NZ625852B2 - Treatment of seborrhoea - Google Patents

Abstract

The disclosure relates to the use of a composition in the treatment of seborrhoea in a patient, which comprises an effective amount of (24RS) scymnol, an ester thereof or a pharmaceutically acceptable salt of a said ester, together with a pharmaceutically acceptable carrier or diluent.

Description

- 1 — TREATMENT OF SEBORRHQEA FIELD OF THE INVENTION [00011The present inVention relates to treatment of seborrhoea in a patient, and in particular relates to! the use of scymnol, racemic at C24, and-its esters (particularly its sulphate ester), in methods and compositions for the treatment of seborrhoea. _ BACKGROUND OF THE INVENTION Seborrhoea (or hyperseborrhoea) is a l condition characterised by excessive secretion by the sebaceous glands of sebum, an oily substance consisting mainly of fats which is produced by the disintegration of the cells in the sebaceous, glands. The sebum reaches the skin surface h small ducts that lead from the sebaceous glands and open. into the hair follicles. Some parts of the skin have many ous glands, other parts have few such glands, and the activity of the sebaceous glands varies with age, the glands being most active at y.

In a patient with seborrhoea, the sebaceous glands are enlarged, ally beside the nose and other parts of the face. The condition predisposes to acne and is common at puberty, usually lasting for a few years. [00041 Acne ps as a result of blackages in follicles. Hyperkeratiniaation and formation of a plug of keratin and sebum (a microcomedo) is the earliest change. The microcomedo may enlarge to form an open comedone (blackhead) or closed comedone (miiia). Comedones are the direct result of sebaceous glands becoming clogged with sebum, a naturally occurring oil, and dead skin cells. In these conditions, the lly occurring largely commensal bacterium Prcpionibacterium acnes can cause inflammation, leading to inflammatory lesions (papules, infected es, or nodules) in the dermis around the microcomedo or comedone, which results in s and may result in scarring or hyperpigmentation. {0005] The compound 24R—(+)-SB-cholestane-3a,7a,l2a,?4,26,27-hexol (designated as 24R—scymnol) occurs as a sulphate ester in fishes, raysand sharks, and. is regarded as a typical component of the bile of all branch fish. Hammarsten siol.Chem. (1898) 23; 322) first described scymnol as an alcohol occurring as a sulphate in the bile of the northern shark Scymnus b’orealis'. . [0006} The chemical structure of scyrnnol was reported by Bridgewater et al (Biochem. J. (1962) Q: 285) as SB-cholestan-3a,7a,12d,24s,26,27—hexol (or Sfl-scymnol). _However, the ’stereochemical configuration at the 24-position of scymnol was not identified by Bridgewater et al - there are three possibilities in the configuration at this position, namely 24R,248 or a racemic mixture of 24R and 24S. Bridgewa'ter er al also disclosed a method‘ for the isolation of scymnol from its lly occurring sulphate, as well as a partial synthesis of scyrnnol (as a racemic mixture of the 24R and 24S compounds) from cholic acid. More recently, Ishida et a1 (Chem. Pharm. Bull. (Jpn), (1988) ) isolated, purified and examined both scymnol and its sulphate by nuclear magnetic resonance (n.rn.r.) spectroscopy, and fiilly confirmed the structure of 24R-scymnol.

In prior International Patent Application No. PCT/AU87/0028l there is disclosed a process for the isolation and preparation of an active principle by extraction from particular tissues of sharks. This active principle, now termed "isolutrol", was isolated in good yield from an aqueous extract of the livers and/or gall bladders of sharks, and the active component therein identified as 3o., 7a,]20.,24,26-pentahydroxy-coprostane—27— sodium te ester (sodium 24R-scymnol sulphate). This active ent was also disclosed as being effective in the treatment of seborrhoea, particularly when used lly, for example in a topical cosmetic composition. Subsequently, it was disclosed in ' ational Patent Application No. PCT/AU89/00064 that .24R-scymnol can be prepared from the active component disclosed in International Patent Application No.

PCT/AU87/00281, and that 24R—scymnol has activity in the treatment of liver ction.

In work leading to the present ion, it has now been found that Scymnol, racemic at C24, nafter ed to as (24RS)scymnol), and its esters, particularly its sulphate esters, and phannaceutically acceptable salts of the esters, are effective. in the treatment of seborrhoea.

SUMMARY OF THE INVENTION According to one aspect of the present invention, there is ed a method for the treatment of seborrhoea in a patient which comprises administering to the t an effective‘amount of (24RS) or (248) scymnol, an ester thereof or a phannaceutically able salt of a said ester, or of (24R) scymnol.

Preferably, the administration is by the topical, dermal or transdermal route. ' [0011] The present invention also extends to a composition for use in the'treatment of seborrhoea in a t, which comprises an effective amount of (24RS) or (248) ‘scymnol, an ester thereof or a pharmaceutically acceptable salt of a said ester, or bf"(24R) l, er with a phannaceutically acceptable r or diluent.

Preferably, the composition is a topical, dermal or transdermal composition.

The present invention thither extends to use of (24RS) or (248) scymnol, an ester thereof or a phannaceutically acceptable salt of a said ester, or of (24R) scymnol, in the manufacture ofa medicament for use in the treatment of seborrhoea in a patient.

In- yet another aspect, the invention provides (24RS) or (248) scymnol, an ester thereof. or a pharmaceutically able salt of a said ester, or (24R) scymnol, for use in the treatment of seborrhoea in a patient.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other r or step or group of integers or. steps.

The reference to any prior art in this specification is not, and should not be taken -as, an acknowledgment or any form of suggestion that that prior art forms part of the common general. knowledge in Australia.

DETAILED DESCRIPTION OF THE INVENTION- The preparation of scyrr'mol, racemic at C24, 01-04st i, using cholic acid as starting material is described by Amiet et a1 (Aust J. Chem (1993) fl; 1347-1354) and Hamey and Macrides ids (2008) 13.1 9); the contents of both of these publications are incorporated herein by reference. Hamey and Macrides (2008) also describe the preparation of a sulphated (24RS) scymnol, which is monosulphated at C27, as a sodium salt, g to a (24RS, 25RS) epimeric mixture of alcohols whereas the natural sodium scyrnnol sulphate purified from shark bile comprises the (24R, 25R) and/or (24R, 25$) epimers.

The structure of'natural (24R,25RS) sodium scymnol sulphate is set out below: Also set out below are the structures of the four stereoisomers in the synthetic, c (24RS, ZSRS) sodium scymnol sulphate prepared as described by Hamey and Macrides (2008): Manual (amoraneuomm - on on (24R. 255) ral mwlutertomm CH; 9” OH CH: ‘ s and receptors in cells commonly select for one enantiomcr of a chiral binding molecule (substrate or ligand) over the other enantiomer, because of the chirally- selective pockets inside their active sites. This is why most natural biological‘moleculcs (e.g. amino acids and ) are present in cells in only one chiral form.

Therefore, it is common for a Specific enantiomer of a chiral biomolecule or drug to easily fit into the active site of 5 target enzyme or receptor with high binding affinity and strong bioactivity, whereas the other enantiomer either fits and binds differently, or doesn't fit at all. Thus, one drug omer may produce a d beneficial effect, while the other enantiomer may cause different beneficial effects and/or adverse effects. The presence of the‘non-beneflcial enantiomer in a racemic mixture of chiral drug may result in a range of outcomes, e.g. halved beneficial bioactivity from the overall dose (if it is W0 2013/090986 inactive compared to the ial enantiomer), or even less than half of the beneficial bioactivity (if it antagonises the beneficial enantiomer), .or unwanted and/or adverse side effects (if it has a ent bioactivity and/or ty profile to the beneficial enantiomer).

Given the common occurrence of chiral drugs and biomolecules having enantiomers with ent bioactivities, a person skilled with this field would not assume that a racemic mixture and both of the individual enantiomers of a. chiral bioactive molecule each have the same bioactivity profile, especially as such an assumption could be potentially dangerous. It is therefore necessary to investigate on a case-by-case basis and compare the bioactivity profile of a racemic mixture with its individual isomers, and elucidate their mechanisms of action, in order to accurately determine the overall bioactivity of a racemic e.

Consequently, the finding by the present inventors of the anti-sebum properties of c scymnol and l sulphate, and the individual non—natural enantiomers of scymnol and scymnol sulphate is surprising, as these could not be ied from the known anti-sebum properties of the natural scymnol and scymnol sulphate enantiomers.

According to one aspect of the present invention, there is provided a method for the treatment of seborrhoea in a patient which comprises administering to the t an effectiVe. amount of (24RS) or (248) l, an ester thereof or a pharmaceutically [acceptable salt of a said ester, or of (24R) scymnol.

As disclosed above, the present invention also extends to a ition for use in the treatment of seborrhoea in a patient, which comprises an effective amount of (24RS) or (248) scymnol, an ester thereof or a phannaceutically acceptable salt of a said ester, or of (24R) l, together with a phannaceutically acceptable carrier or diluent.

In another aspect, the present invention further extends to use of (24RS) or (248) scymnol, art-ester thereof or a pharmaceutically acceptable salt of a said ester, or of (24R) l, in the manufacture of a medicament for use in the treatment of seborrhoea in a W0 2013/090986 In yet another aspect, the invention provides (24RS) or (24S)'scymnol, an ester thereof or a pharmaceutically acceptable salt of a said ester, or (24R) scymnol, for use in the treatment ofseborrhoeain a patient.

The esters of (24RS) or (248) scymnol which may be used in accordance with the present invention include , with inorganic acids such as sulphuric acid or organic acids such as acetic acid,- propionic acid or butyric acid. Where the ester is an ester with an inorganic acid such as riciacid, it. may be in the form of a pharmaceuticaliy ' able salt such as a , potaSsium, m or ammonium salt, or an c amine salt.

Preferably, the active substance is a sulphated form of (24RS) scymnol, more preferably the racemic (24RS,25RS) sodium l sulphate prepared as disclosed by Hamey and Macrides (2008) (hereinafier referred to as "synthetic racemic (24RS); scymnol“). {0030] As used herein, references to treatment of seborrhoea include treatment of hyperseborrhoea or increased sebum production, as well as treatment of acne and other skin conditions which are connected with increased sebum production. .

-In accordance with this invention, the active substance will normally be administered dermally, transdennally or topically in the form of pharmaceutical preparations comprising an effective amount of the active substance in a pharmaceutically acceptable dosage form including a pharmaceutically acceptable carrier or diluent. , Suitable phannaceutically acceptable dosage forms are well known and are described, by way of example, in Remington's Pharmaceutical Sciences, l8“h Edition, Mack Publishing Company, Pennsylvania, USA. The dosage ‘form may be a solid, semisolid or liquid ation. Usually the active substance will constitute between 0.1 and 99% by weight of the preparation. Dermal, transdermal or topical administration. would normally e 0.11-l0% by weight, more cally (XS-5% by weight, of the active nce in a suitable , transdermal or topical carrier or vehicle.

Preferably, the active substance is formulated so as to be administered topically or’ transdermally. In such formulations, an effective amount of the active nce is' incorporated into a suitable carrier material as“ a topical pharmaceutical/cosmetic composition which may be made up in a y of product types including, for example, lotions, creams, oils, gels, sticks, sprays, ointments, pastes, mousses and cosmetics.

Suitable topical ceutical/cosmetic carrier materials for such compositions are also well known and are described, by way of example, in International Patent ation No. PCT/USQl/02400. IAs described therein, in addition to ‘the active substance and suitable r material, such topical pharmaceutical/cosmetic compositions may also include one or more penetration enhancing agent(s), and/or anti~inflammatory agent(s), as well as sunscreen or sunblock agent(s) to. enhance protection of the skin against the effects ofUV irradiation.

The compositions of the present . invention may also incorporate known pharmaceuticals or other active ingredients, for example, otics or other antibacterial substances. When formulated as a. cosmetic composition, the active substance is formulated with a cosmetic base material, together with other cosmetic materials typically incorporated'in ic compositions.

The active substance is administered in the therapeutically effective amounts. A therapeutically effective amount means that amount necessary at least partly to attain the desired effect, or to delay the onset of, inhibit the progression of, or halt ther, the onset or progression of the particular condition being treated, Such amounts will depend, of course, on the particular condition being treated, the severity of the condition and individual patient parameters ing age, physical condition, size, weight and concurrent treatment. These'factors are well known to those of ordinary skill in the art and WO 90986 can be addressed with no more than routine experimentation. ItIs preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical ent. It will be understood by those of ordinary skillin the art, however, that a lower dose or tolerable dose may be administered for medioal reasons, psychological reasons or ,.for virtually any other reasons.

The following examples illustrate the use of active substances in aceordanee with this invention in methods and Compositions for the treatment of seborrhoea. It is to be understood, however, that this detailed description is included solely for the purposes of exemplifying the present invention, and should not be understood in anyway as a restriction on the broad descriptioniof the invention as set out above.

EXAMPLE 1. - l Compositions The following itions demonstrate typical compositions for topioal use in the treatment of seborrhoea. 1. Cold cream Spennacetti 6.0 g Beeswax 6.0 g Carbopol 934 10.0 g Sodium ate 4.75 3 Rose water 5.0 ml Expressed almond oil 56.0 g Active substance 0.05 g Distilled water ' ' 20.6 2. Lotion ~ Ethanol 30 ml Active substance - . 20 mg Distilled water — sufficient quantity to make 100 EXAMPLE 2 — Clinical s In an initial pilot study in humans, 3 topical formulations were ted for iveness in reduction of sebum or treatment of acne. e- The active substance in each of these formulations was: Formulation 1 —~ natural isolutrol (sodium 24R- scymnol sulphate).

Formulation 2 — synthetic (24R) — scymnol.

Formulation 3 ~. tic racemic (24RS) — scymnol.

In each formulation, the active substance was incorporated at 0.015% w/w into an oil-freetopical lotion. In the pilot study, each test formulation was applied to one side of the face of a test subject, twice daily, for 28 days in the case of Formulations l and 2, and for 42 days‘in the case of Formulation 3. For each test formulation, lO‘healthy female test subjects participateddn thepilot study.

For the evaluation of sebum reduction, a Sebumeter SM810PC ge + .Khazaka electronic GmbH)-was used to obtain measurement of skin sebum (skin surface lipids) on days 0, 3, 7, 14; 21, 28, 35 and 42. omplish this, a special purpose film of > the cartridge measuring head was” applied for 30 s to the relevant skin area. The cartridge was inserted into the Sebumeter SM810 PC for electronic determination of film transparency ions. The play of the instrument presents the result in terms of ug/cmz. Duplicated measurements were obtained on the same site at each visit, and the results were averaged.

For evaluation of anti-acne treatment, ion in total acne lesion (pustules, pap'ules and comedones) counts Was'measured. i0044] The results of this initial study are shown in the accompanying figures, as follows: Figure 1- evaluation of sebum reduction using ation I; Figure 2 - evaluation of sebum reduction using Formulation 2; Figure 3 - evaluation of sebum reduction using Formulation 3; Figure 4 — ion in total acne lesion counts using Formulation ‘3. ' These results show that the active substance of Formulation 2, scymnol, was surprisingly at least as effective in sebum reduction as the active substance of Formulation.

W0 2013/090986 1, natural sodium (24R)—scynmol sulphate after 28 days.

These s also show that the active substance of Formulation 3 used in both the sebum study and the acne study, racemic (24RS)—-scymnol, was surprisingly at least as ive in sebum reduction, as the active substances of Formulations 1 and 2, natural sodium (24R)~scymnol sulphate and scymnol, respectively, after 28 days, and that sebum reduction continued when the test period was extended to 42 days. This active substance was also effective in reduction of total acne lesion counts over the 42 day test period. In particular, these results show that the presence of the tural (24S)— scymnol enantiomer in the racemic (24RS)~scymnol of Formulation 3 has no adverse effect in the sebum study. [0047} Persons skilled in this :art will appreciate that variations and modifications may be made to the invention as broadly described herein, other than those cally, described without departing form the spirit and scope of the invention. It is to‘be understood that this invention extends to include all such variations and modifications. -]2_

Claims (4)

CLAIMS :

1. Use of (24RS) scymnol, an ester thereofor a pharmaceutically able salt of a said ester, in the manufacture of a medicament for the treatment of seborrhoea in a patient.

2. The use of claim 1, wherein racemic (24RS, ZSRS) sodium scymnol te is used.

3. The use of claim 1 or claim 2, wherein the medicament is a topical, dermal 01' transdermal composition.

4. The use of any one of claims 1 to 3, wherein the medicament comprises a pharmaceutically acceptable carrier or diluent.