WO2004012695A1 - Utilisation d'alkylurees pour le traitement de l'acne - Google Patents

Utilisation d'alkylurees pour le traitement de l'acne Download PDF

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Publication number
WO2004012695A1
WO2004012695A1 PCT/US2003/023916 US0323916W WO2004012695A1 WO 2004012695 A1 WO2004012695 A1 WO 2004012695A1 US 0323916 W US0323916 W US 0323916W WO 2004012695 A1 WO2004012695 A1 WO 2004012695A1
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WO
WIPO (PCT)
Prior art keywords
acne
urea
alkyl urea
alkyl
carbon atoms
Prior art date
Application number
PCT/US2003/023916
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English (en)
Inventor
Arye Rubinstein
Original Assignee
Arye Rubinstein
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 Arye Rubinstein filed Critical Arye Rubinstein
Priority to AU2003257951A priority Critical patent/AU2003257951A1/en
Publication of WO2004012695A1 publication Critical patent/WO2004012695A1/fr
Priority to US11/049,377 priority patent/US20050272819A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the present invention generally relates to a treatment for skin disorders involving the pilosebaceous units of the skin.
  • the invention also relates to a treatment of skin disorders such as acne vulgaris, acne conglobara, acne fulminans, and comedonal acne.
  • Acne is an inflammation of the pilosebaceous units of certain body areas such as the face, neck, trunk, and buttocks. Acne often manifests itself as comedones (comedonal acne), papulopustules (papulopustular acne), or nodules and cysts (nodulocystic acne and acne conglobara). Pitted, depressed, or hypertrophic scars may follow all types of acne, but especially nodulocystic acne and acne conglobora. Severe acne often includes one or more of the following: persistent or recurrent inflammatory nodules, extensive papulopustular lesions, active scarring, and/or presence of sinus tracts.
  • Noninflammatory acne is characterized by closed comedones (whiteheads) and open comedones (blackheads), consisting of compact masses of keratin, sebum, and bacteria which dilate the follicular duct.
  • Inflammatory acne is characterized by papules (pimples), pustules, and nodulocystic lesions which may lead to scarring.
  • Androgens cause the sebaceous glands to mature and produce large quantities of sebum, which explains, in part, why acne is seen most during puberty.
  • the primary source of androgens is the testes, whereas in the female, the ovaries and adrenals produce these hormones.
  • Blackheads and whiteheads are the hallmark of acne vulgaris and are thought to be the initial lesion in acne. They represent inspissated sebum and keratin debris filling and blocking the sebaceous gland opening. By obstructing the flow of sebum, normal function is altered and the gland is rendered more susceptible to inflammation. This results from the physical stretching of the follicle walls by the enlarging comedone, and the stagnating sebum which is unable to exit. This sebum serves as an inviting culture media for resident bacteria. With resulting leakage of irritating components into the surrounding dermis through these compromised follicular walls, an inflammatory response begins to be mounted. After this first insult, the other familiar clinical features of a full blown acne lesion follow, namely the papule, pustule, and cyst.
  • Propioni bacterium acnes The third factor contributing to the pathogenesis of acne is the gram positive bacillus, Propioni bacterium acnes, which is found in the follicles and sebaceous ducts of patients both with and without acne. Sebum synthesized by the sebaceous gland is almost pure triglyceride and is non-irritating. If triglyceride was the only lipid leaking into the dermis due to comedo obstruction, little inflammatioin would occur. However, Propioni bacterium acnes is a bacterium that metabolizes triglycerides. More specifically, it transforms the triglycerides into irritating essential fatty acids via a lipase enzyme system. These free fatty acids make up the principal irritants initiating the inflammatory process in acne.
  • Topical retinoids (tretinoin, Retin-A R Avita R ) are effective in comedonal and papulopustular acne but rquire detailed instructions regarding usage and potential side effects including:
  • alkyl urea containing compounds were able to rapidly cure superficial as well as deep acne.
  • An alkyl urea is a non-aromatic amide.
  • the basic formula for an alkyl urea is R-HN-CO-NH 2 .
  • R represents an alkyl group.
  • alkyl refers to a monovalent alkane (hydrocarbon) derived radical group.
  • the alkyl group of the present invention includes both short chain and medium chain alkyl groups.
  • short chain alkyl or “lower alkyl” refers to an alkyl group of 1 to 6 carbon atoms.
  • Medium chain alkyl refer to an alkyl group of 7 to 12 carbon atoms.
  • the alkyl groups of the present kinvention may be a straight chain, branched, or cycloalkyl groups. Specifically, the alkyl groups of the present invention contain from 1 to 8 carbon atoms.
  • alkyl groups which may be used with the present invention include, but are not limited to the following: methyl, ethyl, poropyl, isopropyl, n-butyl, l-butly, isobutyl, pentyl, hexyl, isohexyl, heptyl, and octyl.
  • the alkyl component of an alkyl urea is non-polar and hydrophobic. It should be noted that hydrophobic forces are an important determinant of protein structure, folding and stability.
  • the urea component, (-NH-CO-NH2) is polar and hydrophilic.
  • non-polar and polar moieties are referred to as amphiphilic or amphipathic in character.
  • These ureas have surfactant properties, and are considered to be Class II Additives having hydrogen bonding properties.
  • All stereoisomers of the compounds of the present invention are contemplated and within the scope of the invention, either in admixture or in pure or substantially pure form.
  • the definition of the compounds according to the invention embraces all possible stereoisomers and their mixtures. It very particularly embraces the racemic forms and the isolated optical isomers having the specified activity.
  • the racemic forms can be resolved by physical methods such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by column chromatography.
  • the individual optical isomers can be obtained from the racemates by conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
  • alkyl urea of the present invention is butyl urea (BU). It is a mono-substituted lower alkyl urea.
  • the chemical formula for butyl urea is:
  • BU has a molecular weight of 116.6 and a melting point of 96-98°C.
  • Short chain and medium chain alkyl urea compounds uniquely combine the keratolytic/hydrating properties of ureas, with the lipid disrupting abilities of the non- polar alkyl groups.
  • the effect of BU on acne may be related to a variety of interrelated factors:
  • BU is a small bipolar molecule with a hydrophobic and hydrophilic "pole.” By this token it intercalates into lipophilic cell walls and may dissolve pilosebaceous secretions.
  • BU is highly hygroscopic and rapidly increases fluid retention in the sebaceious cyst accelerating the secretion of fluid from the acne lesion.
  • BU is in the used concentration toxic to lymphocytes, neutrophils and macrophages and thus decreasing the local inflammatory reaction in the acne cyst.
  • BU has direct anti viral and bacterial properties. A 5-6 log reduction in bacterial counts was noted with 0.4M BU on E. Coli, Pseudomonas aeroginosa, Proteus mirabilis and Proteus vulgaris. The mechanisms by which BU might kill bacteria may also be responsible for its other favorable effects on acne.
  • Urea and alkylureas such as BU can denature proteins by altering their tertiary structure. Urea predominantly denatures proteins by affecting interactions mediated by hydrogen bond formation of peptide groups while alkylureas alter protein conformational structures by disrupting hydrophobic forces.
  • alkylurea concentration of an alkylurea required to denature most soluble proteins is significantly less than that of urea and depends on the length of the alkyl chain.
  • alkylureas such as BU denature membrane proteins more potently than they denature soluble proteins because the increased lipid solubility conferred by the hydrophobic alkyl chain allows them to intercalate into the membrane.
  • molecules which prefer the hydrophobic regions of lipid bilayer membranes and hydrophobic domains of proteins will also prefer the hydrophobic regions of nucleic acids. Preferential binding to nucleic acids may explain the sparing by BU of red blood cells that do not contain nucleic acids, whereas viruses and bacteria that do not have nucleic acids are affected.
  • the alkyl ureas of the present invention may be used alone or in various concentrations with any pharmaceutically acceptable carrier.
  • the alkyl ureas may be topically applied in a non-toxic-hypoallergenic pharmaceutical carrier, such as aqueous solution of distilled water, or as a solution in a non-toxic polar organic solvent or as a suspension or as an emulsion in a non-toxic cream composition or non-toxic polymer gel.
  • a preferred range of concentration of BU in an aqueous solution is from 0.1 molar (1.2% w/v) to 0.5 molar (5.8% w/v).
  • Topical alkyl ureas may be incorporated into a vehicle containing liposomes.
  • Liposomes are comprised of phospholipd groups.
  • Liposomal vesicles may be formed when combining liposomes with an aqueous solution. Liposomes may vary in shape and size and may be designed with specific characteristics. Liposomes can be used to target specific areas, control the pharmacokinetics of a medicatioin, or to enhance efficacy of a medication.
  • Liposomal bases which may be used in the present invention are available from a variety of vendors.
  • suitable non-toxic polar or organic solvents include lower alkanols of 2 to 6 carbon atoms, such as ethanol, lower alkanetriols of 3 to 6 carbon atoms, such as glycerol, and alkanehexols, such as sorbital.
  • non-toxic cream compositions include a suspension or an emulsion of the alkyl urea in a non-toxic, non-hydrophobic cream, for example, a silicone emulsion or a polyethylene-glycol emulsion.
  • composition may be applied in various types of applications. I.e. rollerball, perforated dome tipped tube or cylinder, or transdermal patch.
  • BU in polymer gels BU incorporated in a polymer gel designed to release the chemical within 30 minutes to 3 hours was administered topically to 11 patients with inflamed cystic lesions of acne.
  • the BU end concentration to be released was between 0.4 to 0.5 molar.
  • Applications to the lesions alone were made 3x daily for 1 week. In all 11 patients no local adverse reactions were noted. Most of the lesions resolved by the end of the treatment. The purulent discharge as well as the inflammatory component of all lesions resolved often within 24 hours.
  • BU in an squeous solution A 0.5 molar (5.8% w/v) solution of BU was applied twice daily with Q tips to acne lesions in 5 adolescents. BU was applied to cystic purulent lesions, to non cystic lesions with erythema and to early lesions with minimal inflammation. The inflammatory response resolved in all lesions within 24-48 hours, whereas purulent cystic lesions healed without scarring within 3-7 days.
  • 0.6ml of culture suspension was inoculated into 0.44M BU and saline control tube for each organism tested and mixed. After one hour contact time a 1.0ml sample culture mixer was diluted serially into 10 6 into 9.0ml GBL Stat Broth (TSB;' 0.5% Leethen; 4% Tween 20 and 0.1% Na 3 S 2 O 3 ).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Cosmetics (AREA)

Abstract

Cette invention porte sur des méthodes de traitement de l'acné. Ces méthodes consistent à appliquer sur les boutons d'acné une alkylurée contenue dans un excipient pharmaceutiquement acceptable. Cette invention porte également sur l'utilisation d'une alkylurée dans la fabrication d'un médicament destiné au traitement de l'acné, ainsi que sur des compositions d'alkylurées contenues dans un excipient pharmaceutiquement acceptable.
PCT/US2003/023916 2002-08-02 2003-07-31 Utilisation d'alkylurees pour le traitement de l'acne WO2004012695A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003257951A AU2003257951A1 (en) 2002-08-02 2003-07-31 The use of alkylureas for treating acne
US11/049,377 US20050272819A1 (en) 2003-07-31 2005-02-02 Use of alkylureas for treating acne

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US40051802P 2002-08-02 2002-08-02
US60/400,518 2002-08-02

Publications (1)

Publication Number Publication Date
WO2004012695A1 true WO2004012695A1 (fr) 2004-02-12

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/023916 WO2004012695A1 (fr) 2002-08-02 2003-07-31 Utilisation d'alkylurees pour le traitement de l'acne

Country Status (2)

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AU (1) AU2003257951A1 (fr)
WO (1) WO2004012695A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5389683A (en) * 1991-08-23 1995-02-14 Adir Et Compagnie Naphthylethylureas

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5389683A (en) * 1991-08-23 1995-02-14 Adir Et Compagnie Naphthylethylureas

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AU2003257951A1 (en) 2004-02-23

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