WO2008000454A2

WO2008000454A2 - Composition for the treatment of skin comprising ink sack liquid of cephalopods

Info

Publication number: WO2008000454A2
Application number: PCT/EP2007/005674
Authority: WO
Inventors: Jose Luis Lopez Diaz; Diaz Maria De La Soledad Lopez; Martinez Antonio Sanchez; Boronat Raul Insa
Original assignee: Isdin
Priority date: 2006-06-30
Filing date: 2007-06-27
Publication date: 2008-01-03
Also published as: TW200822932A; AR061769A1; WO2008000454A8; CL2007001929A1; WO2008000454A3

Abstract

The present invention relates to a composition comprising as active mixture ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally further components of cephaiopods, the use of said liquid to prepare a drug tor the prophylaxis and/or treatment of mycosis, preferably onychomycosis and other pathological skin conditions, and to the use of such composition as a cosmetical composition.

Description

Composition for the treatment of skin

The present invention relates to a composition comprising the natural ink sack liquid of cephalopods and optionally further components of cephalopods, the use of said liquid to prepare a drug for the treatment of mycosis, preferably onychomycosis and other pathological skin conditions, and to the use of such composition as a cosmetical composition.

Pathological skin conditions such as mycosis are disorders that affect many people worldwide. Mycosis refers to conditions according to which fungi infect the human body on areas, which can be invaded easily such as the skin, the nails or body caves. These diseases are commonly treated with either topical and/or systemically active agents. However, in many cases treatment is not always successful and/or antimycotic drugs show in many cases severe side effects.

Thus, it was an object of the present invention to provide a composition for the treatment of pathological skin conditions such as mycosis, preferably onychomycosis, which shows a faster and/or a better therapeutical efficacy than conventional drugs.

Surprisingly it has been found that a therapeutical treatment of mycosis-infected skin areas with ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally at least one further component of cephalopods results in a recovery of said infected areas. Thus, infected skin areas are cured or damaged nails start growing like healthy nails. Surprisingly, these effects can already be observed after only one month of treatment. This is significantly faster than any therapeutical treatment with known antimycotic agents.

Moreover, since the composition comprising ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally further components of a cephalopod is predominantly based on a natural composition, the risk of any side effects on the human body is minimized. Therefore, the present invention relates to a new composition preferably for the treatment of mycosis, especially onychomycosis and/or other pathological skin conditions and optionally superinfections associated with mycosis and/or other pathological skin conditions. Said composition comprises the ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally at least one further component of a cephalopod.

Preferably a composition comprising ink sack liquid, preferably the natural ink sack liquid of cephalopods as the only active component is particularly suitable for topical application and/or oral administration.

The term "natural ink sack liquid", according to the present invention, means the original (untreated) contents of the ink sack of cephalopods as such.

In a preferred embodiment of the present invention the inventive composition further comprises besides the ink sack liquid, preferably the natural ink sack liquid of cephalopods at least a part of at least one cephalopod's component selected from the group comprising an organ, a tissue of an organ, a liquid of an organ, a tissuepf an organ, a secretion of an organ, a microorganism associated with an organ and at least one metabolic compound produced by such microorganism, wherein said organ(s) is/are close to the ink sack according to the natural arrangement in a cephalopod.

Preferably, such further components of a cephalopod are derived from an ink sack except the ink, from a nidamental gland, from an accessory nidamental gland and/or from an ovary, optionally including eggs. If the eggs are used they are preferably used with the gelatinous matrix enveloping them.

According to the present invention as further cephalopod's component at least one microorganism associated with a cephalopod's organ and/or the metabolic compounds produced by such microorganism can also be used. Preferably, such microorganism is at least one bacterial strain having an antimicrobial or an antifungal effect, whereby at least one metabolic compound of such bacterial strain could have an antimicrobial or an antifungal effect, too. Preferably such microorganism is associated with at least one cephalopocTs organ mentioned above.

The amount of the further cephalopod's component ranges preferably from 0.001 to 40%, more preferably from 0.05 to 30%, most preferably from 0.1 to 25% per weight, based on the total weight of the inventive composition.

In a preferred embodiment of the present invention the ink sack liquid and any further component of cephalopods are taken from the same kind of cephalopod.

Cephalopods belong to the mollusc class Cephalopoda which is characterized by bilateral body symmetry, a prominent head, and a modification of the mollusc foot, a muscular hydrostat, into the form of arms or tentacles. The species useful for the present invention have an ink sac containing a dark fluid used in danger for protection or defense.

A systematic overview of these organisms is shown below in scheme 1 :

Scheme 1 :

• CLASS CEPHALOPODA o Subclass Nautiloidea: nautilus o Subclass Coleoidea: squid, octopus, cuttlefish

^■ Superorder Octopodiformes

^■ Superorder Decapodiformes

■ Order Spirulida: Ram's Horn Squid

■ Order Sepiida: cuttlefish

■ Family Sepiadariidae ' Family Sepiidae • Order Sepiolida: bobtail squid

■ Order Teuthida: squid

The inventive composition comprises preferably the natural ink sack liquid of cephalopods belonging to the subclass of Coleoideae, more preferably to the superorder of Decapodiformes and/or Octopodiformes, even more preferably to the order of Spirulidae, Sepiidae, Sepiolidae, and/or Teuthidae. Most preferably, the inventive composition comprises the natural ink sack liquid of cephalopods belonging to the family of Sepiadariidae and/or Sepiidae.

Any further cephalopod's components being present optionally in the inventive composition are selected accordingly to the selection of the ink.

According to the present invention the inventive composition may contain ink sack liquid, preferably the natural ink sack liquid and optionally any further cephalopod's component of animals of a different systematical group or of the same systematical group.

More preferably, the inventive composition comprises the ink sack liquid, preferably the natural ink sack liquid and optionally any further cephalopod's component of animals of the same systematical group, wherein the systematical group may be a class, a subclass, a superorder, an order, a family, a genus or a species. Most preferably, the systematical group is a family, especially a genus or a species.

In order to obtain said preferably natural liquid of the ink sack of cephalopods, the ink sack is isolated from cephalopods. The isolation is preferably carried out by common surgery methods well known by those skilled in the art, optionally cleaning the removed ink sack containing the liquid and squeezing or pressing the sack optionally mechanically to gather the liquid.

Alternatively, said preferably natural ink sack liquid may be obtained by endoscopic or laparoscopic methods such as e.g. catheter, canulation, punctation or similar techniques. These techniques are well known by those skilled in the art.

The term "colorless liquid", according to the present invention, means an ink sack liquid, preferably a natural ink sack liquid of cephalopods containing up to 10% of the original amount of dye and/or pigment. Preferably, said percentage is 5%, more preferably 3%, most preferably 1 % by weight of the original amount. In a preferred embodiment of the present invention the inventive composition comprises colorless ink sack liquid of cephalopods, especially in cosmetical compositions.

Optionally, the inventive composition can comprise the ink sack liquid, preferably the natural ink sack liquid diluted or undiluted. Such dilution is in a range of 1 :1 to 1 :10000, preferably from 1 :1 to 1 :1000, more preferably in a range of 1 :1 to 1 :100. Most preferably, the dilution is in a range of 1 :1 to 1 :10. For the dilution, water or water soluble organic, preferaby skin-compatible solvents like ethanol are used.

If the inventive composition comprises the ink sack liquid, preferably the natural ink sack liquid concentrated, such concentration is preferably 1-1000-fold, more preferably 1-100-fold, most preferably 1-10 fold of the natural ink sack liquid. Preferably the ink sack liquid is used neither diluted nor concentrated.

Optionally, the ink sack liquid, preferably the natural ink sack liquid can also be centrifuged and/or passed through a filter with a pore diameter of 0.1 to 100 μm, preferably 0.1 to 10, more preferably 0.1 to 1 μm to remove the pigments from the ink sack liquid in order to obtain a colorless liquid before it is used for the inventive composition.

If besides the natural ink sack liquid the inventive composition further comprises at least one part of the aforementioned cephalopod's components, such a part can be derived from the cephalopod separately from deriving the ink sack liquid or together with the ink sack liquid.

If necessary, the further cephalopod's components can be comminuted and/or homogenized by standard methods known by those skilled in the art, optionally mixed and/or added to the ink sack liquid before formulated to the inventive composition.

Depending of which kind the further cephalopod's component(s) is/are, this/these component(s) can be extracted, filtered, concentrated and/or centrifuged. Optionally, these optionally treated cephalopod's components can be dissolved, suspended or diluted. Such dilution can be in the range of 1 :1 to 1 :10000, preferably from 1 :1 to 1 :1000, more preferably in a range of 1 :1 to 1 :100. Most preferably, a dilution can be in a range of 1 :1 to 1 :10. For the dissolution, suspension or dilution, water or water mixable organic, preferaby skin-compatible solvents like ethanol can be used.

The ink sack liquid, preferably the natural ink sack liquid can be stored cooled or even frozen if not used immediately. This is also possible with any optionally treated further cephalopod's component mentioned above.

The inventive composition can only be composed of the natural ink sack liquid, diluted or undiluted, or of such ink sack liquid and any further cephalopod's component mentioned above and adapted for the respective application.

In one embodiment of the present invention the inventive composition comprising ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally any further component mentioned above of cephalopods is provided as a pharmaceutical composition.

Such inventive pharmaceutical composition comprising ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally any further component mentioned above of cephalopods is applied locally and/or administered systemically, preferably locally, most preferably topically. For this purpose, the pharmaceutical composition of the present invention may be in liquid, semi-solid or solid form.

The pharmaceutical composition of the present invention can be preferably formulated for local, preferably topical treatment containing optionally usual auxiliary agents.

For such application, the pharmaceutical composition according to the present invention can be formulated as liquid, fluid, foam, cream, gel, paste, balsam, spray, ointment, lotion, conditioner, tonic, milk, mousse, emulsion, serum, oil, stick, roller, shampoo, jelly, suspension, dispersion, lacquer, paint or patch. Such inventive liquids, fluids, foams, creams, gels, pastes, balsams, sprays, lotions, ointments, conditioners, tonics, milks, mousses, emulsions, sera, oils, sticks, rollers, shampoos, jellies, paints, suspensions, dispersions, lacquers or patches are preferably applied topically to the skin, the nails, the scalp, the hair and/or to the various mucous membranes of the body, including but not limited to those of the oral, buccal, ocular, nasal, vaginal or rectal cavities. Preferably, these locally, preferably topically applied pharmaceutical compositions are in form of a rinse-off or a leave-on formulation.

In another preferred embodiment of the present invention, the inventive pharmaceutical composition comprising preferably the natural ink sack liquid of cephalopods and optionally any further component mentioned above of cephalopods is administered orally.

For such oral administration, the pharmaceutical composition according to the present invention can be preferably formulated as tablet, capsule, pill, coated tablet, dragee, hard and soft gelatine capsule, troche, suspension, lozenge, elixir, drops O£ powder, wherein the powder is preferably inside a sachet.

The inventive pharmaceutical composition can also be provided in form of a patch for topical and/or transdermal application.

In order to prepare the inventive pharmaceutical compositions auxiliary agents like gelling agents, thickening agents, hydrophilic or hydrophobic polymers, emulsifying agents, emollients, water and/or alcohols, such as ethanol can be used.

Optionally, if applied in liquid form, said pharmaceutical composition is preferably applied by means of a brush, a sponge, a dispenser or a pipette, optionally before cleaning the defect skin, nail and so on.

The inventive pharmaceutical composition is also suitable for administration and/or application in combination with at least one systemically and/or topically active antimycotic drug comprising itraconazole, ketoconazole, miconazole, fluconazole and/or terbinafine.

Another objective of the present invention was to provide a cosmetical composition to keep scalp, skin, hair and/or nails in good conditions, i.e. especially for moisturizing the skin, treating dry skin successfully and/or against skin ageing, photoageing and/or rash.

Therefore the present invention also relates to the inventive composition comprising ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally any further component of cephalopods mentioned above used as a cosmetical composition.

Such an inventive cosmetical composition can also contain usual auxiliary agents known by those skilled in the art.

Preferably, the inventive cosmetical composition comprises preferable the natural ink sack liquid of cephalopods, but colorless and optionally any further component of cephalopods mentioned above.

For cosmetical use the inventive composition is preferably in liquid, semi-solid or solid form and is formulated as liquid, fluid, foam, cream, gel, paste, balsam, spray, ointment, lotion, conditioner, tonic, milk, mousse, emulsion, serum, oil, stick, roller, shampoo, jelly, suspension, dispersion, lacquer or paint. Such liquids, fluids, foams, creams, gels, pastes, balsams, sprays, lotions, ointments, conditioners, tonics, milks, mousses, emulsions, sera, oils, sticks, rollers, shampoos, jellies, suspensions, dispersions, lacquers or paints containing the inventive composition are preferably applied topically to the skin, the nails, mucous membranes, the hair and/or the scalp. Preferably, these inventive compositions are in form of a rinse-off or a leave-on formulation.

Formulated as ointments, such ointments comprise oily, oil-in-water or water-in-oil emulsion-type base. Preferably the inventive cosmetical compositions are suitable for keeping scalp, skin, hair and/or nails in good conditions.

Moreover, the inventive cosmetical compositions are particularly appropriate for moisturizing the skin, treating dry skin successfully and/or against skin ageing, photoageing and/or rash.

The cosmetical compositions according to the present invention preferably contain usual auxiliary agents such as e.g. emulsifiers, emollients, surfactants, film formers, biological additives to enhance performance and/or consumer appeal such as amino acids, proteins, vanilla, aloe extract, bioflavinoids, etc., buffering agents, chelating agents such as ethylenediaminetetra-acetic acid (EDTA) or oxalic acid, emulsion stabilizers, pH adjusters; thickening agents, fragrances, preservatives and/or opacifying agents.

Emulsifiers are preferably used in certain inventive cosmetical compositions in such an amount which are effective to provide uniform blending of ingredients of the composition. Useful emulsifiers include anionics such as fatty acid soaps, e.g., potassium stearate, sodium stearate, ammonium stearate, and triethanolamine stearate; polyol fatty acid monoesters containing fatty acid soaps, e.g., glycerol monostearate containing either potassium or sodium salt; sulfuric esters (sodium salts), e.g., sodium lauryl 5 sulfate, and sodium acetyl sulfate; and polyol fatty acid monoesters containing sulfuric esters, e.g., glyceryl monostearate containing sodium lauryl surfate; (ii) cationics chloride such as N(stearoyl colamino formylmethyl) pyridium; N-soya-N-ethyl morpholinium ethosulfate; alkyl dimethyl benzyl ammonium chloride; diisobutylphenoxytheoxyethyl dimethyl benzyl ammonium chloride; and acetyl pyridium chloride; and (iii) nonionics such as polyoxyethylene fatty alcohol ethers, e.g., monostearate; polyoxyethylene lauryl alcohol; polyoxypropylene fatty alcohol ethers, e.g., propoxylated oleyl alcohol; polyoxyethylene fatty acid esters, e.g., polyoxyethylene stearate; polyoxyethylene sorbitan fatty acid esters, e.g., polyoxyethylene sorbitan monostearate; sorbitan fatty acid esters, e.g., sorbitan; polyoxyethylene glycol fatty acid esters, e.g., polyoxyethylene glycol monostearate; and polyol fatty acid esters, e.g., glyceryl monostearate and propylene glycol monostearate; and ethoxylated lanolin derivatives, e.g., ethoxylated lanolins, ethoxylated lanolin alcohols and/or ethoxylated cholesterol.

Emollients may be used in the inventive cosmetical compositions in such an amount which is effective to prevent or relieve dryness. Useful emollients include, without limitation hydrocarbon oils and waxes; silicone oils; triglyceride esters; acetoglyceride esters; ethoxylated glyceride; alkyl esters; alkenyl esters; fatty acids; fatty alcohols; fatty alcohol ethers; etheresters; lanolin and derivatives; polyhydric alcohols (polyols) and polyether derivatives; polyhydric alcohol (polyol) esters; wax esters; beeswax derivatives; vegetable waxes; phospholipids; sterols; and/or amides.

Surfactants may also be used in certain inventive cosmetical compositions. Suitable surfactants may include, for example, those surfactants generally grouped as cleansing agents, emulsifying agents, foam boosters, hydrotropes, solubilizing agents, suspending agents and nonsurfactants (facilitates the dispersion of solids in liquids).

Suitable film formers which are preferably used in the inventive cosmetical compositions keep the composition smooth and even and include, without limitation: acrylamide/sodium acrylate copolymer; ammonium acrylates copolymer; Balsam Peru; cellulose gum; ethylene/maleic anhydride copolymer; hydroxyethylcellulose; hydroxypropylcellulose; polyacrylamide; polyethylene; polyvinyl alcohol; pvm/MA copolymer (polyvinyl methylether/maleic anhydride); PVP (polyvinylpyrrolidone); maleic anhydride copolymer, Polyvinylpyrrolidon (PVP)/hexadecene copolymer; acryliclacrylate copolymer; and the like.

Certain inventive cosmetical compositions may also comprise pH adjusters. These pH adjusters preferably comprise, but are not limited to ammonium hydroxide, triethanolamine or citric acid. Thickening agents used for the inventive compositions preferably comprise but are not limited to candelilla, carnauba, and microcrystalline waxes, carbomer and polyethylene thickeners.

The components of the inventive cosmetical compositions have to be used in amounts which are in compliance with the Council Directives 76/768/EEC and Commission Directive 95/17/EC on the approximation of the laws of the Member States relating to cosmetic products.

A further aspect of the present invention relates to the use of ink sack liquid of cephalopods, preferably the natural (untreated) ink sack liquid as mentioned above and optionally any further component mentioned above of cephalopods to prepare a drug for the prophylaxis and/or treatment of mycosis, preferably onychomycosis and optionally superinfection(s) associated with mycosis, preferably onychomycosis and/or pathological skin conditions comprising psoriasis, dermatitis, acne, hair loss, immunological skin diseases, skin cancer, actinic keratosis, pemphigoid, dermatofibroma, lupus erythematosus, eczema, erythema, foliculitis, impetigo, lichen, pityriasis, tinea, pruritus, rosacea, urticaria, and optionally superinfection(s) associated with said pathological skin conditions, provided that such superinfections are associated with said pathological skin conditions, wherein the superinfection(s) is (are) preferably caused by bacteria and/or moulds.

The terms "to treat" or "treatment", according to the invention are defined as including the treatment of symptoms of mycosis and/or pathological skin conditions, preferably certain subtypes of mycosis such as onychomycosis, the treatment of the disease or disease consequences causing the symptoms, as well as the prevention/prophylaxis of the symptoms of mycosis, preferably onychomycosis and/or pathological skin conditions.

Moreover, the terms "to treat" or "treatment", according to the present invention include any ameliorating effect, wherein "ameliorating effect" in the context of this invention means any improvement on the situation of the patient treated - either subjectively (feeling of or on the patient) or objectively by healing of the infection. Mostly preferred is the use of the ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally any further cephalopod's component mentioned above to prepare a drug for the prophylaxis and/or treatment of mycosis, preferably onychomycosis, and optionally superinfections associated with mycosis and/or onychomycosis.

Mycoses can be classified according to the tissue levels initially colonized:

1. Superficial mycoses are limited to the outermost layers of the skin and hair.

2. Cutaneous mycoses extend deeper into the epidermis, as well as invasive hair and nail diseases. These diseases are restricted to the keratinized layers of the skin, hair, and nails. Unlike the superficial mycoses, host immune responses may be evoked, resulting in pathologic changes expressed in the deeper layers of the skin. The organisms that cause these diseases are called dermatophytes. The resulting diseases are often called ringworm (even though there is no worm involved) or tinea. Cutaenous mycoses are caused by Microsporum, Trichophyton, and Epidermophyton fungi, which together comprise actually 41 known species.

3. Subcutaneous mycoses involve the dermis, subcutaneous tissues, muscle, and fascia. These infections are chronic and can be initiated by piercing trauma to the skin, which allows the fungi to enter. These infections are difficult to treat and may require surgical interventions such as debridement.

4. Systemic mycoses originate primarily in the lungs and may spread to many organ systems. Organisms that cause systemic mycoses are inherently virulent. All fungi that generally cause systemic mycoses except Cryptococcus are dimorphic fungi.

5. Opportunistic mycoses are infections of patients with immune deficiencies who would otherwise not be infected. Examples of immunocompromised conditions include AIDS, alteration of normal flora by antibiotics, immunosuppressive therapy, and metastatic cancer. Examples of opportunistic mycoses include Candidiasis and Aspergillosis.

Preferably, the inventive composition comprising ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally any further component mentioned above of cephalopods is suitable for the preparation of a drug for the prophylaxis and/or treatment of superficial mycoses, cutaneous mycoses, subcutaneous mycoses, systemic mycoses or opportunistic mycoses. More preferably, such inventive composition is suitable for the preparation of a drug for the prophylaxis and/or treatment of superficial mycoses, subcutaneous mycoses. Most preferably such inventive composition is suitable for the preparation of a drug for the prophylaxis and/or treatment of onychomycosis.

Onychomycosis (OM) is a fungal infection of the nails. This condition may affect toe- or fingernails, but toenail infections are particularly common. Different clinical patterns of infection depend on the way and the extent by which fungi colonise the nail:

• Distal subungual onychomycosis: presents as a thickened and opacified nail plate, subungual hyperkeratosis, and onycholysis. Discoloration ranges from white to brown. The edge of the involved area is often dystrophic, while the edge of the nail itself becomes severely eroded.

• Proximal subungual onychomycosis: presents as a milky white discoloration of the nail plate, but, in contrast to distal subungual onychomycosis, no evidence of subungual hyperkeratosis or onycholysis is present.

• White superficial onychomycosis: is usually confined to the toenails and manifests as small, white speckled or powdery patches on the surface of the nail plate. The nail becomes roughened and crumbles easily.

• Endonyx onychomycosis: presents as an area of leukonychia in the proximal nail fold, and it may extend to deeper layers of the nail. The nail plate becomes white proximally and remains normal distally.

• Total dystropic onychomycosis: presents as a thickened, opaque, and yellow- brown nail and involves the entire nail plate and matrix. In a preferred embodiment of the present invention, said onychomycosis comprises distal subungual onychomycosis, proximal subungual onychomycosis, white superficial onychomycosis, endonyx onychomycosis, and/or total dystropic onychomycosis.

Preferably, the above mentioned inventive pharmaceutical composition is suitable for the preparation of a drug for the prophylaxis and/or treatment of onychomycosis, more preferably for the prophylaxis and/or treatment of distal subungual onychomycosis, proximal subungual onychomycosis, white superficial onychomycosis, endonyx onychomycosis, and/or total dystropic onychomycosis. Even more preferably, the above mentioned inventive composition is suitable for the reparation of a drug for the prophylaxis and/or treatment of distal subungual, proximal subungual onychomycosis, white superficial onychomycosis, endonyx onychomycosis, and/or total dystropic onychomycosis. Most preferably, the aforementioned inventive composition is suitable for the preparation of a drug for the prophylaxis and/or treatment of onychomycosis, more preferably for the prophylaxis and/or treatment of distal subungual and/or proximal subungual onychomycosis.

Dermatophytes are the fungi, which are most commonly responsible for onychomycosis. Two dermatophyte species, Trichophyton rubrum and Trichophyton interdigitale, cause the majority of onychomycosis cases worldwide. Other causal fungi include yeasts, e.g., Candida, and non-dermatophytic moulds, in particular members of the mould genera Scytalidiυm, Scopulariopsis and Aspergillus. Yeasts mainly cause fingernail onychomycosis in people whose hands are often submerged in water. Scytalidium mainly affects people in the tropics, though it persists if they later move to areas of temperate climate. Other moulds mainly affect people over the age of 60, and their presence in the nail reflects a slight weakening in its ability to defend itself against fungal invasion.

The above mentioned inventive pharmaceutical composition is preferably suitable for the preparation of a drug for the prophylaxis and/or treatment of onychomycosis caused by dermatophytes, yeasts and non-dermatophytic moulds, more preferably for the prophylaxis and/or treatment of at least one member of the group of: Epidermophyton floccosum, Microsporum audouinii, Microsporum canis, Microsporum gypseum, Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton schoenleinii and Trichophyton tonsurans, the yeasts selected from the group consisting of: Candida spp. and/or by at least one member selected from the group of moulds consisting of: Acremonium sp., Aspergillus sp.,Fusarium oxysporum, Scopulariopsis brevicaulis, Onychocola canadensis, and Scytalidium dimidiatum.

The present invention further refers to the use of an ink sack liquid, preferably a natural ink sack liquid and optionally any further cephalopod's components mentioned above, to prepare a drug for the prophylaxis and/or treatment of pathological skin conditions comprising psoriasis, dermatitis, acne, hair loss, immunological skin diseases, skin cancer, actinic keratosis, pemphigoid, dermatofibroma, lupus erythematosus, eczema, erythema, folliculitis, impetigo, lichen, pityriasis, tinea, pruritus, rosacea and/or urticaria.

Psoriasis is a chronic and recurrent papulosquamous disease producing distinctive erythematous patches covered with a silvery scale. These injuries are characterized by dry, well-defined, symmetrical papules and plaques_^ of various sizes. Psoriasjs ]s_ not contagious. The prevalence of psoriasis has been estimated to be between 2% and 3% in the general population. Both sexes are affected equally. Psoriasis is most common in North Americans and northern Europeans, more in white people than in black and Asian people. The prevalence increases with the age of the population studied. The precise causes of psoriasis are not known. It is known to have a genetic component, but genetics alone cannot explain the onset of the disease.

Dermatitis and seborrheic dermatitis are inflammatory conditions of the skin. Atopic dermatitis causes an inflamed allergic skin response. In nearly half of all patients with childhood atopic dermatitis, the disease improves or clears with age. Contact dermatitis is a cutaneous reaction to either topical irritation or allergy. Seborrheic dermatitis is a papulosquamous skin disease manifested by various degrees of scaling and erythema in areas of high oil gland concentration such as the scalp, eyebrows, etc. It is not curable. The highest incidence of Atopic dermatitis occurs in children, with most cases developing in those younger than five years of age. Atopic dermatitis: The characteristic features depend on the age at onset. But pruritus is always present. The predominant lesion in children is an oozing, crusting, coalescent papules. Older children and young adults have thickening of the skin, along with fine, dry scaling and some papules. Seborrheic dermatitis: Common manifestations are cradle cap in newborns and dandruff in adolescents and adults.

Acne is a common disease of the pilosebaceous glands. It produces unsightly lesions and sometimes permanent scarring and disfigurement. Etiologically, acne involves multiple factors such as sex hormones, heredity, bacterial flora of the skin, stress, mechanical occlusion, and cosmetic use. The sludging of sebaceous oils and deposits of loose epithelial cell, which cause an obstruction of the follicular canal, causes acne. Continued oil production and bacterial growth in this obstructed follicle may cause rupture of the wall or sebaceous gland and result in an inflamed lesion. Acne usually develops when the sebaceous glands and the lining of the hair follicle begin to work overtime, as they do in adolescence. Normally, the lining of the hair follicle sheds cells that are carried to the surface of the skin by the sebum. When the follicle is overworked and clogged, cells and sebum accumulate, forming a plug (comedo). If the plug stays below the surface of the skin, it is called a "closed" comedo or whitehead. If the plug enlarges and pops out of the duct, it is called an "open" comedo or blackhead because the top is dark. This is not dirt and will not wash away. The discoloration is due to the way light is absorbed by the skin cells within the opening.

Hair loss or alopecia is a condition where there is a loss of hair. The cause of simple baldness or excessive hair growth are not completely understood but may result from serious illness, drugs, endocrine disorders, certain forms of dermatitis, hereditary factors, radiation or physiological changes as a part of the ageing process. The causes of simple hair loss and excessive hair growth are not completely understood but may result from serious illness, drugs, endocrine disorders, certain forms of dermatitis, hereditary factors, radiation or physiological changes as a part of the ageing process. Skin cancer is an increasingly common condition, in part attributed to increased exposure to ultraviolet radiation. The increased exposure is mainly due to the recent popularity of sun tanning (sun bathing). Lighter-skinned individuals are more vulnerable. In the United States, about one out of every three new cancers arises from skin. The most common types are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) which may be locally disfiguring but unlikely to spread to other parts of the body. The most dangerous type is malignant melanoma, which can be fatal if not treated early, but forms only a small proportion of all skin cancers. Actinic keratosis is one type of skin cancer which appears as rough, red or brown, scaly patches on the skin. It is a precancerous condition and develops sometimes into squamous cell cancer.

Mucous membrane pemphigoid is an autoimmune reaction that occurs at the level of the basement membrane. Commonly affects gingiva. Desquamating/blistering disease in which epithelial separation takes place at the level of the basement membrane.

that range in size from about 0.5 to 1 cm. They are hard papules (rounded bumps) that may appear in a variety of colors, usually brownish to tan. Typical dermatofibromas cause little or no discomfort, although itching and tenderness can occur. Some physicians and researchers believe dermatofibromas form as a reaction to previous injuries such as insect bites or thorn pricks. They are composed of disordered collagen laid down by fibroblasts. Rarely, basal cell carcinoma may develop in a dermatofibroma.

Systemic lupus erythematosus (SLE or lupus) is a chronic, potentially debilitating or fatal autoimmune disease in which the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage. SLE can affect any part of the body, but often harms the heart, joints (rheumatological), skin, lungs, blood vessels and brain/nervous system. Lupus erythematosus is treatable, mainly with immunosuppression, though there is currently no cure for it. Eczema is a form of dermatitis, or inflammation of the upper layers of the skin. The term eczema is broadly applied to a range of persistent or recurring skin rashes characterized by redness, skin edema, itching and dryness, with possible crusting, flaking, blistering, cracking, oozing or bleeding. Areas of temporary skin discoloration sometimes characterize healed lesions, though scarring is rare.

Erythema is an abnormal redness of the skin caused by capillary congestion. It is one of the cardinal signs of inflammation. It can be caused by infection, massage, electrical treatments, allergies, exercise or solar radiation (sunburn), any of which can cause the capillaries to dilate, resulting in redness.

Folliculitis is inflammation of one or more hair follicles. The condition may occur anywhere on the skin. Folliculitis starts when hair follicles are damaged by friction from clothing, blockage of the follicle, or shaving. In most cases of folliculitis, the damaged follicles are then infected with the bacteria Staphylococcus sp.

Impetigo is a superficial skin infection most common among children age 2-6 years (rare among people not in this age group). Impetigo is usually caused by the same streptococci strains as those that cause strep throat. It can also be caused by Staphylococcus infection. Scratching may spread the lesions.

Lichen sclerosus is a long-term problem of the skin. It mostly affects the genital and anal areas. Sometimes, lichen sclerosus appears on the upper body, breasts, and upper arms.

Pityriasis commonly refers to flaking of the skin. Types include: Pityriasis lichenoides chronica, Pityriasis lichenoides et varioliformis acuta, Pityriasis rosea, Pityriasis rubra pilaris and Pityriasis versicolor. Pityriasis lichenoides chronica, short form PLC, is the chronic version of the Pityriasis lichenoides et varioliformis acuta, also called Mucha Habermann's Disease. Pityriasis Lichenoides et Varioliformis Acuta, or Mucha Habermann's Disease, short form PLEVA, is a disease of the immune system. It is the more severe version of Pityriasis lichenoides chronica. The disease is characterized by rashes and small lesions on the skin. Pityriasis rosea is a skin disease marked by patches of pink, oval rash. Although its exact cause is unknown and its onset is not linked to food, medicines or stress, it is thought that this essentially non-contagious condition is set off by a virus. Pityriasis rosea can occur at any age, however, it occurs most often in teenagers and young adults. Pityriasis rubra pilaris (PRP) is a rare and chronic skin disorder that often has a sudden onset. Symptoms may include reddish-orange patches on the skin, severe flaking, uncomfortable itching, and thickening of the skin on the feet and hands. For some, early symptoms may also include generalized swelling of the legs, feet and other parts of the body. PRP has a varied clinical progression and a varied rate of improvement. There is no known cause or cure. Tinea versicolor or pityriasis versicolor is a common skin infection caused by the yeast Malassezia furfur or Pityrosporum orbiculare. This yeast is normally found on the human skin and only becomes troublesome under certain circumstances, such as a warm and humid environment. It is occasionally referred to by its colloquial Hawaiian moniker, "haole rot".

Pruritus is a sensation felt on an area of skin that makes a person or animal want to scratch it. It is a distressing symptom that can cause discomfort. Scratching may cause breaks in the skin that may result in infection. Pruritus can be related to anything from dry skin to undiagnosed cancer.

Rosacea is a common but often misunderstood condition that is estimated to affect over 45 million people worldwide. It begins as flushing and redness on the central face and across the cheeks, nose, or forehead but can also less commonly affect the neck, chest, scalp or ears. As rosacea progresses, other symptoms can develop such as permanent redness, red bumps (some with pus), red gritty eyes, burning and stinging sensations, small blood vessels visible near the surface of the skin, and in some advanced cases a bulbous nose.

Urticaria or hives is a relatively common form of allergic reaction that causes raised red skin welts. Urticaria is also known as nettle rash or uredo. These welts can range in diameter from 5 mm (0.2 inches) or more, itch severely, and often have a pale border. Urticaria is generally caused by direct contact with an allergenic substance, or an immune response to food or some other allergen. Hives can also be caused by stress.

Preferably, the inventive cosmetical composition comprising ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally any further cephalopod's component mentioned above can be used for the prophylaxis and/or treatment of skin in order to achieve good skin conditions by preventing and/or improving for instance skin ageing, photoageing, dry skin and/or rash.

Skin ageing is a normal process of life but one that many individuals do not take gracefully. With increasing age, cellular cohesion is reduced, renewal time is slower and the elastic tissue degenerates resulting in wrinkles and sagging. Degenerative changes in elastic tissue begin at about 30. The rate of age related changes is influenced by heredity, personal hygiene practices, nutrition, general health and history of sun, radiation and chemical exposure. During the ageing process, cellular cohesion is reduced, the renewal time of the cell layer slows, the moisture content is diminished. The elastic tissues are degraded by enzymes. Photoageing is characterised by chronic inflammation, elastosis.

A rash is a change in the skin which affects its appearance or texture. A rash may be localised to one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, dry, cracked or blistered, swell and may be painful. The causes, and therefore treatments for, rashes vary widely. Diagnosis must take into account such things as the appearance of the rash, other symptoms, what the patient may have been exposed to, occupation, and occurrence in family members.

Dry skin (Xerosis) is common. It happens more often in the winter when cold air outside and heated air inside cause low humidity. Forced-air furnaces make skin even drier. The skin loses moisture and may crack and peel, or become irritated and inflamed. Bathing too frequently, especially with harsh soaps, may contribute to dry skin. Eczema may cause dry skin. Depending on the severity of the infection, the immunological status of the subject and other treatment parameters, the term of treatment can preferably last from 15 days to 24 months, more preferably from 15 days to 18 months, most preferably, the treatment shall be carried out for at least 1 month.

The inventive pharmaceutical composition is preferably adapted at least for a once a day, twice or three times a day, preferably for twice a day application and/or administration.

Since onychomycosis and/or pathological skin conditions can be often accompanied by superinfections of bacteria or moulds, which results in a change of color of the nail into yellow/brown mostly, such superinfections should also be treated.

Surprisingly, the inventive pharmaceutical composition comprising ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally any further cephalopod's components mentioned above is also suitable for the preparation of a drug for the prophylaxis and/or treatment of such superinfections associated not only with mycoses, but also for the treatment of superinfections associated with other pathological skin conditions like psoriasis, dermatitis, acne, hair loss, immunological skin diseases, skin cancer, actinic keratosis, pemphigoid, dermatofibroma, lupus erythematosus, eczema, erythema, foliculitis, impetigo, lichen, pityriasis, tinea, pruritus, rosacea and/or urticaria, provided that some these pathological skin conditions do not have associated superinfections.

In severe mycosis and/or pathological skin conditions it might be appropriate to treat the infection systemically by topical application of the inventive drug as well as by administration of systemically and/or topically active antimycotic drugs.

Preferably, the inventive pharmaceutical composition comprising ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally any further cephalopod's component mentioned above is suitable for the preparation of a drug for administration and/or application in combination with at least one systemically and/or topically active antimycotic drug comprising itraconazole, ketoconazole, miconazole, fluconazole and/or terbinafine.

An embodiment of the present invention refers to a combination, preferably a kit comprising a pharmaceutical composition containing as active mixture the ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally any further cephalopod's component mentioned above and a drug with at least one systemically/and or topically active antimycotic agent wherein said systemically and/or topically active antimycotic drug preferably comprises itraconazole, ketoconazole, miconazole, fluconazole and/or terbinafine, more preferably itraconazole, fluconazole and/or terbinafine as active agent.

Systemically and/or topically active antimycotic agents actually used for the treatment of mycoses preferably comprise itraconazole, ketoconazole, miconazole, fluconazole, and/or terbinafine.

Preferably, the inventive pharmaceutical composition is simultaneously administered and/011 applied topicajjy iwith a systemically ajτd/prjppjcaliy_active Lantjmyj?αtjc_agejτt comprising itraconazole, ketoconazole, miconazole, fluconazole, and/or terbinafine, more preferably comprising itraconazole and/or terbinafine.

Both the active antimycotic agent and the inventive pharmaceutical composition can also be used with a time difference of 0 to 30 days, more preferably 0 to 15 days, more preferably 0 to 10 days, even more preferably 0 to 5 days, yet more preferably 0 to 48 hours.

If applied topically, for repeated application of the inventive pharmaceutical composition an optional cleaning step of the site of infection may be necessary before reapplication.

In an additional preferred embodiment, the inventive drug comprising ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally any further cephalopod's component mentioned above is applied in a consecutive order to the therapeutical treatment with a systemically active antimycotic agent. The term "consecutive", according to the present invention, means the immediate beginning of another treatment after finishing a first treatment. Therefore, in accordance with the present invention, a treatment with a systemically active antimycotic agent can start after finishing the treatment with the inventive pharmaceutical composition or vice versa.

Systemically and/or topically active antimycotic drugs are available on the market and are administered after prescription.

A further aspect of the present invention refers to the use of a cosmetical composition comprising ink sack liquid, preferably the natural ink sack liquid of cephalopods and optionally any further cephalopod's component mentioned above for the prophylaxis and/or care against skin conditions comprising skin ageing, photoageing, dry skin and/or rash, preferably skin ageing and/or dry skin.

The cosmetical composition is preferably adapted at least for a oηce_a_day,Jwice _or_ three times a day, preferably for twice a day application.

EXAMPLES

Example 1

A) Animals

Animals (Sepia officinalis) were caught in the Mediterranean sea for subsequent isolation of the filled ink sack and parts of the organs being srrsngsd closely to the ink sack.

The ink sacks were isolated after opening the abdomen with a scalpel. The whole isolated ink sacks were then pressed mechanically and the natural ink sack liquid was collected into a recipient at room temperature. Parts of the accessory nidamental gland, the nidamental gland and the overy including gages were also derived from the above mentioned animals , homogenized and mixed with ink sack liquid in a weight ration of 30:70. Afterwards, this mixture was frozen and stored for 6 days for later processing. The unfrozen, undiluted mixture was then used for subsequent treatment.

B) Pharmacological data

Experimental protocol

Patients

1 ) A 66 year old woman, diagnosed with persistant onychomycosis for 30 years. Former treatment with local and systemic antymycotics such as itraconazole, amorolfina, terbinafina etc. did show only little or no effect. The clinical manifestation of the infection included ungual hyperkeratosis, together with a onycholysis (separation of the nail plate from the nail bed) and distal enlargement of the nail bed.

2) A 52 year old man, diagnosed with persistant onychomycosis for 4 years. The clinical manifestation comprised a partial destruction of the nail plate, onycholysis of the distal part of said nail plate as well as yellowish/brown nail plate (indicator for superinfection with bacteria/moulds). 3) A 62 year old woman, diagnosed with persistant, asymptomatic onychomycosis of the nails of hands and feet for several years, clinical manifestation of the infection included lesion of the infected nails.

4) A 37 year old man was diagnosed with lesions which affected among others the big toe of the right foot.

The patients were treated with the above obtained, undiluted mixture by topical application on the infected nails for up to 11 weeks. Pictures of the affected toes or fingers were taken before the treatment with the mixture and approximately one month to 11 weeks after said treatment of each patient. Before taking the pictures, the toes/fingers were cleaned to remove the dark color of the cephalopod ink for a better visualization.

C) Results:

Patient 1: The photo documentation according to Fig.1 shows in photo 1B that the treatment with the above mentioned- mixture improves the infection already after two days. The yellowish/brown color of the nail observed before the treatment does no longer exist. In picture of Figure 1C it can be observed that the overall infection of the nail has improved considerably after one month of treatment.

Patient 2: The photo documentation according to Fig.2 shows in photo 2B that the topical treatment with the above mentioned mixture over one month results in significant improvement of the clinical manifestation of the infection.

Patient 3: The photo documentation according to Fig.3 shows in photo 3B that the treatment with the above mentioned mixture results in an improvement of the infected nail. The black-brown color of the thumb nail caused by bacterial superinfection does no longer exist.

Patient 4: The photo documentation according to Fig.4 shows in photo 4B an improvement of the infection of the big toe after treatment with the above mentioned mixture for 6 weeks. After 6 weeks of treatment the nail already grows normally. After treatment for 11 weeks with the above mentioned mixture a complete recovery of the nail can be observed (photo 4C).

Figures:

Fig. 1 A shows the picture of the toes of patient 1 before the treatment with the above mentioned mixture. The picture was taken on 07/03/2006.

Fig. 1B and 1C show the improvement of the infeciton during treatment. The nail infection significantly improves already after two days of treatment. Picture 1 B was taken on 09/03/2006, picture 1C was taken on 28/03/2006.

Fig. 2A shows the picture of the toes of patient 2 before treatment with the above mentioned mixture. The partial destruction of the nail plate, the onycholysis as well as the brown nail plate is clearly observable. The picture was taken on 23/02/2006.

Fig. 2B shows the considerable improvement of the nail infection after topical treatment for one month with the above mentioned mixture. The picture was taken on 28/03/2006.

Fig. 3A shows the picture of the thumb of patient 3 before the treatment with the above mentioned mixture_^ The picture was taken on 16/03/200JSL. Fig. 3B shows the considerable improvement of the nail infection after topical treatment for three weeks with the above mentioned mixture. The picture was taken on 06/04/2006.

Fig. 4A shows the picture of the toes of patient 4 before the treatment with the above mentioned mixture. The picture was taken on 02/02/2006.

Fig. 4B and 4C show the improvement of the infection during treatment. The nail infection significantly improves after six weeks of treatment (Fig.4B) and is gone after 11 weeks of treatment with above mentioned mixture (Fig.4C). The picture of figure 4B was taken on 16/03/2006, the picture of figure 4C was taken on 20/04/2006.

Claims

1. A composition comprising natural ink sack liquid of cephalopods for topical application and/or oral administration.

2. A composition according to clθ.im 1 , wherein the ink sank liquid is the natural ink sack liquid of Coleoideae.

3. A composition according to claim 2, wherein the ink sack liquid is the natural ink sack liquid of Decapodiformes and/or Octopodiformes.

4. A composition according to claim 3, wherein the ink sack liquid is the natural ink sack liquid of Spirulidae, Sepiidae, Sepiolidae, and/or Teuthidae.

5. A composition according to claim 4, wherein the ink sack liquid is the natural ink sack liquid of Sepia officinalis.

6. A composition according to anyone of claims 1 to 5, wherein the natural ink sack liquid is the only active, component in the composition.

7. A composition according to anyone of claims 1 to 5, wherein the composition further comprises at least a part of at least one cephalopod's component selected from the group comprising an organ, a tissue of an organ, a liquid of an organ, a secretion of an organ, a microorganism associated with an organ and a metabolic compound produced by such microorganism, wherein said organ(s) is/are close to the ink sack according to the natural arrangement in a cephalopod.

8. A composition according to claim 7, wherein said further cephalopod's components are derived from an ink sack except the ink, from a nidamental gland, from an accessory nidamental gland and/or from an ovary, optionally including eggs.

9. A composition according to claim 7 or 8, wherein the associated microorganism is at least one bacterial strain having an antimicrobial or an antifungal effect.

10. A composition according to anyone of claims 1 to 9, wherein the ink sack liquid is diluted or undiluted, preferably undiluted.

11. A composition according to anyone of claims 1 to 10, wherein the composition is a pharmaceutical composition containing optionally usual auxiliary agents.

12. A composition according to claim 11 , wherein the pharmaceutical composition is liquid, semi-solid or solid.

13. A composition according to claim 12, wherein the pharmaceutical composition is formulated as liquid, fluid, foam, cream, gel, paste, balsam, spray, ointment, lotion, conditioner, tonic, milk, mousse, emulsion, serum, oil, stick, roller, shampoo, jelly, suspension, dispersion, lacquer, paint, elixir, drop or patch.

14. A composition according to claim 12, wherein the pharmaceutical composition is formulated as tablet, capsule, pill, coated tablet, dragee, hard and soft gelatine capsule, troche, suspension, lozenge or powder.

15. A composition according to anyone of claims 11 to 14, wherein the pharmaceutical composition is adapted at least for a once a day, preferably for twice a day application and/or administration.

16. A composition according to anyone of claims 1 to 10, wherein the composition is a cosmetical composition containing usual auxiliary agents.

17. A composition according to claim 16, wherein the cosmetical composition is liquid, semi-solid or solid.

18. A composition according to claim 17, wherein the cosmetical composition is formulated as liquid, fluid, foam, cream, gel, paste, balsam, spray, ointment, lotion, conditioner, tonic, milk, mousse, emulsion, serum, oil, stick, roller, shampoo, jelly, suspension, dispersion, lacquer and/or paint.

19. A composition according to anyone of claims 16 to 18, wherein the cosmetical composition is suitable for topical application.

20. A composition as claimed in claim 19, wherein the cosmetic composition is suitable for keeping scalp, skin, hair and/or nails in good conditions.

21. A composition according to anyone of claims 1 to 10, wherein the composition comprises at least one systemically and/or topically active antimycotic drug.

22. A composition according to claim 21 , wherein the systemically and/or topically active antimycotic drug comprises itraconazole, ketoconazole, miconazole, fluconazole and/or terbinafine.

23. Use of ink sack liquid of cephalopods according to anyone of claims 1 to 10 to prepare a drugjor the prophylaxis and/or treatment of mycosis, superinfections associated with mycosis and/or other pathological skin conditions.

24. Use according to claim 23, for the prophylaxis and/or treatment of onychomycosis, preferably distal subungual onychomycosis, proximal subungual onychomycosis, white superficial onychomycosis, endonyx onychomycosis, and/or total dystropic onychomycosis.

25. Use according to claim 23 or 24, wherein the superinfection(s) is (are) caused by bacteria and/or moulds.

26. Use according to claim 23, wherein the pathological skin conditions comprise psoriasis, dermatitis, acne, hair loss, immunological skin diseases, skin cancer, actinic keratosis, pemphigoid, dermatofibroma, lupus erythematosus, eczema, erythema, folliculitis, impetigo, lichen, pityriasis, tinea, pruritus, rosacea and/or urticaria.

7. Use of a cosmetical composition according to anyone of claims 16-20 for the prophylaxis and/or treatment against skin conditions comprising skin ageing, photoageing, dry skin and/or rash.