Classifications

• • 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
• • 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
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/34—Alcohols
• • 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
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/35—Ketones, e.g. benzophenone
• • 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
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
  • A61K8/361—Carboxylic acids having more than seven carbon atoms in an unbroken chain; Salts or anhydrides thereof
• • 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
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/37—Esters of carboxylic acids
  • A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
• • 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
  • A61K8/41—Amines
• • 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
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
  • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
  • A61K8/86—Polyethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
  • A61Q1/02—Preparations containing skin colorants, e.g. pigments
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q15/00—Anti-perspirants or body deodorants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/005—Antimicrobial preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q5/00—Preparations for care of the hair
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q5/00—Preparations for care of the hair
  • A61Q5/02—Preparations for cleaning the hair

Definitions

• the present invention relates to compositions of certain antimicrobial skin pids and to methods of preparing and using these pids
• the invention also relates to non irritating compositions comprising these anti microbial skin pids
• the skin functions as a barrier between the outside world and the internal organs of the body It serves the protective function of keeping harmful microbial organisms from colonizing the interior of an animal Part of this protective function can be ascribed to the hpids present in epidermis, sebaceous secretions, or otherwise present at the skin surface
• the distribution of lipid types at the skin differs markedly from the distribution found in internal organs See, Nicolaides, Science, 1 86 1 9-26 ( 1 974)
• Some of these skin-derived hpids have been reported to have pharmaceutical activity in inhibiting the growth of microbial organisms See, Kabera et al , Antimicrobial Agents and Chemotherapy, 2 23-28 ( 1 972), However, many of the fatty acids among these antimicrobial lipids are known
• Non-irritating natural lipid compositions that prevent infection or biological decay are desirable, since they are unlikely to cause adverse reactions Therefore, what is needed in the art are such compositions formulated with non irritating lipids or such compositions wherein the antimicrobial action of the lipids is accentuated so that the lipids can be present at concentrations less than the threshold concentration for irritation Summary of the Invention
• a + b equals from 11 to 14 and b is an integer from 1 to 14, wherein R 5 is (a) CH 2 NR 1 R 22 , wherein R 21 and R 22 are independently hydrogen or C1 to C6 hydrocarbon, preferably C1 to C4 hydrocarbon, (b) C(0)-R 23 , R 23 is (i) NR 2 R 25 , wherein R 24 and R 25 are independently hydrogen or C1 to C6 hydrocarbon, preferably CI to C4 hydrocarbon, (n) OR 26 , wherein R 26 is glyceryl or a glyceryl fatty acid ester, wherein said fatty acid is about C15 to about C18, or (in) a hydroxyl, or (c) CH 2 OH
• R 5 is (a) CH 2 NR 1 R 22 , wherein R 21 and R 22 are independently hydrogen or C1 to C6 hydrocarbon, preferably C1 to C4 hydrocarbon, (b) C(0)-R 23 , R 23 is (i) NR 2 R 25 , wherein
• n is an integer from 3 to 6 and R 1 , R 2 , R 3 and R 4 ⁇ re independently (a) CH 2 NR 11 R 12 , wherein R 11 and R 12 are independently hydrogen or C1 to C6 hydrocarbon, preferably C1 to C4 hydrocarbon, (b) C(0)-R 13 , wherein R 13 is (i) NR 14 R 15 , wherein R 14 and R 15 are independently hydrogen or C1 to C6 hydrocarbon, preferably C1 to C4 hydrocarbon, (n) OR 16 , wherein R 16 is glyceryl or a glyceryl fatty acid ester, wherein said fatty acid is about C15 to about C18, or (in) a hydroxyl, or (c) CH 2 OH
• the hydrocarbon moieties referred to herein are preferably alkyl
• the formulas below describing fatty acid compounds are helpful to understanding the invention H H o i i II
• fatty acids ( 1 a)-(4a) described above have antimicrobial activity, particularly against a broad spectrum of gram positive bacteria, but also against other microorganisms including a number of gram negative bacteria They further inhibit the adherence of bacteria and fungi to animal skin Additionally, they are believed to be active against pid-coated viral particles C 1 6 1 ⁇ 6 and C 1 6 1 ⁇ 9 were surprisingly found to be non irri g ating, even at concentrations as high a 1 0% w/v These results were for example obtained by contacting skin with the fatty acid in a hydroxypropyl methylcellulose gel and in the presence of alcohol as high as 75 % Surprisingly, compounds of the formulas ( 1 ) - (5) have been shown to been found to have much greater antimicrobial activity when combined with an alcohol or a polyalkylene glycol
• the invention provides an antimicrobial composition
• a + b equals from 11 to 14 and b is an integer from 1 to 14, wherein R 5 is (a) CH 2 NR 21 R 22 , wherein R 21 and R 22 are independently hydrogen or C1 to C6 hydrocarbon, (b) C(0)-R 23 ,
• R 23 is (i) NR 2 R 25 , wherein R 24 and R 25 are independently hydrogen or C1 to C6 hydrocarbon, (ii) OR 26 , wherein R 26 is glyceryl or a glyceryl fatty acid .ester, wherein said fatty acid is about C15 to about C18, or (iii) a hydroxyl, or (c) CH 2 OH, or a pharmaceutically acceptable salt thereof.
• the invention provides an antimicrobial composition
• a pharmaceutically acceptable excipient and (II) an isolated compound of formula
• R 1 and R 2 are independently (a) CH 2 NR 11 R 12 , wherein R 11 and R 12 are independently hydrogen or C1 to C6 hydrocarbon, (b) C(O)- R 13 , wherein R 13 is (i) NR 14 R 15 , wherein R 14 and R 15 are independently hydrogen or C1 to C6 hydrocarbon, (ii) OR 16 , wherein R 16 is glyceryl or a glyceryl fatty acid ester, wherein said fatty acid is about C15 to about C18, or (iii) a hydroxyl, or (c) CH 2 OH, or a pharmaceutically acceptable salt thereof.
• compositions of the first and second embodiments have a number of preferred or alternative embodiments.
• the compound is according to one of the following formulas
• n is an integer from 3 to 6 and R 3 and R 4 are independently as set forth for R 5 , or a pharmaceutically acceptable salt thereof.
• the compound is of one of the following formulas
• R 1 , R 2 and R 3 are independently (d) CH 2 NR 21 R 22 , (e) C(0)-R 13" , wherein R 13' is (i) OR 26 or (n) a hydroxyl, or (f) CH 2 OH, or a pharmaceutically acceptable salt thereof.
• the compound is an ester with a monoglyce ⁇ de having a mono- or di- unsaturated fatty acyl component.
• the compound comprises an acid whereby R 1 , R 2 or R 3 comprises COOH, or a pharmaceutically acceptable salt thereof.
• the salt comprises a sodium, ammonium, silver, copper, calcium, barium, zinc or mono-, di- , t ⁇ - or quaterniary alkylammonium salt, wherein said alkyl substituents on ammonium are independently C1 to C8.
• the alkyl substituents on ammonium are independently C1 to C4 alkyl groups
• the compositions of the invention can be formulated for a device for dwelling on the skin, such as a wound dressing, ostomy device, IV tape, or the like
• such devices comprise a hydrocolloid gel
• the compositions of the invention can be adapted for application to an epithelial surface of a mammal
• the composition can be a toothpaste, mouthwash, shampoo, hair styling composition, skin ointment, make-up composition, anti-oderant or antipersperant
• the compositions of the invention can be used to treat or prevent an infection of the gastrointestinal tract comprising administering an antimicrobially effective amount of an antimicrobial composition of the invention
• the infection to be treated or prevented can be a Helicobacter pylori infection
• the compositions of the invention can be used to treat or prevent acne by administering an antimicrobially effective amount of an antimicrobial composition of the invention
• the amount of the antimicrobial composition administered is effective
• the invention further provides a lipid-replenishing skin treatment ointment comprising (a) the antimicrobial composition of claim 1 , and (b) a plurality of lipids selected from the pids normally present on skin
• compositions of the invention can be adapted for topical or oral administration, such as a cream adapted for topical administration
• the invention provides a method of treating or preventing infection, the method comprising applying or administering to an animal a composition comprising an antimicrobially effective amount of a compound selected from the group consisting of H H
• n is an integer from 3 to 6 and R 4 is (a) CH 2 NR 31 R 32 , wherein R 31 and R 32 are independently hydrogen or C 1 to C6 hydrocarbon, (b) C(O)-R 33 , wherein R 33 is (i) NR 34 R 35 , wherein R 34 and R 35 are independently hydrogen or C 1 to C6 hydrocarbon, (n) OR 36 , wherein R 36 is glyceryl or a glyceryl fatty acid ester, wherein said fatty acid is about C 1 5 to about C 1 8, or (in) a hydroxyl, or (c) CH 2 OH, or a pharmaceutically acceptable salt of said compound
• the invention provides a method of treating or preventing infection, comprising-
• a + b equals from 1 1 to 1 4 and b is an integer from 1 to 1 4, wherein R 5 is as set forth above, or a pharmaceutically acceptable salt thereof, and
• R 1 and R 2 are independently (d) CH 2 NR 21 R 22 , (e) C(0)-R 1 3 ' , or (f) CH 2 OH, or a pharmaceutically acceptable salt thereof. All of the preferred or alternative embodiments described above for the compositions are, of course, applicable to these methods.
• the infection to be treated or prevented is caused by gram negative bacteria.
• the infection to be treated or prevented is caused by a drug-resistant microbe, such as a drug-resistant bacteria, which can be a MRSA.
• the infection to be treated or prevented is caused by a fungus.
• the treatment and prevention methods of the invention can also be used to prevent the adherence of a microbe to epithelial surfaces.
• the component is applied prior to the compound of formula ( 5) .
• the invention provides transdermal administration forms and methods .
• a transdermal administration form for a biological agent comprising : (a) a bioactive agent; and (b) a transdermal transport effective amount of a compound as follows:
• the method of transdermal administration of a biological agent comprises the steps of: (a) topically applying a biological agent to a site on an animal; and (b) applying to the site a transdermal transport effective amount of a compound as follows:
• a + b equals from 1 1 to 1 4 and b is an integer from 1 to 1 4, wherein R 5 is as set forth above, or a pharmaceutically acceptable salt thereof.
• the applying step (b) occurs prior to or concurrently with applying step (a) .
• the invention provides a preservation method and preserved materials. Accordingly, the invention provides a method of preserving a biologically degradable composition comprising contacting the composition with a preservation effective amount of a a compound as follows:
• a + b equals from 1 1 to 1 4 and b is an integer from 1 to 14, wherein R 5 is as set forth above, or a pharmaceutically acceptable salt thereof.
• the invention also provides preserved compositions comprising the product of the method.
• antimicrobial activity encompasses killing microbes, inhibiting the reproduction of microbes, and inhibiting the adherence of microbes to animal tissue.
• An antimicrobially effective amount of a compound of formulas ( 1 )-(5) is an amount effective to either (a) reduce the symptoms of a microbial disease sought to be treated, (b) induce a pharmacological change relevant to treating a microbial disease sought to be treated, (c) inhibit or prevent infection or re-infection by a microbial agent, or (d) reduce the adherence of a microbial agent to a tissue. Since the compositions of the inventions can accentuate the activity compounds of formulas
• an antimicrobially effective amount is an amount effective when delivered in the relevant composition.
• an effective amount includes an amount which, if regularly applied, prevents the occurrence of infection.
• a bioactive agent is an agent that is useful for diagnosing or imaging or that can act on a cell, organ or organism, including but not limited to drugs (pharmaceuticals) to create a change in the functioning of the cell, organ or organism.
• Such agents can include but are not limited to nucleic acids, polynucleotides, antibacterial agents, antiviral agents, antifungal agents, anti-parasitic agents, tumoricidal or anti-cancer agents, proteins, toxins, enzymes, hormones, neurotransmitters, glycoproteins, immunoglobulins, immunomodulators, dyes, radiolabels, radio-opaque compounds, fluorescent compounds, polysaccharides, cell receptor binding molecules, anti-inflammatories, anti-glaucomic agents, mydriatic compounds and local anesthetics.
• an excipient is an inert substance used as a diluent or carrier for a pharmaceutically active substance.
• an ionizable group is a moiety that is predominantly in an ionized form at physiological pH.
• an isolated compound is a compound having at least about 60% wt/wt purity.
• a microbe is a bacteria, mycoplasma, yeast or fungi, virus or parasite (such as a malaria parasite) .
• a microbe adherence inhibiting effective amount of a compound is an amount that causes a reduction in the portion of a defined inoculum of a microbe that adheres to a tissue to which the microbe normally adheres
• oral administration includes any administration into the gastrointestinal tract, including rectal administration
• a substantially purified compound shall be one that has a purity of at least about 85% wt/wt • topical administration includes administration to the tissues that form a barrier between the external environment and the internal organs of an animal, including without limitation administration to the skin, gums, buccal tissue, nasal and sinus tissue, ocular tissue, mtraurethral tissue, rectal tissue or intravaginal tissue • a transdermal transport effective amount of a compound shall be an amount of the compound that leads to an increase in the amount of a topically applied biological agent that reaches the blood stream of an animal to which the biological agent was applied.
• Figure 1 shows a schematic for a synthesis of C 1 6 1 ⁇ 6
• Figure 2 shows a timecourse for the adherence of C albicans to stratum corneum
• Figure 3 shows the adherence activity of various Candida isolates
• Figure 4 shows the adherence of C albicans to stratum corneum, stratum corneum with added skin li id, and lipid depleted stratum corneum
• Figure 5 shows the effect of adding various fractions of skin lipid to stratum corneum discs
• Figure 6 shows the effect of adding C 1 6 1 ⁇ 6 and C 1 6 1 ⁇ 9 to stratum corneum discs
• Figure 7 shows the bacteriocidal activity C 1 6 : 1 ⁇ 6 against 5. aureus.
• compositions containing a fatty acid or derivative of formulas ( 1 )-( 5) comprise a substantially purified fatty acid or derivative of formulas ( 1 )-( 5)
• the fatty acid or derivative shall comprise at least about 0 01 % wt/wt of the composition More preferably the fatty acid or derivative will comprise at least about 0 05 % of the composition, still more preferably at least about 0. 1 % .
• the composition includes a compound of formulas ( 1 )-( 5) that lacks an tonizable group in the R 1 , R 2 , R 3 , R 4 , or R 5 group, but which is convertible to an tonizable group by either a hydrolysis or oxidation reaction.
• the compound is convertible by a hydrolysis reaction
• the compound is converted to an acid, or a salt thereof More preferably, the convertible compound is an ester of an acid
• Preferred fatty acids or derivatives for use in the invention will have a primary dermal irritation index of less than about 2 PDI I grade when 0 2 mg of fatty acid or derivative is applied to a 1 0 cm 2 portion of a rabbit ear, more preferably less than about 1 PDII grade under these conditions
• a suitable non-irritating diluent for use in comparative irritation measurements comprises a gel ointment of 2.5% hydroxypropyl methylcellulose in a water/alcohol mixture comprising from 5 to 75 % of an alcohol such as ethanol or propanol.
• the gel can contain other suitable exipients or carriers.
• the compounds of formulas ( 1 ) - ( 5) will comprise between about 0 1 % and 5.0% (w/v) of the composition , more preferably between about 0 3% and 3.0% , still more preferably between about 0 4% and 1 0% .
• compositions of the invention can be administered to an animal such as a human in need of protection from microorganisms or of treatment for an infection Typical modes of administration will include topical, oral, parenteral or pulmonary (by use of an aerosol) administration
• the compositions can be administered alone, or they can be combined with a pharmaceutically-acceptable excipient according to standard pharmaceutical practice
• excipients will be selected to be appropriate to allow the formation of an aerosol
• the fatty acids and derivatives of the invention are used in the form of tablets, capsules, lozenges, chewing gum, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like
• carriers that is used include lactose, sodium citrate and salts of phosphoric acid
• dismtegrants such as starch, and lubricating agents such as magnesium stearate and talc, are commonly used in tablets
• useful diluents are commonly used in tablets.
• Suppository forms of the fatty acids and derivatives of the invention are useful for vaginal, urethral and rectal administrations
• Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature
• the substances commonly used to create such vehicles include theobroma oil, glyce ⁇ nated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weighty and fatty acid esters of polyethylene glycol See, Remington's Pharmaceutical
• Analogous gels or creams can be used for vaginal, urethral and rectal administrations
• compositions of the invention are preferably administered via devices for dwelling on the skin such as wound dressings, ostomy devices, IV tapes, and the like
• the wound dressing will preferably be designed to administer to the wound or adjacent skin an antimicrobial effective amount c f a compound of formulas ( 1 ) (5)
• suitable dressings a-e found, for example, in U S Patent Nos 4,909, 243, 4, 538, 603, 5, 244,457 and 5,308,31 3
• the compositions of the invention are formulated in hydrocolloid gels Such gels typically include water soluble hydrocolloids such as pectin, gelatin, guar gum, locust bean gum, gum karaya, and mixtures thereof Pectin and gelatin are preferred
• the invention is believed to function by limiting the growth of bacteria or limiting the skin adherence of bacteria, where the bacteria is associated with the formation of acne lesions.
• the invention also provides for the treatment or prevention of gram negative infections or infections by microbes that have acquired drug resistance, such as methacillin resistant Staphy/ococc ⁇ s a ⁇ reus ("MRSA") .
• MRSA methacillin resistant Staphy/ococc ⁇ s a ⁇ reus
• Preferred gram negative targets for treatment or prevention include Pseudomonas infections, such as those caused by P. acidovorans, P. aeruginosa, P. cepacia, P. diminuta, P. fluorescens, P. maltophilia, P. pseudoalcaligenes, P. pseudomallei, P. pyocyanea and P. stutzeri, Escherichia infections such as those caused by E.
• Preferred parasite targets for treatment or prevention include Echinococcus infections.
• Preferred fungal treatment or prevention targets include for example Candida fungi such as C. Albicans, Pityrosporum fungi such as P. ovale or P. orbiculore, Trichosporon funge such as T. rubr ⁇ mi, T. tonurans or T. interigitale, Microsporum fungi such as M. canis or M. a ⁇ douinii, Aspergillus fungi, Pyrenochaeta fungi, Scopulariopsis fungi such as S. brevicaulis and Acrononium fungi. All of the above-recited fungi are classified as yeast.
• the preferred tissues for treatment with the anti-adherence compounds of the invention are skin, stomach, urinary tract, and intravagmal tissues. Skin is most preferred.
• the ointment will generally comprise no more than about 5 % (wt/wt) of a compound according to formula (5) .
• the ointment will comprise no more than about 1 % of a compound according to formula (5) , more preferably, no more than about 0.5% .
• the transdermal administration form of the invention can be used to administer biological agents across any of the several barrier tissues separating the outside environment from the internal organs, including without limitation the skin, gums, buccal tissue, rectal tissue, nasal tissue and sinus membranes
• the compounds of formulas ( 1 )-(5) can be applied to the subject before, concurrently with, or after the application of the biological agent that is to be transdermally administered
• the animals to be treated with the various compositions of the invention are preferably mammals, particularly humans.
• the invention encompasses using a cream or ointment according to the invention in conjunction with ostomy products
• a cream of the invention can be used to coat the face plates or seals on ostomy products See, for example, U.S. Patent Nos. 4,465,486, 4,490, 1 45, 4,460,363 and 4,826,493.
• the invention further encompasses using the fatty acids or derivatives as additives to antimicrobial compositions that further include other active agents such as antimicrobials (such as antibiotics, including bacitracm) , antifungal agents (such as miconazole and t ⁇ conazole) , spermicidals (such as nonoxynol-9), and the like.
• antimicrobials such as antibiotics, including bacitracm
• antifungal agents such as miconazole and t ⁇ conazole
• spermicidals such as nonoxynol-9
• compositions of the invention are preferably formulated to have pH less than about 7, to minimize irritation to the treatment subject
• the component of the invention is preferably a (C2-C7) alkyl alcohol or a polyf alkylene oxide) wherein the alkylene moieties are C2 to C4, or mixtures of alcohol and polyfalkylene oxide)
• the alcohol is C2-C4, more preferably C3, still more preferably isopropanol
• the alkylene of the polyfalkylene oxide) is preferably C2 C3
• the polyfalkylene oxide) can be a copolymer of differing alkylene subunits Isopropyl alcohol is a preferred alcoholic component used with the invention.
• Preferred alkyleneoxide polymers include those with ethyleneoxide or propyleneoxide polymer building blocks such as polyethylene glycol and polypropylene glycol.
• the average molecular weight of the polymer is preferably between about 400 and about 1 ,000, more preferably between about 400 and about 800.
• Various weight-range polymer compositions can be mixed to obtain the consistency desired for a particular composition.
• Compositions of fatty acid-related compounds according to formulas ( 1 )-(5) and an alcoholic component have the following preferred compositions:
• compositions of fatty acid-related compounds according to formulas ( 1 )- (5) and a polymeric component have the following preferred compositions:
• compositions of fatty acid-related compounds according to formulas ( 1 )- (5), an alcoholic component and a polymeric component have the following preferred compositions:
• the solvent conditions must be sufficiently basic to favor proton abstraction from decyne.
• a mixture of ammonia and NaNH 2 in tetrahydrofuran is a preferred reaction medium Temperatures that are low enough to maintain the ammonia in liquid form are preferred.
• the undecyne (for example, from Lancaster Co. , Windham, NH) is added to the basic solvent incrementally.
• the solvent is preferably anhydrous and aprotic
• the solvent is also polar Dimethylsulfoxide (“DMSO”) is a preferred solvent
• DMSO Dimethylsulfoxide
• Potassium cyanide is the preferred source of cyanide anion
• the nit ⁇ le functionality is converted to a carboxylate functionality
• a hydrolytic reaction such as using acidic or basic hydrolytic conditions, as will be recognized by those of ordinary skill
• the hydrolysis is accomplished in an acidic, alcoholic solvent
• Particularly preferred is a mixture of methanolic HCI and concentrated H 2 S0 4 These preferred conditions will generate the alcohol ester derivative of the nit ⁇ le
• the fourth reaction comprises a hydrolysis reaction
• Conditions effective to hydrolyze an ester are well known to those of ordinary skill
• One such method is base-catalyzed hydrolysis, for instance using 0 5% wt/v NaOH in a mixture of 1 00 ml H 2 0 and 300 ml methanol (which is added to increase the solubility of the ester)
• ester hydrolyses proceed at a modest temperature, such as room temperature
• the catalyst is preferably palladium on barium sulfate (for example, 5% palladium on sulfate from Ald ⁇ ch Chemical Co , Milwaukee, WI)
• the solvent is selected to "poison" the catalyst to adjust its reactivity
• Pyridine and quinoline are appropriate solvent components for so adjusting catalyst reactivity
• Anhydous pyridine is the preferred solvent
• the amine compounds of formulas ( 1 ) - (5) can be synthesized, for example by reducing the corresponding amides with a hydride as described, for example, in Section 4 1 of Carey and Sundberg, Advanced Organic Chemistry, Part B, Plenum Press, New York, 1 977 or by Hoffmann rearrangement to remove the carbonyl moiety, as described in Wallis and Lane, Org. React. 3: 267, 1 946.
• the amide compounds of formulas ( 1 ) - (5) can be synthesized, for instance, by conducting a dehydration reaction between the corresponding fatty acid and NHR 1 R 15 .
• Such a reaction can be conducted by first forming an activated derivative of the acid such as an anhydride or an N-hydroxysuccinimide ester.
• the dehydration reaction can be conducted using a carbodiimide compound to form a reactive intermediate with the acid moiety.
• the acid synthesized as described above can be converted to the acid halide, for instance by reaction with a halogen gas in the presence of phosphorus or with a halogen-substituted phosphorus compound such as phosphorus trichloride, and subsequently reacted with the amine moiety.
• care should be taken to limit ⁇ -halogenation.
• the alcohol compounds of formulas ( 1 ) - (5) wherein R 1 , R 1 , R 1 , R 3 , R 4 , or R 5 is an ester with glycerol or monoglyceride or can be formed using the same dehydration reactions described above.
• the alcohol compounds of formulas ( 1 ) - (5) wherein R 1 , R 1 , R 1 , R 1 , R 3 , R 4 , or R 5 is an ester with glycerol or monoglyceride or can be formed using the same dehydration reactions described above.
• R 3 , R 4 , or R 5 is CH 2 OH
• R 3 , R 4 , or R 5 is CH 2 OH
• R 3 , R 4 , or R 5 is CH 2 OH
• the flask was cooled to -78 ° C in a solid carbon dioxide (dry ice)-acetone bath .
• a mixture of dry ice and acetone was also used to cool the cold trap.
• Ammonia 1 00 ml was condensed in the cold trap.
• the ammonia was then condensed into the flask and 1 2 g (0.3 mol) of NaNH 2 was added under N 2 , creating a milky white mixture.
• 38 ml (30 g, 0.2 mol) undecyne was added dropwise over a 1 0 minute period .
• the mixture then became thick and viscous .
• Additional THF was added (70 ml) to reduce the viscosity and allow continued stirring .
• the reaction mixture was then allowed to gradually warm to 25 ° C and stirred under positive nitrogen pressure for 1 5 hours . After this, the reaction was quenched by the addition of 20 g NH 4 CI .
• the reaction mixture was then poured into 200 ml cold deionized (" Dl " ) water and 200 ml hexane was added to the resulting mixture .
• the organic layer was separated , and the aqueous layer was extracted twice more with 1 00 ml hexane.
• the combined organic layers were washed ( 1 ) with 200 ml Dl water and ( 2) with 200 ml brine (i .e. , an aqueous solution saturated with sodium chloride at 25 ° C) .
• the methyl ester product was converted to the corresponding acid by refluxing it in a solution of 20 g NaOH dissolved in 300 ml methanol and 1 00 ml Dl water for 3 hours or until completion as measured by silica gel TLC (RF for free acid is 0.35 in 70: 30: 2 PE: EE :acet ⁇ c acid) .
• RF for free acid is 0.35 in 70: 30: 2 PE: EE :acet ⁇ c acid
• the solvent was removed in vacuo to give a quantitative yield of 6-hexadecynoic acid as an oil (Optionally, the product can be recrystallized at 20 ° C from hexane to yield white crystals (M . P. 37 ° C) . However, the recrystal zation results in only 70% recovery and may be omitted) .
• the 6-hexadecyno ⁇ c acid was added to a 1 L flask with 300 ml anhydrous pyridine (Aldrich) along with 1 .0 g of 5 % Pd on BaS0 4 catalyst (oxidized from) and sealed with a rubber septum.
• the catalyst is available from Aldrich Chemical Co. , Milwaukee, WI .
• the flask (which was vented with a needle vent) was first purged with nitrogen then hydrogen through a needle cannula .
• the flask was kept under 2 lbs. positive H 2 pressure, and the reaction monitored by the uptake of hydrogen .
• HPI 1 human pathogenic Candida fungi
• HPI 2 Three strains of human pathogenic Candida fungi (HPI 1 , HPI 2 and HPI 3) (isolated from symptomatic patients)
• one candidal strain of human commensurate i e , symbiotic, non pathogenic) fungi (HCI 1 ) (isolated from asymptomatic individual)
• HCI 1 symbiotic, non pathogenic fungi
• Candida parasitosis were tested for their ability to adhere to stratum corneum using the method outlined in Example 3
• a ethanol extract of surface skin lipid was prepared as described in Wertz et al , J Invest Dermatol 84 410-41 2, 1 985 Briefly, human volunteers positioned the wrist portions of their arms over a stainless steel basin, with the hand and the rest of the arm angled up and away from the basin A 250 ml portion of 95% ethanol was slowly poured over each wrist and the lipids that extracted into the ethanol were recovered by evaporating the solvent
• a part of the skin lipid extract described in Example 5 was fractionated on a preparative (0 25 mm thick) silica gel plate (Adsorbosil plus one ® , Alltech Associates, Deerfield, IL) developed with hexane ethyl ether acetic acid, 70.30 1 (v.v) Lipid fractions were located using a scanning photodensitometer set at 21 0 nm The lipid-containing regions of the plate were scrapped and the lipids eluted using chloroform:methanol water, 50: 50 1 . By this method, fractions containing ( 1 ) squalene ("SQ”), (2) wax esters and cholesterol esters
• Example 7 Inhibition of C. albicans adherence by C 1 6 : 1 ⁇ 6 and C 1 6 : 1 ⁇ 9 Using the methodology of Example 5, 0 1 , 1 0 and 1 0 0 mg of C 1 6. 1 ⁇ 6 or C 1 6 1 ⁇ 9 was applied to 1 cm stratum corneum discs and the effect of adherence by C albicans was measured The results are shown in Figure 6
• Example 8 Effect of Lipid on Bacteria A preparation of skin surface lipid prepared by extracting human hair clippings with chloroform methanol, 2 1 , for 2 hours at room temperature Following the extraction, the lipids were recovered by evaporating the extraction solvent The lipids of hair clippings are believed to reflect the composition of sebum free of lipid derived from sweat gland secretions The skin pids or other lipid preparations were suspended or dissolved in beef heart infusion broth (BHIB, Difco, Livonia, Ml) by so ⁇ ication (taking care not to overheat the broth)
• the lipid extracted from skin has been shown to be bacteriocidal towards S. aureus, Streptococcus salivarius, Eichinella corodens and F ⁇ sobacteri ⁇ m nucleatum (a gram negative anaerobic bacteria involved in gum disease), and to be bacteriostatic (i.e. , to prevent growth) against E. fascalis. Activity was not detected against P. aeruginosa.
• Example 9 Inhibitory Activity of Specific Lipids
• Example 8 The procedures of Example 8 were repeated using specific fatty acids and testing against both 5. aureus and S. salivarius. In this experiment, the optical density of the cultures was used to indicate the relative numbers of bacteria present, rather than measuring CFU values. The results, in terms of minimum inhibitory concentrations ( " MICs") were as follows:
• MRSA methicillin-resistant S. Aureus
• Example 1 1 - The Primary Dermal Irritation Index for Specific Compositions
• the primary dermal irritation index (“PDII”) of various compositions was measured using an albino rabbit, single insult patch test. Two test areas per rabbit were prepared by shaving both areas, and abrading one of the areas. Similarly, two matching control areas were prepared on each animal.
• the test material 0.5 ml each application, was applied to 2.5 x 2.5 cm gauze patches, and held against the test area with an impervious Vetrap brand bandage (3M, St. Paul, MN) . The patches were held in place for 24 h, at which time the treatment sites were wiped clean. The evaluations were based on observations at this 24 h timepoint and on observations at the 72 h timepoint.
• a gel composition containing a prospective antimicrobial agent was layered over the filter paper, with care taken to avoid air pockets formed between the gel and the filter. This amount of bacteria is in excess of the amount ( 1 x 1 0 5 ) considered to constitute an infection when present in one gram of tissue.
• the filters with bacteria and gel compositions were maintained at room temperature for 20 minutes.
• the filters were then placed in 25 ml of Trypticase Soy Broth Z-49 medium (available from GIBCO (Grand Island, NY) and incubated in a shaker incubator for 24 hours at 38 6 ° C at 1 32 rpm. Positive results were scored when bacteria could not be observed microscopically in the culture medium
• the polyethylene glycol was PEG-400, available from
• the gelatin was obtained from Hormel, Davenport, IA
• the pectin was obtained from Citrus Colloids, Hereford,
• compositions 1 , 3 and 4 were transparent liquids
• Composition 2 was a liquid when freshly prepared, but subsequently separated into two phases
• Compositions 5 and 6 were gels
• NaCMC sodium carboxymethylcellulose
• composition 1 0 and a corresponding composition 1 0-CMP, which lacked the fatty acid component, were tested for antimicrobial activity against E. co// using the method of Example 1 2.
• the following average optical densities were obtained for cultures grown from filters treated as indicated :

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