# US 2021/0275598 A1 · Compositions and methods for treating heart disease

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- Number: US 2021/0275598 A1
- Document ID: US20210275598A1
- Status: Published application
- Kind: A1
- Application number: 17/205,597
- Filed: 2021-03-18
- Published: 2021-09-09
- Earliest claimed: 2016-07-05
- Inventors: Asher HOLZER
- Web page: https://patentgrep.com/patent/US20210275598A1

## CPC

- A61K 35/545: Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
- 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 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 35/28: Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
- A61K 35/34: Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes (vascular smooth muscle A61K35/44)
- 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 47/38: Cellulose; Derivatives thereof
- A61M 25/10: Balloon catheters ({A61M25/0125 takes precedence; embolectomy A61B17/22032; retractors A61B17/02;} inflatable balloons for placing stents or stent-grafts A61F2/958 {; stomach balloons for treatment of obesity A61F5/0003; oesophagal tubes A61J15/00})
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61M 2025/105: {having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes}
- A61M 2230/04: Heartbeat characteristics, e.g. ECG, blood pressure modulation
- 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)}
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides methods and compositions for treating damage to the heart tissue. In particular, the present invention provides pharmaceutical compositions comprising stem cells embedded in biocompatible thermoreversible hydrogels and use thereof in treating myocardium infarction.

## Claims

### Claim 1

A method for treating a cardiac disease or disorder in a subject in need thereof, the method comprises administering between the pericardium layer and the epicardium layer of said subject a pharmaceutical composition comprising stem cells and/or progenitor cells embedded in a biodegradable thermoreversible hydrogel, wherein the hydrogel is characterized by a viscosity of less than 200 Pa's between 4° C. and 12° C., and a viscosity of more than 1,000 Pa's at 37° C., and/or wherein said hydrogel comprises ethylene oxide/propylene oxide block copolymer, hydroxypropylmethylcellulose (HPMC) and an adhesive agent.

### Claim 2 (depends on 1)

The method of claim 1, wherein the hydrogel is characterized by flexibility sufficient to allow the tissue to which said composition is applied to move, contract, and/or expand with no significant loss of its original flexibility.

### Claim 3 (depends on 1)

The method of claim 1, wherein said method comprising the step of applying two different layers having different mechanical properties and/or different diffusion coefficients.

### Claim 4 (depends on 1)

The method of claim 1, wherein the hydrogel is characterized by peel strength adhesiveness according to ASTM standard D2256-03 of 0.5-5.0 N cm−2 at 37° C.

### Claim 5 (depends on 1)

The method of claim 1, wherein the hydrogel comprises carboxymethyl cellulose (CMC).

### Claim 6 (depends on 1)

The method of claim 1, wherein the stem cells are selected from the group consisting of: embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), myoblasts, bone marrow stem cells (BMSCs), mesenchymal stem cells, cardiac stem cells, and any combination thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition comprises lineage specific precursor/progenitor (LSP) cells.

### Claim 8 (depends on 1)

The method of claim 1, wherein the progenitor cells are of the mesodermal lineage.

### Claim 9 (depends on 1)

The method of claim 1, wherein the hydrogel is characterized by peel strength adhesiveness according to ASTM standard D2256-03 of 0.5-5.0 N cm−2 at 37° C.

### Claim 10 (depends on 1)

The method of claim 1, wherein the hydrogel is characterized by a viscosity of more than 3×103 Pa·s at 37° C.

### Claim 11 (depends on 1)

The method of claim 1, wherein the hydrogel is characterized by a peak detachment force of at least 0.001 N.

### Claim 12 (depends on 1)

The method of claim 1, wherein the hydrogel comprises between 15% and 35% (w/w) ethylene oxide/propylene oxide block copolymer.

### Claim 13 (depends on 1)

The method of claim 1, wherein the hydrogel comprises between 0.01% and 1% (w/w) hydroxypropylmethylcellulose (HPMC).

### Claim 14 (depends on 1)

The method of claim 1, wherein the hydrogel comprises PEG.

### Claim 15 (depends on 1)

The method of claim 1, wherein the hydrogel comprises between 20% and 30% (w/w) ethylene oxide/propylene oxide block copolymer; between 0.05% and 0.5% (w/w) hydroxypropylmethylcellulose (HPMC); between 0.1% and 2.5% (w/w) polyethylene glycol (PEG)-400; in addition to nutrients and isotonicity agents required for sustaining cell viability and the balance water.

### Claim 16 (depends on 1)

The method of claim 1, wherein the hydrogel comprises between 20% and 30% (w/w) of an ethylene oxide/propylene oxide triblock copolymer characterized by an average molar mass of 13,000 and a general formula E106 P70 E106; between 0.05% and 0.3% HPMC; between 0.4% and 2.5% PEG-400; in addition to nutrients and isotonicity agents required for sustaining cell viability and the balance water.

### Claim 17 (depends on 1)

The method of claim 1, wherein the hydrogel further comprises a component selected from the group consisting of adhesive and thickening compounds; bonding agents; pH-modifying substances; diffusion coatings; plasticizers; components for increasing permeability within the hydrogel; swellable excipients; matrix forming polymers; tight junction modifiers/cell membrane permeability enhancers; and any combination thereof.

### Claim 18 (depends on 1)

The method of claim 1, wherein the cardiac disease or disorder is myocardial infarction or arrhythmia.

### Claim 19 (depends on 1)

A method for accurate delivery of a pharmaceutical composition to a precise location beneath the pericardium without penetrating the cardiac muscle, the method comprising:
(i) mixing of stem cells and/or progenitor cells and the biodegradable thermoreversible hydrogel according to claim 1;
(ii) inflating a balloon to open a cavity between the myocardium and the pericardium, and adjacent to the presumptive scar tissue localization;
(iii) identifying the heart scar tissue localization; and
(iv) releasing the mixture of step (i) into the scar tissue localization identified in step (iii).

### Claim 20 (depends on 19)

The method of claim 19, wherein step (iii) comprises detecting ECG signal levels for identifying the heart scar tissue localization