# US 11,998,564 B2 · Stable cardioplegic solution for cardiac surgery

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- Number: US 11,998,564 B2
- Document ID: US11998564B2
- Status: Granted
- Kind: B2
- Application number: 17/413,567
- Filed: 2018-12-14
- Published: 2022-03-24
- Granted: 2024-06-04
- Earliest claimed: 2018-12-14
- Assignees: National Taiwan University
- Applicants: National Taiwan University
- Inventors: Yih-Sharng Chen; Li-Jiuan Shen; Mei-Hsin Lin; Heng-Wen Chou
- Web page: https://patentgrep.com/patent/US11998564B2

## CPC

- A61K 33/06: Aluminium, calcium or magnesium; Compounds thereof {, e.g. clay}
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 31/047: having two or more hydroxy groups, e.g. sorbitol
- A61K 31/133: having hydroxy groups, e.g. sphingosine
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/191: having two or more hydroxy groups, e.g. gluconic acid
- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61K 33/04: Sulfur, selenium or tellurium; Compounds thereof
- A61K 33/14: Alkali metal chlorides; Alkaline earth metal chlorides
- 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 is a cardioplegic solution that demonstrates better stability in pH, particulate matter formation and osmolality but at the same time demonstrates superior ability to preserve heart functions than currently available cardioplegic solutions. The cardioplegic solution comprises potassium (K+), magnesium (Mg2+), sodium (Na+), chloride (Cl−), gluconate, acetate, sulfate (SO42−), THAM and mannitol dissolved in water.

## Claims

### Claim 1

A cardioplegic solution comprising potassium (K+), magnesium (Mg2+), sodium (Na+), chloride (Cl−), gluconate, acetate, sulfate (SO42−), tris(hydroxymethyl)aminomethane (THAM) and mannitol dissolved in water, wherein the potassium (K+) concentration is about 27 to about 33 mEq/L, the magnesium (Mg2+) concentration is about 16 to about 20 mEq/L, the sodium (Na+) concentration is about 120 to about 146 mEq/L, the chloride (Cl−) concentration is about 106 to about 130 mEq/L, the gluconate concentration is about 20 to about 24 mmol/L, the acetate concentration is about 22 to about 28 mmol/L, the sulfate (SO42−) concentration is about 6 to about 9 mmol/L, the THAM concentration is between about 5 to about 30 mmol/L, mannitol concentration is about 2 to about 5 g/L and the cardioplegic solution is capable of maintaining a pH of about 8.2 to about 8.6 for 365 days wherein the term “about” as a modifier to a quantity is intended to mean+ or −5% inclusive of the quantity being modified.

### Claim 2 (depends on 1)

The cardioplegic solution of claim 1 wherein the potassium (K+) concentration is about 29.63 mEq/L, the magnesium (Mg2+) concentration is about 18.39 mEq/L, the sodium (Na+) concentration is about 133.80 mEq/L, the chloride (Cl−) concentration is about 118.51 mEq/L, the gluconate concentration is about 21.98 mmol/L, the acetate concentration is about 25.81 mmol/L, the sulfate (SO42−) concentration is about 7.76 mmol/L, the THAM concentration is 20 mmol/L and mannitol concentration is about 3.116 g/L.

### Claim 3 (depends on 1)

The cardioplegic solution of claim 1 further comprising lidocaine wherein the lidocaine concentration is about 0.1 mg/mL to about 0.14 mg/mL within the cardioplegic solution.

### Claim 4 (depends on 1)

A cardioplegic solution and patient blood composition comprising fully oxygenated patient blood at a ratio of about 1:1 to about 1:8 ratio by volume of the fully oxygenated blood of the patient to the cardioplegic solution of claim 1.

### Claim 5 (depends on 1)

The cardioplegic solution of claim 1, wherein the cardioplegic solution is calcium free.

### Claim 6 (depends on 1)

The cardioplegic solution of claim 1, wherein the cardioplegic solution is free of sodium bicarbonate.

### Claim 7 (depends on 1)

A method for preparing the cardioplegic solution of claim 1, comprising the first step of addition of sodium chloride, sodium gluconate, sodium acetate trihydrate, potassium chloride, magnesium chloride, magnesium sulfate and mannitol in water to form a solution; the second step of mixing THAM and glacial acetic acid to the solution resulting from the first step,
wherein the concentration of sodium chloride is about 75 to about 95 mmol/L, the concentration of sodium gluconate is about 20 to about 24 mmol/L, the concentration of sodium acetate trihydrate is about 22 to about 28 mmol/L, the concentration of potassium chloride is about 27 to about 33 mmol/L, the concentration of magnesium chloride is about 1.2 to about 1.6 mmol/L, the concentration of magnesium sulfate is about 6 to about 9 mmol/L and the concentration of mannitol is about 15 to about 20 mmol/L in water and wherein the step of mixing THAM and glacial acetic acid to the solution resulting from the first step of the method adjusts the solution to pH range of about 8.2 to about 8.6 as well as to achieve about 5 to about 30 mmol/L of THAM concentration.

### Claim 8 (depends on 7)

The method of claim 7, wherein the concentration of sodium chloride is about 86.02 mmol/L, the concentration of sodium gluconate is about 21.99 mmol/L, the concentration of sodium acetate trihydrate is about 25.85 mmol/L, the concentration of potassium chloride is about 29.59 mmol/L, the concentration of magnesium chloride is about 1.41 mmol/L, the concentration of magnesium sulfate is about 7.76 mmol/L and the concentration of mannitol is about 17.1 mmol/L in water and wherein the step of mixing THAM and glacial acetic acid to the solution resulting from the first step of the method adjusts the solution to desired pH range of about 8.2 to about 8.6 as well as to achieve about 20 mmol/L or 10 mmol/L of THAM concentration.

### Claim 9 (depends on 7)

The method of claim 7, further comprising the step of addition of lidocaine to a concentration of about 0.1 mg/mL to about 0.14 mg/mL within the cardioplegic solution.

### Claim 10 (depends on 1)

A method of making a cardioplegic solution and patient blood composition comprising the step of addition of fully oxygenated blood of a patient at a ratio of about 1:1 to about 1:8 ratio by volume of the fully oxygenated blood of the patient to the cardioplegic solution of claim 1.

### Claim 11 (depends on 7)

The method of claim 7, wherein the cardioplegic solution is free of calcium.

### Claim 12 (depends on 7)

The method of claim 7, wherein the cardioplegic solution is free of sodium bicarbonate.

### Claim 13 (depends on 7)

The method of claim 7, wherein the steps are performed up to 365 days prior to use.

### Claim 14 (depends on 1)

A method for preparing the cardioplegic solution of claim 1 comprising the first step of mixing mannitol, magnesium sulfate, THAM, and potassium chloride to a base solution to form a solution, and
the second step of combining THAM and glacial acetic acid to the solution of the first step to adjust the solution to a pH of about 8.2 to about 8.6, wherein the base solution per liter consists of Na+, K+, Mg2+, Cl−, acetate and gluconate.

### Claim 15 (depends on 14)

The method of claim 14, wherein mannitol, magnesium sulfate, THAM, and potassium chloride are added to the base solution up to 365 days prior to use.

### Claim 16 (depends on 14)

The method of claim 14, further comprising the step of addition of lidocaine to a concentration of about 0.1 mg/mL to about 0.14 mg/mL within the cardioplegic solution.

### Claim 17 (depends on 14)

The method of claim 14, wherein the cardioplegic solution is stored at room temperature.

### Claim 18 (depends on 1)

A method for inducing temporary cardiac arrest comprising the step of administering the cardioplegic solution of claim 1 to a patient in need thereof during cardiac surgery.

### Claim 19 (depends on 18)

The method of claim 18, wherein the cardioplegic solution is administered at hypothermia.

### Claim 20 (depends on 18)

The method of claim 18, wherein the cardioplegic solution is administered at normothermia.

### Claim 21 (depends on 18)

The method of claim 18, wherein the cardioplegic solution is administered once during surgery.

### Claim 22 (depends on 18)

The method of claim 18, wherein the cardioplegic solution is administered more than once during surgery.