WO2015028035A1

WO2015028035A1 - Dermatological composition

Info

Publication number: WO2015028035A1
Application number: PCT/DK2014/050265
Authority: WO
Inventors: Flemming Licht
Original assignee: UNIGROUP APS
Current assignee: UNIGROUP APS
Priority date: 2013-09-02
Filing date: 2014-09-01
Publication date: 2015-03-05
Anticipated expiration: 2016-03-02
Also published as: EP3041460A1

Abstract

The present invention relates to a composition comprising ethyl lactateand kigelia. In particular, it relates to a dermatological composition for the treatment of acneand/or diaper dermatitis.

Description

Dermatological Composition

The present invention relates to a composition comprising ethyl lactate and kigelia. In particular, it relates to a dermatological composition for the treatment of dermatitis, such as diaper dermatitis and/or imperfections of the skin, such as acne, pimples and folliculitis.

Technical Background

The patent GB 1388836 describes a composition for treating skin, in particular acne, which composition comprises ethyl lactate (lactic acid ethyl ester). According to this patent, the composition should be water-free to prevent hydrolysis of the ester.

The patent GB 1555796 describes a composition for treating skin, in particular acne, which composition comprises ethyl lactate. According to this patent, it is necessary to employ water in the composition to ensure that the skin does not become excessively dehydrated. Ethyl lactate is stabilized in the presence of water using a buffer to control the pH.

The patent US 4613592 describes a water-in-oil emulsion for topical application to human skin for the treatment of acne, particularly a water-in-oil cream containing ethyl lactate. The emulsion comprises a silicone oil ingredient and an emulsifier, in addition to a buffer. According to this patent, a fluid lotion tends to flow away from acne lesions, and there exists consumer reluctance to accept that a clear liquid possesses curative active ingredients.

Folliculitis (also known as "Hot Tub Rash") is the inflammation of one or more hair follicles.

According to Wikipedia, the condition may occur anywhere on the skin with the exception of the palms of the hands and soles of the feet.

Diaper dermatitis is one of the most common skin disorders of infants and children. The reported incidence and age of onset vary worldwide, related to differences in diaper use, toilet training, hygiene, and child-rearing practices in different countries (Singalavanija S, Frieden IJ. Diaper dermatitis. Pediatr Rev 1995; 16:142. Levy M. Diaper rash syndrome or dermatitis. Cutis 2001; 67:37. Ward DB, Fleischer AB Jr, Feldman SR, Krowchuk DP. Characterization of diaper dermatitis in the United States. Arch Pediatr Adolesc Med 2000; 154:943. Scheinfeld N. Diaper dermatitis: a review and brief survey of eruptions of the diaper area. Am J Clin Dermatol 2005; 6:273).

The term "irritant dermatitis" in a broad sense represents response to the physical or toxic effects of a wide range of environmental exposures. Dermatitis arises when the defense or repairing capacity of the skin is exhausted, or when the penetration of chemicals excites an inflammatory response. The three main factors involved in the pathogeneses of irritant dermatitis are, disturbed barrier function, epidermal cell change and release of inflammatory mediators and cytokines (Wilkinson SM, Back MH .Contact dermatitis: Irritant in: Burns T, Breathnach S, Cox N, Griffiths S C; editors. Rooks Text Book of Dermatology, 7th edition; Blackwell Science, Oxford 2004 : pl9.1, 19.3, 19.18). In diaper dermatitis , factors like moisture, friction, urine, feces, and sometimes micro organism, result in dermatitis. The barrier function of the skin is affected, which results in an increase in irritant chemical penetration and pathogen replication (Boiko

S .Treatment of diaper dermatitis. Dermatol clinics 1999; 17 (1) : 235 - 240. Guin JD. Complication of topical hydrocortisone. J AM Acad Dermatol 1981 ; 4 : 417- 22. Bhat RM, Chavda R, Ribet V. To evaluate the efficacy and safety of "RV2427B" cream in Irritant dermatitis care. Ind Derm Online J 2013;4:18-4).

The treatment of this irritant dermatitis like diaper rash involves the elimination of the causal or favoring factor, the control of aggravating factors and administration of topical agents. Even though corticosteroids are extensively used in these conditions to reduce the inflammation, it can also result in undesirable side effects. In cases of diaper dermatitis, the occlusion of the wet diaper raises the absorption of the topical steroid and may lead to purple nodules termed granuloma gluteale infantum.

Summary of the invention

According to an aspect of the present invention, it concerns a topical composition comprising kigelia and one or more C1-C4 alkyl esters of lactic acid, malic acid, tartartic acid or citric acid.

According to an aspect of the present invention, it concerns a composition, preferably a topical composition, comprising ethyl lactate and kigelia.

The mode of action of ethyl lactate has been described in the article: "The mode of action of ethyl lactate as a treatment of acne", C. Prottey et al., British Journal of Dermatology, 110, 475-485 (1984). Without being bound by any theory, it is speculated that ethyl lactate may counteract keratinisation. According to GB 1555796 the primary symptom of acne is a disorder in the keratinasation of the upper part of the pilosebaceous follicle. The follicular ostium becomes obstructed by hyperkeratinised and cohesive horny cells. By counteracting keratinisation, ethyl lactate may arrest hyperkeratinisation.

It is an optional aim of the present invention to identify a suitable buffer for an ethyl lactate composition. In particular, it is an aim to find a buffer which is suitable for topical, such as skin application, such as for the treatment of acne or diaper dermatitis.

According to Wikipedia, kigelia is a genus of flowering plants in the family Bignoniaceae. The genus comprises only one species, Kigelia africana.

The word "kigelia" will be used to refer to the fruit extract of Kigelia africana.

According to an aspect of the present invention, kigelia is used as a buffer. Kigelia may stabilize the composition at pH about 5.5, which appears to be a preferred value for the skin. It is proposed that kigelia is particularly suitable for stabilizing the pH in a composition according to the invention. Note that the pH may be lowered slightly in the presence of a citric acid buffer. Further, kigelia appears to have antibacterial, anti-inflammatory and analgesic properties, which may be desirable in a composition according to the invention.

According to an aspect of the present invention, kigelia is used as a preservative or a stabilizer of ethyl lactate. Ethyl lactate is subject to be broken down by the sun light. This is in particular a problem upon using ethyl lactate in a composition for skin treatment, such as acne treatment, as the composition may be administered topically in a thin layer, exposing the external surface to sun light and humidity, and the internal surface to humidity or water emerging from the skin. It appears that kigelia is an effective stabilizer of ethyl lactate subjected to sun light and humidity. According to an aspect kigelia may act as an antioxidant. Antioxidant properties of kigelia are usually attributed to the contents of steroidic saponoside.

Additionally, kigelia is derived from a natural source, which is likely to lead to acceptance to consumers.

It thus appears kigelia is particularly suitable for a composition according to the present invention, combining buffer effect, antioxidant properties and preservative properties.

According to another aspect of the invention, it concerns a patch comprising a composition according to the invention. A patch is useful for keeping the composition in the intended place. Further, a discrete patch may conceal acne. In addition, a patch may protect ethyl lactate from degradation from sun light, humidity or water.

According to an aspect of the invention, it concerns a pen or stick comprising a composition according to the invention. A pen or stick is particularly useful for the precise application of a composition of the invention.

According to an aspect of the invention, it concerns a use of kigelia as a pH stabilizer for a skin product, preferably for application to the face.

According to an aspect of the invention, it concerns a use of kigelia as a preservative, preferably for ethyl lactate.

According to an aspect of the invention, it concerns a use of kigelia as an active ingredient. Ethyl lactate may improve the penetration of the active ingredient.

According to an aspect of the invention, it concerns a use of kigelia against Propionibacterium acnes (P. acnes).

According to an aspect of the invention, it concerns a use of a composition comprising ethyl lactate and kigelia for the prevention or treatment of imperfections of the skin, comprising, but no limited to, acne and pimples.

According to another aspect, the invention concerns a use of ethyl lactate for the prevention or treatment of dermatitis, such as diaper dermatitis. Diaper dermatitis may be associated with increased pH, caused by bacteria breaking down urea to ammonia. By lowering the pH, the ammonia production may be inhibited. Thus, the inventor of the present invention speculates that by adjusting the pH of the skin, symptoms of diaper dermatitis are alleviated or prevented.

According to an aspect, the invention concerns a composition of the invention, for the prevention or treatment of diaper dermatitis. Detailed Disclosure

According to an embodiment, the invention concerns a topical composition comprising kigelia and one or more C1-C4 alkyl esters of lactic acid, malic acid, tartartic acid or citric acid. Suitable C1-C4 alkyi esters comprise the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl esters. In the esters of the polybasic acids malic acid, citric acid and tartaric acid the C1-C4 alkyi groups contained in the ester groups can be the same or different. In the aforementioned polybasic acids all carboxylic groups or only a part of the carboxylic groups can be esterified. In consequence, also the corresponding malic acid and tartaric acid mono alkyi esters are considered in addition to malic acid and tartaric acid di-Cl-C4 alkyi esters. Of the C1-C4 alkyi esters of citric acid the corresponding mono-, di- and tri-alkyl esters are suitable. Preferred esters are the ethyl esters. Further preferred esters are the isopropyl esters. A preferred single compound is lactic acid ethyl ester. Further preferred single compounds are malic acid diethylester and malic acid di-isopropylester.

Of the above mentioned, C1-C4 alkyi lactates are suitable. Particularly suitable C1-C4 alkyi lactates comprise, but are not limited to, ethyl lactate, n-propyl lactate, iso-propyl lactate, n-butyl lactate, iso-butyl lactate and tert-butyl lactate, and mixtures thereof.

According to an embodiment, the invention concerns a composition, comprising kigelia and an ethyl ester of lactic acid, malic acid, tartaric acid or citric acid.

According to an embodiment, the invention concerns a composition comprising kigelia together with lactic acid ethyl ester and/or malic acid diisopropylester

According to an embodiment, the invention concerns a topical composition comprising ethyl lactate and kigelia.

According to an embodiment, the invention concerns a composition for application to the skin.

According to an embodiment, the invention concerns a composition, for the prevention or treatment of Acne.

According to an embodiment, the invention concerns a composition, comprising a total amount of C1-C4 alkyi ester of lactic acid, malic acid, tartartic acid and/or citric acid selected among 1-80%, 2-50%, 3-40%, 5-30%, 10-25% and 15-20%.

According to an embodiment, the invention concerns a composition, comprising an amount of ethyl lactate selected among 1-80%, 2-50%, 3-40%, 5-30%, 10-25% and 15-20%.

According to an embodiment, the invention concerns a composition, comprising an amount of kigelia selected among 1-60%, 2-50%, 3-40%, 5-30%, 10-25% and 15-20%.

According to an embodiment, the invention concerns a composition, which is a solid at room temperature. A solid composition is particularly useful for a stick. The solid composition may preferably be provided as a powder. The powder may exhibit a buffer effect upon contact with the skin of a user.

According to an embodiment, the invention concerns a composition, comprising an amount of alcohol, preferably ethanol, selected among 1-80%, 2-50%, 3-40%, 5-30%, 10-25% and 15-20%. According to an embodiment, the invention concerns a composition, comprising an amount of water selected among 1-90%, 2-50%, 3-40%, 5-30%, 10-25% and 15-20%. The presence of water may be used for a lotion.

According to an embodiment, the invention concerns a composition, comprising an antioxidant, preferably a vitamin selected among vitamin E and vitamin C, more preferred vitamin C.

According to an embodiment, the invention concerns a composition, comprising an amount of vitamin selected among 0.1-60%, 0.2-50%, 0.3-40%, 1-30%, 2-20% and 5-10%.

According to an embodiment, the invention concerns a composition, further comprising a preservative and/or a moisturizer.

According to an embodiment, the invention concerns a composition, in form of a liquid, a lotion, an ointment, or a cream.

According to an embodiment, the invention concerns a patch comprising a composition according to the invention. A patch is useful for keeping the composition in the intended place. Further, a discrete patch may conceal acne upon application. In addition, a patch may protect ethyl lactate from degradation from sun light, humidity or water.

According to an embodiment, the invention concerns a patch, wherein said patch is a hydrocoiloid patch. A hydrocoiloid plaster may act as a moisturizer. This allows administering ethyl lactate in the absence of water, potentially degrading ethyl lactate, without dehydrating the skin. Thus, a storage stable product is provided.

In an embodiment, a hydrocoiloid plaster acts as a moisturizer.

In an embodiment, the hydrocoiloid patch does not require the presence of a buffer, due to the absence of water in the composition.

According to an embodiment, the invention concerns a pen or stick comprising a composition according to the invention. A pen or stick is particularly useful for the precise application of a composition of the invention.

According to an embodiment, the invention concerns a use of kigelia as a pH stabilizer, in particular providing stability against photodegradation.

According to an embodiment, the invention concerns a use of kigelia as a pH stabilizer for a skin product, preferably for application to the face. According to an embodiment, the invention concerns a use of kigelia as a preservative, preferably for ethyl lactate.

According to an embodiment, the invention concerns a use of kigelia against Proplonibacterium acnes (P. acnes). According to an embodiment, the invention concerns a use of a composition comprising ethyl lactate and kigelia for the prevention or treatment of acne.

According to an embodiment, the invention concerns a use of a composition comprising ethyl lactate and kigelia for the prevention or treatment of folliculitis.

According to an embodiment, the invention concerns a composition of the invention, for the prevention or treatment of diaper dermatitis.

According to another embodiment, the invention concerns a use of ethyl lactate for the prevention or treatment of diaper dermatitis.

All rations and percentages are weight/weight unless otherwise mentioned.

All cited references are incorporated by reference.

The accompanying Figures and Examples are provided to explain rather than limit the present invention. It will be clear to the person skilled in the art that aspects, embodiments and claims of the present invention may be combined.

Examples

An embodiment of a composition according to the invention may be made with the ingredients listed in Table I, Example A. Kigelia africana fruit extract dissolved in water.

Table I - Example A

Measurement of ethyl lactate stability in presence of Kigelia africana fruit extract

The aim of this set of experiments was to test whether the use of Kigelia africana fruit extract increases the stability against degradation. In particular, it was found that K. africana extract increases the stability against photodegradation, as well as provides improved storage stability.

Experiment 1

Stability against photodegradation

1) A 0,02 M citric acid buffer solution is prepared at pH=5.5 from citric acid and trisodium citrate.

2) A 0,02 M citric buffer solution is prepared at pH=5,5 from citric acid and sodium

phosphate, dibasic.

3) Three versions of an antiacne product are made with the two buffers and K. africana extract (purchased from Blue Sky Botanies), respectively.

4) Samples are put in solar light at 24°C ±2°C, and pH is measured daily for up to 50 days.

In order to prepare 100 mL of citric-citrate buffer, 23,25 mL of 0,02 M citric acid and 76,75 mL of trisodium citrate is mixed. In order to prepare 100 mL of citric-phosphate buffer, 43,125 mL of 0,02 M citric acid and 56,875 mL of sodium phosphate, dibasic is mixed. The pH of the buffers is adjusted with triethanolamine.

Three samples of 10 g (about 10 mL) of each solution is prepared, i.e. a total of 9 samples.

Experiment 2

Storage stability

2) A 0,02 citric buffer solution is prepared at pH=5,5 from citric acid and sodium

phosphate/dibasic.

3) Three versions of the antiacne product are made with the two buffers and the K. africana extract, respectively.

4) Samples are kept in an oven at 50°C and pH is measured daily for up to 50 days.

The oven is preheated to 50°C. The oven should stay at this temperature during all of the experiment. Again, three samples of each formulation are used and their pH is measured every day, three times a day. The compositions are the same as above.

Experiment 3

The inventor of the present invention envisages a composition or use for dermatitis, such as diaper dermatitis, according to the present invention, may be used or tested as follows. A composition for a spray is prepared by mixing ethyl lactate, kigelia oil, canola oil, sweet almond oil, Cll-13 isoparaffin, vitamin E, borage oil, squalane, and C12-15 alkyl benzoate.

Children with irritant dermatitis due to diaper rash are included in the study. The role of the spray in the reduction of trans epidermal water loss (TEWL) is investigated. Comparison with a tube of cream comprising a composition according to the invention may be undertaken, applying the cream or spray twice daily (morning and evening). Subjects are evaluated for efficacy, tolerance and TEWL. The effect on day 0 is compared with day 7 and day 21.

Figures

Fig. 1 shows a photo-oxidation study. The figure shows how kigelia stabilizes the pH better than the comparison examples, with buffers of citric-citrate and citric-phosphate.

Fig. 2 shows a chemical oxidation study indicating the storage stability of the samples. The figure shows how kigelia stabilizes the pH better than the comparison examples, with buffers of citric- citrate and citric-phosphate.

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Claims

1. A use of kigelia as a preservative.

The use of kigelia according to claim 1, as a preservative for ethyl lactate.

3. The use of kigelia according to any of the preceding claims, as a pH stabilizer for a skin product.

4. The use of kigelia according to any of the preceding claims, as a pH stabilizer for a skin product for application to the face.

5. The use of kigelia according to any of the preceding claims, to improve stability against photodegradation.

A composition comprising kigelia and one or more C1-C4 alkyl esters of lactic acid, ma acid, tartartic acid or citric acid.

The composition according to claim 6, comprising kigelia and an ethyl ester of lactic acid, malic acid, tartaric acid or citric acid.

8. The composition according to claim 6 or 7, comprising kigelia and ethyl lactate.

The composition according to any of the claims 6 - 8, comprising a total amount of C1-C4 alkyl ester of lactic acid, malic acid, tartartic acid and/or citric acid selected among 1-80%, 2-50%, 3-40%, 5-30%, 10-25% and 15-20%.

10. The composition according to any of the claims 6 - 9, comprising an amount of ethyl lactate selected among 1-80%, 2-50%, 3-40%, 5-30%, 10-25% and 15-20%.

11. The composition according to any of the claims 4 - 10, comprising an amount of kigelia selected among 1-60%, 2-50%, 3-40%, 5-30%, 10-25% and 15-20%.

12. The composition according to any of the claims 6 - 11, which is a solid at room

temperature.

13. The composition according to any of the claims 6 - 12, comprising an amount of alcohol, preferably ethanol, selected among 1-80%, 2-50%, 3-40%, 5-30%, 10-25% and 15-20%.

14. The composition according to any of the claims 6 - 13, comprising an amount of water selected among 1-90%, 2-50%, 3-40%, 5-30%, 10-25% and 15-20%.

15. The composition according to any of the claims 6 - 14, comprising an additional

antioxidant.

16. The composition according to any of the claims 6 - 15, comprising a vitamin selected among vitamin E and vitamin C

17. The composition according to any of the claims 6 - 16, comprising vitamin C.

18. The composition according to any of the claims 6 - 17, comprising an amount of vitamin selected among 0.1-60%, 0.2-50%, 0.3-40%, 1-30%, 2-20% and 5-10%.

19. The composition according to any of the claims 6 - 18, further comprising a moisturizer and/or an additional preservative.

20. The composition according to any of the claims 6 - 19, in form of a liquid, a lotion, an ointment, a foam, a gel, or a cream.

21. The composition according to any of the claims 6 - 20, for topical application.

22. The composition according to any of the claims 6 - 21, for application to the skin.

The composition according to any of the claims 6 - 22, for medical application.

24. The composition according to any of the claims 6 - 23, for the prevention or treatment of imperfections of the skin, such as acne and pimples.

The composition according to any of the claims 6 - 24, for the prevention or treatment of dermatitis.

26. The composition according to any 25, for the prevention or treatment of irritant

dermatitis.

27. The composition according to claim 25 or 26, for the prevention or treatment of diaper dermatitis.

28. The composition comprising ethyl lactate and kigelia for a use comprising the prevention or treatment of imperfections of the skin.

29. The composition according to claim 28, for a use comprising the prevention or treatment of acne.

30. A patch comprising a composition according to any of the claims 6 - 29.

31. The patch according to item 30, wherein said patch is a hydrocolloid patch.

32. A pen or stick comprising a composition according to any of the claims 6 - 29.

33. A use of kigelia against Propionibacterium acnes (P. acnes).

34. A use of a composition comprising ethyl lactate and kigelia for medical purposes and/or the prevention or treatment of imperfections of the skin.

35. A use of a composition comprising ethyl lactate and kigelia for the prevention or

treatment of acne.

36. A use of a composition comprising ethyl lactate and kigelia for the prevention

treatment of folliculitis.

37. A use of ethyl lactate for the prevention or treatment of dermatitis.

38. The use of ethyl lactate according to claim 37 for the prevention or treatment of irritant dermatitis.

The use of ethyl lactate according to claim 37 or 38 for the prevention or treatment of diaper dermatitis.

A method of treatment comprising application of a composition according to any of the claims 6 - 29 for the alleviation of symptoms or prevention of a dermatological disorder.