WO2008113992A2 - Compositions de gels - Google Patents

Compositions de gels Download PDF

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Publication number
WO2008113992A2
WO2008113992A2 PCT/GB2008/000928 GB2008000928W WO2008113992A2 WO 2008113992 A2 WO2008113992 A2 WO 2008113992A2 GB 2008000928 W GB2008000928 W GB 2008000928W WO 2008113992 A2 WO2008113992 A2 WO 2008113992A2
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WO
WIPO (PCT)
Prior art keywords
compound
general formula
composition
solvent
gel
Prior art date
Application number
PCT/GB2008/000928
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English (en)
Other versions
WO2008113992A3 (fr
Inventor
Vesna Caplar
Leo Frkanec
Milan Jokic
Janja Makarevic
Tomislav Portada
Mladen Zinic
Zelimir Jelcic
Original Assignee
Pliva Hrvatska D.O.O.
Bucks, Teresa Anne
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.)
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Publication date
Application filed by Pliva Hrvatska D.O.O., Bucks, Teresa Anne filed Critical Pliva Hrvatska D.O.O.
Publication of WO2008113992A2 publication Critical patent/WO2008113992A2/fr
Publication of WO2008113992A3 publication Critical patent/WO2008113992A3/fr

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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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • 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
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • 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
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A61K8/442—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof substituted by amido group(s)
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
    • 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
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • C07K5/06069—Ser-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06147—Dipeptides with the first amino acid being heterocyclic and His-amino acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to compounds which are capable of forming gels when mixed with an appropriate solvent and to methods of preparing these compounds.
  • the invention also relates to the gels formed by the compounds, methods for making them, compositions comprising the gels and to the use of the gels in various application.
  • Supramolecular hydrogels are used in many applications including food and cosmetic thickeners, formation of contact lenses, vehicles for drug delivery and tissue replacement matrices. They are of particular interest as drug delivery vehicles because of their generally favourable biocompatibility. Because of their high water content they are particularly attractive for the delivery of delicate bioactive agents such as proteins.
  • Gels may be either chemical or physical gels. Chemical gels consist of solid components which are covalently linked to one another and gel formation is irreversible. Physical gels are generally formed from smaller subunits which are linked non-covalently into a network. Physical gels tend to be thermoreversible.
  • Hydrogels may be formed either by polymers or by low molecular weight gelators (LMWGs).
  • LMWGs low molecular weight gelators
  • the molecules are assembled in well ordered arrays and the gels are thermoreversible and strong. In addition, they tend to have low minimal gelation concentrations and high tolerance towards salts and other additives.
  • hydrogels formed from chemically cross- linked hydrophilic polymers there are many examples of documents relating to hydrogels formed from chemically cross- linked hydrophilic polymers.
  • a hydrogel is formed from a cross-linked polymerised hydrophilic polymer with an olefinic bond, an amino acid polymer, a cross- linking agent and a lower alcohol.
  • WO-A-97/05185 relates to macromers which can be ionically or covalently cross-linked to form hydrogels.
  • the macromers are block co-polymers which have hydrophilic blocks and blocks which are more hydrophobic.
  • WO-A-03/089506 also relates to hydrogels as well as to hydrogel foams and superporous hydrogels. These hydrogels are said to consist of two or more interpenetrating polymer networks which provide enhanced elasticity and mechanical strength properties.
  • WO-A-2004/104021 again relates to hydrogels which, in this case, are intended to provide controlled release of active agents by utilising repeat sequence protein polymers.
  • hydrogelator compounds formed by combining 11-aminoundecanoioc acid, lauric acid and aromatic and aliphatic amino acid units in the same molecule. These molecules were low molecular weight compounds derived from amino acids and connected through amide bonds with long aliphatic chains ending in a carboxylic acid functional group and have the general formula:
  • R can be isopropyl, isobutyl, benzyl or phenyl.
  • chiral bis(amino acid)oxalyl amides and chiral bis(amino alcohol)oxalyl amide are capable of forming hydrogels (Makarevic et al, Chem.Eur.J. 2001, 7, 3328 - 3341, Makarevic et al,. Croat. Chem. Acta. 2004, 77, 403-414).
  • the present invention relates to novel non-polymeric compounds which, in water, are able to form hydrogels without the need for chemical cross-linking.
  • the compounds are also able to form gels in solvents other than water, including organic solvents and oils. It is thought that the gels are formed by the self-assembly of the molecules into nanofibrous networks.
  • a gel composition comprising a gelating agent and a solvent, characterised in that the gelating agent is a compound of general formula (I):
  • R 1 is hydrogen or C 1-14 alkyl
  • R 3 is OH or a group:
  • R 4 is hydrogen or C 1-6 alkyl, optionally substituted with OR 9 , COR 9 or COOR 9 ;
  • R 9 is hydrogen, C 1-6 alkyl or benzyl;
  • R 2 is hydrogen, C 1-6 alkyl or benzyl, either of which may optionally be substituted with OH or, when R is
  • R 2 may also be R 7 ;
  • R 7 is a 5 or 6 membered aromatic or heteroaromatic ring system which is optionally further substituted with C 1-6 alkyl, benzyl or hydroxy;
  • R 1 can be C 4 -C 18 linear or branched alkyl alkyl
  • Y can be NH
  • A can be CO
  • X can be NH
  • Z can be COO " one of a and b is an amino acid side chain and the other is hydrogen
  • n can be 1.
  • WO 2005/107812 relates to a topical or transdermal composition of an anticholinergic or antispasmodic agent which also comprises a urea containing compounds as a penetration enhancing agent.
  • the urea containing compounds have the formula:
  • R 1 , R 2 , R 3 and R 4 are very broadly defined.
  • the preferred form of the composition is a gel but the urea containing compounds are not gelating agents.
  • JP07304755 teaches that L-leucine-N-[N-(aminocarbonyl)-L-leucyl] methyl ester can be used as a reagent in the preparation of compounds which are inhibitors of human renin.
  • WO 01/14328 relates to compounds of general formula:
  • R 1 can be hydrogen or alkyl
  • R 2 , R 3 and R 5 can be hydrogen
  • R 4 can be hydrogen or optionally substituted alkyl, aryl etc.
  • R 6 can be NR d R e ; where R d is H and R e can be alkyl substituted with COOH.
  • the compounds are said to be cell adhesion inhibitors and there is no suggestion in this document that they could be used to form gels.
  • the compounds of general formula (I), and especially their salts have the advantages that they can form gels in both water and organic solvents and that the properties of the gels can easily be manipulated by adjusting the temperature, pH or the type and amount of solvent present.
  • gel forming compound refers to any molecule, whether a small organic molecule (such as the compounds of general formula (I)) or a polymer, which forms a gel when dissolved by heating, with either an aqueous or a non-aqueous solvent, and allowed to cool to room temperature
  • C 1 -C 6 alkyl refers to a straight or branched saturated hydrocarbon chain having one to six carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl and n-hexyl.
  • aromatic moiety and "aryl” in the context of the present specification refer to an aromatic ring system having from 5 to 10 ring carbon atoms and containing one or two rings.
  • aromatic moieties are benzene, naphthalene and biphenyl ring systems.
  • Heteroaromatic and “heteroaryl” refer to aromatic ring systems as defined above but in which one or more ring atoms is replaced by a nitrogen, oxygen or sulphur atom.
  • heteroaromatic ring systems include pyridine, quinoline, isoquinoline, quinazoline, thiazole, benzthiazole, benzoxazole, benzimidazole, indole, indazole and imidazole ring systems.
  • Salts of the compounds of general formula (I) are preferably pharmaceutically acceptable and include salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, salts of phosphoric and sulfonic acids; and salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanoate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3- phenylpropionate, picrate, pivalate, propionate, lac
  • a chiral centre or another form of isomeric centre is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be covered herein.
  • Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • the compound of general formula (I) is suitably the sole gelating agent; i.e. no other gelating agent is present.
  • the solvent may be an aqueous solvent such as water, sodium chloride solution or aqueous acetic acid or a mixture of water with an organic solvent such as DMSO or another suitable organic solvent.
  • suitable compounds of general formula (I) are those in which, independently or in any combination:
  • R 1 is hydrogen, or unsubstituted C 1-14 alkyl, more preferably hydrogen or Ci -12 alkyl; and R 2 is hydrogen, C 1-4 alkyl optionally substituted with OH or, when R 3 is a group:
  • R 2 is R 7
  • R 7 is phenyl or a 5- or 6- membered nitrogen containing heteroaromatic ring system, either of which is optionally substituted with OH or benzyl.
  • R 2 is hydrogen or methyl optionally substituted with hydroxy, imidazolyl, 1- benzylimidazolyl, or hydroxyphenyl.
  • R 4 is hydrogen, methyl, ethyl or benzyl, any of which is optionally substituted with OR 9 or COOR 9 ;
  • R 9 is hydrogen, methyl, ethyl or benzyl
  • R 4 is hydrogen, methyl or ethyl wherein the methyl or ethyl groups may optionally be substituted COOH or COO-benzyl.
  • Preferred salts of compounds of general formula (I) are the hydrochloride salts.
  • Particularly suitable compounds of general formula (I) include
  • R 1 is as defined for general formula (I)
  • R 5 is either R 2 as defined in general formula (I) or, when R 2 contains a hydroxyl group, a protected version of R 2
  • R 10 is C 1-6 alkyl or benzyl.
  • the conversion of the ester group to a carboxylic acid may be achieved by any known method, for example by hydrogenolysis in which a solution of the ester is hydrogenated over a suitable catalyst (typically palladium/carbon) or alternatively by hydrolysis using a base such as lithium hydroxide.
  • R 5 is a protected version of R 2
  • the protecting group is chosen so that it can be removed at the same time as the R 10 moiety.
  • R 5 is benzyl ether.
  • hydrolysis is used for alkyl esters and hydrogenolysis for benzyl esters.
  • Esters of general formula (II) are new and they form a further aspect of the invention.
  • R 5 is as defined above and the two R 10 groups may be the same or different and are as defined above for general formula (II).
  • the removal of the R 10 groups may be achieved by any known method, for example by hydrogenolysis, in which a solution of the ester is hydrogenated over a suitable catalyst (typically palladium/carbon) or, alternatively by hydrolysis using a base such as lithium hydroxide.
  • An ester of general formula (II) or (Ha) may be prepared by the reaction of an amino acid ester of general formula (III):
  • R 5 and R 10 are as defined for general formula (II); or a salt of such an ester, typically a hydrochloride or/?-toluenesulfonate salt; with an isocyanate of general formula (IV) or (IVa):
  • the reaction may be conducted in a dry organic solvent, for example dichloromethane and in the presence of a tertiary amine, typically triethylamine.
  • a dry organic solvent for example dichloromethane and in the presence of a tertiary amine, typically triethylamine.
  • R 4 is as defined above can be written as compounds of general formula (Ia):
  • R 1 is as defined for general formula (I)
  • R 5 and R 5a are respectively either R 2 and R 4 as defined in general formula (I) or, when R 2 or R 4 contains a hydroxyl or carboxylic acid group, a protected version of R 2 or R 4 ; and R 10 as defined for general formula (II).
  • the conversion of the ester group to a carboxylic acid may be achieved by any known method, for example by hydrogenolysis, in which a solution of the ester is hydrogenated over a suitable catalyst (typically palladium/carbon) or, alternatively by hydrolysis using a base such as lithium hydroxide.
  • R 5 is a protected version of R 2 or R 4 the protecting group is chosen so that it can be removed at the same time as the R 10 moiety.
  • R 5 is a benzyl ether or ester.
  • esters of general formula (VI) are new and they form a further aspect of the invention.
  • R 5 and R 5a are as defined above for general formula (VI) and the two R 10 groups may be the same or different and are as defined above for general formula (II).
  • the removal of the R 10 groups may be achieved by any known method, for example by hydrogenolysis, in which a solution of the ester is hydrogenated over a suitable catalyst (typically palladium/carbon) or, alternatively by hydrolysis using a base such as lithium hydroxide
  • An ester of general formula (VI) or (Via) may be prepared by the reaction of a dipeptide ester of general formula (VII):
  • R 5 and R 5a are as defined for general formula (VI) and R 10 is as defined for general formula (II); or a salt of such an ester, typically a trifluoroacetate, hydrochloride or j?-toluenesulfonate salt; with an isocyanate of general formula (FV) or (IVa) as defined above.
  • the reaction may be conducted in a dry organic solvent, for example dichloromethane and in the presence of a tertiary amine, typically triethylamine.
  • R 5 and R 5a are as defined for general formula (VI)
  • R 10 is as defined for general formula (II)
  • P 1 is an amine protecting group such as t-butoxycarbonyl (BOC), benzyloxycarbonyl (Z) or any other suitable protecting group.
  • BOC t-butoxycarbonyl
  • Z benzyloxycarbonyl
  • the method for removal of the protecting group will depend upon the particular protecting group which is used. For example, hydrogenation over a suitable catalyst, for example palladium or platinum, is particularly appropriate when P 1 is Z but when P 1 is BOC, it is more easily removed by stirring with trifluoroacetic acid and in this case, the compound of general formula (VII) will be a trifluoroacetate ester salt.
  • compounds of general formula (I) and acid addition salts of these compounds are capable of forming gels when dissolved in water or other solvents.
  • a process for preparing a gel of the first aspect of the invention comprising mixing a compound of formula (I) or a salt thereof with a solvent. Heating and then cooling the solution are necessary for gel formation.
  • the solvent may be an aqueous solvent such as water, sodium chloride solution or aqueous acetic acid or a mixture of water with an organic solvent such as DMSO or another suitable organic solvent.
  • a gel may be formed in situ and in such a case, the aqueous solvent may be a physiological fluid, for example stomach acid or saliva.
  • the solvent may be an organic solvent such as DMSO, ethanol, n- decanol, propylene glycol, polyethylene glycol, tetrahydrofuran, dichloromethane, acetonitrile, toluene, /?-xylene, or tetraline.
  • organic solvent such as DMSO, ethanol, n- decanol, propylene glycol, polyethylene glycol, tetrahydrofuran, dichloromethane, acetonitrile, toluene, /?-xylene, or tetraline.
  • the compound of the present invention are also capable of forming gels in oils such as glycerine, oleic acid, octyldodecanol and cocoyl caprylocaprate, which is sold under the trade mark Cetiol® LC (Cognis).
  • the compounds of general formula (I) have extremely good gelation properties and relatively low concentrations are needed to cause gelation, although clearly the concentration required depends on the solvent.
  • the compound of general formula (I) or the salt thereof is present in a concentration of at least 0.2 mg/mL, but more preferably at least 1 mg/mL and in ascending order of preference at least 2, 3, 4, 5, 6, 7, 8, 9, 10 mg/mL or at larger suitable concentrations.
  • the concentration of the compound needed to form a gel (minimal gelation concentration or MGC) varies according to the solvent and will, for example be different for an aqueous solution of sodium chloride and pure water.
  • MGC minimum gelation concentration
  • concentration of the solution For an aqueous solution of, for example, sodium chloride or acetic acid, the MGC also varies according to the concentration of the solution.
  • MGC was determined visually by the vial inversion method in which sample vials were put in an inverted position and the MGC was defined as the concentration just before the gel started to flow. In practice, this requires the elastic modulus of the gel to be greater than about 65 Pa.
  • the MGC also depends upon the pH of the solvent used.
  • the compounds of the invention can form gels in solutions which have acidic and neutral pH but are not so effective in alkaline solution, and particularly at pH 10 and above. More preferably, the pH of the solution is 7 or less.
  • gels formed by the compounds of general formula (I) and their salts are able to flow when subjected to stresses above a threshold level, for example when extruded through an orifice or cannula, when packed into a delivery site using a spatula or when sprayed onto a delivery site.
  • the threshold stresses of the gels are typically in the range of Ik Pa to 100 kPa. When subjected to stresses below the threshold level, however, the gels remain immobile.
  • the gel can be injected into a mould or extruded from a nozzle tip to form, for instance, line or sheet structures to cover a desired surface, which may be, for example, a skin surface or the surface of a body cavity.
  • the gels can be formed into desired shapes means that they are ideally suited for purposes such as support matrices for tissue replacement as they can be applied to and conform to sites on or in tissue including tissue surfaces and defined cavities such as intravertebral spaces.
  • the gels formed by the compounds of the present invention are stable at room temperature for several months, they have high water content and therefore exhibit excellent biocompatibility and they are therefore ideal for pharmaceutical and cosmetic use. Furthermore, the mucoadhesive and drug release properties of the gels can be adjusted by the degree of gelation, which is affected by the concentration above the minimal gelation concentration (MGC).
  • MMC minimal gelation concentration
  • composition comprising: i. a compound of formula (I) or a salt thereof; and ii. an active agent.
  • compositions may additionally comprise a solvent, in which case they may be in gel form. In some cases, however, the composition may be a dry composition which is intended to form a gel in situ.
  • compositions may be pharmaceutical compositions, in which case the active agent is a pharmaceutically or biologically active substance. Alternatively, however, they may be intended for the administration of other active agents, for example, dietary supplements.
  • the active agent is preferably water soluble and the solvent is preferably water or an aqueous solvent.
  • the solvent is preferably water or an aqueous solvent.
  • anaesthetics such as benoxinate, bupivacaine, dibucaine hydrochloride, dyclonine hydrochloride, etidocaine cocaine, hexylcaine, lidocaine, mepivacaine, naepaine, phenacaine hydrochloride, piperocaine, prilocaine, proparacaine hydrochloride, and tetracaine hydrochloride
  • analgesics such as aspirin, acetaminophen and diflunisal
  • angiogenesis inhibitors such as aspirin, acetaminophen and diflunisal
  • antibiotics such as bacitracin, carbenicillin, cefazolin, cefoxitin, cephaloridine, chloramphenicol, chibrorifamycin, n- formamidoylthienamycin, gramicidin, neomycin
  • the drug delivery systems of the present invention may be designed to release appropriate biologically active substances.
  • biologically active substances should be intended for example proteins and their fragments, peptides and polynucleotides, growth factors, enzymes, vaccines and substances used in the treatment of diseases associated with genetic defects.
  • compositions of the invention may also contain other agents, such as preservatives and buffering agents.
  • Suitable water soluble preservatives which may be employed in the drug delivery systems of the present invention include ascorbate, benzalkonium chloride, benzylalcohol, chlorobutanol, sodium bisulfite, sodium thiosulfate, parabens, phenylethanol, phenylmercuric borate and thimerosal. These agents may be present in amounts of from 0.001 to 5% by weight and preferably 0.01 to 2%.
  • Suitable water soluble buffering agents are alkali or alkali earth carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates and the like, such as sodium phosphate, citrate, borate, acetate, bicarbonate and carbonate. These agents may be present in amounts sufficient to maintain a pH of the system of referably from 4 up to 8. The buffering agent therefore may be much as 5% by weight of the total composition.
  • hydrogel-based drug delivery systems prepared in accordance with the present invention include, but are not limited to: inoculation or injection (e.g., intraarticular, intra-aural, intra-marnmary, intra-muscular, intra-peritoneal, subcutaneous, etc.), topical application (e.g., on areas, such as eyes, ears, in or on afflictions such as wounds, burns, etc.), and by absorption through epithelial or mucocutaneous linings (e.g., vaginal and other epthelial linings, gastrointestinal mucosa, etc.).
  • the compositions formulated using hydrogel matrices may include previously known pharmaceutical carriers or excipients, adjuvants, etc.
  • compositions of the present invention are particularly advantageous as the gel formed by the compound of formula (I) or a salt thereof and a solvent is an ideal matrix for the sustained release of the active agent.
  • the basic principle is to dissolve a water-soluble drug in solution that is then absorbed by the hydrogel. The drug is then released by diffusion. The release of water-soluble drug, entrapped in a hydrogels, occur only after water penetrates the networks to swell the gel and dissolve the drug, followed by diffusion along the aqueous pathways to the surface of the device. Drug release depends on two simultaneous rate processes, water migration into the device and drug diffusion through continuously swelling hydrogels.
  • a major element of the release of the active agent is related to the migration of its molecules through channels formed by the gel forming molecules, which may occur by one of two mechanisms, bulk flow and diffusion.
  • the rate of diffusion of an active agent through a gel is modified by tortuosity ( ⁇ ), which is defined by the equation:
  • D is the diffusion coefficient in water and D* is the apparent diffusion coefficient in gel. Diffusion coefficients were observed to be in order of lO ⁇ 6 (cm 2 /sec). Tortuosity summarises the hindrance imposed by gel network structures and is also sensitive to the viscosity of the matrix and to molecular size. In practice, this means that increasing the elastic modulus of the gel or the size of the active agent molecule decreases the rate at which the active agent is released from the drug matrix.
  • the elastic modulus of gels formed from compounds of general formula (I) or their salts is relatively easy to manipulate as it is affected by the solvent, the pH and the concentration of the compound of general formula (I) or its salt.
  • compositions containing them can be formed required shapes, for instance tablets, lozenges, transdermal patches or suppositories. They can also easily be loaded into capsules.
  • the composition may be intended for topical, transdermal, rectal, buccal or sublingual administration and may be a pharmaceutical composition, in which the active agent is a biologically active compound.
  • the composition may be a cosmetic composition intended for topical administration, in which case the active agent may be a cosmetically acceptable compound, for example a natural product or a vitamin.
  • the solvent in topical, transdermal, rectal, buccal or sublingual compositions may be either an aqueous solvent, a mixture of an aqueous and organic solvent or pharmaceutical oil such as glycerine, oleic acid, octyldodecanol or cocoyl caprylocaprate (Cetiol ® LC).
  • Oleic acid is a particularly useful oily solvent in such compositions because it has been found to reduce the irritation associated with many transdermal and topical products which is caused by other ingredients of the composition.
  • penetration enhancing agents such as alcohols or glycols are known to cause skin irritation but oleic acid has been shown to reduce this (US 6,319,913).
  • oleic acid is itself a penetration enhancing agent and so is particularly suitable solvent for transdermal products.
  • a composition for application to the skin may be also made up into a cream, ointment, jelly, solution or suspension etc.
  • Cream or ointment formulations are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia.
  • tack is defined as the ability of an adhesive to form a bond after brief contact with light pressure. Insufficient tack may prevent attachment to the skin, whereas if the tack is too high, adhesive residue may be left on the skin after removal or the gel may cause dermal irritation.
  • a gel it is therefore preferable for a gel to have a probe tack value of at least 0.25 N as if it is lower than this, the skin adhesiveness is insufficient and the gel is likely to peel off with even a small amount of movement. Adhesives with high tack may form strong bonds with the skin on initial application and may therefore be difficult to remove and if the probe tack value of the gel exceeds 1.2 N, skin irritation is likely to occur (US 6,914,169).
  • compositions may also be formulated for oral administration and they may be pharmaceutical compositions, in which case the active agent is a biologically active compound. Alternatively, however, they may be intended for the administration of, for example, dietary supplements.
  • the compounds of the first aspect of the invention are particularly useful for the formation of oral compositions as they are capable of retaining their gel structure at low pH and therefore are ideal for use as matrices for the sustained release of active agents in the stomach.
  • the solvent for the oral compositions may be an aqueous solvent, an organic solvent, a mixture of aqueous and organic solvents or oil and may be chosen according to the active compound.
  • hydrophobic compounds are preferably formulated in a gel which includes a hydrophobic solvent whereas for hydrophilic compounds an aqueous solvent may be preferred.
  • the composition may be formulated without a solvent since the compound of general formula (Ia), (Ib) or salt thereof is capable of forming a gel in the stomach so that a matrix is formed around the active agent in situ.
  • Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, sachets or tablets each containing predetermined amounts of the compound of general formula (Ia), (Ib) or salt thereof and active agent; as a powder or granules; as a gel composition in an aqueous liquid or a non-aqueous liquid etc.
  • Oral compositions whether pharmaceutical or not, may also include an acceptable carrier.
  • the term "acceptable carrier” includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the compound of general formula (Ia), (Ib) or salt thereof and active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored.
  • compositions suitable for oral administration include lozenges comprising the compound of general formula (Ia), (Ib) or salt thereof and the active agent in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound of general formula (Ia), (Ib) or salt thereof and the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia.
  • compositions of the invention may be formed simply by mixing the compound of general formula (I) or a salt thereof with an active compound and optionally adding a solvent. This method forms yet another aspect of the present invention.
  • gels formed by compounds of general formula (I) or their salts include thickeners for foodstuffs or cosmetic compositions.
  • a compound of general formula (I) in the preparation of a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of general formula (I), and a biologically active agent;
  • FIGURE 1 is a typical curve of tack probe measurement: force (in g) vs distance (or displacement in mm).
  • Reagents were purchased from Aldrich, Bachem, Fluka, Kemika, Merck and Sigma, and were used without further purification. All solvents were purified and dried according to standard procedures. The reactions were monitored by thin-layer chromatography (t.l.c.) on Merck Kieselgel HF254 plastic sheets and spots were made visible using a UV lamp (254 nm) or I 2 vapors. Prepared compounds were purified chromatographically by preparative T.L.C. using silica gel Merck HF 254 and by column chromatography using silica 0.063-0.2 mm (Merck). Reaction yields are not optimised.
  • NMR spectra were recorded on a Bruker Avance spectrometer at 300/75 MHz with tetramethylsylane (TMS) as an internal standard. Chemical shifts (S) were given in ppm, coupling constants (J) in Hz. Spin multiplicities; s (singlet), d (doublet), t (triplet), q (quadruplet), p (pentet) and m (multiplet).
  • IR spectra were taken in KBr pellets on a ABB Bomen MB 102 FTIR-spectrometer, wave numbers (v) are reported in cm "1 .
  • NMR 171.5, 158.6 (CO), 135.4, (C Bz i), 128.6, 128.4, 128.2 (CH Bz i), 66.9 (CH 2 , Bz i), 42.2 (CH 2 ,Giy), 35.1 (CH 2 N E ,), 15.4 (CH 3 , Et ); IR: 3397, 3383, 3292, 3265, 1738, 1726, 1677, 1625,
  • Two compounds were particularly effective in gelating a mixture of ethanol and water: 10 mg of Compound 13 gelates a mixture of 1.75 mL ethanol and 4.0 mL water; 10 mg of Compound 16 gelates a mixture of 1.98 mL ethanol and 4.2 mL water.
  • Compound 12 forms a gel-like structure, composed of micrometric, fibrilous aggregates.
  • Compound 22 hydrochloride salts is the most soluble of the compounds in water and 10 mg of Compound 22 hydrochloride gelates 5.4 mL water.
  • Example 3 Gelation of Compounds in Oils Gelation of Compound 22 hydrochloride (at 10 mg/1 mL) in various pharmaceutical oils (glycerine, oleic acid, octyldodecanol and Cetiol ® LC) is shown in Table 1.
  • Many transdermal and topical products show high incidences of adverse skin reactions such as scaling, pruritic erythema, and vesicobollous irritant and allergic contact dermatitis.
  • the problem has also been approached by the additional inclusion of non-irritating ingredients such as glycerine.
  • the skin irritation caused by the drug-gel formulations can be completely avoided.
  • Oleic acid (cis-9-octadecenoic acid) is a monounsaturated fatty acid and makes up 55-85% of olive oil.
  • the ability of oleic acid to lessen the irritation caused by other penetration enhancing agents and/or other formulation components to a greater extent than oleyl alcohol has been described previously (United States Patent 6,319,913 Penetration enhancing and irritation reducing systems).
  • the gelled combination of oleic acid with a gelling agent (a supramolecular hydrogelator), such as referred here, and/or other irritation reducing agents, can result in drug formulations that produce markedly reduced levels of skin irritation.
  • Compound 22 hydrochloride formed a gel in glycerine at a concentration of 10 mg/mL, although at this concentration it did not form a gel in the other pharmaceutical oils tested.
  • Tack is the ability of an adhesive to form a bond after brief contact with light pressure. Insufficient tack may prevent attachment to the skin, whereas excessive tack may leave adhesive residue on removal or cause dermal irritation. If the probe tack value of gel is less than 0.25 N, then the skin adhesiveness of gel becomes insufficient, so that it is likely to peel off even upon a little movement.
  • Adhesives with a very high tack could form strong initial bonds with the skin upon application and thus may be difficult to remove. If the probes tack value of gel exceeds the 1.2 N value, the skin irritation increases so much that rashes in the skin and pains upon peeling are likely to occur.
  • Measurements of probe tack using an inverted probe machine were based on the method described in ASTM D2979-01 Standard Test Method for Pressure-Sensitive Tack of Adhesives Using an Inverted Probe Machine.
  • the probe tack tester defined in ASTM D 2979-01, after one bottom face of a cylinder (probe) made of steel having a diameter of 12.5 mm and a gel layer surface are brought into contact with each other at a contact load of 4.9 ⁇ 0.01 N for a contact time of 10.0 ⁇ 0.01 seconds, the probe is separated from the adhesive layer surface in the perpendicular direction of the latter at a separating speed of 0.5 ⁇ 0.1 mm/s.
  • the probe tack value refers to the force [N] required at the time of separation.
  • Figure 1 shows a typical curve of tack probe measurement: force (in g) vs. distance (or displacement in mm).
  • Probe tack or Adhesive Peak Force
  • the average force at maximum is average of 10 repeated measurements. Adhesion throughout the contact surface was achieved only for a short period of time, as indicated by the shape of the curve. The area under the curve of tack force vs.
  • Tables 2 show the effect of acidity on the tack force of Compound 22 by comparing the effect on the tack force of using as a solvent acetic acid of varying concentrations and therefore varying pH.
  • the results from the table show that at a pH of 2.17, the tack force will make the gel formed by Compound 22 hydrochloride show the tackiness at ordinary temperatures to permit easy temporary adhesion to adherends, suitable for use in bioadhesive systems
  • the quality of gels as usable objects was checked by measuring the gel texture using the viscosity values. Viscosity often determines the flow of products and controls the productivity.
  • the fiowability of the gel e.g. the ability to be extruded through a syringe
  • the fiowability of the gel is the ability of the gel to be applied onto and conform to sites on or in tissue, including tissue surfaces and defined cavities (intravertebral spaces, tissue).
  • the gel flow when subjected to stresses above a threshold level, for example when extruded through an orifice or cannula, when packed into a delivery site using a spatula, when sprayed onto the delivery site, or the like.
  • the threshold stresses are typically in the range of several kPa.
  • compositions will remain generally immobile when subjected to stresses below the threshold level.
  • a minimum pressure gradient is required to extrude a given gel through orifice. Once this minimum pressure gradient is exceeded, the pressure gradient during gel extrusion is insensitive to the flow rate.
  • Example 14 Compound 22 hydrogel compounded with water soluble drug
  • the chosen model drug, water soluble, is valacyclovir.
  • the example hydrogel compounds contain the constant amount of Compound 22 (1 wt./vol. %) and various contents of valacyclovir form 0.5 up to 5 (wt./vol. %) in water. In this concentration range the gelation has been observed.
  • the prefferable concentration range would be for Compound 22 from 0.2 (wt./vol. %) up to 10 (wt./vol. %) in water, and the prefferable concentration of valacyclovir form 0.2 up to 10 (wt./vol. %) in water.
  • the chosen model drug that is water insoluble was ibuprofen.
  • the example hydrogel compounds contain the constant amount of Compound 22 (1 wt./vol. %) and various contents of ibuprofen form 0.02 up to 2 (wt./vol. %) in water. In this concentration range the gelation has been observed. The observed tackiness is given in Table 4.
  • the prefferable concentration range would be for Compound 22 from 0.2 (wt./vol. %) up to 10 (wt./vol. %) in water, and the prefferable concentration of ibuprofen form 0.02 up to 2 (wt/vol. %) in water.
  • Example 16 Diffusion in Compound 22 hydrogel compounded with water insoluble drug
  • the release rate of drug from formulated hydrogel bases should be diffusion controlled, which can be described by the simplified Higuchi diffusion equation [Higuchi, W. Analysis of data on the medicament release from ointments. J. Pharm. Sci. 1962, 51 (8), 802-804.):

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Abstract

L'invention porte sur la composition dun gel comprenant un gélifiant et un solvant. le gélifiant est un composé de formule générale I): dans laquelle: R1 est hydrogène ou C1-14 alkyle; R3 est OH ou un groupe: R4 est hydrogène ou C1-6 alkyle, facultativement substitué par OR9, COR9 ou COOR9; R9 est hydrogène, C1-6 alkyle ou benzyle; R2 est hydrogène, C1-6 alkyle ou benzyle, dont l'un peut être facultativement substitué par OH ou, si R3 est R2 peut aussi être R7; R7 est un cycle aromatique ou hétéroaromatique à 5 ou 6 éléments pouvant de plus être facultativement substitué par C1-6 alkyle, benzyle ou hydroxy; ou l'un de leurs sels.
PCT/GB2008/000928 2007-03-20 2008-03-14 Compositions de gels WO2008113992A2 (fr)

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WO2011117851A1 (fr) * 2010-03-25 2011-09-29 Ipsen Manufacturing Ireland Limited Administration transdermique de peptides
WO2013033300A1 (fr) * 2011-09-01 2013-03-07 Milliken & Company Agents gélifiants de type biurée et compositions associées
WO2013126017A1 (fr) 2012-02-22 2013-08-29 Agency For Science, Technology And Research Organogels et émulsions pour des applications biologiques et non biologiques
US8546517B2 (en) 2009-12-22 2013-10-01 Dow Global Technologies Llc Poly(bisoxalamides)
WO2012174091A3 (fr) * 2011-06-13 2014-06-26 The Procter & Gamble Company Compositions de soins personnels comprenant un agent gélifiant à ph accordable et procédés d'utilisation
US9956164B2 (en) 2014-04-16 2018-05-01 Veyx-Pharma Gmbh Veterinary pharmaceutical composition and use thereof
WO2020230697A1 (fr) * 2019-05-10 2020-11-19 国立大学法人九州大学 Matériau polymère composite contenant un agent gélifiant à base de peptide-lipide et un oxyde de polyalkylène

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ESTROFF L A ET AL: "EFFECTIVE GELATION OF WATER USING A SERIES OF BIS-UREA DICARBOXYLIC ACIDS" ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, WILEY VCH VERLAG, WEINHEIM, vol. 39, no. 19, 1 January 2000 (2000-01-01), pages 3447-3450, XP001182155 ISSN: 1433-7851 *
FAGES-F VÖGTLE AND M ZINIC F: "Systemic Design of Amide- and Urea-Type gelators" TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 256, 1 January 2005 (2005-01-01), pages 77-131, XP009105871 ISSN: 0340-1022 *
GUJUN WANG ET AL.: "LOW MOLECULAR WEIGHT ORGANOGELATORS FOR WATER" CHEMICAL COMMUNICATIONS, no. 3, 2003, pages 310-311, XP002499287 SEINSTITUTE OF INORGANIC AND PHYSICAL CHEMISTRY, STOCKHOLM, cited in the application *
MAAIKE DE LOOS ET AL.: "DESIGN AND APPLICATIONS OF SELF-ASSEMBLED LOW MOLECULAR WEIGHT HYDROGELS" EUROPEAN JOURNAL OF ORGANIC CHEMISTRY., no. 17, September 2005 (2005-09), pages 3615-3631, XP002499285 DEWILEY-VCH VERLAG, WEINHEIM. cited in the application *
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8546517B2 (en) 2009-12-22 2013-10-01 Dow Global Technologies Llc Poly(bisoxalamides)
WO2011117851A1 (fr) * 2010-03-25 2011-09-29 Ipsen Manufacturing Ireland Limited Administration transdermique de peptides
WO2012174091A3 (fr) * 2011-06-13 2014-06-26 The Procter & Gamble Company Compositions de soins personnels comprenant un agent gélifiant à ph accordable et procédés d'utilisation
JP2014524900A (ja) * 2011-06-13 2014-09-25 ザ プロクター アンド ギャンブル カンパニー ｐＨ調整可能なゲル化剤を含むパーソナルケア組成物及び使用方法
WO2013033300A1 (fr) * 2011-09-01 2013-03-07 Milliken & Company Agents gélifiants de type biurée et compositions associées
US8668918B2 (en) 2011-09-01 2014-03-11 Milliken & Company Bisurea gelling agents and compositions
WO2013126017A1 (fr) 2012-02-22 2013-08-29 Agency For Science, Technology And Research Organogels et émulsions pour des applications biologiques et non biologiques
US9988423B2 (en) 2012-02-22 2018-06-05 Agency For Science, Technology And Research Organogels and emulsions for biological and non-biological applications
EP2816999B1 (fr) * 2012-02-22 2018-10-31 Agency For Science, Technology And Research Organogels et émulsions pour des applications biologiques et non biologiques
US9956164B2 (en) 2014-04-16 2018-05-01 Veyx-Pharma Gmbh Veterinary pharmaceutical composition and use thereof
WO2020230697A1 (fr) * 2019-05-10 2020-11-19 国立大学法人九州大学 Matériau polymère composite contenant un agent gélifiant à base de peptide-lipide et un oxyde de polyalkylène

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