DK2794550T3 - Oftalmisk formulering - Google Patents

Oftalmisk formulering Download PDF

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Publication number
DK2794550T3
DK2794550T3 DK12860686.0T DK12860686T DK2794550T3 DK 2794550 T3 DK2794550 T3 DK 2794550T3 DK 12860686 T DK12860686 T DK 12860686T DK 2794550 T3 DK2794550 T3 DK 2794550T3
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ophthalmic formulation
compound
use according
formula
branched
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DK12860686.0T
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English (en)
Inventor
Thomas Millar
Burkhart Schuett
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Univ Of Western Sydney
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Priority claimed from AU2011905421A external-priority patent/AU2011905421A0/en
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Publication of DK2794550T3 publication Critical patent/DK2794550T3/da

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/533—Monocarboxylic acid esters having only one carbon-to-carbon double bond
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/08—Solutions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/24—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with monohydroxylic compounds
    • C07C69/26—Synthetic waxes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/533—Monocarboxylic acid esters having only one carbon-to-carbon double bond
    • C07C69/58—Esters of straight chain acids with eighteen carbon atoms in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
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    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
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    • 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
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    • A61K9/127—Liposomes
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    • C07—ORGANIC CHEMISTRY
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    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/24—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with monohydroxylic compounds

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Ophthalmology & Optometry (AREA)
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  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (21)

1. Oftalmisk formulering til anvendelse ved behandling af tørt øje, hvilken formulering omfatter en forbindelse med formlen (I):
hvor R1 er et ligekædet eller forgrenet C9-C33-alkyl eller et ligekædet eller forgrenet C9-C33-alkenyl med 1 til 4 dobbeltbindinger; R2 er et ligekædet eller forgrenet C9-Ci9-alkyl eller et ligekædet eller forgrenet C9-Ci9-alkenyl med 1 til 4 dobbeltbindinger; og en oftalmologisk acceptabel bærer.
2. Oftalmisk formulering til anvendelse ifølge krav 1, hvor HOOC-R1- er valgt fra gruppen bestående af: capryl (C10:0), lauryl (C12:0), myristyl (C14:0), palmityl (C16:0), stearyl (C18:0), oleoyl (C18:l), linoleoyl (w6) (C18:2) og linoleoyl (ω3) (C18:3).
3. Oftalmisk formulering til anvendelse ifølge krav 1 eller 2, hvor R2 er ligekædet eller forgrenet Ci7-alkyl eller ligekædet eller forgrenet Ci7-alkenyl med 1 eller 2 dobbeltbindinger.
4. Oftalmisk formulering til anvendelse ifølge krav 1 eller 2, hvor R2 er ligekædet eller forgrenet Ci9-alkenyl med 4 dobbeltbindinger.
5. Oftalmisk formulering til anvendelse ifølge et hvilket som helst af kravene 1 til 4, hvor forbindelsen med formlen (I) er valgt fra gruppen bestående af:
og
6. Oftalmisk formulering til anvendelse ifølge krav 1, hvor forbindelsen med formlen (I) er (0-oleoyl)-16-hydroxypalmitinsyre.
7. Oftalmisk formulering til anvendelse ifølge krav 1, hvor den oftalmologisk acceptable bærer er, eller omfatter, vand, og hvor den oftalmiske formulering valgfrit endvidere omfatter en oftalmologisk acceptabel excipiens.
8. Oftalmisk formulering til anvendelse ifølge krav 7, hvor den oftalmologisk acceptable excipiens er valgt fra gruppen bestående af slimhindrende midler, blødgøringsmidler, hypertonicitetsmidler, konserveringsmidler, buffere og pH-justerende midler.
9. Oftalmisk formulering til anvendelse ifølge et hvilket som helst af kravene 1 til 8, hvor den oftalmiske formulering er en olie i vand-emulsion.
10. Oftalmisk formulering til anvendelse ifølge et hvilket som helst af kravene 1 til 9, hvor den oftalmiske formulering omfatter liposomer.
11. Oftalmisk formulering til anvendelse ifølge krav 1, hvilken formulering omfatter en forbindelse med formlen (I) som defineret i krav 1, vand og en emulgator.
12. Oftalmisk formulering til anvendelse ifølge krav 1, hvilken formulering omfatter en forbindelse med formlen (I) som defineret i krav 1, vand og én eller flere oftalmologisk acceptable excipienser, der er valgt fra gruppen bestående af polyethylenglycol, propylenglycol, glycerin, polyvinylalkohol, povidon, polysorbat 80, hydroxypropylmethylcellulose, carmellose, carbomer 980, natriumhyaluronat og dextran.
13. Oftalmisk formulering til anvendelse ifølge et hvilket som helst af kravene 1 til 11, hvilken formulering endvidere omfatter en aktiv farmaceutisk bestanddel til behandling af en tilstand eller sygdom i øjet.
14. Oftalmisk formulering, der omfatter en forbindelse, som er valgt fra gruppen bestående af:
og
og en oftalmologisk acceptabel bærer, hvor den oftalmologisk acceptable bærer er, eller omfatter, vand, og hvor den oftalmiske formulering endvidere omfatter en oftalmologisk acceptabel excipiens, hvor den oftalmologisk acceptable excipiens er valgt fra gruppen bestående af slimhindrende midler, blødgøringsmidler, hypertonicitetsmidler, konserveringsmidler, buffere og pH-justerende midler.
15. Oftalmisk formulering ifølge krav 14, hvor forbindelsen er (0-oleoyl)-16- hydroxypalmitinsyre.
16. Oftalmisk formulering ifølge et hvilket som helst af kravene 14 til 15, hvor den oftalmiske formulering er en olie i vand-emulsion.
17. Oftalmisk formulering ifølge et hvilket som helst af kravene 14 til 16, hvor den oftalmiske formulering omfatter liposomer.
18. Oftalmisk formulering, der omfatter en forbindelse som defineret i krav 14, vand og en emulgator.
19. Oftalmisk formulering, der omfatter en forbindelse som defineret i krav 14, vand og én eller flere oftalmologisk acceptable excipienser, der er valgt fra gruppen bestående af polyethylenglycol, propylenglycol, glycerin, polyvinylalkohol, povidon, polysorbat 80, hydroxypropylmethylcellulose, carmellose, carbomer 980, natriumhyaluronat og dextran.
20. Oftalmisk formulering ifølge et hvilket som helst af kravene 14 til 19, der endvidere omfatter en aktiv farmaceutisk bestanddel til behandling af en tilstand eller sygdom i øjet.
21. Forbindelse med én af følgende formler:
DK12860686.0T 2011-12-23 2012-12-21 Oftalmisk formulering DK2794550T3 (da)

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Application Number Priority Date Filing Date Title
AU2011905421A AU2011905421A0 (en) 2011-12-23 Ophthalmic Formulation
PCT/AU2012/001595 WO2013091020A2 (en) 2011-12-23 2012-12-21 Ophthalmic formulation

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DK2794550T3 true DK2794550T3 (da) 2019-04-08

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US (3) US10385003B2 (da)
EP (2) EP2794550B1 (da)
JP (1) JP6087374B2 (da)
KR (3) KR20210104916A (da)
CN (1) CN104271548B (da)
AU (1) AU2012318266B2 (da)
BR (1) BR112014015430B1 (da)
CA (1) CA2859997C (da)
CO (1) CO7101242A2 (da)
DK (1) DK2794550T3 (da)
ES (1) ES2716806T3 (da)
HK (1) HK1203480A1 (da)
HU (1) HUE042760T2 (da)
MX (1) MX364693B (da)
PL (1) PL2794550T3 (da)
PT (1) PT2794550T (da)
RU (1) RU2625301C2 (da)
SI (1) SI2794550T1 (da)
TR (1) TR201902752T4 (da)
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KR20210104916A (ko) * 2011-12-23 2021-08-25 웨스턴 시드니 유니버시티 안과용 제형물
US11058713B2 (en) * 2017-06-29 2021-07-13 Advaite LLC. Treatment and diagnosis of ocular surface disorders
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