# US 10,864,200 B2 · Stable formulations for immune-modulatory macrolides

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- Number: US 10,864,200 B2
- Document ID: US10864200B2
- Status: Granted
- Kind: B2
- Application number: 16/562,629
- Filed: 2019-09-06
- Published: 2019-12-26
- Granted: 2020-12-15
- Earliest claimed: 2017-03-07
- Assignees: Roche Diagnostics Operations, Inc.
- Applicants: Roche Diagnostics Operations, Inc.
- Inventors: Ewelina Hegel; Hans-Peter Josel; Eloisa Lopez-Calle; Josef Roedl; Noah Weiss; Benjamin Tiemann
- Web page: https://patentgrep.com/patent/US10864200B2

## CPC

- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 35/16: Blood plasma; Blood serum (umbilical cord blood A61K35/51)
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61P 37/02: Immunomodulators
- 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 description relates to a liquid composition having at least one immune-modulatory macrolide compound and an essentially cell-free blood hemolysate. The present description further relates to a method for manufacturing a stabilized immune-modulatory macrolide calibration solution, by a) preparing a solution comprising an essentially cell-free blood hemolysate, b) admixing a predetermined amount of at least one immune-modulatory macrolide into said solution comprising an essentially cell-free blood hemolysate, and, thereby c) manufacturing a stabilized immune-modulatory macrolide calibration solution. Furthermore, the present description relates to kits, uses, devices, methods and to an immune-modulatory macrolide compound calibration solution related thereto.

## Claims

### Claim 1

A liquid composition comprising at least one immune-modulatory macrolide compound and an essentially cell-free blood hemolysate, wherein said immune-modulatory macrolide is at least one immune-modulatory macrolide selected from the group consisting of everolimus, sirolimus, tacrolimus, pimecrolimus and temsirolimus, and wherein essentially cell free is a number of less than 10 viable cells/ml.

### Claim 2 (depends on 1)

The liquid composition of claim 1, wherein essentially cell free is a number of less than 1 viable cell/ml.

### Claim 3 (depends on 1)

The liquid composition of claim 1, wherein said liquid composition is an aqueous solution.

### Claim 4 (depends on 1)

The liquid composition of claim 1, wherein said immune-modulatory macrolide is at least one immune-modulatory macrolide selected from the group consisting of everolimus, sirolimus and tacrolimus.

### Claim 5 (depends on 1)

The liquid composition of claim 1, wherein said liquid composition further comprises a preservative.

### Claim 6 (depends on 5)

The liquid composition of claim 5, wherein said preservative is alexidine.

### Claim 7 (depends on 1)

The liquid composition of claim 1, wherein said liquid composition has a pH of from 7.5 to 4.

### Claim 8

A method for manufacturing a stabilized immune-modulatory macrolide calibration solution, comprising
a) preparing a solution comprising an essentially cell-free blood hemolysate,
b) admixing a predetermined amount of at least one immune-modulatory macrolide into said solution comprising an essentially cell-free blood hemolysate, and, thereby
c) manufacturing a stabilized immune-modulatory macrolide calibration solution,
wherein said immune-modulatory macrolide is at least one immune-modulatory macrolide selected from the group consisting of everolimus, sirolimus, tacrolimus, pimecrolimus and temsirolimus, and wherein essentially cell free is a number of less than 10 viable cells/ml.

### Claim 9 (depends on 8)

The method of claim 8, wherein said preparing a solution comprising an essentially cell-free blood hemolysate comprises freezing and thawing whole blood, thereby providing a blood hemolysate; and/or wherein said preparing a solution comprising an essentially cell-free blood hemolysate comprises stirring said blood hemolysate for at least 5 min.

### Claim 10 (depends on 9)

The method of claim 9, wherein said preparing a solution comprising an essentially cell-free blood hemolysate comprises centrifuging said blood hemolysate.

### Claim 11 (depends on 1)

A kit comprising a liquid composition according to claim 1 and an immune-modulator detection agent.

### Claim 12 (depends on 5)

The liquid composition of claim 5, wherein the preservative does not interfere with immune-modulatory macrolide determination.

### Claim 13 (depends on 5)

The liquid composition of claim 5, wherein the preservative comprises a bis-biguanide.