WO2011039144A1 - Substances renfermant des groupes disulfure pour véhicules auto-organisés permettant la libération contrôlée d'un principe actif - Google Patents

Substances renfermant des groupes disulfure pour véhicules auto-organisés permettant la libération contrôlée d'un principe actif Download PDF

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WO2011039144A1
WO2011039144A1 PCT/EP2010/064272 EP2010064272W WO2011039144A1 WO 2011039144 A1 WO2011039144 A1 WO 2011039144A1 EP 2010064272 W EP2010064272 W EP 2010064272W WO 2011039144 A1 WO2011039144 A1 WO 2011039144A1
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group
chemical
formula
chemical group
substances
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PCT/EP2010/064272
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German (de)
English (en)
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Holger Egger
Axel Eble
Juergen Liebscher
Andreas Herrmann
Martin Loew
Anna Arbuzova
Nicolai Brodersen
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Bayer Technology Services Gmbh
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Priority to EP10757427A priority Critical patent/EP2482801A1/fr
Publication of WO2011039144A1 publication Critical patent/WO2011039144A1/fr

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • A61K9/1271Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids

Definitions

  • the present invention relates to novel substances for the preparation of self-assembled drug carriers in the form of a liposome comprising a disulfide group for the controlled release of a drug contained therein, as well as a method for the release of drugs using the aforementioned carrier.
  • Drug release drug delivery systems based on liposome carriers of about 100 nm in size are generally known in the medical arts. They are generally regarded as advantageous if a substance which is toxic to certain organs but which can be used as a medicinal agent in other places of the human body should only be released at those desired sites.
  • liposome carriers a substance group consisting of non-toxic phospholipids.
  • polymers such as polyethylene glycols, which are characterized by improved stability in the circulation of treated patients in such liposome carriers, since the aforementioned polyethylene glycols form a form of steric protection around the actual liposome carrier. This gives so-called lipopolymers.
  • liposome carriers are also described by J. Davidsen et al. in "Secreted phospholipase A2 as a novel enzymatic trigger mechanism for localized liposomal drug release and absorption in diseased tissue" published in Biochimica et Biophysica Acta 1609 (2003) 95 - 101. Further, J. Davidsen et al Drug carrier in the form of the above-mentioned liposome carrier can depend in particular on their release behavior of a variety of chemical and physical parameters whose interaction is not fully understood.
  • the liposome carrier can be prepared from l, 2-hexadecanoyl-sn-glycero-3-phosphocholine (DPPC) and / or 1,2-hexadecanoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol) -2000] (DPPE - PEG2000) and / or 1-0-hexadecanoyl-2-hexanodecnoyl-sn-glycero-3-phosphocholine (1-O-DPPC) and / or 1 -0-hexadecanoyl-2-hexanodecnoyl-sn-glycero-3-phospho ethanolamine-N- [methoxy (Polyethylene glycol) -350] (1-O-DPPE-PEG350).
  • DPPC 2-hexadecanoyl-sn-glycero-3-phosphocholine
  • DPPC 2-hexadecanoyl-sn
  • calcein can be included in the liposome formulation comprising 1-O-DPPC and 10 mol% of 1-O-DPPE-PEG350. Calcein is referred to as a model substance for drugs. Release of calcein may be as disclosed by J. Davidsen et al. by treatment of this liposome formulation with phospholipase A2 (PLA2). Release is by hydrolytic cleavage of either DPPC or 1-O-DPPC, or 1-O-DPPE-PEG350, which is catalyzed by PLA2 to give a lysolipid and a fatty acid.
  • PLA2 phospholipase A2
  • J. Davidsen et al. no cleavage into a hydrophobic and a hydrophilic portion.
  • J. Davidsen et al. not that the liposome carrier can comprise a disulfide bond.
  • the disclosed mode of action of the materials is based on the possibility of bond cleavage of the disulfide group, which either dissolves the polymers or separates the polyethylene glycol side chains attached to the polymers with the disulfide group, thereby recognizing and degrading the particle after its application in the patient becomes. Accordingly, the release from the drug carrier according to the disclosure of Meng et al. either upon dissolution of a solid by cleavage of polymeric bonds or through degradation of the solid by the patient's immune system after the particle has become recognizable to them. In no case will the drug be released directly.
  • lipid compositions consist of a hydrophobic "tail group” and a hydrophilic "head group”, wherein the latter hydrophilic "head group” is covalently attached to the hydrophobic "tail group".
  • hydrophilic "head group” a distinction is made between a first and a second region, wherein these two regions are linked by a disulfide group which can be cleaved, such as by glutathione.
  • the first region of the hydrophilic "head group” carries a positive charge at physiological pH according to WO 2000/059474 AI and the second region carries a negative charge at physiological pH.
  • the first region is covalently attached to the hydrophobic "tail group”.
  • the chemical formula of the abovementioned lipid compositions generally disclosed in WO 2000/059474 A1 is X - Y - S - S - Z.
  • the chemical group X forms the abovementioned hydrophobic "tail group” and Y and Z the first or second region
  • the chemical group X as a hydrophobic "tail group” can be a group which is substantially similar to the glycerol core of a fat and to which the chemical group Y is attached another chemical group W is attached.
  • the chemical group W can be selected from the list consisting of CHR 3 , NR 3 , N + (R 3 ) 2 , O, S, C (O) NH, NH (CO), OC (O) NH and OP (0 ) (OR 3 ) 0.
  • the chemical group R 3 further contained in the chemical group W may be hydrogen or a C 1 -C 4 alkyl radical.
  • the chemical group Y can be a C 1 -C 12 alkyl radical, a C 2 -C 12 alkenyl radical or a C 2 -C 12 alkynyl radical having substituents in the form of alkyl radicals, amino radicals, aminoalkyl radicals, guanidine radicals, guadinealkyl radicals, amido radical or amidoalkyl radical, where the said alkyl, alkenyl, or alkynyl radicals of chemical group Y may be further interrupted by NR 3 , N + (R 3 ) 2 , C (O), NHC (NH), C (NH) NH, NHC (NH) NH.
  • the chemical group Y may also be an amino acid residue or a peptide.
  • the chemical group Z can be a C 1 -C 12 -alkyl radical, alkenyl radical or an alkynyl radical which in turn is substituted by alkyl radicals, carboxyl radicals, carboxyalkyl radicals, amino acid radicals, peptides, oligonucleotides or so-called "target molecule radicals" can be.
  • the abovementioned chemical groups X, Y and Z must in any case be designed so that the groups X and Y in their entirety have a positive charge at physiological pH and the group Z has a negative charge at physiological pH. Accordingly, the cleavage of substances of the formula X - Y - S - S - Z on the disulfide group according to WO 2000/059474 A1 results in a group of the type X - Y - S which is positively charged and has a chemical group of the type S - Z, which is negatively charged.
  • the group of the species X-Y-S in that it still comprises the "hydrophobic tail group" and a positive charge, is a chemical group having amphiphilic properties, ie, being hydrophobic in one region and hydrophilic in a region
  • the group of the type S - Z is by its negative charge and by the fact that it comprises a C 1 -C 12 alkyl radical, alkenyl radical or an alkynyl radical either also amphiphilic or even - in the case of particularly short alkyl radicals, alkenyl radicals or alkynyl radicals - only hydrophilic ,
  • WO 2000/059474 AI further discloses that the abovementioned substances are suitable for the preparation of liposome carriers, by means of which a targeted release of substances at one site of action can take place. The release is based on the chemical cleavage of the disulfide group.
  • WO 2000/059474 A1 does not disclose that a cleavage of a previously amphiphilic substance into a hydrophilic and a hydrophobic fraction can be achieved.
  • glutathione is a reducing agent that is particularly found in the vicinity of tissue in which a significant number of cells are exposed to a stressful situation, such as that caused by disease of the tissue in question.
  • Another object is to provide a method for drug release using the aforementioned drug carrier, which makes it possible to produce a medicine which is suitable for the targeted treatment of tumor diseases, for example, by the drug only in the immediate vicinity of the site of action of the human body and as quantitative as possible the medicine is released.
  • the first subject of the present invention therefore, substances suitable for the preparation of drug carriers in the form of a liposome according to the formula (I)
  • the substances according to formula (I) have in X on one side of the disulfide group a hydrophilic chemical group comprising at least five carbon atoms and comprising at least one ether group and / or amine group or ammonium group, and wherein (b) on the other side of the disulfide group is a hydrophobic group in which n and m are independently of one another a natural number from 1 to 30, but the sum of n and m is at least 16.
  • the substances according to the invention of the formula (I) are particularly advantageous because they have in the radicals having 1 to 30 carbon atoms chemical groups which have hydrophobic properties and at the same time cause sterically that when introducing the substances according to the formula (I) in a polar medium these substances arrange themselves so that it comes to the formation of spherical structures.
  • This spherical arrangement can be selectively resolved on the disulfide group also provided in the compounds of the formula (I) by selectively cleaving them so that hereinafter a hydrophilic chemical group consisting of the chemical groups X and a sulfur radical and a hydrophobic chemical group comprising the radicals having 1 to 30 carbon atoms.
  • a hydrophilic chemical group consisting of the chemical groups X and a sulfur radical
  • a hydrophobic chemical group comprising the radicals having 1 to 30 carbon atoms.
  • radicals with n, m carbon atoms according to the formula (I) are usually saturated hydrocarbon radicals, as also shown in the formula (I).
  • the radicals with n, m carbon atoms can also be monounsaturated or polyunsaturated radicals.
  • the radicals with n, m carbon atoms can also have one or more double and / or triple bonds.
  • the formula (I) is not to be understood in terms of the hydrocarbon radicals having n, m carbon atoms shown therein, in that these radicals are exclusively saturated hydrocarbon radicals with n, m carbon atoms.
  • the chemical group X in preferred embodiments comprises at least eight carbon atoms. It is likewise preferred if the chemical group X also comprises at least one carboxylic acid ester group in addition to the at least one ether group and / or amine group or ammonium group.
  • the chemical group X comprises either at least two ether groups or at least one amine group or ammonium group and at least two carboxylic acid ester groups.
  • the at least one amine group or ammonium group of the chemical group X of the substances according to the formula (I) is a quaternary ammonium group.
  • the substance according to the formula (I) carries at least one positive charge and is present in combination with at least one single or multiple negatively charged counterion.
  • counterions may be, for example, halogen ions, such as chloride, bromide and / or iodide, but also any other counterions with negative charges.
  • the chemical group X of the substances according to the formula (I) comprises at least three ether groups.
  • the chemical group X is attached via a carboxylic acid ester group to a chemical group Y according to the further preferred embodiment described below.
  • the chemical group X which then more preferably contains only one amine group or ammonium group, is also preferably attached via this amine group or ammonium group to the rest of the substance according to the formula (I) ,
  • This embodiment is particularly advantageous because the amine group or ammonium group and the at least three ether groups in their entirety result in a particularly hydrophilic property of the chemical group X.
  • the chemical group X also comprises a phosphate group.
  • a chemical group Y is attached to the chemical group X, the chemical group Y being a chemical group selected from the list consisting of biotin, protein, peptide, nucleic acid nucleoside and glycoal is.
  • glyco groups according to the present invention are, for example, mannose groups or glucose groups.
  • the substances of this further preferred embodiment are substances according to the formula (I *).
  • the chemical group Y is biotin in preferred embodiments of the present invention.
  • the Y chemical group is biotin
  • it may be attached to the X chemical group by either an amide bond or via a carboxylic acid ester group.
  • the chemical group Y can be present at the chemical group X terminal or as a side group.
  • the chemical group Y is the (bio) chemical identification of the substances according to formula (I).
  • the group Y is recognized in the case of using biotin according to the preferred embodiment (bio) chemically clear by streptavidin, can attach to this another chemical and / or biological group, the substance according to the formula (I *) more gives (bio-) chemical properties.
  • an antibody conjugated to streptavidin may be bound to the biotin which then enables the compound of formula (I *) to preferentially accumulate on target molecules via the action of the antibody.
  • Particularly preferred substances according to the formula (I *) are those according to the formula (Ia)
  • the chemical group X comprises two carboxylic acid ester groups, a first amine group or ammonium group and a second amine group or ammonium group, so that the chemical group Y to the chemical group X via an amide bond is connected.
  • the chemical group X comprises a further chemical fluorescent dye group X 'as its constituent, which is covalently bound to the chemical group X.
  • the fluorescent fluorescent dye group X comprises a dansyl group. This is already present, for example, in the particularly preferred substances according to the formulas (Ib) and (Ic).
  • Another object of the present invention is a process for the preparation of the substances according to the invention according to the formula (I), which is characterized in that a substance according to the formula with a substance of the formula or a substance of the formula
  • the chemical groups FGi, FG 2 , FG 3 , FG 4 indicated in the above formulas (IIa), (IIIa), (IIb) and (IIIc) are groups selected from the list consisting of hydrogen, halogen, phthalimido, succinimido , a sulfonyloxy group such as benzenesulfonyloxy, tosylate, and triflate.
  • the chemical groups FGi, FG 2 and FG 4 are preferably hydrogen and the chemical group FG 3 is tosyl.
  • the chemical groups X ! Given in the above formulas (IIb), (IHb), (IIc) and (IIIc) . and X 2 are each components of the chemical group X according to formulas (I), (Ia), (Ib) and / or (Ic).
  • the covalent bond between Xi and X 2 with elimination of FG 3 in the case of the chemical reaction between the substances of the formula (IIb) and (IIIb) thus leads to the formation of the chemical group X as a constituent of the substances according to the formulas (I), (I *), (Ia), (Ib) and / or (Ic).
  • the substances of the formulas (IIIb) and (IIIc) are obtained from substances of the formula (IIIa) by adding an azodicarbonyl compound, preferably 4-phenyl-1,2,4-triazoline-3,5 -dione to which substance according to the formula (IIIa) is added in a solvent (LM) and thereafter to the resulting reaction solution a thioalcohol, preferably a substance selected from the list consisting of cysteinol, 2-aminoethanethiol and 2-dimethylaminoethanethiol and cysteine, preferably 2-dimethylaminoethanethiol is added.
  • Such purification steps may be, for example, the preparative chromatographic methods well known to those skilled in the art, such as thin film, or column chromatography methods.
  • the solvent (LM) in which the aforesaid reactions are carried out is selected, for example, from the list consisting of acetonitrile (MeCN), halogenated hydrocarbons, non-halogenated hydrocarbons and alcohols, without being limited thereto.
  • Preferred halogenated hydrocarbons are dichloromethane (DCM) and trichloromethane (TCM).
  • DCM dichloromethane
  • TCM trichloromethane
  • the reaction of the substances (IIa) and (IIIa) or (IIb) and (IIIb) usually takes place at temperatures from room temperature (23 ° C.) to 80 ° C. Preferably at temperatures of 40 ° C to 80 ° C.
  • a further chemical fluorescent dye group X 'as its constituent, as defined above, is covalently bound to the chemical group X.
  • This bonding of the chemical fluorescent dye group X ' usually takes place before the reaction of the substances of the formula (IIa) and (IIIa) or (IIb) and (IIIb). It may be necessary, especially when the attachment of the fluorescent fluorescent dye group X 'is carried out after the reaction of the substances of the formula (IIa) and (IIIa) or (IIb) and (IIIb), that contain chemically functional groups in the chemical Group X, such as amino or carboxyl groups must be previously protected with protecting groups prior to reaction with the chemical fluorescent dye group X '.
  • a protecting group is, for example, a tert-butyl-diphenyl-silyl radical.
  • the chemical fluorescent dye group X 'as a constituent of the chemical group X may in the context of the process according to the invention also contain more chemical groups than those which are responsible for the actual fluorescence property.
  • fractions of the groups contained later in the chemical group X of the substance according to the formula (I) can first be introduced by linking the chemical fluorescent dye group X 'into this chemical group X of the substances according to the formula (I).
  • Preferred embodiments of the process according to the invention are those in which the substances according to the formula (IIa) or (IIa *) are reacted with those of the formula (IIIa) or in which compounds of the formula (IIb) or (IIb *) be reacted with those of formula (IHb).
  • a further subject of the present invention is a self-organized active substance carrier in the form of a liposome, characterized in that this active substance carrier comprises at least one substance according to the formula (I)
  • (a) in X have a chemical group comprising at least five carbon atoms and comprising at least one ether group and / or amine group or ammonium group, wherein
  • n and m independently of each other is a natural number from 1 to 30, but where the sum of n and m is at least 16 found.
  • the substances according to the formula (I) are selectively cleavable in such a liposome, but at the envisaged disulfide group, so that hereinafter a hydrophilic chemical group consisting of the chemical group X and a sulfur radical, and a hydrophobic chemical group comprising the radicals with 1 arise up to 30 carbon atoms.
  • this active substance carrier may also contain at least one substance according to the formula (I *)
  • the abovementioned active substance carrier according to the invention usually comprises at least one further substance with at least one chemical group having lipophilic properties and at least one chemical group having hydrophilic properties.
  • Such further substances are preferably lipids.
  • Such lipids are usually those from the class of phospholipids, in particular phosphatidylcholine and / or phosphatidylethanolamine.
  • Preferred lipids are those selected from the list consisting of La-phosphatidylcholine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, ammonium (l, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-lisamine rhodamine B sulfonyl).
  • the active substance carrier according to the invention which comprises the abovementioned further substances usually contains these at a molar proportion of at least 50%, preferably of at least 70%, particularly preferably of 80 to 90%.
  • this comprises two lipids as further substances.
  • one of the two lipids is preferably La-phosphatidylcholine.
  • the La-phosphatidylcholine that La-phosphatidylcholine, which can be obtained from eggs of chickens.
  • this consists of a molar fraction of La-phosphatidylcholine between 70 and 90%, a molar proportion of ammonium (l, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamin-N-lissamine rhodamine B sulfonyl) between 0.01 and 2% and a proportion of a substance of formula (I), so that a total of 100% molar fraction are obtained.
  • ammonium l, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamin-N-lissamine rhodamine B sulfonyl
  • this consists of a molar fraction of La-phosphatidylcholine between 10 and 30%, a molar fraction of l, 2-dioleoyl-sn-glycero-3-phosphoethanolamin between 50 and 65% and a proportion a substance according to the formulas (I), (I *), so that a total of 100% molar fraction are obtained.
  • the active substance carriers according to the invention are liposomes which comprise so-called lipid bilayers, the hydrophilic chemical groups X of the substances according to the formulas (I), (I *) which are part of these active compound carriers being oriented toward the polar solvent, whereas the hydrophobic chemical groups X.
  • Groups of substances according to the formulas (I), (I *) or the above-described lipids of both layers are oriented inside the lipid bilayer.
  • a final object of the present invention is a process for the release of an active substance from the active substance carriers according to the invention in the form of a liposome, characterized in that amphiphilic substances according to the formula (I) or (I *) at their disulfide group chemically in a hydrophobic and a hydrophilic portion be split.
  • the chemical cleavage according to the method of the invention may be an enzymatically catalyzed chemical cleavage or may be a non-enzymatically catalyzed reduction in which the disulfide group of the compounds of formula (I) and / or (I *) is cleaved as a result of their reduction.
  • the chemical cleavage an enzymatically catalyzed cleavage.
  • the enzyme which catalyzes such a chemical cleavage is preferably a thioreductase, thiooxidase, thiooxireductase or thidisulfide oxidoreductase.
  • reducing agent a substance selected from the list consisting of glutathione, Cysteine, tris (2-carboxyethyl) phosphine (TCEP) dithiothreitol (DTT) and 1,4-dithioerythritol (DTE).
  • this reducing agent is tris (2-carboxyethyl) phosphine (TCEP).
  • the abovementioned reducing agents are particularly advantageous because they usually have a reduction potential which is only sufficient to reduce at least one of the two sulfur atoms of the disulfide group of the compounds of formula (I) and / or (I *), thereby cleaving their bond.
  • the reduction potential of the abovementioned reducing agents does not suffice to reduce other chemical groups of the substances according to the formula (I) and / or (I *) or groups of the further substances of the active substance carriers according to the invention in the form of a liposome. This ensures in particular that a cleavage of the amphiphilic substances according to the formula (I) or (I *) takes place in a hydrophobic and a hydrophilic portion, whereby the release according to the invention is particularly advantageous.
  • Glutathione and cysteine are substances which also occur in particularly high concentrations in the body of mammals, in particular humans, at sites which are changed in an inflammatory manner, as a result of which targeted release is made possible, in particular with the present invention.
  • the method according to the invention for the release of an active substance is based on the surprising finding that it is sufficient to cleave the substances contained in the active substance carriers according to the formulas (I) and / or (I *) into a hydrophilic part and a hydrophobic part, which without Being bound to a theory results in the liposome being destabilized to break up and release the active ingredient contained in it.
  • FIG. 2 shows a part of the test results according to Example 11. Shown is the relative fluorescence intensity (F *) at a wavelength of 520 nm over the time (t) from the addition of TCEP to the solution of the composition III according to Example 9 at temperatures of 30 ° C (purple), 35 ° C (Illb) and 40 ° C (IIIc).
  • F * relative fluorescence intensity
  • FIG. 3 shows a part of the test results according to Example 11. Shown is the relative fluorescence intensity (F *) at a wavelength of 520 nm over time (t) from the addition of TCEP according to Example 9 at temperatures of 30 ° C (IVa), 35 ° C (IVb)
  • Example 5 Preparation of a Substance According to Formula (IIb *) Comprising a Chemical Group X '
  • Example 6 Production of a Substance According to the Formula (I), in Particular According to the Formula (Ib) Comprising a Chemical Fluorescence Dye Group X '
  • the attached tert-butyldiphenylsilyloxy radical serves as a protective group in the following, in order to enable subsequent attachment of a chemical fluorescent dye group X '.
  • 3.72 g (8.5 mmol) of the obtained 1- (benzythio) -3- (tert-butyldiphenylsilyloxy) propan-2-ol were taken together with 2.41 g (9.2 mmol) of triphenylphosphane and 1.39 g (9, 4 mmol) of phthalimide dissolved in 68 ml of dry tetrahydrofuran (THF).
  • N- (1-mercapto-3- (tert-butyldicyclohexa-2,5-dienylsilyloxy) propan-2-yl) biotinamide corresponds to the substance of the formula (IIa *), where 2-biotinyl corresponds to the chemical group Y. , the chemical group FGi corresponds to hydrogen and the 3- (tert-butyldicyclohexa-2,5-dienylsilyloxy) propane passed amide radical of the chemical group X comprising the protective group 3- (tert-butyldicyclohexa-2,5-dienylsilyloxy ) corresponds.
  • Example 8 Preparation of a Substance of the Formula (I), in Particular According to the Formula (Ic) 91 mg (0.15 mmol) of 3-mercapto-l, 2-bis-O- (octadecyl) -propane from Example 1 were dissolved under argon in 3.4 ml of dry dichloromethane and 1.2 ml of dry acetonitrile and stirred 26 mg (0.15 mmol) 4-phenyl-l, 2,4-triazoline-3,5-dione (PTAD) was added.
  • PTAD 4-phenyl-l, 2,4-triazoline-3,5-dione
  • the chemical fluorescent dye group X ' was obtained by first suspending 5 g (18.5 mmol) of dansyl chloride in 50 ml of dry pyridine and slowly adding 1.63 g (18.5 mmol) of N, N-dimethylaminoethyleneamine. The reaction mixture was stirred at room temperature for two hours and then the solvent was removed by distillation. Subsequently, the residue was taken up in 100 ml of chloroform and washed with 100 ml an ammonium hydroxide solution (2.5%). The organic phase was separated and dried over magnesium sulfate.
  • Example 9 Preparation of Active Ingredient Carriers According to the Invention Substances according to Formula (I)
  • Stock solutions of the substances obtained from Examples 4, 6 and 8 were prepared by mixing the substances according to Examples 4 and 6 in a chloroform / methanol solution (5: 1 ) were dissolved, or the substance was dissolved in chloroform according to Example 8.
  • La-phosphatidylcholine eggPC
  • DOPE 2-dioleoyl-sn-glycero-3-phosphoethanolamine
  • Rh-DPPE ammonium
  • eggPC 2-dioleoyl-sn-glycero-3-phosphoethanolamine-N -lissamine rhodamine B sulfonyl
  • Table 1 further provides information in the last column as to whether or not an active substance has been incorporated into the respective unilamellar vesicles (active ingredient carriers) obtained from compositions I to VII.
  • active ingredient carriers active ingredient carriers obtained from compositions I to VII.
  • calcein has been used as the water-soluble substance which can be easily detected spectroscopically in replacement of a pharmaceutically active substance.
  • compositions I to VII were freed from the solvent (- mixture) in a rotary evaporator, so that the solid mixtures of the substances precipitated as a film on the wall of the glass flask.
  • the precipitated film was reacted with a 176 mM sucrose solution containing 2- (4- (2-hydroxyethyl) -1-piperazinyl) -ethanesulfonic acid (HEPES) at 10 mM concentration and having a pH of 7.4 recorded at 40 ° C.
  • HEPES 2- (4- (2-hydroxyethyl) -1-piperazinyl) -ethanesulfonic acid
  • the resulting suspension was subjected to five freezing and thawing operations. The freezing was carried out by immersing the glass flask in an isopropanol-dry ice mixture and thawing respectively by immersion in a water bath at 50 ° C.
  • the suspension was passed 10 times through a polycarbonate filter with 100 nm pore diameter (Nucleopore GmbH) at a temperature of 40 ° C and the resulting unilamellar vesicles (drug carriers) were centrifuge for one hour at 100,000 x g. The supernatant was discarded and the pellet of the resulting drug carrier was resuspended in 100 mM potassium chloride solution with 10 mM HEPES at pH 7.4.
  • compositions III to VII the precipitated films were taken up in cyclohexane (in the case of compositions III to V, cyclohexane with an additional 5% by volume of ethyl acetate), the solutions frozen in glass tubes at -80 ° C and lyophilized overnight.
  • compositions III-V a 70 mM calcein solution prewarmed to 70 ° C with 10 mM HEPES, 1 mM ethylenediaminetetraacetate (EDTA) was added at pH 7.4.
  • EDTA ethylenediaminetetraacetate
  • the resulting suspensions were subjected to five freezing and thawing operations in the same manner as those of Compositions I and II, except that the thawing was done with a 70 ° C water bath. In the same way, the suspension was passed through a polycarbonate filter 10 times.
  • compositions VI and VII was analogous method, with the only difference that no calcein solution, but the o. Potassium chloride solution was used.
  • compositions III to V unilamellar vesicles (excipients), which are loaded with calcein, of excess calcein, which is not inside the drug carriers After freeing, the permeate of the above-mentioned filtration was passed through a column located in a centrifuge unit column (Sephadex G 50, Quiagen, centrifugation: 3 minutes at 530 xg).
  • Example 10 Demonstration of the Formation of Unilamellar Vesicles (Active Ingredient Carriers) Without Active Ingredient
  • the unilamellar vesicles (active ingredient carriers) obtained from the composition VII were introduced into the respective solutions in a temperature-controlled spectroscopic measuring cell with stirrer (Aminco type: Bowman series 2) and in Range of wavelengths from 350 to 650 nm under excitation at 330 nm with respect to the emitted fluorescent light measured.
  • composition VII has in the used material (Ib) with the dansyl radical a fluorescent group and further in the further substance ammonium (l, 2-dipalmitoyl-sn-glycero-3-phosphoethanolamin-N-lissamine rhodamine B sulfonyl ) (Rh-DPPE) with the rhodamine group another fluorescence-active group.
  • FRET Forster resonance energy transfer
  • the fluorescence signals of the unilamellar vesicles (drug carrier) obtained from composition VII were measured and compared with the fluorescence signals of the same sample after incubation with 10 ⁇ of 20% polyethylene glycol p- (1,1,3,3-tetramethylbutyl) - phenyl ether (Triton X 100) was added.
  • Triton X 100 is a non-ionic detergent that generally dissolves unilamellar vesicles.
  • the fluorescence signals of the unilamelallaric vesicles (active ingredient carriers) obtained from the composition VII have an unchangeable measurement rash - and in particular no - at 590 nm directly after their production (A) and at least over a period of two hours (B) Measuring at 520 nm, as it would be unique for a dansyl radical - has.
  • Triton X 100 the separated fluorescence signals of the dansyl residue and the rhodamine (C) can be seen.
  • compositions III to IV were investigated in a similar manner as in the previous example 10, with the difference that that was excited not at 330 nm, but at 492 nm. This is the wavelength of the approximate excitation maximum of calcein.
  • the results of the experiments with the compositions III are shown in FIG.
  • the results with compositions IV are shown in FIG.
  • the relative fluorescence intensity (F *) over the measuring time (t) for the measurements at 30 ° C, 35 ° C and 40 ° C is plotted.
  • Relative fluorescence intensity (F *) here means in each case the fluorescence intensity which was measured, based on a theoretical maximum fluorescence intensity value of the pure calcein in solution.
  • composition IV unlike that according to III, contains only 10 mol% of the substance according to formula (Ia), it is also obvious that its presence is responsible for the improved, spontaneous release.
  • the particularly rapid release takes place in the range of 35 ° C to 40 ° C.

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Abstract

La présente invention concerne de nouvelles substances pour la préparation de véhicules de principes actifs auto-organisés sous forme de liposomes, lesquelles substances renferment un groupe disulfure permettant la libération contrôlée d'un principe actif contenu dans lesdits véhicules, ainsi qu'une méthode de libération de principes actifs au moyen du véhicule susmentionné.
PCT/EP2010/064272 2009-09-29 2010-09-27 Substances renfermant des groupes disulfure pour véhicules auto-organisés permettant la libération contrôlée d'un principe actif WO2011039144A1 (fr)

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DE200910043342 DE102009043342A1 (de) 2009-09-29 2009-09-29 Stoffe für selbstorganisierte Träger zur kontrollierten Freisetzung eines Wirkstoffs

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