# US 11,077,056 B2 · Residence structures and related methods

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- Number: US 11,077,056 B2
- Document ID: US11077056B2
- Status: Granted
- Kind: B2
- Application number: 17/126,786
- Filed: 2020-12-18
- Published: 2021-04-22
- Granted: 2021-08-03
- Earliest claimed: 2014-06-11
- Assignees: Massachusetts Institute of Technology; The Brigham and Women's Hospital, Inc.
- Applicants: Massachusetts Institute of Technology; The Brigham and Women's Hospital, Inc.
- Inventors: Andrew Bellinger; Shiyi Zhang; Carlo Giovanni Traverso; Robert S. Langer; Stacy Mo; Tyler Grant; Mousa Jafari; Dean Liang Glettig; Angela DiCiccio; Lowell L. Wood, Jr.; Philip A. Eckhoff
- Web page: https://patentgrep.com/patent/US11077056B2

## CPC

- A61K 9/0065: {Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 31/357: having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K 31/65: Tetracyclines
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone}
- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61K 47/40: Cyclodextrins; Derivatives thereof
- A61K 47/42: Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34)
- A61K 47/58: obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K 47/6901: {Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors}
- A61M 31/002: {Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time (artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50)}
- C08G 18/4277: {Caprolactone and/or substituted caprolactone}
- C08G 18/73: acyclic
- C08G 63/08: Lactones or lactides
- C08G 83/006: {After treatment of hyperbranched macromolecules}
- C08L 33/02: Homopolymers or copolymers of acids; Metal or ammonium salts thereof
- C08L 33/08: Homopolymers or copolymers of acrylic acid esters
- C08L 33/14: of esters containing halogen, nitrogen, sulfur, or oxygen atoms in addition to the carboxy oxygen
- C08G 2230/00: Compositions for preparing biodegradable polymers
- C08L 2203/02: for biomedical use
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Residence structures, systems, and related methods are generally provided. Certain embodiments comprise administering (e.g., orally) a residence structure to a subject (e.g., a patient) such that the residence structure is retained at a location internal to the subject for a particular amount of time (e.g., at least about 24 hours) before being released. The residence structure may be, in some cases, a gastric residence structure. In some embodiments, the structures and systems described herein comprise one or more materials configured for high levels of active substances (e.g., a therapeutic agent) loading, high active substance and/or structure stability in acidic environments, mechanical flexibility and strength in an internal orifice (e.g., gastric cavity), easy passage through the GI tract until delivery to at a desired internal orifice (e.g., gastric cavity), and/or rapid dissolution/degradation in a physiological environment (e.g., intestinal environment) and/or in response to a chemical stimulant (e.g., ingestion of a solution that induces rapid dissolution/degradation). In certain embodiments, the structure has a modular design, combining a material configured for controlled release of therapeutic, diagnostic, and/or enhancement agents with a structural material necessary for gastric residence but configured for controlled and/or tunable degradation/dissolution to determine the time at which retention shape integrity is lost and the structure passes out of the gastric cavity. For example, in certain embodiments, the residence structure comprises a first elastic component, a second component configured to release an active substance (e.g., a therapeutic agent), and, optionally, a linker. In some such embodiments, the linker may be configured to degrade such that the residence structure breaks apart and is released from the location internally of the subject after a predetermined amount of time.

## Claims

### Claim 1

A gastric residence system, comprising:
one or more arms comprising a first polymeric component, wherein the first polymeric component comprises an active substance or salt thereof,
a second polymeric component; and
a linker component, said linker coupling the one or more arms with the second polymeric component;
wherein the system is configured to be folded and physically constrained during administration and is configured to assume an open retention shape upon removal of a constraint, wherein change between the folded shape and the open retention shape is mediated by the second polymeric component that undergoes elastic deformation when the residence system is in the folded shape and recoils when the gastric residence system assumes the open retention shape,
wherein the system is configured such that it is retained at the location internally of a subject for at least about 24 hours in the open retention shape, and
wherein the system releases between about 0.05 wt % and about 50 wt % of the active substance during the first day of release.

### Claim 2 (depends on 1)

A gastric residence system as in claim 1, wherein the system releases between about 0.05 wt % and about 30 wt % of the active substance during the first day of release.

### Claim 3 (depends on 1)

A gastric residence system as in claim 1, wherein the gastric residence system releases less than 20 wt % of the active substance during the first 6 hours of release.

### Claim 4 (depends on 1)

A gastric residence system as in claim 1, wherein the second polymeric component is free of active substance.

### Claim 5 (depends on 1)

A gastric residence system as in claim 1, wherein the first polymeric component comprises at least 10 wt % active substance of the total weight of the first polymeric component.

### Claim 6 (depends on 1)

A gastric residence system as in claim 1, wherein the linker component comprises an enteric polymer.

### Claim 7 (depends on 1)

A gastric residence system as in claim 1, wherein the gastric residence system is retained in the stomach for at least about 1 week.

### Claim 8 (depends on 1)

A gastric residence system as in claim 1, wherein the gastric residence system can be retained in the stomach for at least about 48 hours in the open retention shape.

### Claim 9 (depends on 1)

A gastric residence system as in claim 1 wherein the linker component, after at least about 48 hours, degrades, dissolves, disassociates, and/or mechanically weakens in the gastric environment under gastrointestinal physiological conditions which results in loss of the open retention shape and passage of the gastric residence system out of the stomach through the gastric pyloric orifice.

### Claim 10 (depends on 1)

A gastric residence system as in claim 1, wherein the active substance is a biological macromolecule, a small molecule, a vitamin, or a supplement.

### Claim 11 (depends on 1)

A gastric residence system as in claim 1, wherein the active substance is a selective serotonin reuptake inhibitor, a blood thinning agent, a steroid, an antagonist, a cardiac glycoside, an alpha blocker, a cholesterol absorption inhibitor, a metabolite, an antihistamine, an opioid, a proton-pump inhibitor, an antibiotic, an anti-malarial agent, sulfonamides, a substance abuse treatment, a contraceptive, a stimulant, an analgesic, an anti-analgesic, an anti-inflammatory drug, a nonsteroidal anti-inflammatory drug, an antipyretic, an immunosuppressant, a neuroprotective agent, an antipsychotic, a statin, an antidepressant, an antiepileptic, an anti-proliferative, an anti-cancer agent, an antimigraine drug, an antimicrobial, an antifungal, an antiviral agent, an antiretroviral agent, an antiparasitic, an antimuscarinic, an anxiolytic, a bacteriostatic, a sedative, a hypnotic, a bronchodilator, an anti-asthma drug, a cardiovascular drug, an anesthetic, an anti-coagulant, a dopaminergic, an electrolyte, a gastro-intestinal drug, a muscle relaxant, a parasympathomimetic, an anorectic, an anti-narcoleptic, a protein, a peptide, a hormone, a nucleic acid, a gene construct, 3-hydroxy-3-methyl-glutaryl (HMG) co-A reductase inhibitor, a mineral, a prostaglandin, a nutritional supplement, a corticosteroid, a nutraceutical, a plant extract, or a phytohormone.

### Claim 12 (depends on 1)

A gastric residence system as in claim 1, wherein the active substance is a selective serotonin reuptake inhibitor, an antidepressant, an anxiolytic, a sedative, a hypnotic, an opioid, an antimigraine drug, a cholesterol absorption inhibitor, a substance abuse treatment, an immunosuppressant, an HMG co-A reductase inhibitor, a blood thinning agent, a cardiac glycoside, an antibiotic, a contraceptive, an analgesic, an anesthetic, a nonsteroidal anti-inflammatory drug, an antiepileptic, or an alpha blocker.

### Claim 13 (depends on 1)

A gastric residence system as in claim 1, wherein the active substance is meloxicam, escitalopram, clopidogrel, prasugrel, prednisone, naloxone, montelukast, digoxin, tamsulosin, ezetimibe, colchicine, loratadine, cetirizine, loperamide, omeprazole, entecavir, ciprofloxacin, azithromycin, quinine, lumefantrine, chloroquine, amodiaquine, pyrimethamine, proguanil, chlorproguanil-dapsone, sulfadoxine, sulfamethoxypyridazine, mefloquine, atovaquone, primaquine, halofantrine, clindamycin, artemisinin, artemisinin derivatives, artemether, dihydroartemisinin, arteether, artesunate, synthroid/levothyroxine, varenicline, risperidone, memantine, methadone, rosuvastatin, doxycycline, buprenorphine, aripiprazole, caffeine, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, or vitamin D.

### Claim 14 (depends on 1)

A gastric residence system as in claim 1, wherein the active substance is prednisone, risperidone, memantine, methadone, rosuvastatin, doxycycline, buprenorphine, aripiprazole, meloxicam, or azithromycin.

### Claim 15 (depends on 1)

A gastric residence system as in claim 1, wherein the active substance is chemically bonded to a polymer of the first polymeric component.

### Claim 16 (depends on 1)

A gastric residence system as in claim 1, wherein the first polymeric component comprises polycaprolactone (PCL).

### Claim 17 (depends on 1)

A gastric residence system as in claim 1, wherein the first polymeric component comprises, poly(ethylene-co-vinyl acetate), or polyethylene glycol (PEG).

### Claim 18 (depends on 1)

A gastric residence system as in claim 1, wherein the active substance is loaded into the first polymeric component by a process comprising powder mixing, solvent loading, melt loading, or physical blending.

### Claim 19 (depends on 1)

A gastric residence system as in claim 1, wherein the open retention shape is selected from the groups consisting of square, circle, oval, polygon, tubes, rings, and star or star-like/stellate.

### Claim 20 (depends on 1)

A gastric residence system as in claim 1, comprising three or more arms comprising the first polymeric component.

### Claim 21 (depends on 1)

A gastric residence system as in claim 1, comprising a plurality of active substances.

### Claim 22 (depends on 1)

A gastric residence system as in claim 1, wherein the first polymeric component comprises the active substance or salt thereof entrapped within a polymer matrix.

### Claim 23 (depends on 1)

A gastric residence system as in claim 1, wherein the subject is a human.

### Claim 24

A gastric residence system, comprising:
a first polymeric component; and
an active substance or a salt thereof present within the first polymeric component; wherein:
as measured using simulated gastric fluid, the active substance or salt thereof is released from the first polymeric component on a fifth day of release at a rate of at least about 1% of an initial average rate; and
at least about 0.05 wt % of the active substance or salt thereof is released during the second day of release;
at least about 0.05 wt % of the active substance or salt thereof is released during the fifth day of release; and
the gastric residence-system is configured to be folded and physically constrained during administration and is configured to assume an open retention shape upon removal of a constraint, wherein change between the folded shape and the open retention shape is mediated by a second polymeric component that undergoes elastic deformation when the residence system is in the folded shape and recoils when the gastric residence system assumes the open retention shape.

### Claim 25 (depends on 24)

A gastric residence system as in claim 24, wherein at least about 5 wt % of the active substance or salt thereof is released during the second day of release.

### Claim 26 (depends on 24)

A gastric residence system as in claim 24, wherein at least about 5 wt % of the active substance or salt thereof is released during the fifth day of release.

### Claim 27 (depends on 24)

A gastric residence system as in claim 24, wherein the active substance or salt thereof is released from the first polymeric component on the fifth day of release at a rate of at least about 2% of the initial average rate.

### Claim 28 (depends on 24)

A gastric residence system as in claim 24, wherein at least about 5 wt % of the active substance is released within five days of initial release.

### Claim 29 (depends on 24)

A gastric residence system as in claim 24, wherein the active substance is an antiviral.

### Claim 30 (depends on 24)

A gastric residence system as in claim 24, wherein the second polymeric component is free of active substance.

### Claim 31 (depends on 24)

A gastric residence system as in claim 24, wherein the first polymeric component comprises at least 10 wt % active substance of the total weight of the first polymeric component.

### Claim 32 (depends on 24)

A gastric residence system as in claim 24, further comprising at least one degradable linker coupled to the first polymeric component.

### Claim 33 (depends on 32)

A gastric residence system as in claim 32, wherein the at least one degradable linker, after at least about 48 hours, degrades, dissolves, disassociates, and/or mechanically weakens in the gastric environment under gastrointestinal physiological conditions which results in loss of the open retention shape and passage of the residence system out of the stomach through the gastric pyloric orifice.

### Claim 34 (depends on 32)

A gastric residence system as in claim 32, wherein the at least one degradable linker comprises an enteric polymer.

### Claim 35 (depends on 24)

A gastric residence system as in claim 24, wherein the gastric residence system is retained in the stomach for at least about 1 week.

### Claim 36 (depends on 24)

A gastric residence system as in claim 24, wherein the gastric residence system can be retained in the stomach for at least about 48 hours in the open retention shape.

### Claim 37 (depends on 24)

A gastric residence system as in claim 24, wherein the active substance is a biological macromolecule, a small molecule, a vitamin, or a supplement.

### Claim 38 (depends on 24)

A gastric residence system as in claim 24, wherein the active substance is a selective serotonin reuptake inhibitor, a blood thinning agent, a steroid, an antagonist, a cardiac glycoside, an alpha blocker, a cholesterol absorption inhibitor, a metabolite, an antihistamine, an opioid, a proton-pump inhibitor, an antibiotic, an anti-malarial agent, sulfonamides, a substance abuse treatment, a contraceptive, a stimulant, an analgesic, an anti-analgesic, an anti-inflammatory drug, a nonsteroidal anti-inflammatory drug, an antipyretic, an immunosuppressant, a neuroprotective agent, an antipsychotic, a statin, an antidepressant, an antiepileptic, an anti-proliferative, an anti-cancer agent, an antimigraine drug, an antimicrobial, an antifungal, an antiviral agent, an antiretroviral agent, an antiparasitic, an antimuscarinic, an anxiolytic, a bacteriostatic, a sedative, a hypnotic, a bronchodilator, an anti-asthma drug, a cardiovascular drug, an anesthetic, an anti-coagulant, a dopaminergic, an electrolyte, a gastro-intestinal drug, a muscle relaxant, a parasympathomimetic, an anorectic, an anti-narcoleptic, a protein, a peptide, a hormone, a nucleic acid, a gene construct, 3-hydroxy-3-methyl-glutaryl (HMG) co-A reductase inhibitor, a mineral, a prostaglandin, a nutritional supplement, a corticosteroid, a nutraceutical, a plant extract, or a phytohormone.

### Claim 39 (depends on 24)

A gastric residence system as in claim 24, wherein the active substance is a selective serotonin reuptake inhibitor, an antidepressant, an anxiolytic, a sedative, a hypnotic, an opioid, an antimigraine drug, a cholesterol absorption inhibitor, a substance abuse treatment, an immunosuppressant, an HMG co-A reductase inhibitor, a blood thinning agent, a cardiac glycoside, an antibiotic, a contraceptive, an analgesic, an anesthetic, a nonsteroidal anti-inflammatory drug, an antiepileptic, or an alpha blocker.

### Claim 40 (depends on 24)

A gastric residence system as in claim 24, wherein the active substance is meloxicam, escitalopram, clopidogrel, prasugrel, prednisone, naloxone, montelukast, digoxin, tamsulosin, ezetimibe, colchicine, loratadine, cetirizine, loperamide, omeprazole, entecavir, ciprofloxacin, azithromycin, quinine, lumefantrine, chloroquine, amodiaquine, pyrimethamine, proguanil, chlorproguanil-dapsone, sulfadoxine, sulfamethoxypyridazine, mefloquine, atovaquone, primaquine, halofantrine, clindamycin, artemisinin, artemisinin derivatives, artemether, dihydroartemisinin, arteether, artesunate, synthroid/levothyroxine, varenicline, risperidone, memantine, methadone, rosuvastatin, doxycycline, buprenorphine, aripiprazole, caffeine, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, or vitamin D.

### Claim 41 (depends on 24)

A gastric residence system as in claim 24, wherein the active substance is prednisone, risperidone, memantine, methadone, rosuvastatin, doxycycline, buprenorphine, aripiprazole, meloxicam, or azithromycin.

### Claim 42 (depends on 24)

A gastric residence system as in claim 24, wherein the active substance is chemically bonded to a polymer of the first polymeric component.

### Claim 43 (depends on 24)

A gastric residence system as in claim 24, wherein the first polymeric component comprises polycaprolactone (PCL).

### Claim 44 (depends on 24)

A gastric residence system as in claim 24, wherein the first polymeric component comprises, poly(ethylene-co-vinyl acetate), or polyethylene glycol (PEG).

### Claim 45 (depends on 24)

A gastric residence system as in claim 24, wherein the active substance is loaded into the first polymeric component by a process comprising powder mixing, solvent loading, melt loading, or physical blending.

### Claim 46 (depends on 24)

A gastric residence system as in claim 24, wherein the first polymeric component comprises the active substance entrapped within a polymer matrix.

### Claim 47 (depends on 24)

A gastric residence system as in claim 24, wherein the gastric residence system is configured such that it is retained at the location internally of the subject for at least about 24 hours in the open retention shape.