WO2008107193A1

WO2008107193A1 - Topical composition comprising retinoid receptor agonist for treatment of acne

Info

Publication number: WO2008107193A1
Application number: PCT/EP2008/001805
Authority: WO
Inventors: Sabine Fielhauer; Fritjof Evers; Klaus Treudler; Henning Mallwitz
Original assignee: Almirall Hermal GmbH
Current assignee: Almirall Hermal GmbH
Priority date: 2007-03-06
Filing date: 2008-03-06
Publication date: 2008-09-12
Anticipated expiration: 2009-09-06
Also published as: EP1967180A1

Abstract

The invention relates to a topical composition comprising (a) a retinoid receptor agonist, (b) benzoyl peroxide, (c) a gel former and (d) a phospholipid. The invention also relates to a process for the preparation of the topical composition and to the use of the topical composition for the treatment of skin diseases.

Description

TOPICAL COMPOSITION COMPRISING RETINOID RECEPTOR AGONIST

FOR TREATMENT OF ACNE

The invention relates to a topical composition which comprises a retinoid receptor agonist and which is particularly suitable for use in the treatment of skin diseases such as acne.

Acne vulgaris is the most prevalent dermatological disease worldwide. Almost all adolescents at the age of 12 to 17 years are afflicted with acne diseases. However, some patients suffer from this condition even in later adulthood.

There are several causes for the development of acne. Among these are excessive sebum production, proliferation of bacteria such as propionibacterium acnes, inflammations as well as the increase in the production of androgens associated with the onset of puberty, which results in excessive scaling off of follicular corneocytes. Acne therapy is individually adjusted to the severity and the type of the acne disease according to localization and skin type. In the treatment of mild and intermediate acne, generally a topical medication is suggested.

Different active agents for the treatment of acne are known. For instance, retinoid receptor agonists such as adapalene are used in the treatment of certain forms of acne. Biochemical and pharmacological studies have shown that adapalene is a modulator of cell differentiation, keratinization and inflammatory processes. Adapalene binds to specific retinoic acid receptors. Although the particular mode of action of adapalene is not known, it is believed that topically applied adapalene normalizes differentiation of follicular epithelial cells resulting in reduced microcomedone formation. Clinical studies have shown that adapalene is an effective therapeutic agent in the treatment of mild and intermediate acne vulgaris.

Another active agent used in the treatment of acne is benzoyl peroxide (BPO) . Benzoyl peroxide has been used in dermatology for the treatment of acne vulgaris for a long time. The therapeutic effect of benzoyl peroxide on acne appears to be due to reduction of bacterial flora, such as of propionibacterium acnes, as well as its mild sebostatic and keratolytic effect. Benzoyl peroxide has been used for decades in concentrations of up to 10 %.

WO 03/55472 describes a gel composition for preventing or treating different disorders, including acne, which comprises a formulation of at least one retinoid, dispersed benzoyl peroxide, and at least one pH-independent gelling agent in a physiologically acceptable medium.

However, it has been found that a growing number of acne patients have at least partially dry skin. Moreover, many patients perceive anti-acne agents, such as adapalene or benzoyl peroxide, as skin drying. There is therefore a need for a composition for the treatment of skin diseases such as acne which minimizes skin drying when topically applied and which antagonizes skin drying properties of anti-acne agents.

This problem is surprisingly solved by the composition according to claims 1 to 14 and 17. The invention also relates to the process according to claim 15 and 16 and to the use of the composition according to claims 18 and 19.

The topical composition according to the invention is characterized in that it comprises

a) a retinoid receptor agonist; b) benzoyl peroxide; c) a gel former; and d) a phospholipid.

In the composition according to the invention a gel former as gelling component is combined with a phospholipid as lipid component. Due to the combination of the gel component and the lipid component a quasi-emulsion is formed. This quasi- emulsion comprises at least one retinoid receptor agonist, which preferably acts as an anti-acne agent.

The composition according to the invention represents a new formulation wherein, surprisingly, certain properties of gels and creams have been combined such that an improved suitability for the treatment of skin diseases such as acne is achieved in a broad population of patients.

In particular, due to the cream content of the formulation, skin drying is minimized and aggravation of a condition of dry skin caused by anti-acne agents is prevented. Moreover, due to the hydrogel content of the formulation and the use of phospholipid in the cream portion, excessive administration of fat to the skin surface is prevented. Thus, a fatty skin feeling remaining after the application is also prevented. This is particularly important because many acne diseases are associated with excessive sebum production. In addition, the cooling effect of gels is advantageous particularly in inflammatory acne.

Particularly when applying higher dosages of benzoyl peroxide in the known formulations of anti-acne compositions, many patients have complained of skin drying. It is therefore a particular advantage of the composition according to the invention that it allows to substantially prevent or at least substantially reduce skin drying even in a combination product comprising a retinoid receptor agonist and benzoyl peroxide.

Moreover, the composition according to the invention has good cosmetic properties and a high acceptance with patients.

A composition is preferred, wherein the retinoid receptor agonist is selected from the group consisting of adapalene, tretinoin, isotretinoin, motretinide, tazarotene and retinol. The retinoid receptor agonist adapalene is particularly preferred. It is also preferred that the composition comprises from 0.01 to 1.0 wt.-%, particularly from 0.025 to 0.3 wt.-% of retinoid receptor agonist.

According to a preferred embodiment, the composition according to the invention comprises from 0.5 to 15.0 wt.-%, particularly from 2.5 to 7.5 wt.-% of benzoyl peroxide.

The composition according to the invention comprises at least one gel former. The term "gel former" as used herein refers to an ingredient of the composition which in agueous phase forms a viscoelastic mass consisting of colloidal suspensions. Different gel formers are suitable for use in the composition according to the invention. A composition is preferred which comprises at least one gel former selected from the group consisting of cellulose ethers, xanthan gum, carbomers, alginates and magnesium-silicate. Among these, carbomers are particularly preferred. Examples of suitable cellulose ethers are alkyl celluloses such as methyl cellulose and hydroxyethyl cellulose.

Carbomers are in particular homopolymers and copolymers of acrylic acids which are cross-linked with polyalkenyl polyether. Examples of suitable carbomers include Carbomer 934, Carbomer 940 (Synthalene K) and Carbomer 941.

Alginates are salts or esters of alginic acid. Examples of suitable alginates include sodium alginate and propylene glycol alginate.

Depending on the nature of the gel former used, the desired level of gel formation is achieved by different amounts of the gel former. Suitable gel formation can for example be achieved by a composition comprising:

0.1 to 5.0 wt.-%, preferably 0.5 to 2.5 wt.-% of cellulose ether; 0.1 to 5.0 wt. -%, preferably 0.5 to 2.5 wt.-% of xanthan gum;

0.1 to 3.0 wt.-%, preferably 0.4 to 2.0 wt.-% of carbomer;

0.1 to 5.0 wt.-%, preferably 0.5 to 2.5 wt.-% of alginate; and/or

0.1 to 8.0 wt.-%, preferably 0.5 to 5.0 wt.-% of magnesium silicate.

A composition comprising 0.2 to 5.0 wt.-%, particularly 0.5 to 2.5 wt.-%, and more particularly 1.0 to 2.0 wt.-% of gel former is particularly preferred.

It has surprisingly been found that a composition according to the invention is stable when it comprises, for example, carbomer as gel former and benzoyl peroxide as a further antiacne agent. Thus, the influence on the stability of the gel phase of benzoic acid liberated by decomposition of benzoyl peroxide can surprisingly be compensated for by using sufficiently high amounts of carbomer within the ranges defined above. The composition according to the invention comprises a phospholipid. It is preferred that the phospholipid is a phosphoglyceride, more preferably a non-hydrogenated or hydrogenated phosphatidylcholine, such as a hydrogenated soy lecithin. Preferably, the composition comprises a lecithin fraction having a high content of non-hydrogenated and/or hydrogenated phosphatidylcholine. Suitable lecithin fractions are for example available under the name Phospholipone^® 90 NG

(non-hydrogenated) or Phospholipone^® 80 H (hydrogenated) from Phospholipid GmbH, Germany. It is further preferred that the composition comprises 1.0 to 10.0 wt.-%, particularly 2.0 to

7.5 wt.-%, more particularly 2.5 to 5.0 wt.-% of phospholipid.

In a preferred embodiment, the composition according to the invention does not comprise substantial amounts of further lipid components, such as fatty acid esters of monovalent, divalent and/or trivalent alkanols. Such lipid components, particularly such fatty acid esters, have been found to often lead to undesired spreading of composition upon application to the skin, which may be problematic especially where a composition is to be applied to skin areas close to the eyes. These lipid components, particularly fatty acid esters, may also be comedogenic. Moreover, they are often effective emollients, which may cause an undesirable skin feeling. It has also been found that preparation of a phospholipid phase is often technologically more demanding when such phase comprises a higher level of lipid components, such as the above mentioned fatty acid esters. It is further preferred that the composition according to the invention comprises less than 5 wt.-%, particularly less than 2 wt.-%, more particularly less than 0.5 wt.-% of fatty acid ester of monovalent, divalent and/or trivalent alkanol.

The composition according to the invention may optionally comprise further ingredients.

In a preferred embodiment, the composition additionally comprises at least one non-ionic emulsifier. Examples for suitable non-ionic emulsifiers are ethoxylated sugar alcohol fatty acid esters, particularly ethoxylated sorbitan fatty acid esters, more particularly polyoxyethylene sorbitan monooleate, such as the polyoxyethylene (20) sorbitan monooleate commercially available under the name Polysorbate 80 or Tween^® 80, and (mixed) polyalkylene glycols, particularly diblock and triblock copolymers of polypropylene glycol and polyethylene glycol, such as poloxamers. It is further preferred that the composition according to the invention comprises 0.2 to 2.0 wt.-%, particularly 0.5 to 1.0 wt.-% of non-ionic emulsifier.

In another embodiment, the composition according to the invention is substantially free of additional emulsifiers.

In a further preferred embodiment, the composition according to the invention additionally comprises at least one polyol. Examples for suitable polyols are polyvalent alkanols, such as glycols, particularly C₂-C₆ alkylene glycols, or glycerol, and linear or cyclic sugar alcohols, such as sorbitol or inositol. A particularly preferred polyol is 1,3-butylene glycol. As a component of the composition according to the invention, polyols may act as humectants and may thus enhance the moisturizing effects of the formulation. It is further preferred that the composition according to the invention comprises 2.0 to 20.0 wt.-%, particularly 5.0 to 15.0 wt.-% of polyol .

In a preferred embodiment, the composition according to the invention does not comprise substantial amounts of monovalent alcohol, such as a monovalent aliphatic or aromatic alcohol. Monovalent alcohols have been found to often have an irritating effect, particularly when applied onto skin areas which are afflicted with acne lesions. Moreover, many monovalent alcohols have an unpleasant smell which is undesirable in cosmetic compositions. It is further preferred that the composition according to the invention comprises less than 5 wt.-%, particularly less than 2 wt.-%, more particularly less than 0.5 wt.-% of monovalent aliphatic or aromatic alcohol. Compositions according to the invention can optionally also comprise further active agents, such as further anti-acne agents. Examples for suitable anti-acne agents include α-hydroxy acids, salicylic acid, antibiotics and azelaic acid. Combination products offer the advantage of better treatment results and, thus, higher patient acceptance due to their improved efficiency and the associated higher compliance.

The composition according to the invention may also comprise a base or a buffering agent in order to adjust the composition to a desired pH value. Examples of suitable bases include inorganic bases, such as alkaline or alkaline earth metal hydroxides, or organic bases such as primary, secondary or tertiary amines or quaternary organic ammonium hydroxides. Particularly preferred bases are alkaline metal hydroxides, such as sodium hydroxide. It is further preferred that the composition comprises 0.1 to 5.0 wt.-%, particularly 0.5 to 2.0 wt.-%, more particularly 0.7 to 1.2 wt . -% of a base or buffering agent. Where the gel former is a carbomer, the ratio (wt/wt) of carbomer to base or buffering agent is preferably 5:1 to 1:2, particularly 2:1 to 1:1, more particularly 1.5:1 to 1.1:1.

According to a particularly preferred embodiment, the composition comprises

(a) 0.01 to 1.0 wt.-%, particularly 0.05 to 0.3 wt.-% of retinoid receptor agonist, preferably adapalene, (b) 0.5 to 15.0 wt.-%, particularly 2.5 to 7.5 wt.-% of benzoyl peroxide, (c) 0.2 to 3.0 wt.-%, particularly 0.5 to 2.5 wt.-%, more particularly 1.0 to 2.0 wt.-% of gel former, preferably carbomer, (d) 1.0 to 10.0 wt.-%, particularly 2.0 to 5.0 wt.-% of phospholipid, preferably non-hydrogenated and/or hydrogenated phosphatidylcholine, more preferably hydrogenated soy lecithin, (e) 0.2 to 2.0 wt.-%, particularly 0.5 to 1.0 wt.-% of non- ionic emulsifier, preferably ethoxylated sorbitan fatty acid ester, more preferably polyoxyethylene sorbitan monooleate, (f) 2.0 to 20.0 wt.-%, particularly 5.0 to 15.0 wt.-% of polyol, preferably C₂-C₆ alkylene glycol, more preferably 1,3-butylene glycol,

(g) 0.1 to 5.0 wt.-%, particularly 0.5 to 3.0 wt.-%, more particularly 1.0 to 2.0 wt.-% of base or buffering agent, particularly alkaline metal hydroxide, more particularly sodium hydroxide, and

(h) 50.0 to 90.0 wt.-%, particularly 70.0 to 85.0 wt.-% of water.

The composition according to the invention will generally have a pH suitable for topical application, preferably an eudermic pH. It is preferred that the composition has a pH in the range of 3.5 to 9.0, particularly 5.0 to 7.5, more preferably 6.0 to 6.5.

Finally, the composition according to the invention typically comprises water. It is preferred that the composition comprises 50.0 to 90.0 wt.-%, particularly 70.0 to 85.0 wt.-% of water.

The invention is also directed to a process for the preparation of a topical composition according to the invention.

The composition according to the invention can be prepared according to a relatively simple process. Typically, the process comprises the steps of

(i) mixing the phospholipid with a portion, preferably 20 to 60 wt.-%, of the total amount of water and adding the retinoid receptor agonist, (ii) dispersing the benzoyl peroxide and the gel former in the remaining amount of water, and (iii) mixing the resulting gel of step (ii) with the phospholipid phase obtained in step (i) .

Preferably, the process for the preparation of the composition of the invention is carried out using conventional mixing equipment without applying very high shear forces, such as the very high shear forces involved in technologies like high pressure homogenization. More particularly, apart from the step of dispersing the gel former, the process according to the invention can be carried out using e.g. anchor mixers or planetary paddle mixers operated at up to 100 RPM. Moreover, the process does not require the use of monovalent alcohols.

According to a preferred embodiment, the process comprises the steps of

(i) heating and mixing the phospholipid with the non-ionic emulsifier and a portion, preferably 20 to 60 wt.-%, of the total amount of polyol at a temperature in the range of 50 to 90 ⁰C, preferably 60 to 80 ⁰C, and subsequently emulsifying the resulting mixture with a portion, preferably 20 to 60 wt.-%, of the total amount of water, (ii) suspending the retinoid receptor agonist in a portion, preferably 5 to 30 wt.-%, of the total amount of polyol and adding the resulting suspension to the phospholipid phase obtained in step (i), (iii) mixing the remaining amount of water with the remaining amount of polyol and dispersing the benzoyl peroxide into this mixture, (iv) optionally milling the dispersion obtained in step (iii), preferably until the particle size of the benzoyl peroxide is below 100 μm, (v) dispersing the gel former in the suspension of benzoyl peroxide obtained in step (iii) or (iv) , and optionally neutralizing the resulting gel with a base or buffering agent, and (vi) mixing the gel obtained in step (v) with the phospholipid phase obtained in step (ii) . The invention also relates to a topical composition obtainable by any one of the processes described immediately above.

The invention also relates to the use of the composition according to the invention for the treatment of skin diseases. The skin disease is preferably acne, more preferably acne vulgaris .

The invention is further illustrated by way of the following examples which do not limit the scope of the invention in any way.

Examples :

Examples 1 to 7 :

Compositions according to the invention were prepared according to the following procedure:

The components Polysorbate 80, phospholipid and 40 wt.-% of the butanediol were heated together to about 70 ⁰C. This phase was emulsified with about 40 wt.-% of the specified amount of water. Adapalene was suspended in 10 wt.-% of the butanediol. This suspension was added to the phospholipid phase.

The remaining amount of water was mixed with the remaining amount of butanediol. Into this mixture the benzoyl peroxide was carefully dispersed. The resulting suspension was milled in a mill until the particle size of the benzoyl peroxide was below 100 μm. The gel former (methyl cellulose, xanthan gum or carbomer) was added to this fine suspension of benzoyl peroxide and was dispersed without clotting. Optionally, this phase was subsequently neutralized with sodium hydroxide.

The resulting gel was carefully mixed with the phospholipid phase .

The resulting products had the following composition (wt.-%):

Example 1:

Example 2 :

Example 5:

Example 6:

Adapalene 0.10

Benzoyl peroxide 7.50

Polysorbate 80 0.75

1, 3-Butanediol 8.00

Carbomer 940 (Synthalene K) 1.75

Sodium hydroxide 1.50

Hydrogenated phospholipid (Phospholipon 80 H) 3.00

Water, purified 77.40

Example 7 :

Claims

1. Topical composition comprising

(a) a retinoid receptor agonist;

(b) benzoyl peroxide;

(c) a gel former; and

(d) a phospholipid.

2. Composition according to claim 1, wherein the retinoid receptor agonist is selected from adapalene, tretinoin, isotretinoin, motretinide, tazarotene and/or retinol.

3. Composition according to claim 2, wherein the retinoid receptor agonist is adapalene.

4. Composition according to any one of claims 1 to 3, wherein the gel former is a cellulose ether, xanthan gum, a carbomer, an alginate and/or a magnesium silicate.

5. Composition according to any one of claims 1 to 4, wherein the phospholipid is a phosphoglyceride, preferably non- hydrogenated and/or hydrogenated phosphatidylcholine.

6. Composition according to any one of claims 1 to 5 comprising 0.01 to 1.0 wt.-%, preferably 0.025 to 0.3 wt. -% of retinoid receptor agonist.

7. Composition according to any one of claims 1 to 6 comprising 0.5 to 15.0 wt.-%, preferably 2.5 to 7.5 wt.-% of benzoyl peroxide.

8. Composition according to any one of claims 1 to 7 comprising 0.2 to 3.0 wt.-%, preferably 0.5 to 2.5 wt.-%, more preferably 1.0 to 2.0 wt.-% of gel former.

9. Composition according to any one of claims 1 to 8 comprising 1.0 to 10.0 wt.-%, preferably 2.0 to 7.5 wt.-% of phospholipid.

10. Composition according to any one of claims 1 to 9 additionally comprising 0.2 to 2.0 wt.-%, preferably 0.5 to 1.0 wt. -% of non-ionic emulsifier.

11. Composition according to any one of claims 1 to 10 additionally comprising 2.0 to 20.0 wt.-%, preferably 5.0 to 15.0 wt. -% of polyol.

12. Composition according to any one of claims 1 to 11 additionally comprising 50.0 to 90.0 wt.-%, preferably 70.0 to 85.0 wt. -% of water.

13. Composition according to any one of claims 1 to 12 comprising

(a) 0.01 to 1.0 wt. -% of retinoid receptor agonist, preferably adapalene,

(b) 0.5 to 15.0 wt. -% of benzoyl peroxide,

(c) 0.2 to 3.0 wt. -% of gel former, preferably carbomer,

(d) 1.0 to 10.0 wt. -% of phospholipid, preferably non- hydrogenated and/or hydrogenated phosphatidylcholine, more preferably hydrogenated soy lecithin,

(e) 0.2 to 2.0 wt. -% of non-ionic emulsifier, preferably ethoxylated sorbitan fatty acid ester, more preferably polyoxyethylene sorbitan monooleate,

(f) 2.0 to 20.0 wt. -% of polyol, preferably C₂-C₆ alkylene glycol, more preferably 1,3-butylene glycol,

(g) 0.1 to 5.0 wt.-% of base or buffering agent, preferably alkaline metal hydroxide, more preferably sodium hydroxide, and

(h) 50.0 to 90.0 wt. -% of water.

14. Composition according to any one of claims 1 to 13 having a pH in the range of 3.5 to 9.0, preferably 5.0 to 7.5, more preferably 6.0 to 6.5.

15. Process for the preparation of the composition according to any one of claims 1 to 14 comprising the steps of (i) mixing the phospholipid with a portion, preferably 20 to 60 wt.-l, of the total amount of water and adding the retinoid receptor agonist,

(ii) dispersing the benzoyl peroxide and the gel former in the remaining amount of water, and

(iii) mixing the resulting gel of step (ii) with the phospholipid phase obtained in step (i).

16. Process according to claim 15 comprising the steps of

(i) heating and mixing the phospholipid with the non- ionic emulsifier and a portion, preferably 20 to 60 wt.-%, of the total amount of polyol at a temperature in the range of 50 to 90 ⁰C, preferably 60 to 80 ⁰C, and subsequently emulsifying the resulting mixture with a portion, preferably 20 to 60 wt.-%, of the total amount of water,

(ii) suspending the retinoid receptor agonist in a portion, preferably 5 to 30 wt.-%, of the total amount of polyol and adding the resulting suspension to the phospholipid phase obtained in step (i) ,

(iii) mixing the remaining amount of water with the remaining amount of polyol and dispersing the benzoyl peroxide into this mixture,

(iv) optionally milling the dispersion obtained in step (iii) , preferably until the particle size of the benzoyl peroxide is below 100 μm,

(v) dispersing the gel former in the suspension of benzoyl peroxide obtained in step (iii) or (iv) , and optionally neutralizing the resulting gel with a base or buffering agent, and

(vi) mixing the gel obtained in step (v) with the phospholipid phase obtained in step (ii).

17. Topical composition obtainable by the process according to claim 15 or 16. 14 and 17 for the treatment of skin diseases.

19. Use according to claim 18, wherein the skin disease is acne, preferably acne vulgaris.