(19) 1 Europaisches Patentamt
`
`European Patent Office
`
`Office europeen des brevets
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`
`(11)
`
`EP 0 872 230 A1
`
`(12)
`
`EUROPEAN PATENT APPLICATION
`
`(43) Date of publication:
`21.10.1998 Bulletin 1998/43
`
`(21) Application number: 97201102.7
`
`(22) Date of filing: 14.04.1997
`
`(51) Int. Cl.6: A61 K 7/50, A61 K 7/48,
`A61 K 7/06
`
`(84) Designated Contracting States:
`AT BE CH DE DK ES Fl FR GB GR IE IT Ll LU MC
`NL PTSE
`Designated Extension States:
`ALLTLVROSI
`
`(71) Applicant:
`JANSSEN PHARMACEUTICA N.V.
`2340 Beerse (BE)
`
`(72) Inventors:
`• Embrechts, Roger Carolus Augusta
`2340 Beerse (BE)
`• Odds, Frank Christopher
`2340 Beerse (BE)
`• de Doncker, Piet R.G.
`2340 Beerse (BE)
`
`(54) Compositions containing an antifungal and a cationic agent
`
`The invention relates to compositions such as
`(57)
`body and hair cleansing products, in particular sham(cid:173)
`poos, comprising one or more antifungals inhibiting fun(cid:173)
`gal ergosterol biosynthesis as a first active ingredient
`and 1 0'-undecen-3-oyl-aminopropyl
`trimethylammo(cid:173)
`nium methylsulfate as a second active ingredient.
`
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`
`

`
`Description
`
`EP 0 872 230 A1
`
`The invention relates to compositions such as body and hair cleansing products, in particular shampoos, compris(cid:173)
`ing one or more antifungals inhibiting fungal ergosterol biosynthesis as a first active ingredient, 10'-undecen-3-oyl-ami-
`nopropyl trimethylammonium methylsulfate as a second active ingredient and as a cationic surface active agent, and
`art-known body or hair cleansing product ingredients as a carrier.
`
`5
`
`Background of the invention
`
`10
`
`Known medicated shampoos are, for example, the ketoconazole shampoos which are marketed in a 2% formula-
`tion and which show a beneficial effect in dandruff and seborrheic dermatitis after topical application. Ketoconazole was
`disclosed by Rosenberg et al. in US-4,569,935 to be useful in the topical treatment of psoriasis and seborrheic derma(cid:173)
`titis. Ketoconazole shampoos that exhibit better cosmetic attributes such as lathering and conditioning, and are accept(cid:173)
`ably stable to degradation so that they can be formulated to contain less than 2% active ingredient are disclosed in US-
`15 5,456,851. Elubiol shampoos having a skin grease regulating action are known from W0-93/18743. W0-96/29983 dis(cid:173)
`closes mild aqueous detergent compositions comprising from about 4 to about 12 % by weight of an anionic surfactant,
`an amphoteric surfactant at a level of at least about 0.75 parts by weight per part by weight of said anionic surfactant,
`and one or more of 111isted therapeutic agents. 10'-Undecen-3-oyl-aminopropyl trimethylammonium methylsulfate is a
`cationic surfactant commercially available under the Trademark Rewocid UTM 185, marketed by Rewo Chemische
`20 Werke GmbH, Steinau (Germany) and by Witco.
`Prior art shampoos comprising anti-dandruff agents are designed in such a way that an optimum balance is
`achieved between efficacy and tolerability ; the concentration of the active ingredient in the medicated shampoos is
`such that as many users as possible are effectively treated and as few as possible suffer adverse effects. Nonetheless,
`there remain substantial numbers of patients who do not benefit from using prior art shampoos, either because they do
`25 not respond to the treatment, or worse, because they do not tolerate the treatment with a particular medicated sham(cid:173)
`poo.
`The number of patients not responding to particular medicated shampoo can be quite high (ketoconazole up to 30
`%; selenium sulfide up to 40 %). Consequently, there is a hard felt need for new shampoos which provide effective anti(cid:173)
`dandruff treatment for a larger proportion of number of patients using such a new shampoo ; i.e. a new shampoo for
`30 which there are fewer non-respondents than with prior art shampoos.
`On the other hand, patients suffering from dandruff or seborrheic dermatitis, as well as the authorities approving
`medicated shampoos, apply increasingly stricter criteria which such shampoos should meet. Amongst these criteria the
`most important are : absence of further aggravation of the condition due to the treatment, lowest possible incidence of
`side effects, further increase in the absence of symptoms such as irritation, pruritus and scaling (both adherent and
`loose scaling) ; improved cosmetic acceptability, in particular, good cleansing properties, absence of odour or stench,
`absence of staining or soiling of the clothes, and overall conditioning (wet and dry combing properties). Dandruff or seb(cid:173)
`orrheic dermatitis are often accompanied by high or excessive oil or sebum production, and compositions having a ben(cid:173)
`eficial effect thereon would clearly constitute a further advance in the treatment of dandruff.
`Thus far, in order to achieve the above desiderata, most efforts have involved reformulating the shampoo base.
`40 There is, however, still a need for increasing the tolerability I acceptability of medicated shampoos, i.e. new shampoos
`are desired that are tolerated better by larger proportions of patients using such new shampoos.
`
`35
`
`Description of the invention
`
`45
`
`The present invention relates to compositions such as body and hair cleansing products, in particular shampoos,
`comprising, consisting essentially of or consisting of one or more antifungals inhibiting fungal ergosterol biosynthesis
`as a first active ingredient, 10'-undecen-3-oyl-aminopropyl trimethylammonium methylsulfate as a second active ingre(cid:173)
`dient, and art-known body and hair cleansing product ingredients as a carrier. In the following description, the invention
`is illustrated using shampoos as examples, but it will be evident to a person skilled in the art that the combinations
`50 according to the present invention can be utilized just as well in other body and hair cleansing products.
`The combination of two differently acting anti-dandruff agents has two distinct advantages over the prior art sham(cid:173)
`poos which contain either of the active ingredients alone. First, the combinations act synergistically and as a conse(cid:173)
`quence thereof, the concentration of one or both of the different types of agent can be lowered, thus increasing the
`tolerability. Secondly, an increased proportion of patients suffering from dandruff or seborrheic dermatitis respond to the
`55 shampoos according to the present invention. Each class of ingredients will now be discussed in turn.
`The antifungal inhibiting fungal ergosterol biosynthesis is preferably an azole, an allylamine, or a mixture thereof.
`Preferred azoles are selected from the group comprising ketoconazole, econazole, elubiol, miconazole, itraconazole,
`fluconazole and mixtures thereof. Preferred allylamines are selected from the group comprising terbinafine, naftifine
`
`2
`
`

`
`EP 0 872 230 A1
`
`and mixtures thereof. The azole compounds ketoconazole, econazole and elubiol are most preferred because they
`harm the normal flora of the skin, in particular of the scalp, the least. Ketoconazole and elubiol are especially preferred
`as they produce a mutual synergistic effect on dermatophyte fungi when in used in combination with 1 0'-undecen-3-oyl(cid:173)
`aminopropyl trimethylammonium methylsulfate (vide infra). Effective amounts of the antifungals in compositions accord-
`ing to the present invention are in the range of from about 0.1 %to about 2.5% (w/w), and preferably from about 0.5%
`to about 1 % (w/w). As will be explained further, at the lower end of this range, special precautions may have to be taken
`in order to ensure that the shampoo does not lose its efficacy due to degradation of the antifungal compound upon stor(cid:173)
`age. Concentrations higher than those indicated do not improve the treatment of the conditions any further, and are on
`the whole more detrimental than beneficial.
`The second active ingredient is 10'-undecen-3-oyl-aminopropyl trimethylammonium methylsulfate having the for-
`mula
`
`0
`
`s
`
`10
`
`15
`
`20
`
`25
`
`Its Chemical Abstracts registry number is [94313-91-4], its CTFA Adopted Name is Undecylenamidopropyltrimo-
`nium Methosulfate. This cationic surfactant is commercially available under the Trademark Rewocid UTM 185, mar(cid:173)
`keted by Rewo Chemische Werke GmbH, Steinau (Germany) and by Witco. The commercial product is an aqueous
`formulation having a solids content in the range of 47 to 49%, appearing as a clear yellow liquid and giving a pH in the
`range of 5 to 7 when diluted to 1 % in water.
`Preferably, the first and the second active ingredients are present in quantities producing a mutual synergistic effect
`on the inhibition of the growth of dermatophyte fungi, in particular the species associated with dandruff and seborrheic
`dermatitis, i.e. Malassezia furfur (Pityrosporum ova/e), but also other fungi such as Epidermophyton, Microsporum,
`Trichophyton species associated with, for example, dermatophytosis, pityriasis versicolor and the like. The ratio of the
`quantities of the first and the second active ingredient will depend on the nature of said active ingredients and on the
`target species. Particularly, it is contemplated that the weight : weight ratio between the first and the second active
`ingredient (antifungal : 10'-undecen-3-oyl-aminopropyl trimethylammonium methylsulfate) may range from about 5: 1
`to about 1 : 150, in particular form about 1 : 1 to about 1 : 25. For example, and as already mentioned, ketoconazole
`and elubiol when in used in combination with 10'-undecen-3-oyl-aminopropyl trimethylammonium methylsulfate, in par(cid:173)
`ticular when used in a weight ratio ranging from about 1 : 1 to about 1 : 25, in particular in a weight range of about 1 :
`35 20, produce a mutual synergistic effect on fungi, in particular on Malassezia furfur. Effective amounts of 10'-undecen-
`3-oyl-aminopropyl trimethylammonium methyl sulfate in compositions according to the present invention are in the range
`of from about 0.04% to about 10 % (w/w).
`The shampoos according to the present invention can conveniently be formulated using art-known shampoo bases
`; the art-known shampoo ingredients comprise one or more of a surfactant, a foaming agent, a thickener, a preservative,
`40 an anti-oxidant, and acid or base or buffer sufficient to give the shampoo a pH in the range of from about 4 to about 10.
`A single ingredient can have two or more functions, e.g. surfactant and foaming agent, or anti-oxidant and buffer.
`Many of the ingredients discussed hereinafter are commercially available in formulations (e.g. aqueous solutions),
`not as pure compounds. The amount of ingredient which can be used in preparing formulations according to the present
`invention are usually expressed as% (w/w) and refer to the amount of the commercially available product to be used,
`45 not the amount of pure product.
`Suitable surfactants for use in the shampoos according to the present invention may be selected from the group
`comprising sodium C14_16 olefin sulfonates, sodium lauryl sulfate, TEA lauryl sulfate, sodium laureth sulfate, cocamido(cid:173)
`propylamine oxide, lauryl amine oxide, lauramido DEA, cocamidopropyl betaine, lauryl dimethyl betaine, cocodimethyl
`sulfopropyl betaine, sodium cocoyl sarcosinate, disodium oleamido MIPA sulfosuccinate, disodium cocamido MIPA sui-
`fosuccinate, disodium laureth sulfosuccinate, cocoamphocarboxyglycinate, disodium oleamido MEA sulfosuccinate,
`amine glycinates, amine propionates and amine sultaines, and mixtures thereof. Preferably, a mixture of two or more
`different surfactants, in particular sodium laureth sulfate and sodium cocoyl sarcosinate; or sodium laureth sulfate and
`disodium laureth sulfosuccinate; or sodium lauryl sulfate, sodium laureth sulfate, TEA lauryl sulfate and cocamidopropyl
`betaine; may be used in the present shampoos. In the shampoos according to the present invention, the total amount
`ss of surfactants may range from about 36% to about 55% (w/w). Preferably, the weight of amphoteric surfactants is less
`than 15 % by weight of the total amount of surfactants.
`In the above definitions, and hereinafter, the term 'MEA' signifies a mono-ethanolamide of formula RCO-NH(cid:173)
`CH2CH2-0H, the term 'DEA' signifies di-ethanol amide of formula RCO-N(CH2CH2-0Hh, 'TEA' signifies triethanolam-
`
`30
`
`so
`
`3
`
`

`
`EP 0 872 230 A1
`
`5
`
`monium ; the term 'MIPA' signifies a mono-isopropanol amide of formula RCO-NH-CH2-CHOH-CH3 ; wherein each
`RCO-group is a fatty acid residue, such as a C13•19alkylcarbonyl or C13•19alkenylcarbonyl group.
`Suitable foaming agents (foam boosters and stabilizers) for use in the shampoos according to the present invention
`may be selected from the group of fatty acid mono- and dialkanol-amides comprising cocamide MEA, cocamide DEA,
`oleamide MEA, oleamide DEA and mixtures thereof. The foaming agent may be present in a range from about 1 to
`about 10% (w/w), preferably from about 2 to about 6% (w/w), in particular about 4 to about 5% (w/w). These ingredi(cid:173)
`ents typically also have a thickening effect on the formulation.
`Suitable preservatives for use in the present shampoos are dermatologically acceptable preservatives, e.g. tetra(cid:173)
`sodium EDTA, methylparaben, propylparaben, butylparaben, ethylparaben, imidazolidinyl urea, phenoxyethanol,
`10 quaternium 15, citric acid, preferably in combinations with one another. Tetrasodium EDTA and citric acid also function
`as chelating agents.
`As disclosed in US-5,456,851, when the concentration of ketoconazole, or for that matter that of any other antifun(cid:173)
`gal, is at the lower end of the ranges mentioned hereinabove, the addition of a carefully controlled amount of an anti(cid:173)
`oxidant selected from the group consisting of butylated hydroxytoluene ("BHT"), butylated hydroxyanisole ("BHA"),
`15 ascorbic acid and N-acetyl-cysteine effectively stabilizes the ketoconazole or other azole present in the shampoo
`against degradation during accelerated aging for 13 weeks at 50°C, which is considered to be predictive of performance
`during storage at ambient temperatures for two years. Effective stability is considered to be a loss of active ingredient
`during storage of not more than about 1 0 percent. The proportion of BHT or BHA that has been found to be most effec(cid:173)
`tive is within the range of from about 0.01 %to about 1 % (w/w). Proportions greater than this amount do not stabilize
`20 ketoconazole as effectively for the 13-week accelerated aging period, although if one extends the accelerated aging
`period longer than 13 weeks, greater proportions of BHT or BHA tend to be more effective, since the BHT or BHA itself
`is also subject to degradation. However, it is well recognized by government regulatory agencies and in the pharmaceu(cid:173)
`tical and cosmetic industries that stability testing for 13 weeks at 50°C is quite sufficient to predict product stability dur(cid:173)
`ing normal shelf life storage for two (2) years at room temperature. It is also equally important that, for safety reasons
`(that is, to minimize the potential for skin sensitization), it is desired to use as small an amount as possible of BHT or
`BHA.
`Since shampoo users expect a shampoo to be slightly viscous, one or more thickeners are often included in the
`formulation which give it a viscosity in the range of 4,000 to 9,000 mPa.s at room temperature. A suitable thickener is a
`carbomer or polycarboxylic acid, such as Carbopol™ 1342, which is thickened by the addition of sodium hydroxide or
`30 sodium chloride at the end of the preparation. Other suitable thickeners are the foaming agents mentioned hereinabove,
`preferably cocamide MEA.
`The shampoo may further comprise a conditioner such as polyquaternium-7 or a similar cationic quaternary poly(cid:173)
`mer, e.g. a quaternary silicone polymer ; one or more pearlizing agents selected from the group consisting of ethylene
`glycol distearate, ethylene glycol monostearate and mixtures thereof ; and/or one or more fragrances and one or more
`35 colorants.
`The pH of the shampoos according to the present invention are conveniently established using dermatologically
`acceptable acids, bases and buffers. The pH can range from about 4 to about 10, but preferably is in the range of about
`6.5 to about 8, in particular from about 6.9 to about 7.4.
`Some of the first active ingredients when at approximately neutral pH (pH 6 to 8), have limited solubility. In order to
`keep these agents homogeneously distributed throughout the shampoo, a suspending agent such as, for example, Avi(cid:173)
`cel RC-591™ (a mixture of sodium CMC and microcrystalline cellulose) may be added. Several of the shampoo base
`ingredients, however, have considerable suspending properties of their own, and therefore the inclusion of particular
`suspending agents in the present shampoos is entirely optional.
`The components of the shampoo are employed in conventional amounts, for example:
`
`25
`
`40
`
`45
`
`50
`
`55
`
`(a) 36% to 55% surfactants,
`(b) 2% to 6% foaming agent,
`(c) 0.1% to 2% antifungal,
`(d) 0.05 to 2% 10'-undecen-3-oyl-aminopropyl trimethyl-ammonium methylsulfate salt
`(e) 0.2% to 1.3% thickener,
`(f) 0.01% to 1% BHT or BHA;
`(g) preservatives sufficient to retard degradation of the final composition in order to give adequate shelf life,
`(h) acid, base or buffer to yield a pH in the desired range, and
`(i) water qs ad 100% (that is, sufficient water to make 100%).
`
`Examples
`
`In the following, a general process for preparing shampoos according to the present invention is presented. Suita-
`
`4
`
`

`
`EP 0 872 230 A1
`
`5
`
`ble amounts for each of the ingredients can be derived from the preceding description and from the exemplary formu(cid:173)
`lations shown in the tables hereinafter.
`A vessel was charged with a 1.64% stock solution of Carbopol 1342 (prepared using a Quadro disperser which
`functions by keeping the powdered polymer evenly divided and pulling the powder by a vacuum into a stream of water)
`and deionized water, and heated to about 70°C. Both surfactants, i.e. sodium laureth sulfate and sodium cocoyl sarcosi(cid:173)
`nate, were added, followed by the foaming agent, cocamide MEA, and a pearlizing agent (ethylene glycol distearate)
`and mixed until complete dissolution. Then the BHT was added and the mixture was stirred until complete dissolution
`thereof. The solution was allowed to cool slightly, whereupon the antifungal ingredient was added while stirring well.
`(The antifungal is added while the pH is slightly acidic, to facilitate dissolution.) Next, a 10'-undecen-3-oyl-aminopropyl
`trimethyl-ammonium methylsulfate was dispersed into the mixture and stirred until homogenously dispersed. The mix(cid:173)
`ture was allowed to cool to about 40°C, at which temperature there were added the conditioner (polyquaternium-7), the
`preservatives quaternium-15 and tetrasodium EDTA, the colorants and fragrances, and the NaCI for thickening the solu(cid:173)
`tion. The pH of the solution was adjusted to 6.9-7.4 with a 25% aq. solution of NaOH and deionized water was added
`to the final volume. Similar shampoo formulations can prepared using analogous processes which will be apparent to
`the person skilled in the art.
`Using the general procedures described above, the following shampoo formulations according to the present inven(cid:173)
`tion can be made ; all quantities hereinafter are parts by weight.
`The formulations according to the present invention are useful in the treatment of disorders such as dandruff, seb(cid:173)
`orrheic dermatitis, the control of psoriasis, the reduction of oil or sebum production of the scalp, and the like disorders
`20 and discomforts. The formulations are to be applied topically to the affected body parts at regular intervals, in particular
`from at least once weekly to about once daily. Preferably they are employed more often in the beginning of the treat(cid:173)
`ment, e.g. from 4 to 7 times a week, and less frequently in a later stage when the desired effect has been obtained and
`relapse is to be prevented (e.g. once or twice a week).
`
`10
`
`15
`
`25 Example 1 : Shampoo formulations for normal hair (with conditioner)
`
`Ingredients
`
`sodium laureth sulfate
`
`sodium cocoyl sarcosinate
`
`cocamide MEA
`
`ketoconazole USP
`
`1 0' -undecen-3-oyl-aminopropyl trimethylammonium methylsulfate
`
`glycol distearate
`
`polyquaternium-7
`
`Carbopol™ 1342
`
`tetrasodium EDTA
`
`perfume oil
`
`sodium chloride
`
`sodium hydroxide 25%
`
`butylated hydroxytoluene
`
`quaternium-15
`
`colorants
`
`deionized water qs ad
`
`(a)
`
`(b)
`
`30
`
`10
`
`4
`
`0.5
`
`0.5
`
`30
`
`10
`
`4
`
`1
`
`1
`
`1.25
`
`1.25
`
`1
`
`0.6
`
`0.5
`
`0.5
`
`0.3
`
`0.92
`
`0.1
`
`0.05
`
`0.001
`
`1
`
`0.6
`
`0.5
`
`0.5
`
`0.3
`
`0.9
`
`0.1
`
`0.05
`
`0.001
`
`100
`
`100
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`5
`
`

`
`Example 2: Shampoo formulations for oily hair (with conditioner)
`
`EP 0 872 230 A1
`
`5
`
`Ingredients
`
`sodium laureth sulfate
`
`sodium cocoyl sarcosinate
`
`cocamide MEA
`
`ketoconazole USP
`
`1 0'-undecen-3-oyl-aminopropyl trimethylammonium methylsulfate
`
`glycol distearate
`
`polyquaternium-7
`
`Carbopol™ 1342
`
`tetrasodium EDTA
`
`perfume oil
`
`sodium chloride
`
`sodium hydroxide 25%
`
`butylated hydroxytoluene
`
`quaternium-15
`
`colorants
`
`10
`
`15
`
`20
`
`25
`
`(a)
`
`33.33
`
`11
`
`4
`
`0.5
`
`0.5
`
`1.25
`
`0.6
`
`0.75
`
`0.5
`
`0.5
`
`0.3
`
`1.18
`
`0.1
`
`0.05
`
`(b)
`
`33.33
`
`11
`
`4
`
`0.75
`
`0.25
`
`1.25
`
`0.6
`
`0.75
`
`0.5
`
`0.5
`
`0.3
`
`1.243
`
`0.1
`
`0.05
`
`(c)
`
`33.33
`
`11
`
`4
`
`1.2
`
`0.8
`
`1.25
`
`0.6
`
`0.75
`
`0.5
`
`0.5
`
`0.3
`
`1.18
`
`0.1
`
`0.05
`
`0.0053
`
`0.0053
`
`0.0053
`
`100
`
`100
`
`100
`
`deionized water qs ad
`
`30
`
`Example 3: Shampoo formulations for dry or damaged hair (with conditioner)
`
`35
`
`Ingredients
`
`(a)
`
`(b)
`
`(c)
`
`sodium laureth sulfate
`
`sodium cocoyl sarcosinate
`
`cocamide MEA
`
`ketoconazole USP
`
`1 0'-undecen-3-oyl-aminopropyl trimethylammonium methylsulfate
`
`glycol distearate
`
`polyquaternium-7
`
`Carbopol™ 1342
`
`tetrasodium EDTA
`
`perfume oil
`
`sodium chloride
`
`sodium hydroxide 25%
`
`butylated hydroxytoluene
`
`quaternium-15
`
`colorants
`
`30
`
`10
`
`4
`
`0.75
`
`0.25
`
`1.25
`
`5
`
`0.5
`
`0.5
`
`0.5
`
`0.4
`
`30
`
`10
`
`4
`
`0.33
`
`0.67
`
`1.25
`
`5
`
`0.5
`
`0.5
`
`0.5
`
`0.4
`
`0.7333
`
`0.733
`
`0.1
`
`0.05
`
`0.1
`
`0.05
`
`30
`
`10
`
`4
`
`1
`
`1
`
`1.25
`
`5
`
`0.5
`
`0.5
`
`0.5
`
`0.3
`
`1.19
`
`0.1
`
`0.05
`
`0.0018
`
`0.0018
`
`0.0018
`
`40
`
`45
`
`50
`
`55
`
`6
`
`

`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`EP 0 872 230 A1
`
`(continued)
`
`Ingredients
`
`deionized water qs ad
`
`(a)
`
`(b)
`
`(c)
`
`100
`
`100
`
`100
`
`In all the formulations given above in Examples 1-3, the proportion of sodium hydroxide may vary slightly, to arrive
`at the preferred pH level of 6.9 to 7.4, and the proportion of salt (NaCI) may vary, to arrive at the desired viscosity.
`
`Example 4 : Combination of 1 0' -undecen-3-oyl-aminopropyl trimethylammonium
`methylsulfate and Ketoconazole (with conditioner)
`
`Ingredients
`
`purified water
`
`sodium laureth sulfate
`
`sodium lauryl sulfate
`
`TEA lauryl sulfate
`
`1 0' -undecen-3-oyl-aminopropyl trimethylammonium methylsulfate
`
`ketoconazole
`
`methylparaben
`
`propylparaben
`
`cocamide MEA
`
`ethylene glycol distearate
`
`polyquaternium-7
`
`imidazolidinyl urea
`
`cocamidopropyl betaine
`
`citric acid
`
`fragrance
`
`Percent
`
`44.30
`
`15.00
`
`10.00
`
`12.00
`
`2.10
`
`1.00
`
`0.20
`
`0.05
`
`5.00
`
`1.25
`
`3.00
`
`0.50
`
`5.00
`
`0.35
`
`0.25
`
`100.00
`
`Example 5 : Combination of 10' -undecen-3-oyl-aminopropyl trimethylammonium
`methylsulfate and elubiol (with conditioner)
`
`Ingredients
`
`purified water
`
`sodium laureth sulfate
`
`sodium lauryl sulfate
`
`TEA lauryl sulfate
`
`Percent
`
`44.30
`
`15.00
`
`10.00
`
`12.00
`
`7
`
`

`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`EP 0 872 230 A1
`
`(continued)
`
`Ingredients
`
`1 0'-undecen-3-oyl-aminopropyl trimethylammonium methyl sulfate
`
`elubiol
`
`methylparaben
`
`propylparaben
`
`cocamide MEA
`
`ethylene glycol distearate
`
`polyquaternium-7
`
`imidazolidinyl urea
`
`cocamidopropyl betaine
`
`citric acid
`
`fragrance
`
`Percent
`
`2.10
`
`1.00
`
`0.20
`
`0.05
`
`5.00
`
`1.25
`
`3.00
`
`0.50
`
`5.00
`
`0.35
`
`0.25
`
`100.00
`
`In the formulations given above in Examples 4 and 5, the proportion of citric acid may vary slightly, to arrive at the
`preferred pH level of 6.9 to 7.4.
`
`Example 6: Ketoconazole (2.1 %) and 10'-undecen-3-oyl-aminopropyl trimethyl(cid:173)
`ammonium methylsulfate 2% and 1 % (w/w) shampoos (without
`conditioner)
`
`ketoconazole
`
`2.100 g
`
`1 0' -undecen-3-oyl-aminopropyl trimethylammonium methylsulfate
`
`2.000 g
`
`imidazolidinyl urea
`
`disodium laureth sulfosuccinate
`
`cocamide DEA
`
`hydrolized laurdimonium
`
`macrogol 120
`
`perfume
`
`hydrocloric acid
`
`red erythrosine (FD & C No. 40)
`
`sodium laureth sulfate
`
`sodium hydroxide
`
`sodium chloride
`
`purified water
`
`2.100 g
`
`1.000 g
`
`0.200 g
`
`15.000 g
`
`2.000 g
`
`1.000 g
`
`1.000 g
`
`0.200 g
`
`0.400 g
`
`0.002 g
`
`0.200 g
`
`15.000 g
`
`2.000 g
`
`1.000 g
`
`1.000 g
`
`0.200 g
`
`0.400 g
`
`0.002 g
`
`38.000 g
`
`38.000 g
`
`0.100 g
`
`0.500 g
`
`0.100 g
`
`0.500 g
`
`q.s. ad 100 g
`
`q.s. ad 100 g
`
`8
`
`

`
`EP 0 872 230 A1
`
`Example 7:
`
`In vitro synergisitic inhibitory effects between ketoconazole and 1 0'-
`undecen-3-oyl-aminopropyl trimethylammonium methylsulfate against
`Malassezia furfur
`
`5
`
`10
`
`15
`
`20
`
`25
`
`Checkerboard interaction experiments involving nine isolates of Malassezia furfur (M. furfur) and the test sub-
`stances with doubling dilution steps showed the combination of test substances to be highly synergistic.
`Ketoconazole was dissolved in DMSO to give a stock solution containing 2000 Jlg/ml. 1 0'-undecen-3-oyl-aminopro(cid:173)
`pyl trimethylammonium methylsulfate was diluted with ethanol to give a stock solution containing 2000 Jlg/ml. A series
`of six further 3.162-fold dilutions of each substances was prepared in the same solvent. (This dilution factor =
`SQRT(1 0), so that every second dilution was therefore a 1 0-fold dilution). Each of the seven concentrations of test sub-
`stance was then further diluted in water to 12 times the final test concentration. An 8x8 checkerboard array of dilutions
`was next prepared in the wells of flat-bottomed, plastic microdilution plates with the ketoconazole dilution series
`arranged vertically and the dilutions of 1 0'-undecen-3-oyl-aminopropyl trimethylammonium methyl sulfate arranged hor(cid:173)
`izontally. Each well contained 10 111 of solution of each test substance. In an extra column of microdilution wells, 10 111
`volumes of matching aqueous dilutions of the solvents alone were pipetted, to provide compound-free controls.
`The panel of 9 M. furfur isolates used in the study was obtained from the fungal stock collection of the Department
`of Bacteriology and Mycology at the Janssen Research Foundation. All of the isolates were originally isolated from clin(cid:173)
`ical material and three of them had been freshly isolated within 9 months prior to the study. The yeasts were maintained
`by subculture on a modification of the medium called "H. Dixon's formulation" by Van Abbe, N.J. (1964) [The investiga(cid:173)
`tion of dandruff. J. Soc. Cosmetic Chemists 15, 609-630]. This medium contained (per 1000 ml water) :malt extract
`(Difco) 36 g; Mycological peptone (Oxoid) 6 g; Bacto-oxgall (Difco) 20 g; Tween 40 (Merck) 10 ml; glycerol (Difco) 2.5
`ml; and Bacto-agar (Difco) 20 g. For use as a broth formulation the agar was omitted. Agar-based and broth versions
`of the medium were autoclaved for 5 min at 100 oc.
`Experimental inocula were prepared by incubation for 2 days at 30 oc in Dixon broth maintained in constant rotation
`at 20 rpm in test tubes angled at so from the horizontal. The broth cultures were standardized spectrophotometrically
`so they all gave an OD reading of 1.0 at 530 nm. These suspensions contained an average of 2x1 06 cell simi as meas(cid:173)
`ured in agar plate counts. The yeasts were diluted 500-fold into Dixon broth to give suspensions containing 3-10x105
`CFU/ml.
`The inoculated medium was added in 100 111 volumes to the microdilution wells already containing dilutions of the
`test substances. The plates were sealed with adhesive stickers and incubated for 5 days at 30 oc. The stickers were
`then removed and growth turbidity measured with the aid of a microplate reader as absorbance at 490 nm. For each
`combination of test substances nine microplates were run in parallel, each inoculated with a different M. furfur isolate.
`A tenth plate was set up inoculated with Dixon broth only, to provide negative control OD readings.
`With the aid of a computer spreadsheet template, the OD490 of each microplate well containing combinations of
`test substances, corrected for absorbance measured in the negative control plate, was expressed as a percentage of
`the mean OD490 of the eight test substance-free positive control wells inoculated with M. furfur. The results were
`expressed in an 8x8 matrix and automatically shaded to indicate growth inhibition at or below 25% of control. In this way
`an indifferent interaction between two test substances would appear as a dark rectangle at the bottom right of the
`graphic, a synergistic interaction would appear as an inverted "L" shape at the bottom right of the graphic and an antag(cid:173)
`onistic interaction would appear as an extension of the rectangle towards the top left of the graphic. From the checker-
`45 board results, minimal inhibitory concentrations (MIG) were determined as the lowest concentrations of test
`compounds, alone and in combination with other compounds, and fractional inhibitory concentrations (FIG) were calcu(cid:173)
`lated for each compound by the formula :
`
`30
`
`35
`
`40
`
`MIG( compound alone)/MIC(compound in presence of second compound)
`
`50
`
`The sum of the two FIGs then gave a result of 1.0 for compounds with no interactive effect (indifference), <1.0 for
`compounds with a synergistic interaction and > 1.0 for compounds with an antagonistic interaction.
`Clearly positive results indicative of possible synergy were obtained with 10'-undecen-3-oyl-aminopropyl trimethy(cid:173)
`lammonium methylsulfate (Rewocid UTM 185). The sum of the fractional inhibitory concentrations (FIG) for the combi(cid:173)
`ss nation ketoconazole and 10'-undecen-3-oyl-aminopropyl trimethylammonium methylsulfate against 9 M. furfur isolates
`in vitro was
`
`9
`
`

`
`5
`
`10
`
`15
`
`EP 0 872 230 A1
`
`M. furfur isolate no. FIC
`
`B 39387
`
`B 45836
`
`B 45838
`
`B 58047
`
`B 58200
`
`B 58968
`
`J95-0821
`
`J95-0822
`
`J95-1435
`
`0.63
`
`0.42
`
`0.42
`
`0.20
`
`0.63
`
`0.42
`
`0.42
`
`0.13
`
`1
`
`The degree of synergy extended well beyond one-dilution effects that could have arisen by chance. The activity of
`20 10'-undecen-3-oyl-aminopropyl trimethylammonium methylsulfate in combination with ketoconazole was therefore fur(cid:173)
`ther investigated against the test panel of nine isolates, but with smaller (two-fold) dilution steps in the concentration
`series. The sum of the fractional inhibitory concentrations (FIC) for the combination ketoconazole and 10'-undecen-3-
`oyl-aminopropyl trimethylammonium methylsulfate against 9 M. furfur isolates in vitro was :
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`M. furfur isolate no. FIC
`
`B 39387
`
`B 45836
`
`B 45838
`
`B 58047
`
`B 58200
`
`B 58968
`
`J95-0821
`
`J95-0822
`
`J95-1435
`
`0.50
`
`0.26
`
`0.13
`
`0.25
`
`0.19
`
`0.25
`
`0.25
`
`0.12
`
`0.19
`
`The results confirm unequivocally that both test compounds indeed interact synergistically with ketoconazole
`against M. furfur in vitro.
`
`Claims
`
`1. A body or hair cleansing composition comprising
`
`(a-1) one or more antifungals inhibiting fungal ergosterol biosynthesis as a first active ingredient,
`(a-2) 10'-undecen-3-oyl-aminopropyl trimethylammonium methylsulfate as a second active ingredient, and
`(b) art-known body or hair cleansing product ingredients as a carrier.
`
`2. A composition according to claim 1 wherein the antifungal inhibiting fungal ergosterol biosynthesis is an azole
`selected from the group comprising ketoconazole, econazole, elubiol, miconazole, itraconazole, fluconazole, or a
`mixture thereof, or is an allylamine selected from the group comprising terbinafine, naftifine, or a mixture thereof.
`
`3. A composition according to claim 2 wherein the first and the second ingredients are present in quantities producing
`
`10
`
`

`
`a mutual synergistic effect on the inhibition of the growth of Malassezia furfur.
`
`EP 0 872 230 A1
`
`4. A composition according to any one of the preceding claims wherein the first ingredient is present