# US 2015/0147403 A1 · Dermatological composition comprising oleosomes and retinoids, process for preparing the same and use thereof

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- Number: US 2015/0147403 A1
- Document ID: US20150147403A1
- Status: Published application
- Kind: A1
- Application number: 14/404,936
- Filed: 2013-05-30
- Published: 2015-05-28
- Earliest claimed: 2012-06-01
- Assignees: Galderma Research & Development
- Applicants: Galderma Research & Development
- Inventors: Amel Djedour
- Web page: https://patentgrep.com/patent/US20150147403A1

## CPC

- A61K 31/4015: having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
- 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 9/107: Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)}
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/402: 1-aryl substituted, e.g. piretanide
- A61P 17/00: Drugs for dermatological disorders
- 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

Compositions including at least 3″-tert-butyl-4′-(2-hydroxy-ethoxy)-4″-pyrrolidin-1-yl-[1,1′;3,1″]-terphenyl-4-carboxylic acid are described. The compositions can be oil-in-water emulsions made up of oily liquid globules each provided with a lamellar liquid crystal coating dispersed in an aqueous phase; a retinoid is either in the oily liquid globules or in the aqueous phase; each oily liquid globule is individually coated with a unilamellar or oligolamellar layer, obtained from at least one lipophilic surfactant, at least one hydrophilic surfactant and at least one separate anionic surfactant, and the coated oily liquid globules have a mean diameter lower than 800 nm.

## Claims

### Claim 1

A composition comprising at least 3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl-[1,1′;3′,1″]-terphenyl-4-carboxylic acid as pharmaceutical active agent, wherein:
the composition is an oil-in-water emulsion formed from oily liquid globules each provided with a lamellar liquid-crystal coating and dispersed in an aqueous phase,
the active agent is dissolved either in the oily liquid globules or in the aqueous phase of the oil-in-water emulsion,
each oily liquid globule is individually coated with a monolamellar or oligolamellar layer obtained from at least one lipophilic surfactant, at least one hydrophilic surfactant and at least one distinct anionic surfactant, and
the coated oily liquid globules have a mean diameter of less than 800 nm.

### Claim 2 (depends on 1)

The composition as claimed in claim 1, wherein the coated oily globules have a mean diameter of less than or equal to 500 nm.

### Claim 3 (depends on 1)

The composition as claimed in claim 1, wherein the lipophilic surfactant has an HLB of between 2 and 5.

### Claim 4 (depends on 3)

The composition as claimed in claim 3, wherein the lipophilic surfactant with an HLB of between 2 and 5 is selected from the group consisting of sucrose distearate, diglyceryl distearate, tetraglyceryl tristearate, decaglyceryl decastearate, diglyceryl monostearate, sorbitan monostearate, sorbitan tristearate, 15 diethylene glycol monostearate, the glyceryl ester of palmitic and stearic acids, polyoxyethylene monostearate comprising 2 oxyethylene units, polyoxyethylene stearyl ether comprising 2 oxyethylene units, glyceryl monobehenate and dibehenate and pentaerythrityl tetrastearate.

### Claim 5 (depends on 1)

The composition as claimed in claim 1, wherein the hydrophilic surfactant has an HLB of between 8 and 12.

### Claim 6 (depends on 5)

The composition as claimed in claim 5, wherein the hydrophilic surfactant with an HLB of between 8 and 12 is selected from the group consisting of polyoxyethylene sorbitan monostearate 4 OE, polyoxyethylene sorbitan tristearate 20 OE, polyoxyethylene monostearate 8 OE, hexaglyceryl monostearate, polyoxyethylene monostearate 10 OE, polyoxyethylene stearyl ether 10 OE, polyoxyethylene distearate 12 OE and polyoxyethylene methylglucose distearate 20 OE.

### Claim 7 (depends on 1)

The composition as claimed in claim 1, wherein the distinct anionic surfactant is a fatty acid or a fatty acid ester, the fatty acid comprising at least one saturated fatty chain containing more than 12 carbon atoms.

### Claim 8 (depends on 1)

The composition as claimed in claim 1, wherein the distinct anionic surfactant is selected from the group consisting of stearic acid, palmitic acid, arachidic acid and behenic acid.

### Claim 9 (depends on 1)

The composition as claimed in claim 1, wherein the surfactants are mixed in the following proportions to coat each oily liquid globule:
lipophilic surfactant: 45-50% by weight of the mixture;
hydrophilic surfactant: 30-35% by weight of the mixture; and
distinct anionic surfactant: 20-25% by weight of the mixture.

### Claim 10 (depends on 1)

The composition as claimed in claim 1, wherein the 3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic acid is present in an amount from 0.00001% to 0.3% by weight relative to the total weight of the composition.

### Claim 11 (depends on 1)

The composition as claimed in claim 1, wherein the oily liquid globules comprise at least one oily solvent selected from the group consisting of polyethoxylated fatty acids, glycol ethers, triglycerides and oils comprising the same, and fatty acid esters.

### Claim 12 (depends on 1)

The composition as claimed in claim 1, wherein the ratio of the total amount of surfactants to the total amount of oily phase constituting the oily liquid globules is from 10% to 25%.

### Claim 13 (depends on 1)

The composition as claimed in claim 1, wherein the 3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic acid is dissolved in the oily liquid globules.

### Claim 14 (depends on 13)

The composition as claimed in claim 13, wherein the composition comprises less than 0.5% by weight of pro-penetrating agent.

### Claim 15 (depends on 13)

The composition as claimed in claim 13, wherein the composition is free of pro-penetrating agent.

### Claim 16 (depends on 1)

The composition as claimed in claim 1, wherein the composition is in a form suitable for topical administration.

### Claim 17 (depends on 1)

The composition as claimed in claim 1, wherein the composition is provided in the form of a medicament.

### Claim 18 (depends on 1)

The composition as claimed in claim 1, wherein the composition is formulated for treating dermatological complaints.

### Claim 19 (depends on 1)

A method of treating dermatological complaints, the method comprising administering to an individual subject in need thereof an effective amount of the composition as claimed in claim 1, wherein the dermatological complaints are selected from the group consisting of:
1) dermatological conditions associated with a keratinization disorder relating to cell differentiation and proliferation, in particular for treating common acne, comedonal acne, polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata, senile acne, secondary acne such as solar acne, acne medicamentosa or occupational acne;
2) keratinization disorders, in particular ichthyosis, ichthyosiform conditions, lamellar ichthyosis, Darier's disease, palmoplantar keratoderma, leukoplakia, pityriasis rubra pilaris and leukoplakiform conditions, cutaneous or mucosal (buccal) lichen;
3) dermatological conditions with an inflammatory immunoallergic component, with or without a cell proliferation disorder, and in particular all forms of psoriasis, whether cutaneous, mucosal or ungual, and even psoriatic arthritis, or else atopic dermatitis and the various forms of eczema;
4) skin disorders caused by exposure to UV radiation, and also for repairing or combating skin aging, whether it is photo-induced or chronological, or for reducing actinic keratoses and pigmentations, or any pathological condition associated with chronological or actinic aging, such as xerosis, pigmentations and wrinkles;
5) any condition associated with benign dermal or epidermal proliferations, whether or not they are of viral origin, such as common warts, flat warts, molluscum contagiosum and epidermodysplasia verruciformis, or oral or florid papillomatoses;
6) dermatological disorders such as immune dermatoses, for instance lupus erythematosus, bullous immune diseases and collagen diseases, such as scleroderma;
7) stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy;
8) cicatrization disorders, or for preventing or repairing stretch marks, or else for promoting cicatrization;
9) in the treatment of any condition of fungal origin at the cutaneous level, such as tinea pedis and tinea versicolor;
10) pigmentation disorders, such as hyperpigmentation, melasma, hypopigmentation or vitiligo; and
11) cutaneous or mucosal cancerous or precancerous conditions, such as actinic keratoses, Bowen's disease, in-situ carcinomas, keratoacanthomas and skin cancers such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous lymphomas such as T lymphoma.

### Claim 20 (depends on 19)

The method as claimed in claim 19, wherein the dermatological complaints are selected from the group consisting of: acne, ichthyosis, ichthyosiform conditions, palmoplantar hyperkeratosis and psoriasis.

### Claim 21 (depends on 1)

A method of improving tolerance to 3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic acid, the method comprising administering an effective amount of the composition as claimed in claim 1 to an individual subject in need thereof.

### Claim 22 (depends on 1)

A method of improving cutaneous penetration of 3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic acid, the method comprising administering to an individual subject in need thereof an effective amount of the composition as claimed in claim 1.

### Claim 23 (depends on 1)

A method of obtaining controlled release of 3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylic acid, the method comprising administering to an individual subject in need thereof an effective amount of the composition as claimed in claim 1, wherein the 3″-tert-butyl-4′-(2-hydroxyethoxy)-4″-pyrrolidin-1-yl[1,1;3′,1″]terphenyl-4-carboxylic acid is dissolved in the oily liquid globules.

### Claim 24

A method of improving tolerance to a retinoid, the method comprising administering a composition to an individual subject in need thereof, wherein the composition comprises at least one retinoid and wherein the composition is an oil-in-water emulsion formed from oily liquid globules each comprising a lamellar liquid-crystal coating and dispersed in an aqueous phase, the retinoid being dissolved either in the oily liquid globules or in the aqueous phase of the oil-in-water emulsion, each oily liquid globule being individually coated with a monolamellar or oligolamellar layer obtained from at least one lipophilic surfactant, at least one hydrophilic surfactant and at least one distinct anionic surfactant, and the coated oily liquid globules having a mean diameter of less than 800 nm.

### Claim 25 (depends on 1)

A method of improving cutaneous penetration of a retinoid, the method comprising administering to an individual subject in need thereof an effective amount of the composition as claimed in claim 1, wherein the composition does not comprise any pro-penetrating agent.

### Claim 26 (depends on 1)

A method of obtaining controlled release of a retinoid, the method comprising administering to an individual subject in need thereof an effective amount of the composition as claimed in claim 1, wherein the active agent is dissolved in the oily liquid globules.

### Claim 27 (depends on 7)

The composition as claimed in claim 7, wherein the fatty acid comprising at least one saturated fatty chain has between 16 and 22 carbon atoms.

### Claim 28 (depends on 14)

The composition as claimed in claim 14, wherein the amount of the pro-penetrating agent is less than 0.3% by weight.

### Claim 29 (depends on 28)

The composition as claimed in claim 28, wherein the amount of the pro-penetrating agent is less than 0.1% by weight.