# US 10,869,874 B2 · Methods and compositions for topical delivery of prostaglandins to subcutaneous fat

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- Number: US 10,869,874 B2
- Document ID: US10869874B2
- Status: Granted
- Kind: B2
- Application number: 15/816,253
- Filed: 2017-11-17
- Published: 2018-06-21
- Granted: 2020-12-22
- Earliest claimed: 2013-05-15
- Assignees: Topokine Therapeutics, Inc.
- Applicants: Topokine Therapeutics, Inc.
- Inventors: Michael S. Singer; Murat V. Kalayoglu
- Web page: https://patentgrep.com/patent/US10869874B2

## CPC

- A61K 31/5575: having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
- A61K 8/34: Alcohols
- A61K 8/345: {containing more than one hydroxy group}
- A61K 8/361: {Carboxylic acids having more than seven carbon atoms in an unbroken chain; Salts or anhydrides thereof}
- A61K 8/37: Esters of carboxylic acids
- A61K 8/69: containing fluorine
- 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 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61Q 19/06: for countering cellulitis
- 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)
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS

## Abstract

Described herein are compositions comprising a prostaglandin FP receptor agonist (PFPRA) compound and a fatty acid, e.g., oleic acid, that, when topically applied to the skin, locally delivers a therapeutically effective amount of the PFPRA compound or active metabolite thereof to subcutaneous fat under the skin. The therapeutic effect is, for example, reduction of the subcutaneous fat under the skin. Further provided are methods of reducing body fat in a subject comprising topically administering the composition to the subject. The present invention also provides kits comprising the composition and instructions for use.

## Claims

### Claim 1

A method for reducing subcutaneous fat in a subject, the method comprising topically administering to the subject a composition comprising a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
each instance of independently represents a single bond or a double bond which can be in the cis or trans configuration;
A is optionally substituted C1-10 alkylene, optionally substituted C2-10 alkenylene, or optionally substituted C2-10 alkynylene, wherein the alkylene, alkenylene, or alkynylene group is optionally interrupted by one or more —O— or —S— groups;
B is hydrogen, optionally substituted C3-7 carbocyclyl, optionally substituted 3-8-membered heterocyclyl, optionally substituted 5-14 membered-heteroaryl, optionally substituted C6-10 aryl, optionally substituted C1-30 alkyl, optionally substituted C2-30 alkenyl, or optionally substituted C2-30 alkynyl;
X is —OR4, —SR4, or —N(R4)2, wherein each instance of R4 is independently hydrogen, optionally substituted C1-30 alkyl, optionally substituted C2-30 alkenyl, optionally substituted C2-30 alkynyl, —C(═O)R5, or —C(═O)OR5, wherein R5 is optionally substituted C1-30 alkyl, optionally substituted C2-30 alkenyl, or optionally substituted C2-30 alkynyl, or two R4 groups are joined to form an optionally substituted 3-8-membered heterocyclyl or optionally substituted 5-14-membered heteroaryl ring;
Z is ═O, ═S, or ═NRZ, wherein RZ is selected from hydrogen, an amino protecting group, —OH, substituted hydroxyl, optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 3-8-membered heterocyclyl, optionally substituted C6-10 aryl, or optionally substituted 5-14-membered heteroaryl, or Z represents two hydrogen atoms; and
one of R1 and R2 is ═O, —OH, or a —O(CO)R6 group and the other one is —OH or —O(CO)R6, or R1 is ═O and R2 is H, wherein R6 is an optionally substituted C1-20 alkyl, optionally substituted C2-20 alkenyl, optionally substituted C2-20 alkynyl, or —(CH2)mR7, wherein m is 0 or an integer of between 1-10, inclusive, and R7 is optionally substituted C3-7 carbocyclyl, optionally substituted 3-8-membered heterocyclyl, optionally substituted C6-10 aryl, or optionally substituted 5-14-membered heteroaryl; and
wherein the composition further comprises a fatty acid.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) is of Formula (I-a):
or a pharmaceutically acceptable salt thereof, wherein:
each instance of independently represents a single bond or a double bond which can be in the cis or trans configuration;
each instance of R3 and R3′ is independently hydrogen, halogen, —OH, substituted hydroxyl, or —O(CO)R8, wherein R8 is optionally substituted C1-20 alkyl, optionally substituted C2-20 alkenyl, optionally substituted C2-20 alkynyl, or —(CH2)mR9 wherein m is 0 or an integer between 1-10, inclusive, and R9 is optionally substituted C3-7 carbocyclyl, optionally substituted C6-10 aryl, or optionally substituted 5-14-membered heteroaryl, or R3 and R3′ are joined to form ═O;
Y is selected from the group consisting of optionally substituted C1-10 alkyl, C1-10 perhaloalkyl, optionally substituted C2-10 alkenyl, optionally substituted C2-10 alkynyl, halo, nitro, cyano, thiol, substituted thiol, hydroxyl, substituted hydroxyl, amino, monosubstituted amino, and disubstituted amino;
G is —O— or —S—;
y is 0, 1, or 2;
x is 0 or 1; and
n is 0 or an integer of from 1 to 5, inclusive.

### Claim 3 (depends on 2)

The method of claim 2, wherein the compound of Formula (I-a) is of Formula (I-d3):
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) is selected from the group consisting of bimatoprost, bimatoprost isopropyl ester, bimatoprost free acid, travoprost, fluprostenol, latanoprost, latanoprost free acid, tafluprost, tafluprost free acid, CAY10509, CAY10509 free acid, and pharmaceutically acceptable salts thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein the concentration of the compound of Formula (I) is between about 0.05 percent and about 0.5 percent, inclusive, by weight of the total weight of the composition.

### Claim 6 (depends on 1)

The method of claim 1, wherein the fatty acid is of the formula:
or a pharmaceutically acceptable salt thereof, wherein RFA1 is optionally substituted C10-20 alkyl or optionally substituted C10-20 alkenyl.

### Claim 7 (depends on 6)

The method of claim 6, wherein RFA1 is an alkenyl group of formula (a):
wherein:
p is an integer between 2 and 8, inclusive;
q is an integer between 1 and 8, inclusive; and
RFA2 is an optionally substituted C1-C10 alkyl, or an optionally substituted C2-C10 alkenyl;
provided the sum of carbons of formula (a) does not exceed 20.

### Claim 8 (depends on 1)

The method of claim 1, wherein the fatty acid is selected from the group consisting of lauric acid, myristic acid, palmitic acid, stearic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, linoleic acid, and a-linoleic acid.

### Claim 9 (depends on 1)

The method of claim 1, wherein the composition comprises between about 1 percent and about 20 percent of fatty acid, inclusive, by weight of the total weight of the composition.

### Claim 10 (depends on 1)

The method of claim 1, wherein the composition comprises between about 1 percent and about 5 percent of fatty acid, inclusive, by weight of the total weight of the composition.

### Claim 11 (depends on 1)

The method of claim 1, wherein the composition comprises between about 2 percent and about 4 percent of fatty acid, inclusive, by weight of the total weight of the composition.

### Claim 12 (depends on 1)

The method of claim 1 further comprising an organic alcohol.

### Claim 13 (depends on 12)

The method of claim 12, wherein the organic alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, 1,3-butanediol, ethylene glycol, propylene glycol, and mixtures thereof.

### Claim 14 (depends on 13)

The method of claim 13, wherein the organic alcohol is ethanol, propylene glycol, or a mixture thereof.

### Claim 15 (depends on 12)

The method of claim 12, wherein the composition comprises between about 5 percent and about 50 percent of organic alcohol, inclusive, by weight of the total weight of the composition.

### Claim 16 (depends on 12)

The method of claim 12, wherein the composition comprises between about 20 percent and about 30 percent of organic alcohol, inclusive, by weight of the total weight of the composition.

### Claim 17 (depends on 12)

The method of claim 12, wherein the composition comprises between about 60 percent and about 80 percent of organic alcohol, inclusive, by weight of the total weight of the composition.

### Claim 18 (depends on 1)

The method of claim 1 further comprising a viscosity-enhancing agent.

### Claim 19 (depends on 18)

The method of claim 18, wherein the viscosity-enhancing agent is glycerin.

### Claim 20 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) is latanoprost.

### Claim 21 (depends on 1)

The method of claim 1, wherein the fatty acid is oleic acid.

### Claim 22 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) is latanoprost; and
the fatty acid is oleic acid.