# US 12,594,246 B2 · Formulations for enteric delivery of therapeutic agents > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,594,246 B2 - Document ID: US12594246B2 - Status: Granted - Kind: B2 - Application number: 17/958,815 - Filed: 2022-10-03 - Published: 2023-02-02 - Granted: 2026-04-07 - Earliest claimed: 2016-10-12 - Assignees: CuriOralRx, LLC - Applicants: CuriOralRx, LLC - Inventors: Indu Javeri; Kaliappanadar Nellaiappan - Web page: https://patentgrep.com/patent/US12594246B2 ## CPC - A61K 9/5161: {Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin} - A61K 9/5138: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates} - A61K 38/28: Insulins - A61K 39/39591: {Stabilisation, fragmentation} - A61P 3/10: for hyperglycaemia, e.g. antidiabetics - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61P 35/00: Antineoplastic agents - C07K 16/11: Paramyxoviridae (F); Pneumoviridae (F), e.g. respiratory syncytial virus [RSV] - C07K 16/241: {Tumor Necrosis Factors} - C07K 16/248: {IL-6} - C07K 16/2863: {against receptors for growth factors, growth regulators} - C07K 16/32: against translation products of oncogenes - A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)} - A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} - C07K 2317/21: from primates, e.g. man - C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## Abstract Formulations containing pH-sensitive nanoparticles for the enteric delivery of therapeutic agents are provided. The nanoparticles include a pH-sensitive polymer that protects the therapeutic agent against degradation in the stomach and allows it to be released in the small intestine or colon. The nanoparticle formulation is particularly effective at protecting sensitive biotherapeutic agents from degradation when administered orally, and makes it possible to avoid administration of such agents by injection. Also provided are methods for producing the formulations, as well as methods of treating diseases employing the formulations. ## Claims ### Claim 1 A method for orally administering a therapeutic agent, the method comprising providing a formulation comprising the therapeutic agent, and orally administering the formulation to a subject in need thereof, wherein the formulation comprises a plurality of nanoparticles, the nanoparticles comprising a pH-sensitive polymer and a therapeutic agent or a combination of therapeutic agents, the therapeutic agent having a molecular weight from about 1000 to about 10000 Daltons, wherein the polymer is insoluble at acidic pH and soluble at neutral or alkaline pH and wherein the pH-sensitive polymer is selected from the group consisting of a copolymer of methacrylic acid and an acrylic or methacrylic ester, methacrylic acid-methylmethacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, a cellulose derivative, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and combinations thereof; wherein a suspension of the nanoparticles is made by a process comprising dissolving the therapeutic agent and suspending the pH-sensitive polymer in an aqueous medium in which the therapeutic agent is soluble and associating the dissolved therapeutic agent and the suspended pH-sensitive polymer in the aqueous medium by adjusting the pH between about 5.5 and about 8 so as to form nanoparticles having a mean particle size of 50 nm or less with mixing alone and without the use of sonication, heat, or any other input of external energy; wherein the therapeutic agent and pH-sensitive polymer do not dissociate from the nanoparticles at acidic pH, with the proviso that the nanoparticles do not contain two different polymers, one polymer present in a core structure and the other polymer present in a shell structure and associated with the therapeutic agent. ### Claim 2 (depends on 1) The method of claim 1, wherein the therapeutic agent is a selected from the group consisting of peptides, proteins, anti-infectious agents, nucleic acids, and enzyme inhibitors. ### Claim 3 (depends on 2) The method of claim 2, wherein the therapeutic agent is a peptide selected from the group consisting of peptide hormones, glucagon-like peptide-1 receptor agonists, analgesic peptides, anesthetic peptides, enkephalin, anti-inflammatory peptides, protease inhibitors, calcitonin, gonadotropin-releasing hormone, and telavancin. ### Claim 4 (depends on 2) The method of claim 2, wherein therapeutic agent is a protein selected from the group consisting of insulin, glucagon, anti-VEGF agents, interferons, cytokines, calcitonin, gonadotropin-releasing hormone, anti-infectious proteins, interferons, anti-TNF alpha agents, and enzymes. ### Claim 5 (depends on 2) The method of claim 2, wherein the therapeutic agent is a nucleic acid selected from the group consisting of aptamers, small interfering RNAs, antisense oligonucleotides, and nucleic acids for gene editing and gene therapy. ### Claim 6 (depends on 1) The method of claim 1, wherein the formulation is lyophilized, suspended in an aqueous medium, a lyophilized powder mixed with juice or a dairy product, in capsule form, or in tablet form. ### Claim 7 A method for orally administering a therapeutic agent, the method comprising providing a formulation comprising the therapeutic agent, and orally administering the formulation to a subject in need thereof, wherein the formulation comprises a plurality of nanoparticles, the nanoparticles comprising a pH-sensitive polymer and a therapeutic agent or combination of therapeutic agents, and wherein the polymer is insoluble at acidic pH and soluble at neutral or alkaline pH, the pH-sensitive polymer is selected from the group consisting of a copolymer of methacrylic acid and an acrylic or methacrylic ester, methacrylic acid-methylmethacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, a cellulose derivative, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and combinations thereof, and the therapeutic agent has a molecular weight of more than 10000 Daltons; wherein a suspension of the nanoparticles is made by a process comprising dissolving the therapeutic agent and suspending the pH-sensitive polymer in an aqueous medium in which the therapeutic agent is soluble and associating the dissolved therapeutic agent and the suspended pH-sensitive polymer in the aqueous medium by adjusting the pH between about 5.5 and about 8 so as to form nanoparticles having a mean particle size of 100 nm or less with mixing alone and without the use of sonication, heat, or any other input of external energy; wherein the therapeutic agent and pH-sensitive polymer do not dissociate from the nanoparticles at acidic pH, with the proviso that the nanoparticles do not contain two different polymers, one polymer present in a core structure and the other polymer present in a shell structure and associated with the therapeutic agent. ### Claim 8 (depends on 7) The method of claim 7, wherein the therapeutic agent is selected from the group consisting of proteins, antibodies, enzymes, vaccines, and viral vectors. ### Claim 9 (depends on 7) The method of claim 7, wherein the therapeutic agent is a protein selected from the group consisting of anti-infectious agents, interferons, interleukins, anti-tumor agents, and anti-TNF alpha agents. ### Claim 10 (depends on 7) The method of claim 7, wherein the therapeutic agent is an antibody selected from the group consisting of monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, recombinant antibodies, diabodies, triabodies, minibodies, nanobodies, single-domain antibodies, scFv, antibody fusion proteins, and anti-tumor antibodies. ### Claim 11 (depends on 7) The method of claim 7, wherein the therapeutic agent is an antibody selected from the group consisting of anti-EGFR, anti-Her2, anti-RSV, anti-interleukin, anti-TNF, cetuximab, trastuzumab, palivizumab, tocilizumab, and adalimumab. ### Claim 12 (depends on 7) The method of claim 7, wherein the therapeutic agent is a viral vector selected from the group consisting of adenoviral vectors and lentiviral vectors. ### Claim 13 (depends on 7) The method of claim 7, wherein the formulation is lyophilized, suspended in an aqueous medium, lyophilized powder mixed with juice or a dairy product, in capsule form, or in tablet form.