# US 11,298,399 B2 · Carbetocin drug product and process for preparing same

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- Number: US 11,298,399 B2
- Document ID: US11298399B2
- Status: Granted
- Kind: B2
- Application number: 17/529,861
- Filed: 2021-11-18
- Published: 2022-03-10
- Granted: 2022-04-12
- Earliest claimed: 2018-09-20
- Assignees: Levo Therapeutics, Inc.
- Applicants: Levo Therapeutics, Inc.
- Inventors: Christopher Bryant; Mark C. Manning; Ryan E. Holcomb
- Web page: https://patentgrep.com/patent/US11298399B2

## CPC

- A61K 38/095: Oxytocins; Vasopressins; Related peptides
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- 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
- 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

The present disclosure includes a method of making an improved carbetocin drug product. The disclosed method for making an improved carbetocin drug product comprises agitating a carbetocin preparation containing an aqueous solution of carbetocin and one or more excipients for a period of time to initiate the formation of aggregate-forming solids and filtering off the aggregates that form before further processing the remaining carbetocin into a final drug product. The present disclosure also relates to an improved carbetocin drug product, wherein the drug product is substantially free of aggregate-forming solids. The disclosed carbetocin drug product can be used for the treatment of a neurodevelopmental disorder, such as Prader-Willi syndrome. Additionally, the disclosed carbetocin drug product shows content uniformity of carbetocin over long periods of time before and after one or more freeze/thaw cycles, provides enhanced convenience and patient compliance, and/or are highly concentrated.

## Claims

### Claim 1

A carbetocin drug product comprising carbetocin or a pharmaceutically acceptable salt thereof with increased resistance to aggregation, wherein the concentration of carbetocin is about 10 mg/mL to about 70 mg/mL and the carbetocin drug product is substantially free of aggregate-forming solids, the carbetocin drug product prepared by a process comprising:
(a) dissolving carbetocin or a pharmaceutically acceptable salt thereof and one or more excipients chosen from a surface active agent, solubilizer, tonicity enhancer, an agent to adjust the pH, and combinations thereof to form an aqueous solution;
(b) agitating the aqueous solution from step (a) for a time period of hours to form aggregate-forming solids;
(c) removing the formed aggregate-forming solids from the agitated solution to form a post-agitation solution; and
(d) adding the post-agitation solution to a container to form a final drug product; wherein the carbetocin drug product has increased resistance to aggregation when tested with shaking stress compared to an aqueous solution of carbetocin that has not been treated according to steps (b) and (c).

### Claim 2 (depends on 1)

The carbetocin drug product of claim 1, wherein the aqueous solution comprising carbetocin comprises a surface active agent, which is a viscoelastic polymer that is a cellulose derivative selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and carboxy methyl ethyl cellulose (CMEC).

### Claim 3 (depends on 1)

The carbetocin drug product of claim 1, wherein the solubilizer is a hydrotrope, amino acid, or cyclodextrin selected from the group consisting of sodium benzoate, sodium salicylate, sodium benzene sulfonate, sodium benzene disulfonate, sodium cinnamate, sodium 3-hydroxy-2-naphthoate, sodium para-toluene sulfonate, sodium cumene sulfonate, nicotinamide, N,N-diethylnicotinamide, N,N-dimethyl benzamide, para-aminobenzoic acid hydrochloride, procaine hydrochloride, caffeine, sodium alkanoate, urea, N,N-dimethyl urea, arginine, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin (RM-β-CD), sulfobutylether-β-cyclodextrin (SBE-β-CD), epichlorohydrin-β-cyclodextrin, and carboxy methyl epichlorohydrin beta cyclodextrin.

### Claim 4 (depends on 3)

The carbetocin drug product of claim 3, wherein the hydrotrope is present in a concentration ranging from about 50 mM to about 500 mM.

### Claim 5 (depends on 2)

The carbetocin drug product of claim 2, wherein the cellulose derivative is present in an amount ranging from 0.0075% to 0.05% w/v.

### Claim 6 (depends on 1)

The carbetocin drug product of claim 1, wherein the carbetocin is present in a concentration of about 10 mg/mL to about 40 mg/mL.

### Claim 7 (depends on 1)

The carbetocin drug product of claim 1, wherein the carbetocin is present in a concentration of about 25 mg/mL to about 40 mg/mL.

### Claim 8 (depends on 1)

The carbetocin drug product of claim 1, wherein the carbetocin is present in a concentration of about 25 mg/mL to about 35 mg/mL.

### Claim 9 (depends on 1)

The carbetocin drug product of claim 1 prepared by a process comprising the steps of:
(i) adding water to a container to form a water preparation and stirring the water preparation;
(ii) adding at least one solubilizer and/or surface active agent to the preparation of step (i) and optionally adding one or more excipients to the preparation to adjust osmolality;
(iii) adding carbetocin to the preparation of step (ii) until carbetocin is completely dissolved in solution and optionally adjusting the solution to a target volume with water, and further filtering the solution to obtain a pre-agitation preparation;
(iv) agitating the pre-agitation preparation from step (iii) for a time period of hours to induce aggregate-forming solids to form and filtering off the aggregate-forming solids from the agitated carbetocin preparation to form a filtrate; and
(v) saving the filtrate that is free of the aggregate-forming solids in a container to obtain a post-agitation carbetocin drug product.

### Claim 10 (depends on 1)

The carbetocin drug product of claim 1, that remains clear with no visible aggregate-forming solids after further agitation for another 24 hours.

### Claim 11 (depends on 9)

The carbetocin drug product of claim 9, wherein the post-agitation carbetocin drug product is stable to aggregation after stirring at 200 rpm for at least 24 hours.

### Claim 12 (depends on 9)

The carbetocin drug product of claim 9, wherein the solubilizer is a hydrotrope, amino acid, or cyclodextrin selected from the group consisting of sodium benzoate, sodium salicylate, sodium benzene sulfonate, sodium benzene disulfonate, sodium cinnamate, sodium 3-hydroxy-2-naphthoate, sodium para-toluene sulfonate, sodium cumene sulfonate, nicotinamide, N,N-diethylnicotinamide, N,N-dimethyl benzamide, para-aminobenzoic acid hydrochloride, procaine hydrochloride, caffeine, sodium alkanoate, urea, N,N-dimethyl urea, arginine, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin (RM-β-CD), sulfobutylether-β-cyclodextrin (SBE-β-CD), epichlorohydrin-β-cyclodextrin, and carboxy methyl epichlorohydrin beta cyclodextrin.

### Claim 13 (depends on 9)

The carbetocin drug product of claim 9, wherein the hydrotrope is present in a concentration ranging from about 50 mM to about 500 mM.

### Claim 14 (depends on 9)

The carbetocin drug product of claim 9, wherein the surface active agent is a cellulose derivative selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and carboxy methyl ethyl cellulose (CMEC), and wherein the cellulose derivative is present in an amount ranging from 0.0075% to 0.05% w/v.

### Claim 15 (depends on 9)

The carbetocin drug product of claim 9, wherein the excipient is chosen from sorbitol, ethylenediaminetetraacetic acid (EDTA), potassium sorbate, acetate, and combinations thereof.

### Claim 16 (depends on 1)

The carbetocin drug product of claim 1, wherein the aqueous solution from step (a) is agitated for at least 12 hours.