# US 10,864,249 B2 · High purity oritavancin and method of producing same

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- Number: US 10,864,249 B2
- Document ID: US10864249B2
- Status: Granted
- Kind: B2
- Application number: 16/437,361
- Filed: 2019-06-11
- Published: 2019-09-26
- Granted: 2020-12-15
- Earliest claimed: 2014-07-17
- Assignees: Melinta Therapeutics, Inc.; AbbVie Inc.
- Applicants: Melinta Therapeutics Inc.; AbbVie Inc.
- Inventors: Adel Rafai Far; Gopal Krishna; Min Ding; Sanjay R. Chemburkar; Carl M. Knable; James P. Petzel; Julie J. Pruyne; Douglas M. Reamer
- Web page: https://patentgrep.com/patent/US10864249B2

## CPC

- A61K 38/14: Peptides containing saccharide radicals; Derivatives thereof {, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- 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
- A61P 31/04: Antibacterial agents
- C07K 9/008: {directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin}
- C12P 21/02: having a known sequence of two or more amino acids, e.g. glutathione
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}

## Abstract

Drug substance preparations of oritavancin having high purity are disclosed, along with pharmaceutical compositions comprising such oritavancin drug substance preparations, and drug products or dosage forms comprising such pharmaceutical compositions.

## Claims

### Claim 1

A method for preparing an oritavancin drug substance preparation, comprising:
a) growing a culture of a chloroeremomycin-producing microorganism under fermentative conditions in a medium free of animal-sourced material (ASM) and under conditions promoting biosynthesis of chloroeremomycin by the culture,
b) recovering chloroeremomycin from fermentation broth produced in a),
c) preparing a solution of the chloroeremomycin of b) and a copper salt in an organic solvent, reacting the solution with 4-chloro-4′-biphenyl carboxaldehyde, and precipitating oritavancin-copper complex from the solution,
d) de-complexing copper from the oritavancin-copper complex of c), and
e) collecting oritavancin, thereby preparing an oritavancin drug substance preparation,
wherein the oritavancin drug substance preparation has a maximum impurity level of not more than 3.0% by peak area of impurity 1 and impurity 7, defined by peak A of FIG. 1 and peak G of FIG. 2, respectively; or
wherein the oritavancin drug substance preparation has about 85% purity or greater by peak area relative to impurities 1-16, defined by peak A of FIG. 1 and peaks B-P of FIG. 2, respectively.

### Claim 2 (depends on 1)

The method of claim 1, wherein the chloroeremomycin is recovered from fermentation broth produced in a) using a polymeric exchange resin.

### Claim 3 (depends on 1)

The method of claim 1, further comprising decolorizing the chloroeremomycin recovered in b) using a polymeric adsorbent resin, chromatographically separating the decolorized chloroeremomycin using a hydrophobic polymeric resin column, and precipitating the separated chloroeremomycin using an organic solvent.

### Claim 4 (depends on 1)

The method of claim 1, wherein the oritavancin-copper complex is precipitated from the solution in c) using acetonitrile.

### Claim 5 (depends on 1)

The method of claim 1, wherein the copper is de-complexed from the oritavancin-copper complex of d) by adding an aqueous acid and separating the de-complexed oritavancin using a polymeric hydrophobic resin, wherein the adding and separating are performed concurrently or sequentially.

### Claim 6 (depends on 5)

The method of claim 5, further comprising collecting oritavancin via:
(i) eluting oritavancin from the polymeric hydrophobic resin,
(ii) concentrating oritavancin eluted from the resin,
(iii) precipitating oritavancin from the concentrate in aqueous ethanol, and
(iv) drying the precipitated oritavancin.

### Claim 7 (depends on 1)

The method of claim 1, wherein the purity level of the oritavancin drug substance preparation is measured by HPLC.

### Claim 8 (depends on 1)

The method of claim 1, wherein the purity level of the oritavancin drug substance preparation is measured by HPLC, and wherein the HPLC measurement utilizes a C18 reverse-phase stationary phase and a gradient of mobile phase B, which is phosphoric acid/water/acetonitrile/tetrahydrofuran at a ratio of about 1/1000/1500/25 (v/v/v/v), in mobile phase A, which is phosphoric acid/water/tetrahydrofuran at a ratio of about 1/1000/10 (v/v/v).

### Claim 9 (depends on 1)

The method of claim 1, wherein the chloroeremomycin-producing microorganism is a microorganism of genus Nocardia, genus Amycolatopsis, or genus Kibdelosporangium.

### Claim 10 (depends on 1)

The method of claim 1, wherein the chloroeremomycin-producing microorganism is Kibdelosporangium aridum.

### Claim 11 (depends on 2)

The method of claim 2, wherein the polymeric exchange resin is a sulfonated macroporous copolymer of styrene and divinylbenzene.

### Claim 12 (depends on 3)

The method of claim 3, wherein the polymeric adsorbent resin or the hydrophobic polymeric resin column is a non-functionalized macroporous copolymer of styrene and divinylbenzene.

### Claim 13 (depends on 5)

The method of claim 5, wherein the polymeric hydrophobic resin is a non-functionalized macroporous copolymer of styrene and divinylbenzene.

### Claim 14 (depends on 1)

The method of claim 1, wherein the organic solvent is methanol.

### Claim 15 (depends on 3)

The method of claim 3, wherein the organic solvent is methanol.

### Claim 16 (depends on 5)

The method of claim 5, wherein the aqueous acid is formic acid and/or phosphoric acid.

### Claim 17 (depends on 6)

The method of claim 6, wherein the concentrating of the oritavancin solution is via distillation of volatile solvents under reduced pressure or ultrafiltration/diafiltration.

### Claim 18 (depends on 6)

The method of claim 6, wherein the drying of the precipitated oritavancin is via drying on a tray or in a Nutsche filter at elevated temperature and reduced pressure.

### Claim 19 (depends on 3)

The method of claim 3, wherein the method further comprises performing a concentrating step and a precipitating step between the decolorizing and chromatography.

### Claim 20 (depends on 1)

The method of claim 1, wherein the method further comprises terminating the reacting step of c) using a hydride reagent.

### Claim 21

A method for preparing an oritavancin drug substance preparation, comprising:
a) growing a culture of a chloroeremomycin-producing microorganism under fermentative conditions in a medium free of animal-sourced material (ASM) and under conditions promoting biosynthesis of chloroeremomycin by the culture,
b) recovering chloroeremomycin from fermentation broth produced in a) using a polymeric exchange resin,
c) decolorizing the chloroeremomycin recovered in b) using a polymeric adsorbent resin, chromatographically separating the decolorized chloroeremomycin using a hydrophobic polymeric resin column, and precipitating the separated chloroeremomycin using an organic solvent,
d) preparing a solution of the precipitated chloroeremomycin of c) and a copper salt in an organic solvent, reacting the solution with 4-chloro-4′-biphenyl carboxaldehyde, and precipitating oritavancin-copper complex from the solution using acetonitrile,
e) de-complexing copper from the oritavancin-copper complex of d) by adding an aqueous acid and separating the de-complexed oritavancin using a polymeric hydrophobic resin, wherein the adding and separating are performed concurrently or sequentially,
f) eluting oritavancin from the polymeric hydrophobic resin of e),
g) concentrating oritavancin eluted from the resin in f),
h) precipitating oritavancin from the concentrate of g) in aqueous ethanol, and
i) drying the precipitated oritavancin, thereby preparing an oritavancin drug sub stance preparation,
wherein the oritavancin drug substance preparation has a maximum impurity level of not more than 3.0% by peak area of impurity 1 and impurity 7, defined by peak A of FIG. 1 and peak G of FIG. 2, respectively; or
wherein the oritavancin drug substance preparation has about 85% purity or greater by peak area relative to impurities 1-16, defined by peak A of FIG. 1 and peaks B-P of FIG. 2, respectively.