# US 12,214,077 B2 · Liposomal formulation for joint lubrication

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 12,214,077 B2
- Document ID: US12214077B2
- Status: Granted
- Kind: B2
- Application number: 17/445,089
- Filed: 2021-08-15
- Published: 2021-12-02
- Granted: 2025-02-04
- Earliest claimed: 2017-08-22
- Assignees: Moebius Medical Ltd.
- Applicants: Moebius Medical Ltd.
- Inventors: Yechezkel Barenholz; Yaniv Dolev; Keren Turjeman; Gadi Sarfati; Maty Ayal-Hershkovitz
- Web page: https://patentgrep.com/patent/US12214077B2

## CPC

- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- 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 31/047: having two or more hydroxy groups, e.g. sorbitol
- A61K 31/685: one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61L 27/50: Materials characterised by their function or physical properties {, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials}
- A61L 27/54: Biologically active materials, e.g. therapeutic substances {(A61L27/227 takes precedence)}
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61L 2300/22: Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
- A61L 2400/06: Flowable or injectable implant compositions
- A61L 2400/10: Materials for lubricating medical devices
- A61L 2430/06: for cartilage reconstruction, e.g. meniscus
- A61L 2430/24: for joint reconstruction
- 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)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a pharmaceutical composition for the lubrication of joints, the pharmaceutical composition comprising a non-ionic tonicity agent comprising a polyol, and liposomes comprising at least one membrane comprising at least one phospholipid (PL) selected from a glycerophospholipid (GPL), said GPL having two C12-C18 hydrocarbon chains, being the same or different, and sphingomyelin (SM) having a C12-C18 hydrocarbon chain, the pharmaceutical composition being essentially free of an additional pharmaceutically active agent, wherein the at least one membrane has a phase transition temperature in the range of about 20° C. to about 39° C. and the joint has a joint temperature which is above the phase transition temperature.

## Claims

### Claim 1

A pharmaceutical composition consisting essentially of:
liposomes consisting essentially of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), wherein said liposomes are multilamellar vesicles (MLV) having at least one membrane and a phase transition temperature in the range of about 20° C. to about 39° C.;
a non-ionic tonicity agent, comprising a polyol which is a sugar or sugar alcohol having at least five hydroxyl groups; and
a fluid medium selected from buffer or water in which the liposomes are suspended;
wherein the pharmaceutical composition is essentially free of any additional pharmaceutically active agents;
wherein the pharmaceutical composition is formulated for intra-articular administration; wherein the pharmaceutical composition provides lubrication of a mammalian joint having a temperature which is above the phase transition temperature;
wherein the polyol is present in an amount sufficient to provide osmolality of the composition in the range from about 200 to about 600 mOsm and to improve lubrication efficacy of the composition; and
wherein the polyol is present in a weight percent ranging from about 0.05% (w/w) to about 10% (w/w), of the total weight of the pharmaceutical composition.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the sugar or sugar alcohol has at least six hydroxyl groups.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the polyol is a linear polyol.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein the polyol is selected from the group consisting of mannitol, dextrose, lactose, trehalose and combinations thereof.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein the polyol does not include xylitol.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein the liposomes consist essentially of a combination of DMPC and DPPC and wherein DMPC is present in a weight percent ranging from about 1% (w/w) to about 10% (w/w) and DPPC is present in a weight percent ranging from about 2% (w/w) to about 12% (w/w).

### Claim 7 (depends on 6)

The pharmaceutical composition of claim 6, wherein the mole percent ratio of DMPC to DPPC is in the range of about 25:75 to about 70:30.

### Claim 8 (depends on 7)

The pharmaceutical composition of claim 7, wherein the mole percent ratio of DMPC to DPPC is about 45:55.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein the weight ratio between the liposomes and the polyol ranges from about 6:1 to about 2:1.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is provided as a dosage unit having from about 30 mg to about 550 mg DPPC, from about 20 mg to about 450 mg DMPC, and from about 20 mg to about 350 mg polyol.

### Claim 11 (depends on 10)

The pharmaceutical composition of claim 10, wherein the dosage unit contains from about 0.5 ml to about 10 ml of the pharmaceutical composition.

### Claim 12 (depends on 1)

The composition of claim 1, wherein said buffer is a histidine buffer.

### Claim 13 (depends on 1)

The composition of claim 1, having a pH of about 5-8.

### Claim 14 (depends on 1)

The composition of claim 1, wherein the liposomes have a mean diameter of between about 0.5 μm to about 10 μm.

### Claim 15 (depends on 1)

The composition of claim 1, wherein the at least one membrane has the phase transition temperature of from 20° C. to 39° C.

### Claim 16 (depends on 1)

A method for treating pain and/or reducing local irritation in a joint of a mammal, the method comprising: administering into a cavity of the joint the pharmaceutical composition according to claim 1 to provide joint lubrication while preventing osmotic shock at the site of administration due to the presence of polyol in the composition.

### Claim 17 (depends on 16)

The method according to claim 16, wherein the pharmaceutical composition is administered by a route selected from the group consisting of intra-articular injection, arthroscopic administration and surgical administration.

### Claim 18 (depends on 17)

The method according to claim 17, wherein the pharmaceutical composition is administered in a dose of from about 0.5 ml to about 10 ml.

### Claim 19 (depends on 1)

The pharmaceutical composition of claim 1 prepared by a process comprising the steps of:
a) dissolving DPPC and DMPC in ethanol,
b) transferring the ethanolic solution of step (a) to a histidine buffer comprising the tonicity agent, and mixing to hydrate the lipids and form a dispersion of the liposomes,
c) centrifuging the dispersion to remove ethanol and performing cold buffer replacement at 4° C.,
d) repeating the centrifugation and cold buffer replacement processes until the osmolality in the dispersion is about 300mOsm.

### Claim 20 (depends on 19)

The pharmaceutical composition of claim 19, wherein the concentration of DPPC and DPMC in the ethanolic solution is 180 mM.

### Claim 21 (depends on 19)

The pharmaceutical composition of claim 19, wherein the process comprises placing the ethanolic solution of step (a) in a water bath at 60° C. for 20 minutes.

### Claim 22 (depends on 19)

The pharmaceutical composition of claim 19, wherein the histidine buffer in step (b) has a pH of 6.5.

### Claim 23 (depends on 19)

The pharmaceutical composition of claim 19, wherein step (d) comprises at least 5 cycles of centrifugation.

### Claim 24 (depends on 23)

The pharmaceutical composition of claim 23, wherein the process comprises centrifugation at 3000 rpm for 40 minutes in the first cycle and at 4000 rpm for 30 minutes in each subsequent cycle.

### Claim 25 (depends on 1)

A method for treating pain and/or reducing local irritation in a joint of a mammal, the method comprising: administering into a cavity of the joint the pharmaceutical composition according to claim 1 to provide joint lubrication while preventing osmotic shock at the site of administration due to the presence of the sugar or sugar alcohol in the composition.

### Claim 26 (depends on 25)

The method according to claim 25, wherein the pharmaceutical composition is administered by a route selected from the group consisting of intra-articular injection, arthroscopic administration and surgical administration.

### Claim 27 (depends on 25)

The method according to claim 25, wherein the pharmaceutical composition is in a form of a parenteral pharmaceutical composition having a suspension of the liposomes and is administered in a dose of from about 0.5 ml to about 10 ml.