# US 9,433,628 B2 · Enzymatic process for obtaining 17α-monoesters of cortexolone and/or its 9,11-dehydroderivatives

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- Number: US 9,433,628 B2
- Document ID: US9433628B2
- Status: Granted
- Kind: B2
- Application number: 14/073,928
- Filed: 2013-11-07
- Published: 2014-06-26
- Granted: 2016-09-06
- Earliest claimed: 2007-08-03
- Assignees: Cassiopea S.P.A.
- Applicants: Cassiopea S.P.A.
- Inventors: Mauro Ajani; Luigi Moro
- Web page: https://patentgrep.com/patent/US9433628B2

## CPC

- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- 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 47/44: Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin (synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14)
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/24: of the sex hormones
- A61P 5/28: Antiandrogens
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/16: Masculine contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/08: Antiseborrheics
- A61P 17/10: Anti-acne agents
- A61P 17/14: for baldness or alopecia
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- C07J 5/0053: {not substituted in position 16}
- C07J 7/008: {substituted in position 21}
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C12P 33/005: {Degradation of the lateral chains at position 17}
- 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
- C07J: STEROIDS (seco-steroids C07C)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- 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

The present invention refers to a new enzymatic process for obtaining 17α-monoesters of cortexolone and/or its 9,11-dehydroderivatives starting from the corresponding 17α,21-diesters which comprises an enzymatic alcoholysis reaction. Furthermore, the present invention refers to new crystalline forms of cortexolone 17α-propionate and 9,11-dehydro-cortexolone 17α-butanoate.

## Claims

### Claim 1

Crystalline form IV of cortexolone-17α-propionate characterized by a DRX as shown in FIG. 28.

### Claim 2

Crystalline form IV of cortexolone-17α-propionate characterized by XRPD peaks at about 4.8, 12.9, 14.4, 15.8, 16, 19.3, and 19.5 degrees 2theta.

### Claim 3

A process for preparing crystalline form IV of cortexolone-17α-propionate, the process comprising crystallizing cortexolone-17α-propionate from a propylene glycol/water or polyethylene glycol/water mixture.

### Claim 4 (depends on 3)

The process of claim 3, wherein the propylene glycol/water mixture has a ratio of propylene glycol to water of from about 1/2 to about 2/1.

### Claim 5 (depends on 4)

The process of claim 4, wherein the ratio of propylene glycol to water is about 1/1.

### Claim 6 (depends on 3)

The process of claim 3, wherein the polyethylene glycol/water mixture has a ratio of polyethylene glycol to water of from about 1/2 to about 2/1.

### Claim 7 (depends on 6)

The process of claim 6, wherein the ratio of polyethylene glycol to water is about 1/1.

### Claim 8 (depends on 3)

The process of claim 3, wherein the propylene glycol/water mixture has a ratio of propylene glycol to water of from about 1/3 to about 3/1.

### Claim 9 (depends on 3)

Crystalline form IV of cortexolone-17α-propionate prepared by the process of claim 3.

### Claim 10 (depends on 4)

Crystalline form IV of cortexolone-17α-propionate prepared by the process of claim 4.

### Claim 11 (depends on 5)

Crystalline form IV of cortexolone-17α-propionate prepared by the process of claim 5.

### Claim 12 (depends on 6)

Crystalline form IV of cortexolone-17α-propionate prepared by the process of claim 6.

### Claim 13 (depends on 7)

Crystalline form IV of cortexolone-17α-propionate prepared by the process of claim 7.

### Claim 14

A pharmaceutical composition comprising crystalline form IV of cortexolone-17α-propionate, water, and at least one physiologically acceptable excipient.

### Claim 15 (depends on 14)

The composition of claim 14, wherein the at least one physiologically acceptable excipient is propylene glycol, cetylic alcohol, glyceryl monostearate, liquid paraffin, or a combination of any of the foregoing.

### Claim 16 (depends on 14)

The composition of claim 14, further comprising mixed tocopherols, polysorbate 80, or a combination thereof.

### Claim 17 (depends on 14)

The composition of claim 14, wherein the composition is in the form of a cream.

### Claim 18 (depends on 14)

The composition of claim 14, wherein the composition further comprises solubilized cortexolone-17α-propionate.

### Claim 19 (depends on 18)

The composition of claim 18, wherein the solubilized cortexolone-17α-propionate and crystalline form IV of cortexolone-17α-propionate together comprise 0.1 to 2% by weight of the composition.

### Claim 20 (depends on 19)

The composition of claim 19, wherein the solubilized cortexolone-17α-propionate and crystalline form IV of cortexolone-17α-propionate together comprise 0.2 to 1% by weight of the composition.

### Claim 21 (depends on 14)

The composition of claim 14, wherein the crystalline form IV of cortexolone-17α-propionate is present at from about 0.1 to about 2% by weight of the composition.

### Claim 22

A pharmaceutical composition comprising crystalline form IV of cortexolone-17α-propionate.

### Claim 23 (depends on 22)

The composition of claim 22, wherein the composition is in the form of a tablet, capsule, powder, pellet, suspension, emulsion, cream, gel, ointment, lotion, or paste.

### Claim 24 (depends on 22)

The composition of claim 22, wherein the composition is in the form of a solid, semi-solid, or a paste.