# US 11,439,587 B2 · Injectable implants

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- Number: US 11,439,587 B2
- Document ID: US11439587B2
- Status: Granted
- Kind: B2
- Application number: 16/335,471
- Filed: 2017-09-19
- Published: 2019-10-03
- Granted: 2022-09-13
- Earliest claimed: 2016-09-22
- Assignees: Yissum Research Development Company of the Hebrew University of Jerusalem
- Applicants: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd.
- Inventors: Michael Friedman; David Kirmayer; Rami Mosheiff; Jacob Rachmilewitz; Amal Khoury; Doron Steinberg
- Web page: https://patentgrep.com/patent/US11439587B2

## CPC

- 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 31/09: having two or more such linkages
- A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 31/366: having six-membered rings, e.g. delta-lactones
- A61K 31/4164: 1,3-Diazoles
- A61K 31/4425: Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
- A61K 31/65: Tetracyclines
- A61K 47/02: Inorganic compounds
- 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 47/38: Cellulose; Derivatives thereof
- 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)

## Abstract

Provided herein injectable implant compositions useful for acceleration of bone fracture healing, treatment of dental or oral pathologies, and controlled drug delivery.

## Claims

### Claim 1

An injectable polymer-based implant composition comprising an ammonio-methacrylate copolymer said copolymer being dissolved in an injectable solvent, an additive which is a water-soluble salt, and optionally a pharmaceutically active agent, wherein upon contact with an aqueous medium polymer(s) of the implant composition form a stable solidified residue, and wherein said injectable solvent is soluble in or miscible with water and is an aprotic solvent, wherein said additive is a calcium-containing salt, and water is present in an amount between 0.5 and 20 weight percent.

### Claim 2 (depends on 1)

The injectable implant of claim 1, wherein said aprotic polar solvent is selected from the group consisting of N-methyl pyrrolidone, dimethyl sulfoxide, and combinations thereof.

### Claim 3 (depends on 1)

The injectable implant of claim 1, wherein the salt is calcium chloride.

### Claim 4 (depends on 1)

The injectable implant of claim 1, further comprising a cosolvent, wherein said cosolvent is selected from the group consisting of polyols, organic acid esters, and pegylated hydrophilic surface active agents,
optionally wherein said polyols being polyethylene glycol with molecular weight between 300 and 4000, propylene glycol, or glycerine; and
optionally wherein said organic acid esters being triethyl citrate or diethyl phthalate.

### Claim 5 (depends on 1)

The injectable implant of claim 1, further comprising a methacrylic acid copolymer, which is selected from copolymers of methacrylic acid and methyl methacrylate, and copolymers of methacrylic acid and ethyl acrylate.

### Claim 6 (depends on 1)

The injectable implant of claim 1, wherein said ammonio methacrylate copolymer is a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride.

### Claim 7 (depends on 1)

The injectable implant of claim 1, further comprising an amino methacrylate copolymer, which is a copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

### Claim 8 (depends on 1)

The injectable implant of claim 1, further comprising at least one further polymer, selected from the group consisting of a polyester, a cellulose derivative, polyvinyl pyrrolidone, a polyethylene glycol, a polyethylene oxide, and a poloxamer.

### Claim 9 (depends on 8)

The injectable implant of claim 8, wherein said cellulose derivative is selected from the group consisting of methyl cellulose, hypromellose, and hydroxypropyl cellulose.

### Claim 10 (depends on 1)

The injectable implant of claim 1, wherein the pharmaceutically active agent is bone-active agent, optionally wherein said bone-active agent is simvastatin.

### Claim 11 (depends on 1)

The injectable implant of claim 1, wherein the pharmaceutically active agent is selected from the group consisting of antibiotics, antifungals, antivirals, antineoplastics, antiepileptics, antiparkinsonics, and hormones.

### Claim 12 (depends on 1)

The injectable implant of claim 1, wherein the pharmaceutically active agent is an antiseptic or a non-steroid anti-inflammatory agent.

### Claim 13 (depends on 12)

The injectable implant of claim 12, wherein the antiseptic is cetyl pyridinium chloride, or wherein said non-steroid anti-inflammatory agent is ibuprofen.

### Claim 14 (depends on 1)

The injectable implant of claim 1, comprising a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride as the ammonio-methacrylate copolymer, calcium chloride as an additive, water, a pharmaceutically active agent, and N-methyl pyrrolidone as said aprotic polar solvent.

### Claim 15 (depends on 14)

The injectable implant of claim 14, further comprising a polymethacrylate selected from a copolymer of methacrylic acid and methyl methacrylate, a copolymer of methacrylic acid and ethyl acrylate, and a mixture thereof.

### Claim 16

Method of accelerating a bone fracture healing in a patient in need thereof by administering perifracturally an injectable polymer-based implant composition comprising an ammonio-methacrylate copolymer, said copolymer being dissolved in an injectable solvent, an additive which is a water-soluble salt, and optionally a bone active agent, wherein upon contact with an aqueous medium polymer(s) of the implant form a stable solidified residue, and wherein said injectable solvent is soluble in or miscible with water and is an aprotic solvent, wherein said additive is a calcium-containing salt, and water is present in an amount between 0.5 and 20 weight percent.

### Claim 17 (depends on 16)

The method of claim 16, wherein said injectable implant composition further comprises a copolymer of methacrylic acid and methyl methacrylate, a copolymer of methacrylic acid and ethyl acrylate, or a mixture thereof.

### Claim 18

Method of treatment of a dental or an oral pathology in a patient in need thereof by administering to said patient an injectable polymer-based implant composition comprising an ammonio-methacrylate copolymer, said copolymer being dissolved in an injectable solvent, an additive which is a water-soluble salt, and a pharmaceutically active agent, wherein upon contact with an aqueous medium polymer(s) of the implant form a stable solidified residue, and wherein said injectable solvent is soluble in or miscible with water and is an aprotic solvent, wherein said additive is a calcium-containing salt, and
water is present in an amount between 0.5 and 20 weight percent.

### Claim 19 (depends on 18)

The method of claim 18, wherein said pharmaceutically active agent selected from an antiseptic, an antibiotic, an antibiofilm agent, an anti-quorum sensing agent, and a non-steroid anti-inflammatory agent.

### Claim 20

Method of treatment of a pathology in a patient in need thereof by administering to said patient intramuscularly, subcutaneously or intraperitoneally an injectable polymer-based implant composition comprising an ammonio-methacrylate copolymer, said copolymer being dissolved in an injectable solvent, an additive which is a water-soluble salt, and a pharmaceutically active agent, wherein upon contact with an aqueous medium polymer(s) of the implant form a stable solidified residue, and wherein said injectable solvent is soluble in or miscible with water and is an aprotic solvent wherein said additive is a calcium-containing salt, and water is present in an amount between 0.5 and 20 weight percent.

### Claim 21 (depends on 1)

The injectable implant according to claim 1, wherein said water-soluble salt is selected from the group consisting of calcium chloride, calcium citrate, and calcium acetate.

### Claim 22 (depends on 1)

The injectable implant according to claim 1, wherein said water-soluble salt is selected from the group consisting of calcium chloride and calcium acetate.

### Claim 23 (depends on 1)

The injectable composition according to claim 1, wherein said amount of water is between 1 and 15 weight percent.