WO2013056994A1 - Améliorations des ou concernant les composés organiques - Google Patents

Améliorations des ou concernant les composés organiques Download PDF

Info

Publication number
WO2013056994A1
WO2013056994A1 PCT/EP2012/069797 EP2012069797W WO2013056994A1 WO 2013056994 A1 WO2013056994 A1 WO 2013056994A1 EP 2012069797 W EP2012069797 W EP 2012069797W WO 2013056994 A1 WO2013056994 A1 WO 2013056994A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition according
pharmaceutical composition
skin
pyrrolidone
zileuton
Prior art date
Application number
PCT/EP2012/069797
Other languages
English (en)
Inventor
Guy Vergnault
Patricia IBARRA
Pascal Grenier
Original Assignee
Jagotec Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jagotec Ag filed Critical Jagotec Ag
Publication of WO2013056994A1 publication Critical patent/WO2013056994A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the present invention is concerned with compositions comprising zileuton that are suitable for topical administration on the human skin, and with a method of treating dermatological conditions using said compositions.
  • Topical application to the skin can offer a comfortable, convenient and non-invasive way of administering drugs.
  • the variable rates of absorption and metabolism encountered in oral treatments can be avoided, and other inherent inconveniences associated with this route, e.g. gastrointestinal irritation and the like, may be eliminated as well.
  • drug delivery by the topical route is not without its complications.
  • the human skin consists essentially of several distinct compartments or layers of tissue.
  • the stratum corneum represents the outermost part of the skin. It consists of dead cells (in general about 15 to 20 layers) named corneocytes.
  • the corneocytes are filled with keratins, and they are embedded in a complex matrix of organized lipid bilayers.
  • the stratum corneum is lipophilic and contains relatively low levels of water.
  • the viable epidermis Immediately underneath the stratum corneum is the viable epidermis, which has a thickness of perhaps 50 to 100 microns. This layer has high water content and has a similar density to water. Beneath the viable epidermis lies the dermis. It is a structural fibrin and ranges in thickness from 2000 to 3000 microns.
  • the stratum corneum is the principle physical barrier to substances that come into contact with the skin. Molecules moving from the surrounding environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. It is believed to be the high degree of keratinization within the corneocytes, their densely packed arrangement, as well as the lipid domains between them, which creates a substantially impermeable barrier to drug penetration.
  • keratinization within the corneocytes, their densely packed arrangement, as well as the lipid domains between them, which creates a substantially impermeable barrier to drug penetration.
  • the formulator must take into consideration the complex structure and properties of each compartment of the skin, and particularly the stratum corneum, in order to understand how, and to what extent, a drug substance is likely to penetrate the skin.
  • the formulator will recognise that owing to the unique physicochemical properties of drug substances (e.g. molar mass, molecular size, logP, the distribution of polar and non-polar parts in the drug substance and the extent of an ionized state), the barrier effect the skin presents to one drug substance may be entirely different to that presented to another.
  • the extent and/or rate of penetration of a drug substance will depend not only on its particular physicochemical properties, but also on the vehicle in which it is formulated and on the interaction between the vehicle and the drug substance, as well as the vehicle with the skin.
  • a major challenge for formulators is to design or tune a vehicle in which the drug is formulated in order that the drug can reach its target site, whether that is on the skin surface, within a compartment of the skin, or within systemic circulation.
  • Formulations adapted for topical application to the skin usually contain one or more agents that modify the rate or extent to which a drug substance permeates the skin.
  • formulations containing chemical skin permeation modifiers for enhancing (or retarding) the flux of a drug substance through the skin are concerned with formulations containing chemical skin permeation modifiers for enhancing (or retarding) the flux of a drug substance through the skin.
  • permeation enhancers to be employed in a system for the transdermal delivery of captopril in an in-vitro permeation study on rat skin.
  • Fatty alcohols were found to provide a pronounced permeation effect, but other agents such as DMSO, N-methyl 2-pyrrolidone, oleic acid, transcutol and polysorbate 20 showed no permeation enhancing effects.
  • a problem with the use of permeation modifiers in topical formulations is that the candidate pool is huge, and what is effective for one drug in a particular delivery vehicle, may not be as effective, if at all, for another drug in the same or even different delivery vehicle. What makes one formulation effective for one drug substance, but not another, is not clearly understood.
  • the quantity of drug that is able to permeate across or into the stratum corneum per unit area per unit time or "flux" is a significant parameter in determining whether or not a particular drug can be effectively delivered for a specific treatment regimen.
  • a drug's propensity to penetrate into the stratum corneum is related to how it partitions between the delivery vehicle in which it is formulated, and the tissue of the stratum corneum.
  • Formulation is clearly the key to successful topical drug delivery, but only by the careful formulation of a drug substance can one balance the modification of the barrier properties of the skin and at the same time optimise how a drug interacts with its delivery vehicle.
  • the problem is that it appears there is no consensus in the literature as to how formulations influence the permeation of drug substances. Presumably this is because frequently the formulations studied do not have the same compositions, the drugs used have very different physicochemical properties, and the targets (i.e. skin surface, compartment of the skin or systemic delivery) are often different. Under such conditions, it would appear that general rules cannot be articulated and that that one would need to carry out permeation testing in appropriate in-vitro or in-vivo models to validate any given formulation approach.
  • a formulation is optimised from the point of view of modifying the barrier properties of the skin, if it is not optimised from a galenic perspective, such a draw back may still make the formulation undesirable for use.
  • the formulation may be difficult to apply mechanically to the skin; or it might be unacceptable from an organoleptic point of view, i.e. it may have an offensive smell, it might feel unpleasant on the skin, or it might have an unsightly appearance; or it might not have sufficient retention time on the surface of the skin to enable a drug substance to penetrate the skin.
  • a formulation is adapted to be used in a delivery device, such as a patch or other device in which the formulation is supported by an occlusive layer, e.g. a bandage or a plaster or the like.
  • Zileuton is an inhibitor of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid.
  • Zileuton has the chemical name ( ⁇ )-l-(l- Benzo[b]thien-2-ylethyl)- 1 -hydroxyurea and the following chemical structure:
  • UVB ultra violet
  • COX2 COX2
  • PGE2 prostaglandin E2
  • the LOX pathway also is strongly implicated in carcinogenesis. Inhibition of the LOX pathway has been demonstrated pre-clinically to be anti-proliferative and pro-apoptotic in cancer cell lines. A number of products of LOX have been identified, which can promote cancer cell growth. Leucotriene B4 (LTB4) inhibits apoptosis and has been demonstrated to be procarcinogenic and is considered a key mediator.
  • LTB4 Leucotriene B4
  • a topical dosage form containing celecoxib has been proposed by Fegn et al in J. Laryngol. Otol. 2009 August 123(8): 880-884.
  • the dosage form was applied as an oil-in-water microemulsion to mice.
  • the paper concludes that the dosage form would be effective in the treatment of skin carcinogenesis.
  • the microemulsion formulation used in this study consisted of 22% propylene glycol dicaprylate(dicaprate) + caprylic/capric mono-/di- glycerides (2: 1), 30% polysorbate 80 and water.
  • the invention provides in a first aspect a pharmaceutical composition adapted for external application to human skin comprising a semi-solid carrier material and zileuton dissolved or dispersed therein.
  • the composition according to the present invention is intended to be applied to an affected area of human skin to treat a dermatological condition of the skin.
  • the composition is adapted to form a depot locally within an affected site in or on the skin, rather than treating the condition system ically.
  • the composition is to be contrasted with compositions that are applied to the skin for transdermal administration of a drug substance.
  • Transdermal delivery relates to drugs that are applied to the skin in order to pass through the skin tissue and enter the systemic circulation to exert a pharmacological effect.
  • semi-solid refers to a composition that is not pourable and does not conform to a container in which it is held at ambient temperatures, and which, furthermore, does not flow in response to low shear stress and exhibits plastic flow behaviour.
  • a semi-solid is contrasted with a liquid, such as a lotion or a solution, which flow with no or little shear threshold, display Newtonian or pseudoplastic flow behaviour and conform to containers in which they are held.
  • rheological properties of a semi-solid may be demonstrated using apparatus and methods well known in the art.
  • viscosity of a sample measured as a function of applied shear can be carried out on a Brooksfield viscometer apparatus such as a
  • Brookfield DV 11+ model RV equipped with T-Bar or Helipath spindles.
  • the semi-solid compositions of the present invention may be applied easily to the skin.
  • the composition may be spread evenly over an affected area of skin, by hand, spatula or the like.
  • the semi-solid composition does not flow as a liquid as a result of the shear forces generated during application. Rather, it retains its semi-solid form. This ensures even coverage of the affected site and also ensures that the drug substance is retained within the composition and in contact with the skin for prolonged periods of time. Retention of the drug substance within its compositional vehicle and in communication with the skin surface for extended periods ensures that the drug substance may pass slowly into the skin and to form local concentrations within the affected site in or on the skin.
  • a method of modifying the flux of zileuton through skin by applying to skin a pharmaceutical composition of the present invention as herein defined.
  • Flux can be observed by measuring the diffusion of zileuton through human or animal, e.g. mouse skin using any suitable in-vitro techniques known in the art, for example using a Franz diffusion apparatus.
  • diffusion cells are divided into two parts. One part is called the donor chamber and is filled with a known amount of a formulation to be tested. The second part is called the receiver or receptor chamber and is separated from the donor chamber by a piece of skin. The receptor chamber is filled with a solution in which the substance under study is soluble. A few aliquots are analysed for drug content at specific times during the experiment and the cumulative amount of drug is then plotted against time. Analysis of samples collected from a Franz cell can be made using known techniques, such as HPLC, again, as more fully described in the Examples below.
  • a method of providing an antiinflammatory response in the tissue of a mammal comprising the step of applying to an affected site on the skin of a subject a pharmaceutical composition of the present invention.
  • a method of providing an anti-inflammatory response in the tissue of a mammal comprising the step of applying to an affected site on the skin of a subject, a pharmaceutical composition of the present invention.
  • the anti-inflammatory response is comparable to the response zileuton administered orally.
  • the anti-inflammatory response to a composition according to the present invention may be measured by conducting an in-vivo study suitable for the purpose.
  • a mouse ear model study can be employed, in which oedema is induced in mouse ears by application of arachadonic acid thereto.
  • Pharmaceutical compositions to be tested and an oral control formulation are then applied to the treated ears and the level of inhibition of arachadonic acid-induced oedema is observed by measuring relative ear-swelling as a function of time.
  • a particular example of a mouse ear-swelling study is disclosed in Katsumi Ishii Jpn J Pharmacol 65 297-303 1994, which is hereby incorporated by reference.
  • the oral dose against which the topical composition is to be compared is typically chosen to be that dose that can provide an at least 50% ear swelling inhibition.
  • a suitable oral dosage form may contain about 40 mg/kg to 80 mg kg of zileuton.
  • a method of providing an anti -inflammatory response in the tissue of a mammal comprising the step of applying to an affected site on the skin of a subject, a pharmaceutical composition of the present invention, said anti-inflammatory response being comparable to the response zileuton administered orally at about 40mg/kg to about 80 mg/kg.
  • an anti-inflammatory response may be considered "comparable" if the level of response is with ⁇ 30% of the oral dosage form response. More particularly, the response is at least as great the oral dosage form response.
  • the composition according to the present invention may comprise one or more additional drug substances.
  • the pharmaceutical composition herein described additionally comprises diclofenac, salicylic acid, 5FU (5-fluorouracil), or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition may contain one or more of the active agents recited above, in addition to zileuton.
  • zileuton may be co-formulated with said one or more additional drug substances, that is, they may be mixed together in the same formulation, or they may be formulated separately, in identical or different pharmaceutical compositions. In the event they are provided in distinct pharmaceutical compositions, they may be applied in therapy simultaneously, separately or sequentially.
  • the pharmaceutical composition contains both zileuton and diclofenac, more particularly sodium diclofenac.
  • Diclofenac sodium is available commercially as Solaraze ® .
  • Solaraze ® is provided as 3% sodium diclofenac in a 2.5% sodium hyaluronate gel.
  • a method of treating actinic keratosis by applying a pharmaceutical composition according to the present invention to an affected site on the skin of a subject in need of treatment.
  • the composition comprises zileuton and diclofenac or a pharmaceutically acceptable salt thereof, e.g. sodium diclofenac.
  • the method of treating actinic keratosis comprises the step of application of a pharmaceutical composition according to the invention to a pre-determined area of affected skin, retaining the composition on the skin, and optionally re-applying the composition, for a sufficient period of time to affect treatment.
  • the application of the pharmaceutical composition to an affected site such as an area of lesions may be performed twice daily.
  • the amount of pharmaceutical composition applied to an affected area will depend on the size of the area. For example, a patient should ensure that enough composition is applied to cover each affected site or lesion. Typically, one might apply about 0.5 g of composition to treat an affected site or lesion site that measures 5 era x 5 cm. In a method according to the present invention the duration of therapy is from 60 days to 90 days.
  • a method for the chemoprevention of skin cancer development in particular, after surgical exeresis of skin lesions, by applying a pharmaceutical composition according to the present invention to an affected site on the skin of a subject in need of treatment.
  • the composition used in the method for the chemoprevention of skin cancer comprises zileuton and diclofenac or a
  • the method for the chemoprevention of skin cancer will involve the application of a pharmaceutical composition according to the invention to a pre-determined area of the skin that is affected, retaining the composition on the skin, and optionally re-application, for a period of time sufficient to provide the treatment.
  • the application of the pharmaceutical composition to an affected site such as an area of lesions may be performed twice daily.
  • the amount of pharmaceutical composition applied to an affected area will depend on the size of the area. For example, a patient should ensure that enough composition is applied to cover each affected site or lesion. Typically, one might apply about 0.5 g of composition to treat an affected site or lesion site that measures 5 cm x 5 cm. In a method according to the present invention the duration of therapy is from 60 days to 90 days.
  • compositions according to the present invention may contain a solvent for zileuton.
  • Particular solvents are those that can dissolve zileuton to a concentration of about 190 mg/g or greater.
  • zileuton is dissolved in the pharmaceutical composition, however, it may be provided in a finely dispersed powder form, more particularly in the micro to nanoparticulate size range, still more particularly 10 nm to 5 ⁇ . In such finely divided form, zileuton will dissolve in response to the displacement of the solubility equilibrium created by the slow absorption of zileuton by the stratum corneum.
  • solvents may be selected from polyethylene glycols or ethylene glycol ethers, or a pyrrolidone or related compound.
  • Said pyrrolidones or related compounds may be selected from the group consisting of N-methyl-2 -pyrrolidone, 1 -butyl-3-dodecyl-2- pyrrolidone, l,3-dimethyl-2-imidazolikinone, 1 ,5-dimethyl-2-pyrrolidone, 44,-dimethyl-2- undecyl-2-oxazoline, 1 -ethyl-2-pyrrolidone, 1 -hexyl-4-methyloxycarbonyl-2-pyrrolidone, 1 -hexyl-2-pyrrolidone, 1 -(2-hydroxyethyl)pyrrolidone, 3 -hydroxy-N-methyl-2-pyrrolidone, 1 -isopropyl-2-undecyl-2-imidazoline, 1 -l
  • the solvent is -methyl-2-pyrrolidone, which is commercially available under the trade name PHARMASOLVE.
  • the pharmaceutical composition according to the present invention has a consistency or body such that when applied to an affected area of human skin, both zileuton and the vehicle in which it formulated are maintained essentially in a reservoir that is in transmitting relationship with the affected surface of the skin.
  • the pharmaceutical composition may be in the form of a gel, ointment, cream or paste.
  • the carrier material may comprise any of those materials known in the art useful in the formation of these types of dosage form. In addition, they should be non-toxic and should not interact with any other components contained in the composition in a deleterious manner.
  • Ointments are semi-solid preparations that are typically based on petrolatum or other petroleum derivatives.
  • the specific ointment foundation to be used is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g. emolliency or the like.
  • the ointment foundation should be inert, stable, non-irritating and non-sensitizing.
  • ointment foundations may be grouped in four classes:
  • Oleaginous ointment foundations include, for example, vegetable oils, fats obtained from animals, and semisolid
  • Emulsifiable ointment foundations also known as absorbent ointment foundations, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
  • Emulsion ointment foundations are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.
  • Preferred water-soluble ointment foundations are prepared from polyethylene glycols of varying molecular weight.
  • Creams are typically in the form of semisolid emulsions, of either oil-in-water or water-in-oil types.
  • Cream foundations are water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also called the "internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is generally a non-ionic, anionic, cationic or amphoteric surfactant.
  • gels are semi-solid, suspension-type systems.
  • Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally an oil.
  • Preferred organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally an oil.
  • macromolecules i.e. gelling agents
  • cross linked acrylic acid polymers such as the "carbomer” family of polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the Carbopol(R) trade mark.
  • hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol
  • cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose
  • gums such as tragacanth and xanthan gum; sodium alginate; and gelatine.
  • Pastes are serai-solid dosage forms in which a drug substance is suspended in a suitable foundation. Depending on the nature of the foundation, pastes are divided between fatty pastes or those made from single-phase, aqueous gels.
  • the foundation in a fatty paste is generally petrolatum or hydrophilic petrolatum or the like.
  • the pastes made from single- phase aqueous gels generally incorporate carboxymethylcellulose or the like as the foundation.
  • compositions of the present invention may also be prepared with liposomes, micelles, and microspheres.
  • Liposomes are microscopic vesicles having a lipid wall comprising a lipid bi layer, and can be used as drug delivery systems herein as well.
  • Liposomal preparations for use in the instant invention include cationic (positively charged), anionic (negatively charged) and neutral preparations.
  • Cationic liposomes are readily available.
  • Anionic and neutral liposomes are readily available as well, or can be easily prepared using readily available materials. Such materials include phosphatidyl choline, cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidyl choline, dioleoylphosphatidyl glycerol,
  • dioleoylphoshatidyl ethanolamine among others. These materials can also be mixed with N-[l-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) in appropriate ratios. Methods for making liposomes using these materials are well know in the art.
  • DOTMA N-[l-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium
  • Micelles are known in the art and are comprised of surfactant molecules arranged so that their polar head groups form an outer spherical shell, while the hydrophobic, hydrocarbon chains are oriented towards the centre of the sphere, forming a core. Micelles form in an aqueous solution containing surfactant at a high enough concentration so that micelles naturally result.
  • Surfactants useful for forming micelles include, but are not limited to, potassium laurate, sodium octane sulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodium lauryl sulfate, docusate sodium, decyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, tetradecyltrimethyl-ammonium chloride, dodecylammonium chloride, polyoxyl 8 dodecyl ether, polyoxyl 12 dodecyl ether, nonoxynol 10 and nonoxynol 30.
  • the carrier material may comprise hyaluronic acid.
  • Hyaluronic acid is well known in the art. Its viscoelastic properties and excellent biocompatibility means that it can be used to provide a strong gel-like matrix support material for both cosmetic or drug delivery applications intended for use on the skin. Hyaluronic acid can form cross-linked gels alone, or in combination with other hydrophilic polymers.
  • hydrophilic polymers examples include other polysaccharides, synthetic and natural, such as hydroxyethyl cellulose, carboxymethyl cellulose, xanthan gum, chondroitin sulfate, heparin, proteins of various types, such as collagen, elastin, albumin, a globulin, sulphated proteins such as keratin sulfate and sulphated
  • aminoglycosaminoglycans synthetic water-soluble polymers, such as polyvinyl alcohol and its co-polymers, co-polymers of poly-(hydroxethyl) methacrylate and the like
  • Hyaluronic acid may be employed typically at about 2 to 3% by weight based on the weight of the pharmaceutical composition.
  • Hyaluronic acid matrices employed in drug delivery vehicles are described in US patents 5,639, 738,5, 985,950, 5,929, 048,5, 792,753, 5,852, 002,5, 914,322 and 6,147, 059, all of which documents are hereby incorporate by reference.
  • the composition comprises a carrier material comprising a crystalline network of monoglycerides.
  • a solution of zileuton is incorporated into a network comprising a dispersion of solid crystals of polar lipids.
  • the lipids may have a crystallisation temperature of between 20°C and 100"C.
  • Preferable lipid crystals are (3 -crystals from a monoglyceride of a fatty acid having a chain length of 12-18 carbon atoms or monoglycerol ethers having ether chains of the
  • fatty acids as well as the ethers may be saturated or unsaturated, preferably saturated ones.
  • the fatty acids may therefore include lauric acid (CI 2), myristic acid (C14), palmitic acid (CI 6) or stearic acid (CI 8), although C13, Clsor CI 7 acids could also be used.
  • CI 2 lauric acid
  • C14 myristic acid
  • CI 6 palmitic acid
  • CI 8 stearic acid
  • C13, Clsor CI 7 acids could also be used.
  • Preferable monoglycerides may be a 1-or 2-monoglyceride, preferably a 1- monolaurin, 1 - monomyristin, 1 -monopalmitin and 1 -monostearin or a mixture of two or more of these such as a mixture of 1 -monolaurin and 1 -monomyristin.
  • Examples of unsaturated monoglycerides are monopalmitolein, monoolein, monolinolein and monoliniolenin.
  • the composition consists essentially of a dispersion of the above lipid crystals in water or any other polar liquid or mixtures thereof having the ability to allow crystal formation.
  • polar lipids for use in accordance with the invention are water, glycerol, propylene glycol and ethylene glycol or mixtures thereof; however other suitable polar lipids may also be used.
  • composition is in the form of a microemulsion.
  • microemulsion can be defined as a system of water, oil, and surfactants, which typically are clear or otherwise transparent, and which are thermodynamically stable liquid.
  • a microemulsion is transparent and bluish (Tyndall scattering) due to light scattering by colloidal droplets that will reflect more or less the light depending on the wavelength.
  • Microemulsions exhibit high solubilisation power due to the combination of surfactant and co-surfactant in presence of oil and water. These systems are very stable and characterized by nano droplets having a size under 200 nm.
  • composition of the present invention is in the form of a
  • microemulsion it should preferably contain a gelling agent or a thickener.
  • Gelling agents may include agents that gel when triggered by triggering agent that is reactive with the gelling agent, or gelling agents may be thermal gelling agents, both of which types of gelling agents are well known in the art.
  • Suitable gelling agents include, but are not limited to, natural gums, acrylic acid and acrylate polymers and copolymers, and cellulose derivatives (e.g. hydroxymethyl cellulose and hydroxypropyl cellulose), hydrogenated butylene/ethylene/styrene copolymer and hydrogenated ethylene/propylene/ styrene copolymer.
  • Particular gelling agents include cross linked acrylic acid polymers such as the "carbomer” family of polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the Carbopol(R) trademark.
  • hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol
  • cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose
  • gums such as tragacanth and xanthan gum; sodium alginate, and gelatine.
  • gelling agents in pharmaceutical compositions according to the invention at about 0.1% and 5%
  • Thickeners include, but are not limited to cellulose and derivatives such as cellulose, carboxymethyl hydroxyethylcellulose, cellulose acetate propionate carboxylate, hydroxyethylcellulose, hydroxyethyl ethyl cellulose, hydroxypropylcellulose,
  • alkyl substituted celluloses examples include those selected from the group consisting of stearyl, isostearyl, lauryl, myristyl, cetyl, isocetyl, cocoyl (i.e. alkyl groups derived from the alcohols of coconut oil), palmityl, oleyl, linoleyl, linolenyl, ricinoleyl, behenyl, and mixtures thereof.
  • the material sold under the trade name Natrosol(TM). CS Plus from Aqualon Corporation may be used.
  • thickeners include acacia, agar, algin, alginic acid, ammonium alginate, amylopectin, calcium alginate, calcium carrageenan, carnitine, carrageenan, dextrin, gelatin, gel lan gum, guar gum, guar hydroxypropyltrimonium chloride, hectorite, hyaluronic acid, hydrated colloidal silica, hydroxypropyl chitosan, hydroxypropyl guar, karaya gum, kelp, locust bean gum, natto gum, potassium alginate, potassium carrageenan, propylene glycol alginate, sclerotium gum, sodium carboxymethyl dextran, sodium carrageenan, tragacanth gum, xanthan gum, and mixtures thereof. Also useful are acrylic acid/ethyl acrylate copolymers and the carboxyvinyl polymers sold by the B.F. Goodrich Company under the trade mark
  • compositions of the present invention may comprise a thickener from about 0.1% to about 20%, by weight preferably 0.1 to 5%.
  • Various additives known to those skilled in the art, may be included in the pharmaceutical composition of the present invention.
  • opacifiers antioxidants, fragrance, colorants, stabilizers, surfactants and the like.
  • Other agents may also be added, such as antimicrobial agents, to prevent spoilage upon storage, i.e. to inhibit growth of microbes such as yeasts and molds.
  • Suitable antimicrobial agents are typically selected from the group consisting of the methyl and propyl esters of p-hydroxybenzoic acid (i.e., methyl and propyl paraben), sodium benzoate, sorbic acid, imidurea, and combinations thereof.
  • compositions of the present invention may also contain irritation-mitigating additives to minimize or eliminate the possibility of skin irritation or skin damage resulting from the drug, or other components of the composition.
  • Suitable irritation-mitigating additives include, for example: [alpha j-tocopherol; monoamine oxidase inhibitors, particularly phenyl alcohols such as 2-phenyl- 1 -ethanol; glycerine; salicylic acids and salicylates; ascorbic acids and ascorbates; ionophores such as monensin; amphiphilic amines;
  • ammonium chloride N-acetylcysteine
  • cis-urocanic acid capsaicin
  • chloroquine chloroquine
  • the concentration of zileuton in the pharmaceutical composition of the present invention will typically depend upon a variety of factors, including the severity of the disease or condition to be treated, the desired effect, possible adverse reactions, the ability and speed of zileuton to reach its intended target, and other factors within the particular knowledge of the patient and physician.
  • Preferred compositions will typically contain on the order of about 0.5-30 wt %, preferably about 5-10 wt %, active agent and will be applied twice daily There follows a series of examples that serve to illustrate the invention.
  • the test was carried out in a Franz Cell apparatus consisting of a cylindrical glass diffusion chamber comprising an upper and lower part. Human skin is clamped between the two parts and represents a permeation barrier. The two halves of the cell are held together by means of a ball and socket clamp.
  • the lower (acceptor) chamber has a volume of approximately 12 mL, while the volume of the upper (donor) chamber may be variable.
  • the acceptor medium is a Krebs Ringer Buffer solution (pH 7.4) with sodium azide added at 0.05% (w/v) as an anti-microbial agent.
  • the temperature of the cell was 32°C and the cell was stirred at 400 rpm.
  • the diffusion area of the skin in the cell was approximately 1.77 cm 2 . Permeation of zileuton through the skin was monitored at 24 and 48 hours by withdrawing 5 200 microlitre samples for analysis. Withdrawn sample volume was replaced with acceptor medium at 32°C.
  • Skin was prepared by excision during surgery and cooled to 4°C after removal and dried. The skin was removed from subcutaneous fatty tissue. The skin thickness was0 approximately 500 microns, but as the stratum corneum is the principle barrier to permeation, the thickness was not an issue.
  • Test samples included zileuton in Transcutol P (135 mg/g); zileuton in PEG 400 (135mg/g); zileuton in mPEG (135mg/g); Pharmasolve (135mg/g).
  • mice Male Swiss mice were allowed to acclimatise for a minimum of 72 hours and then assigned to groups for testing.
  • Treatments were given at To hour. Treatments were given by applying a 20 ⁇ volume of each of the formulations of Examples 1 to 3 to the dorsal surface of both the right and left ears of each animal. A spatula was used to aid even distribution of the material across the dorsal surface of the pinna.
  • unanaesthetised animals received treatment intragastrically via a suitable catheter tube attached to a syringe.
  • animals were challenged with a topical application of 1 mg of arachidonic acid in acetone onto the ventral surface of the left ear.
  • the ventral surface of the right ear received a topical application of acetone only as a negative control.
  • Arachidonic acid was applied in a volume of 20 ⁇ pipetted over gently onto the surface and the head of the anaesthetised animal was held until the material was fully absorbed.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique conçue pour une application externe à la peau humaine, ladite composition pharmaceutique comprenant une substance vectrice semi-solide à l'intérieur de laquelle est dissous ou dispersé du zileuton, et son utilisation dans le traitement de conditions dermatologiques.
PCT/EP2012/069797 2011-10-21 2012-10-05 Améliorations des ou concernant les composés organiques WO2013056994A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1118193.0A GB201118193D0 (en) 2011-10-21 2011-10-21 Improvements in or relating to oranic compounds
GB1118193.0 2011-10-21

Publications (1)

Publication Number Publication Date
WO2013056994A1 true WO2013056994A1 (fr) 2013-04-25

Family

ID=45373214

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/069797 WO2013056994A1 (fr) 2011-10-21 2012-10-05 Améliorations des ou concernant les composés organiques

Country Status (2)

Country Link
GB (1) GB201118193D0 (fr)
WO (1) WO2013056994A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105658202A (zh) * 2013-10-30 2016-06-08 科瑞特有限公司 齐留通乳膏剂型的局部用抗炎症药学组合物
US9855243B2 (en) 2013-10-30 2018-01-02 Qurient Co., Ltd. Topical anti-inflammatory pharmaceutical composition with zileuton cream formulation
WO2018126133A1 (fr) * 2016-12-29 2018-07-05 Cormedix Inc. Formulation de pénétration cutanée à base de taurolidine
CN111110845A (zh) * 2020-01-21 2020-05-08 邢更彦 具有消炎镇痛作用的冲击波治疗新型耦合剂及其制备方法
CN112566623A (zh) * 2018-08-16 2021-03-26 瑞迪博士实验室有限公司 局部用油质组合物
WO2021121645A1 (fr) * 2019-12-20 2021-06-24 Qurient Co., Ltd. Composition pharmaceutique anti-inflammatoire topique comprenant du zileuton

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982003173A1 (fr) 1981-03-17 1982-09-30 Bo Thuresson Ekenstam Composition germicide
WO1987002582A1 (fr) 1985-10-28 1987-05-07 Biogram Ab Micro-capsules
WO1993020812A1 (fr) 1992-04-14 1993-10-28 Bioglan Ab Potentialisation d'effets antimicrobiens
WO1996040090A1 (fr) * 1995-06-07 1996-12-19 University Of Southern California Procede pour la reduction ou la prevention de la formation d'adherences post-chirurgicales a l'aide d'inhibiteurs de 5-lipoxydase
US5639738A (en) 1992-02-20 1997-06-17 Hyal Pharmaceutical Corporation Treatment of basal cell carcinoma and actinic keratosis employing hyaluronic acid and NSAIDs
US5792753A (en) 1991-07-03 1998-08-11 Hyal Pharmaceutical Corporation Compositions comprising hyaluronic acid and prostaglandin-synthesis-inhibiting drugs
US5852002A (en) 1989-09-21 1998-12-22 Hyal Pharmaceutical Corporation Treatment of conditions and disease
US5985950A (en) 1988-08-03 1999-11-16 Ciba Specialty Chemicals Corporation Acid-curable binder systems containing 1,2 disulfones
US6147059A (en) 1992-02-20 2000-11-14 Hyal Pharmaceutical Corporation Formulations containing hyaluronic acid
WO2004054549A1 (fr) 2002-12-13 2004-07-01 Jagotec Ag Preparation topique de spironolactone nanoparticulaire
US20040259920A1 (en) 2001-04-30 2004-12-23 Zouboulis Christos C. Acne treatment
US20070134341A1 (en) * 2005-11-15 2007-06-14 Kipp James E Compositions of lipoxygenase inhibitors
WO2008085875A2 (fr) * 2007-01-05 2008-07-17 Cornerstone Therapeutics Inc. Procédé de traitement de conditions associées à une activité augmentée de la 5-lipoxygénase et/ou du leukotriène
WO2008106081A1 (fr) * 2007-02-26 2008-09-04 Larry Schlesinger Formulations topiques contenant un antagoniste récepteur d'un leucotriène et leurs utilisations traiter ou prévenir la contracture capsulaire, la formation de cicatrice ou l'hyperpigmentation

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1982003173A1 (fr) 1981-03-17 1982-09-30 Bo Thuresson Ekenstam Composition germicide
WO1987002582A1 (fr) 1985-10-28 1987-05-07 Biogram Ab Micro-capsules
US5985950A (en) 1988-08-03 1999-11-16 Ciba Specialty Chemicals Corporation Acid-curable binder systems containing 1,2 disulfones
US5852002A (en) 1989-09-21 1998-12-22 Hyal Pharmaceutical Corporation Treatment of conditions and disease
US5929048A (en) 1989-09-21 1999-07-27 Hyal Pharmaceutical Corporation Treatment of conditions and disease
US5792753A (en) 1991-07-03 1998-08-11 Hyal Pharmaceutical Corporation Compositions comprising hyaluronic acid and prostaglandin-synthesis-inhibiting drugs
US5639738A (en) 1992-02-20 1997-06-17 Hyal Pharmaceutical Corporation Treatment of basal cell carcinoma and actinic keratosis employing hyaluronic acid and NSAIDs
US5914322A (en) 1992-02-20 1999-06-22 Hyal Pharmaceutical Corporation Treatment of disease and conditions
US6147059A (en) 1992-02-20 2000-11-14 Hyal Pharmaceutical Corporation Formulations containing hyaluronic acid
WO1993020812A1 (fr) 1992-04-14 1993-10-28 Bioglan Ab Potentialisation d'effets antimicrobiens
WO1996040090A1 (fr) * 1995-06-07 1996-12-19 University Of Southern California Procede pour la reduction ou la prevention de la formation d'adherences post-chirurgicales a l'aide d'inhibiteurs de 5-lipoxydase
US20040259920A1 (en) 2001-04-30 2004-12-23 Zouboulis Christos C. Acne treatment
WO2004054549A1 (fr) 2002-12-13 2004-07-01 Jagotec Ag Preparation topique de spironolactone nanoparticulaire
US20070134341A1 (en) * 2005-11-15 2007-06-14 Kipp James E Compositions of lipoxygenase inhibitors
WO2008085875A2 (fr) * 2007-01-05 2008-07-17 Cornerstone Therapeutics Inc. Procédé de traitement de conditions associées à une activité augmentée de la 5-lipoxygénase et/ou du leukotriène
US20100273868A1 (en) 2007-01-05 2010-10-28 Cornerstone Therapeutics Inc. R-Zileuton for Use in Conditions Associated with Increased 5-Lipoxygenase and/or Leukotriene Activity (EG Asthma)
WO2008106081A1 (fr) * 2007-02-26 2008-09-04 Larry Schlesinger Formulations topiques contenant un antagoniste récepteur d'un leucotriène et leurs utilisations traiter ou prévenir la contracture capsulaire, la formation de cicatrice ou l'hyperpigmentation

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS
AMMAR ET AL., ASIAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 2, no. 3, 2007, pages 96 - 105
ARELLANO ET AL., EUR J DRUG METAB PHARMACOKINET, 1998
BIGELEISEN P E: "In vitro transdermal diffusion of zileuton from a topical gel", INTERNATIONAL JOURNAL OF PHARMACEUTICAL COMPOUNDING 200609 US, vol. 10, no. 5, September 2006 (2006-09-01), pages 392 - 395, XP009165034, ISSN: 1092-4221 *
BUHSE ET AL., THE INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 295, 2005, pages 101 - 112
FEGN ET AL., J. LARYNGOL. OTOL., vol. 3, no. 8, 12 August 2009 (2009-08-12), pages 880 - 884
FEGN L ET AL: "Topical chemoprevention of skin cancer in mice, using combined inhibitors of 5-lipoxygenase and cyclo-oxygenase-2", JOURNAL OF LARYNGOLOGY AND OTOLOGY, vol. 123, no. 8, August 2009 (2009-08-01), pages 880 - 884, XP009165002, ISSN: 0022-2151, DOI: 10.1017/S0022215109004617 *
KATSUMI ISHII, JPN J PHARMACOL, vol. 65, 1994, pages 297 - 303
MOHAMMADI-SAMANI ET AL., PAK. J. PHARM. SCI., vol. 23, no. 1, 2010, pages 83 - 88
PARK ET AL., DRUG DEV IND PHARM, vol. 27, no. 9, October 2001 (2001-10-01), pages 975 - 80
SUBRAMANIAN ET AL., ACTA POL PHARM, vol. 61, no. 5, September 2004 (2004-09-01), pages 335 - 41
TRIVEDI J S ET AL: "Solubility and stability characterization of zileuton in a ternary solvent system", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, ELSEVIER, AMSTERDAM, NL, vol. 4, 1 January 1996 (1996-01-01), pages 109 - 116, XP002446795, ISSN: 0928-0987, DOI: 10.1016/0928-0987(95)00038-0 *
ZOUBOULIS ET AL., DERMATO ENDOCRINOLOGY, vol. 1, May 2009 (2009-05-01), pages 3 188 - 192

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105658202A (zh) * 2013-10-30 2016-06-08 科瑞特有限公司 齐留通乳膏剂型的局部用抗炎症药学组合物
US20160228353A1 (en) * 2013-10-30 2016-08-11 Qurient Co., Ltd. Topical anti-inflammatory pharmaceutical composition with zileuton cream formulation
EP3064197A1 (fr) * 2013-10-30 2016-09-07 Qurient Co. Ltd. Composition pharmaceutique anti-inflammatoire topique avec une formulation de crème de zileuton
JP2016534079A (ja) * 2013-10-30 2016-11-04 クリエント カンパニー， リミテッドＱｕｒｉｅｎｔ Ｃｏ．， Ｌｔｄ． ジロートンクリーム剤形の局所用抗炎症薬学的組成物
EP3064197A4 (fr) * 2013-10-30 2017-04-26 Qurient Co. Ltd. Composition pharmaceutique anti-inflammatoire topique avec une formulation de crème de zileuton
US9655841B2 (en) * 2013-10-30 2017-05-23 Qurient Co., Ltd. Topical anti-inflammatory pharmaceutical composition with zileuton cream formulation
US9855243B2 (en) 2013-10-30 2018-01-02 Qurient Co., Ltd. Topical anti-inflammatory pharmaceutical composition with zileuton cream formulation
WO2018126133A1 (fr) * 2016-12-29 2018-07-05 Cormedix Inc. Formulation de pénétration cutanée à base de taurolidine
CN112566623A (zh) * 2018-08-16 2021-03-26 瑞迪博士实验室有限公司 局部用油质组合物
WO2021121645A1 (fr) * 2019-12-20 2021-06-24 Qurient Co., Ltd. Composition pharmaceutique anti-inflammatoire topique comprenant du zileuton
CN111110845A (zh) * 2020-01-21 2020-05-08 邢更彦 具有消炎镇痛作用的冲击波治疗新型耦合剂及其制备方法

Also Published As

Publication number Publication date
GB201118193D0 (en) 2011-12-07

Similar Documents

Publication Publication Date Title
Tanaji Emulgel: A comprehensive review for topical delivery of hydrophobic drugs
AU691583B2 (en) Adhesive free topical pharmaceutical formulations
WO2013056994A1 (fr) Améliorations des ou concernant les composés organiques
EA011244B1 (ru) Новые композиции для местной доставки
PT92622B (pt) Processo para a preparacao de uma composicao cosmetica ou farmaceutica contendo microsferas de polimeros ou de corpos gordos carregadas com pelo menos um produto activo
JP2014001218A (ja) 薬物の皮膚送達のための接着性外皮形成製剤とそれを使用する方法
AU2001284321A1 (en) Pharmaceutical compositions for topical delivery of cyclooxygenase-2 enzyme inhibitors
JP2004508405A (ja) 全身作用を有する新規な局所用エストロゲン−プロゲストゲン組成物
CA2564634A1 (fr) Compositions ameliorant la permeation pour agents anticholinergiques
SK282261B6 (sk) Farmaceutický prípravok na vonkajšie použitie a spôsob jeho výroby
Mehta et al. A review on microemulsion based gel: A recent approach for topical drug delivery system
SG186866A1 (en) Topical pharmaceutical composition comprising flurbiprofen
US11826478B2 (en) Transdermal delivery formulation
AU2015313842A1 (en) Topical diclofenac sodium compositions
Tamarkin et al. Emollient foam in topical drug delivery
JP2007530498A (ja) ４−ヒドロキシタモキシフェンの化学的に安定な組成物
JPH07505644A (ja) 過飽和局所用組成物
Panchal et al. TOPICAL EMULGEL: A REVIEW ON STATE OF ART.
JP2022501314A (ja) 局所用組成物
Jain et al. A review on emulgel, as a novel trend in topical drug delivery system
US20160128965A1 (en) Gel compositions
WO2013056993A1 (fr) Améliorations dans ou associées à des composés organiques
JPH0481569B2 (fr)
WO2022108913A1 (fr) Compositions et procédés pour l'administration de médicaments par voie intradermique profonde
Surekha et al. Emulgel-An Overview

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12775210

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12775210

Country of ref document: EP

Kind code of ref document: A1