# US 8,541,359 B2 · Pharmaceutical compositions and methods for peptide treatment

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- Number: US 8,541,359 B2
- Document ID: US8541359B2
- Status: Granted
- Kind: B2
- Application number: 12/562,974
- Filed: 2009-09-18
- Published: 2010-01-14
- Granted: 2013-09-24
- Earliest claimed: 2001-06-22
- Assignees: CPEX Pharmaceuticals, Inc.
- Applicants: Robert J. Gyurik; Carl Reppucci
- Inventors: Robert J. Gyurik; Carl Reppucci
- Web page: https://patentgrep.com/patent/US8541359B2

## CPC

- A61K 9/0043: {Nose}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 9/107: Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)}
- A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)}
- A61K 31/12: Ketones
- A61K 31/365: Lactones
- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 38/02: Peptides of undefined number of amino acids; Derivatives thereof
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/25: Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K 47/08: containing oxygen, {e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides}
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K 47/186: {Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide}
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone}
- 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 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- 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

Disclosed are compositions and methods for treating a patient with a pharmaceutically active agent other than insulin selected from the group consisting of peptides, peptidomimetics, and proteins, wherein the pharmaceutical composition is in the form of an emulsified nasal spray comprising: a macrocyclic permeation enhancer, a liquid carrier comprising water, and a therapeutically effective amount of a pharmaceutically active agent other than insulin selected from the group consisting of peptides, peptidomimetics, and proteins; wherein the macrocyclic permeation enhancer is a Hsieh enhancer emulsified in the liquid carrier.

## Claims

### Claim 1

A pharmaceutical composition in the form of an emulsion suitable for delivery to a mucous membrane comprising: a macrocyclic permeation enhancer, a liquid carrier, a hydrocolloid emulsifying agent, and a therapeutically effective amount of a pharmaceutically active agent other than insulin selected from the group consisting of peptides and proteins; wherein said macrocyclic permeation enhancer is a Hsieh enhancer; said Hsieh enhancer having the following structure:
wherein X and Y are oxygen, sulfur or an imino group of the structure
or ═N—R with the proviso that when Y is the imino group of the structure ═N—R, X is an imino group of the structure
and when Y is sulfur, X is sulfur on an imino group of the structure
A is a group having the structure
wherein X and Y are defined above, m and n are integers having a value from 1 to 20 and the sum of m+n is not greater then 25, p is an integer having a value of 0 or 1, q is an integer having a value of 0 or 1, r is an integer having a value of 0 or 1, and each of R, R1, R2, R3, R4, R5 and R6 is independently hydrogen or an alkyl group having from 1 to 6 carbon atoms which may be straight chained or branched provided that only one of R1 to R6 can be an alkyl group, with the proviso that when p, q and r have value of 0 and Y is oxygen, m+n is at least 11, and with the further proviso that when X is an imino group, q is equal to 1, Y is oxygen and p and r are 0, then m+n is at least 11.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein said Hsieh enhancer is selected from the group consisting of 3-methylcyclopentadecanone, 9-cycloheptadecen-1-one, cyclohexadecanone, cyclopentadecanone, oxacyclohexadecan-2- one and mixtures thereof.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, further comprising a crystallization inhibitor.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, further comprising an enzyme inhibitor.

### Claim 5 (depends on 4)

The pharmaceutical composition of claim 4, wherein said enzyme inhibitor is selected from the group consisting of leupeptin and aprotinin.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, further comprising a non-ionic surfactant or combination of non-ionic surfactants.

### Claim 7 (depends on 6)

The pharmaceutical composition of claim 6, wherein said non-ionic surfactant or combination of non-ionic surfactants has an HLB of from about 7 to about 14.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, further comprising a pH modifier.

### Claim 9

A method for treating a patient with a peptide or a protein, said method comprising administering to a patient in need of peptide treatment or protein treatment , a pharmaceutical composition in the form of an emulsion suitable for delivery to a mucous membrane comprising; a macrocyclic permeation enhancer, a liquid carrier, a hydrocolloid emulsifying agent, and a therapeutically effective amount of a pharmaceutically active agent other than insulin selected from the group consisting of peptides and proteins; wherein said macrocylic permeation enhancer is a Hsieh enhancer; said Hsieh enhancer having the following structure:
wherein X and Y are oxygen, sulfur or an imino group of the structure
or ═N—R with the proviso that when Y is the imino group of the structure ═N—R, X is an imino group of the structure
and when Y is sulfur, X is sulfur or an imino group of the structure
A is a group having the structure
wherein X and Y are defined above, m and n are integers having a value from 1 to 20 and the sum of m+n is not greater than 25, p is an integer having a value of 0 or 1, q is an integer having a value of 0 or 1, r is an integer having a value of 0 or 1, and each of R, R1, R2, R3, R4, R5 and R6 is independently hydrogen or an alkyl group having from 1 to 6 carbon atoms which may be straight chained or branched provided that only one of R1 to R6 can be an alkyl group, with the proviso that when p. q and r have a value of 0 and Y is oxygen, m+n is at least 11, and with the further proviso that when X is an imino group, q is equal to 1, Y is oxygen, and p and r are), then m+n is at least 11.

### Claim 10 (depends on 9)

The method of claim 9, wherein said Hsieh enhancer is selected from the group consisting of 3-methylcyclopentadecanone, 9-cycloheptadecen-1-one, cyclohexadecanone, cyclopentadecanone, oxacyclohexadecan-2-one and mixtures thereof.

### Claim 11 (depends on 9)

The method of claim 9, wherein said pharmaceutical composition further comprises a crystallization inhibitor.

### Claim 12 (depends on 9)

The method of claim 9, wherein said pharmaceutical composition further comprises an enzyme inhibitor.

### Claim 13 (depends on 12)

The method of claim 12, wherein said enzyme inhibitor is selected from the group consisting of leupeptin and aprotinin.

### Claim 14 (depends on 9)

The method of claim 9, wherein said pharmaceutical composition further comprises a non-ionic surfactant or a combination of non-ionic surfactants.

### Claim 15 (depends on 14)

The method of claim 14, wherein said non-ionic surfactant or combination of non-ionic surfactants has an HLB of from about 7 to about 14.

### Claim 16 (depends on 9)

The method of claim 9, wherein said pharmaceutical composition further comprises a pH modifier.