol

  • Enabling Description: The method for treating hypertension or pulmonary hypertension utilizes a telemedicine platform to implement an adaptive dosing protocol for the compound of formula (I) and tadalafil. Patients remotely transmit daily blood pressure, heart rate, oxygen saturation, and activity levels (from connected health devices). A secure telemedicine portal, integrated with an AI-driven clinical decision support system, analyzes these data points against patient-specific therapeutic goals and predefined safety thresholds. Physicians, guided by the AI, can remotely adjust drug dosages or ratios, provide feedback, and schedule virtual consultations, optimizing treatment efficacy while minimizing clinic visits and enabling proactive management of the disease, especially for patients in remote areas.
sequenceDiagram
    participant P as Patient
    participant CH as Connected Health Devices
    participant TP as Telemedicine Platform
    participant AI as AI Decision Support
    participant D as Doctor

    P->>CH: Daily Physiological Monitoring
    CH->>TP: Transmit Data (Securely)
    TP->>AI: Send Patient Data
    AI->>AI: Analyze, Identify Trends, Suggest Adjustments
    AI->>D: Propose Dosing Changes/Alerts
    D->>TP: Review and Approve/Modify
    TP->>P: Send Dosing Instructions / Virtual Consult
    P->>P: Administer ERA-I & PDE5i (Adaptive Dose)

Derivative 10.8: AI-Enhanced Diagnostic and Treatment Stratification

  • Enabling Description: A method for the treatment of hypertension or pulmonary hypertension employs an AI-enhanced diagnostic system for early detection and personalized treatment stratification. This system processes diverse patient data inputs, including high-resolution medical imaging (e.g., cardiac MRI, pulmonary CT angiography processed via DICOM standard), genetic sequencing data, comprehensive biomarker panels (e.g., BNP, endothelin-1 levels), and electronic health record (EHR) data. The AI algorithm identifies subtle patterns indicative of early-stage disease and predicts individual patient response to specific therapeutic combinations. Based on this predictive model, the AI recommends the optimal starting doses, ratios, and administration schedule of the compound of formula (I) and sildenafil, stratifying patients into response groups and guiding the most effective treatment initiation.
flowchart TD
    A[Patient Data Input] --> B(Medical Imaging);
    A --> C(Genetic Data);
    A --> D(Biomarker Panels);
    A --> E(EHR Data);
    B & C & D & E --> F{AI Diagnostic System};
    F --> G[Early Disease Detection];
    F --> H[Predict Individual Response];
    H --> I[Optimal ERA-I & PDE5i Regimen Recommendation];
    I --> J[Personalized Treatment Stratification];

5. The "Inverse" or Failure Mode

Derivative 10.9: Adaptive Dosing with Continuous Physiological Feedback for Hypotension Prevention

  • Enabling Description: A method for treating hypertension or pulmonary hypertension involves administering the compound of formula (I) and tadalafil in an adaptive dosing regimen that dynamically responds to continuous physiological feedback to prevent excessive vasodilation and hypotension. Patients wear a non-invasive, continuous blood pressure monitor (e.g., finger cuff or optical sensor). A micro-controller, in communication with the monitor, autonomously adjusts the dose delivered by a smart pump or modifies the signal to a patient's smart pill dispenser. If blood pressure falls below a predefined safety threshold (e.g., systolic BP < 90 mmHg or a >20% drop from baseline), the system automatically reduces the next scheduled dose or initiates a temporary holding period for one or both drugs. Conversely, if pressure remains elevated, the system may suggest a dose increase within safe limits.
stateDiagram-v2
    state "Normal Treatment" as Normal
    state "Hypotension Risk" as Hypotension
    state "Dose Reduction Initiated" as ReduceDose
    state "Dose Hold Initiated" as HoldDose
    state "BP Stabilized" as Stabilized

    Normal --> Hypotension : BP < Threshold
    Hypotension --> ReduceDose : System Autonomously Acts
    Hypotension --> HoldDose : If severe BP drop
    ReduceDose --> Normal : BP Rises to Normal
    HoldDose --> Normal : BP Rises to Normal
    Normal --> Normal : Continuous Monitoring
    Stabilized --> Normal

Derivative 10.10: Self-Reversing Therapeutic Protocol for Acute Adverse Reactions

  • Enabling Description: A method for treating hypertension or pulmonary hypertension is designed with a self-reversing protocol in case of acute adverse reactions (e.g., severe headache, visual disturbances, or syncope related to over-vasodilation). Upon patient-reported severe symptoms or detection of critical physiological changes (e.g., via a wearable device), the treatment protocol instructs the patient (or an automated system) to immediately discontinue the PDE5 inhibitor (e.g., sildenafil), which typically has a shorter half-life. Concurrently, a pre-loaded, rapid-acting vasoconstrictor (e.g., a low dose of phenylephrine or midodrine) is administered or self-administered as a rescue medication. This allows for a rapid return to baseline vascular tone and mitigation of acute adverse effects, while the endothelin receptor antagonist (macitentan), with its longer half-life, continues to exert a baseline effect, preventing a complete rebound of vasoconstriction.
sequenceDiagram
    participant P as Patient
    participant W as Wearable Device
    participant S as Symptom/BP Monitor
    participant C as Control System
    participant DR as Drug Regimen (ERA-I/PDE5i)
    participant RM as Rescue Medication

    P->>S: Report Acute Symptom / BP Drop
    W->>C: Detect Critical Physiological Change
    C->>DR: Instruct Discontinue PDE5i (Short T1/2)
    C->>P: Instruct Self-Administer RM (Vasoconstrictor)
    DR->>P: ERA-I Continues (Long T1/2)
    RM->>P: Rapid Vascular Tone Restoration
    P->>P: Mitigate Acute Adverse Effects

Combination Prior Art Scenarios

  1. US8268847 + OpenEMR (Open-source Electronic Health Record System):

    • Scenario: The therapeutic compositions and methods of US8268847 (combining macitentan and a PDE5 inhibitor for vasoconstriction-involved diseases) are integrated into a clinical workflow managed by an open-source EHR system like OpenEMR. Patient demographics, diagnoses (e.g., pulmonary hypertension, systemic hypertension), prescription orders for the combination therapy, administration schedules (simultaneous, separate, or over time), and recorded treatment outcomes (e.g., blood pressure readings, symptom severity, quality of life metrics) are meticulously documented within OpenEMR. This integration enables standardized data collection, facilitates adherence to treatment protocols, and allows for population-level studies on the efficacy and safety of the combination therapy within a real-world clinical setting. Furthermore, the OpenEMR system could be extended with custom modules to track specific patient education related to the combination therapy or provide alerts for potential drug-drug interactions with other medications listed in the patient's record.
    graph TD
    A[Patient Admission/Diagnosis] --> B(OpenEMR System);
    B -- Record Dx (HTN/PHN) --> C[Prescription Module];
    C -- Order ERA-I + PDE5i Combo --> D[Pharmacy/Dispensing];
    D --> E[Patient Administration];
    E -- Record Outcome Data (BP, Sx) --> F[Clinical Notes/Tracking];
    F --> B;
    B -- Population Health Analysis --> G[Research/Efficacy Studies];

  2. US8268847 + HL7 (Health Level Seven International) Standards:

    • Scenario: The administration of therapeutic compositions described in US8268847 is facilitated by information exchange adhering to HL7 standards. For instance, a physician's electronic order for the combination product (macitentan + sildenafil for pulmonary hypertension) is transmitted from the EHR to the pharmacy system using an HL7 v2.x or FHIR (Fast Healthcare Interoperability Resources) message. This message precisely specifies the compound of formula (I), the chosen PDE5 inhibitor, dosage, route (e.g., oral), frequency (e.g., twice daily, as per simultaneous administration), and duration of treatment. Subsequently, patient progress notes, lab results (e.g., liver function tests, renal function, hemodynamic parameters), and adverse event reports related to the combination therapy are communicated between different healthcare IT systems (e.g., hospital EHR, specialist's office system) using HL7 compliant interfaces, ensuring semantic interoperability and data integrity across the continuum of care.
    sequenceDiagram
    participant EHR as EHR System
    participant PHS as Pharmacy System
    participant LIS as Lab Information System
    participant OCS as Other Clinic System

    EHR->>PHS: Order (ERA-I + PDE5i) [HL7 ORM]
    PHS->>EHR: Dispense Confirmation [HL7 ORR]
    PHS->>LIS: Drug-Lab Interaction Check [HL7 QRY]
    LIS->>EHR: Lab Results (LFTS, Hemodynamics) [HL7 ORU]
    EHR->>OCS: Patient Summary/Progress [HL7 ADT/CCD]
    OCS->>EHR: Update/Consultation Notes [HL7 MDM]

  3. US8268847 + DICOM (Digital Imaging and Communications in Medicine) Standard:

    • Scenario: The method of treatment described in US8268847 for pulmonary hypertension is critically guided by diagnostic imaging data standardized under DICOM. Before and during the treatment with the combination of macitentan and tadalafil, patients undergo cardiac MRI, CT pulmonary angiography, or echocardiography. The resulting imaging studies, including raw data, processed images, and quantitative measurements (e.g., right ventricular size and function, pulmonary artery diameter, pulmonary blood flow dynamics, mean pulmonary arterial pressure estimated from Doppler echocardiography), are stored and transmitted across different medical devices and workstations using the DICOM standard. This ensures consistent image quality, facilitates comparisons over time, and enables clinicians to precisely monitor disease progression and the efficacy of the combination therapy. AI-powered image analysis tools, also relying on DICOM data, can then quantify changes in vascular morphology and function in response to treatment.
    graph TD
    A[Patient with PHN] --> B(Medical Imaging Acquisition);
    B -- Cardiac MRI / CTPA / Echo --> C[DICOM Image Data];
    C --> D[DICOM Storage Server];
    D -- DICOM Query/Retrieve --> E[Radiologist Workstation];
    D -- DICOM Query/Retrieve --> F[Cardiologist Workstation];
    E & F --> G[Assess Disease Progression/Treatment Efficacy];
    G -- Inform Treatment Decisions --> H[Administer ERA-I & PDE5i];
    H --> A;

Generated 5/17/2026, 6:49:12 AM