# US 2021/0330798 A1 · Treatment of infections

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- Number: US 2021/0330798 A1
- Document ID: US20210330798A1
- Status: Published application
- Kind: A1
- Application number: 17/280,774
- Filed: 2019-09-25
- Published: 2021-10-28
- Earliest claimed: 2018-09-26
- Assignees: Ascendis Pharma A/S
- Applicants: Ascendis Pharma A/S
- Inventors: Kennett SPROGØE; Sebastian STARK; Tobias VOIGT; Lars HOLTEN-ANDERSEN; Nicola BISEK
- Web page: https://patentgrep.com/patent/US20210330798A1

## CPC

- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 9/0007: {Effervescent (A61K9/0065 takes precedence)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0024: {Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue (compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L)}
- A61K 31/06: the aromatic ring being substituted by nitro groups
- A61K 31/74: Synthetic polymeric materials
- A61K 31/765: Polymers containing oxygen
- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 47/645: {Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT}
- A61K 47/6903: {the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel}
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 31/04: Antibacterial agents
- 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

## Abstract

The present invention relates among other aspects to a conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use in a method of preventing or treating an infection, wherein said conjugate is water-insoluble and comprises a polymeric moiety —Z to which a plurality of moieties -L2-X0D-L1-D are covalently conjugated, wherein each -D is independently an antibiotic moiety; each -L1- is independently a linker moiety to which -D is covalently and reversibly conjugated; each —X0D— is independently absent or a linkage and each -L2- is independently either a chemical bond or a spacer moiety.

## Claims

### Claim 1

A conjugate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use in a method of preventing or treating an infection, wherein said conjugate is water-insoluble and comprises a polymeric moiety —Z to which a plurality of moieties -L2-X0D-L1-D are covalently conjugated,
wherein
each -D is independently an antibiotic moiety;
each -L1- is independently a linker moiety to which -D is covalently and reversibly conjugated;
each —X0D— is independently absent or a linkage; and
each -L2- is independently absent or a spacer moiety.

### Claim 2 (depends on 1)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt of claim 1, wherein the infection is an infection in a body compartment.

### Claim 3 (depends on 1, 2)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt of claim 1 or 2, wherein the infection is a joint infection.

### Claim 4 (depends on 1, 2, 3)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of any one of claims 1 to 3, wherein the infection is an infection related to a surgical implant.

### Claim 5 (depends on 4)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of claim 4, wherein the surgical implant is selected from the group consisting of pins, rods, screws, artificial joints, mesh, clips, sutures, wires, tubes, catheters, pumps, filters, prostheses, plates, fasteners, washers, bolts, seeds, beads, staples, nails, shunts, cuffs, buttons, ports, cement, fixators, stents, fillers, wax, wraps, weights, stimulators, anchors, expanders, guidewires, fillers, polymers, film, fixators, drains, lines and cones.

### Claim 6 (depends on 4, 5)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of claim 4 or 5, wherein the surgical implant is an artificial joint.

### Claim 7 (depends on 3, 4, 5, 6)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of any one of claims 3 to 6, wherein administration occurs via intraarticular injection into the infected joint.

### Claim 8 (depends on 3, 4, 5, 6, 7)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of any one of claims 3 to 7, wherein the infected joint is a synovial joint.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7, 8)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of any one of claims 1 to 8, wherein the method of preventing or treating a joint infection also comprises the step of preventing the formation of a biofilm or eradicating an existing biofilm.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of any one of claims 1 to 9, wherein —Z is a hydrogel.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of any one of claims 1 to 10, wherein —Z is degradable.

### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of any one of claims 1 to 10, wherein —Z is a hyaluronic acid-based or PEG-based hydrogel.

### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of any one of claims 1 to 12, wherein each -D is independently selected from the group consisting of aminoglycosides, tetracycline antibiotics, amphenicols, pleuromutilins, macrolid antibiotics, lincosamides, steroid antibiotics, antifolate antibiotics, sulfonamides, topoisomerase inhibitors, quinolones, fluoroquinolones, nitroimidazole antibiotics, nitrofuran antibiotics, rifamycins, glycopeptides, penicillins, cephalosporins, monobactams, beta-lactamase inhibitors, polymyxin antibiotics, lipopeptide antibiotics, oxazolidinon, antimicrobial peptides, porphyrins, azole antifungals, polyenes, antiprotozoal drugs, fosfomycin, cycloserine, and bacitracin.

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of any one of claims 1 to 13, wherein -D is daptomycin.

### Claim 15 (depends on 14)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of claim 14, wherein -L1- is connected via the primary amine of the ornithine side chain.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)

The conjugate or the pharmaceutically acceptable salt thereof or the pharmaceutical composition comprising said conjugate or its pharmaceutically acceptable salt for use of any one of claims 1 to 15, wherein -L1- is of formula (II):
wherein the dashed line indicates the attachment to a nitrogen, hydroxyl or thiol of -D;
—X— is selected from the group consisting of —C(R4R4a)—, —N(R4)—, —O—, —C(R4R4a)—C(R5R5a)—, —C(R5R5a)—C(R4R4a)—, —C(R4R4a)—N(R6)—, —N(R6)—C(R4R4a)—, —C(R4R4a)—O—, —O—C(R4R4a)—, and —C(R7R7a)—;
X1 is selected from the group consisting of C and S(O);
—X2— is selected from the group consisting of —C(R8R8a)— and —C(R8R8a)—C(R9R9a);
═X3 is selected from the group consisting of ═O, ═S, and ═N—CN;
—R1, —R1a, —R2, —R2a, —R4, —R4a, —R, —R, —R6, —R8, —R8a, —R9 and —R9a are independently selected from the group consisting of —H and C1-6 alkyl;
—R3 and —R3a are independently selected from the group consisting of —H and C1-6 alkyl, provided that in case one of —R3 and —R3a or both are other than —H, they are connected to the nitrogen atom to which they are attached through an sp3-hybridized carbon atom;
—R7 is selected from the group consisting of —N(R10R10a) and —NR10—(C═O)—R11;
—R7a, —R10, —R10a and —R11 are independently of each other selected from the group consisting of —H and C1-6 alkyl;
alternatively, one or more of the pairs -R1a/—R4a, —R1a/—R5a, —R1a/—R7a, —R4a/—R5a and —R8a/—R9a form a chemical bond;
alternatively, one or more of the pairs -R1/—R1a, —R2/—R2a, —R4/—R4a, —R5/—R5a, —R8/—R8a and —R9/—R9a are joined together with the atom to which they are attached to form a C3-10 cycloalkyl or 3- to 10-membered heterocyclyl;
alternatively, one or more of the pairs —R1/—R4, —R1/—R5, —R1/—R6, —R1/—R7a, —R4/—R5, —R4/—R6, —R8/—R9 and —R2/—R3 are joined together with the atoms to which they are attached to form a ring A;
alternatively, R3/R3a are joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycle;
A is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl and 8- to 11-membered heterobicyclyl; and
wherein -L1- is substituted with —X0D-L2- and wherein -L1- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by —X0D-L2- or a substituent.

### Claim 17

A water-insoluble conjugate comprising a plurality of antibiotic moieties -D covalently and reversibly bound to a polymeric moiety, wherein the antibiotic moieties are released from the polymeric moiety and wherein a single intra-articular injection provides a concentration of said antibiotic in the intra-articular compartment of at least 1 μg antibiotic/ml synovial fluid for at least 3 days.

### Claim 18 (depends on 17)

The conjugate of claim 17, wherein the concentration in the intra-articular compartment is at least 10 μg antibiotic/ml synovial fluid.

### Claim 19 (depends on 17, 18)

The conjugate of claim 17 or 18, wherein the concentration in the intra-articular compartment is at least 50 μg antibiotic/ml synovial fluid.

### Claim 20 (depends on 17, 18, 19)

The conjugate of any one of claims 17 to 19, wherein the concentration in the intra-articular compartment is at least 100 μg antibiotic/ml synovial fluid.

### Claim 21 (depends on 17, 18, 19, 20)

The conjugate of any one of claims 17 to 20, wherein the concentration is provided for at least 4 days.

### Claim 22 (depends on 17, 18, 19, 20, 21)

The conjugate of any one of claims 17 to 21, wherein the concentration is provided for at least 5 days.

### Claim 23 (depends on 17, 18, 19, 20, 21, 22)

The conjugate of any one of claims 17 to 22, wherein -D is selected from the group consisting of aminoglycosides, tetracycline antibiotics, amphenicols, pleuromutilins, macrolid antibiotics, lincosamides, steroid antibiotics, antifolate antibiotics, sulfonamides, topoisomerase inhibitors, quinolones, fluoroquinolones, nitroimidazole antibiotics, nitrofuran antibiotics, rifamycins, glycopeptides, penicillins, cephalosporins, monobactams, beta-lactamase inhibitors, polymyxin antibiotics, lipopeptide antibiotics, oxazolidinon, antimicrobial peptides, antimicrobial proteins, porphyrins, azole antifungals, polyenes, antiprotozoan drugs, fosfomycin, cycloserine, and bacitracin.

### Claim 24 (depends on 17, 18, 19, 20, 21, 22, 23)

The conjugate of any one of claims 17 to 23, wherein -D is a lipopeptide antibiotic.

### Claim 25 (depends on 17, 18, 19, 20, 21, 22, 23, 24)

The conjugate of any one of claims 17 to 24, wherein -D is daptomycin.

### Claim 26 (depends on 17, 18, 19, 20, 21, 22, 23, 24, 25)

A pharmaceutical composition comprising the conjugate of any one of claims 17 to 25 and at least one excipient.

### Claim 27 (depends on 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)

The conjugate of any one of claims 17 to 25 or the pharmaceutical composition of claim 26 for use as a medicament.

### Claim 28 (depends on 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)

The conjugate of any one of claims 17 to 25 or the pharmaceutical composition of claim 26 for use in the treatment of a joint infection.

### Claim 29 (depends on 28)

The conjugate of use of claim 28, wherein the joint infection is a joint infection related to a surgical implant.

### Claim 30 (depends on 29)

The conjugate for use of claim 29, wherein the surgical implant is an artificial joint.

### Claim 31 (depends on 28, 29, 30)

The conjugate for use of any one of claims 28 to 30, wherein administration occurs via intra-articular administration.

### Claim 32

A sustained-release compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising said compound or its pharmaceutically acceptable salt comprising a plurality of antibiotic moieties -D or antibiotic molecules D-H or D-OH, wherein the antibiotic moieties or molecules are released from said sustained-release compound and provide a concentration in the intra-articular compartment of said antibiotic that is at least 1.1-fold above the minimal biofilm eradicating concentration of the respective antibiotic for at least 3 days after a single intra-articular injection.

### Claim 33 (depends on 32)

The sustained-release compound of claim 32, wherein the concentration is at least 1.3-fold above the minimal biofilm eradication concentration of the respective antibiotic after a single intra-articular injection.

### Claim 34 (depends on 32, 33)

The sustained-release compound of claim 32 or 33, wherein the sustained-release compound is water-insoluble.

### Claim 35 (depends on 32, 33, 34)

The sustained-release compound of any one of claims 32 to 34, wherein -D is selected from the group consisting of aminoglycosides, tetracycline antibiotics, amphenicols, pleuromutilins, macrolid antibiotics, lincosamides, steroid antibiotics, antifolate antibiotics, sulfonamides, topoisomerase inhibitors, quinolones, fluoroquinolones, nitroimidazole antibiotics, nitrofuran antibiotics, rifamycins, glycopeptides, penicillins, cephalosporins, monobactams, beta-lactamase inhibitors, polymyxin antibiotics, lipopeptide antibiotics, oxazolidinon, antimicrobial peptides, antimicrobial proteins, porphyrins, azole antifungals, polyenes, antiprotozoal drugs, fosfomycin, cycloserine, and bacitracin.

### Claim 36 (depends on 32, 33, 34, 35)

The sustained-release compound of any one of claims 32 to 35, wherein -D is a lipopeptide antibiotic.

### Claim 37 (depends on 32, 33, 34, 35, 36)

The sustained-release compound of any one of claims 32 to 36, wherein -D is daptomycin.

### Claim 38 (depends on 32, 33, 34, 35, 36, 37)

The sustained-release compound of any one of claims 32 to 37, wherein -D is embedded in a carrier.

### Claim 39 (depends on 32, 33, 34, 35, 36, 37, 38)

The sustained-release compound of any one of claims 32 to 38, wherein -D is covalently conjugated to a carrier.

### Claim 40 (depends on 32, 33, 34, 35, 36, 37, 38, 39)

The sustained-release compound of any one of claims 32 to 39, wherein -D is reversibly and covalently conjugated to a carrier.

### Claim 41 (depends on 32, 33, 34, 35, 36, 37, 38, 39, 40)

A pharmaceutical composition comprising the sustained-release compound of any one of claims 32 to 40 and at least one excipient.

### Claim 42 (depends on 32, 33, 34, 35, 36, 37, 38, 39, 40, 41)

The sustained-release compound of any one of claims 32 to 40 or the pharmaceutical composition of claim 41 for use as a medicament.

### Claim 43 (depends on 32, 33, 34, 35, 36, 37, 38, 39, 40, 41)

The sustained-release compound of any one of claims 32 to 40 or the pharmaceutical composition of claim 41 for use in the treatment of a joint infection.

### Claim 44 (depends on 43)

The sustained-release compound or the pharmaceutical composition for use of claim 43, wherein the joint infection is a joint infection related to surgical implants.

### Claim 45 (depends on 44)

The conjugate for use of claim 44, wherein the surgical implant is an artificial joint.

### Claim 46 (depends on 43, 44)

The conjugate for use of any one of claims 43 to 44, wherein administration occurs via intra-articular administration.