Lymphatic system-directing lipid prodrugs
Inventors
Bonner, Daniel Kenneth • Karanam, Ketki • Mutamba, James T. • Shyam, Rishab R. • Simpson, Jamie • Han, Sifei • Hu, Luojuan • Porter, Christopher John Hamilton • Quach, Tim • Trevaskis, Natalie
Assignees
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Publication Number
US-11883497-B2
Publication Date
2024-01-30
Expiration Date
Abstract
The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.
Core Innovation
The disclosure describes lipid prodrug compounds and lymphatic system-directing lipid prodrugs based on glycerol or modified-glyceride moieties. A therapeutic agent A is linked through a cleavable, self-immolative group M and a lipid linker L, and the structures are defined to direct therapeutic agents via lymphatic transport and to support release of the parent drug after lymphatic delivery.
The disclosure addresses improving oral delivery, reducing first-pass metabolism and toxicity, improving release of the parent drug after lymphatic delivery, and enhanced lymphatic transport. It also frames lymphatic transport outcomes in connection with mesenteric lymph nodes and concentration behavior in animal contexts, and includes discussion of intestinal lymph transport and release in lymph/tissues associated with lipase.
The document further describes broad structural definitions for linker moieties, self-immolative groups, and formula-based compounds, including acid-triglyceride linkages, self-immolative linkers such as ASI, CM-SI, trimethyl lock, p-hydroxybenzyl carbonyl, flipped-ester self-immolative FSI, and additional formula depictions. It also includes lipid prodrug constructs, pharmaceutically acceptable salts, and pharmaceutical compositions with pharmaceutically acceptable carriers, adjuvants, or vehicles.
The disclosure additionally includes combination therapy contexts for lipid prodrugs, including obstructive or inflammatory airway diseases with anti-inflammatory, bronchodilatory, antihistamine, and anti-tussive drugs, and radiosensitizer use for tumors and radiotherapy. It also presents specific prodrug embodiments and exemplified structures for mycophenolic acid, tacrolimus, cannabidiol, and buprenorphine, together with labeled formula variations and metal-free click chemistry moieties.
Claims Coverage
The consolidated claim coverage centers on one independent claim directed to a compound of Formula X-b, with dependent claims refining substituent definitions and specifying particular therapeutic-agent selections and pharmaceutical compositions. Across the provided items, the recurring inventive framework is a therapeutic-agent substituted lipid prodrug scaffold defined by R1, R2, R3, R4, and A, and in some descriptions by a self-immolative group M and a linker framework L.
Therapeutic-agent substituted compound of Formula X-b
A compound of Formula X-b wherein R1 and R2 are each independently hydrogen or —C(O)R3, each R3 is independently a saturated or unsaturated, straight or branched, optionally substituted C1-37 hydrocarbon chain, each R4 is independently hydrogen or a C1-6 aliphatic group, and A is a therapeutic agent.
Both R1 and R2 as —C(O)R3
The compound wherein R1 and R2 each independently equal —C(O)R3.
R3 limited to saturated or unsaturated unbranched C2-37 hydrocarbon chain
The compound wherein each R3 independently is a saturated or unsaturated, unbranched C2-37 hydrocarbon chain.
R4 methyl and hydrogen pattern
The compound wherein among substituents labeled R4, one is methyl and another is hydrogen.
Therapeutic agent selected from named therapeutics
The compound wherein A is selected from testosterone, mycophenolic acid (MPA), buprenorphine, tetrahydrocannabinol (THC), cannabidiol, celecoxib, or dexamethasone.
Self-immolative linker group incorporated into a therapeutic-agent compound
The compound includes -M-, where -M- is a self-immolative group, and A is a therapeutic agent.
Pharmaceutical composition with pharmaceutically acceptable carrier, adjuvant, or vehicle
A pharmaceutical composition comprising the compound together with a pharmaceutically acceptable carrier, adjuvant, or vehicle.
Overall, the claims cover Formula X-b compounds with substituent-controlled R1/R2/R3/R4 features, therapeutic-agent moiety A, and in some descriptions a self-immolative group M and lipid-linker framework. Dependent claims narrow the substituent patterns, specify named therapeutic-agent options, and extend the coverage to pharmaceutical compositions including a pharmaceutically acceptable carrier, adjuvant, or vehicle.
Stated Advantages
Mimics human lipid processing.
Lipid attachment to the therapeutic agent enhances lipophilicity.
Lipid attachment enables lymphatic uptake.
Enhanced lymphatic transport.
Improved oral bioavailability.
Reduced first-pass metabolism and toxicity.
Improved release of the parent drug after lymphatic delivery.
Documented Applications
Lymphatic drug-release context for attaching therapeutic agents to a lymphatic drug-release moiety using metal-free click chemistry.
Therapeutic agents associated with autoimmune diseases and transplant rejection.
Combination therapy for obstructive or inflammatory airway diseases using lipid prodrugs with anti-inflammatory, bronchodilatory, antihistamine, and anti-tussive drugs.
Radiosensitizer use of lipid prodrugs for tumors and radiotherapy.
Treatment methods involving administering the lymphatic system-directing lipid prodrug or a composition thereof.
Use of specific prodrug examples for mycophenolic acid, including mycophenolate mofetil, and tacrolimus, with lymphatic transport and release described in connection with mesenteric lymph nodes and concentration behavior in rat and mouse contexts.
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