WO2014056939A1 - Biomatériaux lipidiques pour l'encapsulation et la libération déclenchée - Google Patents

Biomatériaux lipidiques pour l'encapsulation et la libération déclenchée Download PDF

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WO2014056939A1
WO2014056939A1 PCT/EP2013/070976 EP2013070976W WO2014056939A1 WO 2014056939 A1 WO2014056939 A1 WO 2014056939A1 EP 2013070976 W EP2013070976 W EP 2013070976W WO 2014056939 A1 WO2014056939 A1 WO 2014056939A1
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lipidic
octanoyl
cubic phase
phase material
octylcyclopropyl
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Ehud Moshe LANDAU
Jay Steven SIEGEL
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Universität Zürich
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    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • A61K9/127—Liposomes
    • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/20—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
    • C07C211/21—Monoamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/03—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/20—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/49—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/02—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides
    • C07C245/06—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings
    • C07C245/08—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings with the two nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings, e.g. azobenzene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/608—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a ring other than a six-membered aromatic ring in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to designed, lipid-based, biocompatible, stable, and transparent materials that can encapsulate active compounds such as drugs, and release them at will by chemical and/or photochemical triggering.
  • Lipidic cubic phases possess the material properties described in section (c). They can be produced by mechanical mixing of the hydrophilic component (typically water or aqueous solution) with the lipophilic component (typically lipid or mixture of lipids) under conditions (composition, temperature) that have been established by independent physical experiments (phase diagram). Such mixing can be accomplished by centrifugation or by mixing in special syringes. Once formed, LCPs are stable, and can be stored and used at the temperature/ hydration range given by the respective phase diagram.
  • hydrophilic component typically water or aqueous solution
  • lipophilic component typically lipid or mixture of lipids
  • LCPs can incorporate various guest molecules (organic, inorganic, biological) with varied properties such as size, charge, and structure, and retain them in their active state. Diffusion in and out of hitherto known LCPs is passive, and can be rationalized in terms of effects of the lipid molecular structure (chain length, degree of unsaturation, position of double bonds, head group characteristics, etc.) on the LCP material structure (bilayer thickness and curvature, unit cell size, radius of aqueous compartment).
  • Additives used in LCPs include lipids with various chain length, degree and posi- tion of unsaturation, and head group (cf. US 6,235,312). They include mono- glycerides, galactolipids, phospholipids, and mixtures thereof (US 5,753,259 and US 2004/0022820A1 ). Further, they include ionic anchor, a tether, and combinations thereof (cf. US 6,936,187): an oftenanchor” is defined as a small molecule which is not an amphiphile, for instance a charged surfactant, that has a head group that provides specific interactions in the head group region. A “tether” is defined as a molecule that is larger than an “anchor", whose head group functions in a similar way to that of an “anchor”. Examples include polymers, polysaccharides, proteins and enzymes.
  • US 6,936,187 describes release and entrapment due to change in pH, addition of salt, or introduction of dielectric solvents.
  • the major disadvantage of this method is the fact that the binding between drug and “anchor” is only transient, and the counterions that are present easily displace the drug.
  • these have two disadvantages: (1 ) These affect the "tether” or “anchor” molecules, and not the amphiphiles, and (2) these are chemical means, which may not be applicable in vivo, as compared with our phototriggering.
  • US 5,753,259 describes controlled release, which is in essence passive: there is no mention of triggering.
  • An object of the present invention is to provide novel and advantageous lipidic compounds, particularly for use as additives in lipidic cubic phase materials. Another object of the present invention is to provide novel and advantageous lipidic cubic phase materials. A further object of the present invention is to provide a novel and improved method of controlled release. These and other objects are achieved by means of the lipidic compound defined in claim 1 , by the lipidic cubic phase materials defined in claim 3 and by the method of controlled relase defined in claim 15. Advantageous embodiments are defined in the dependent claims and in the description following further below.
  • lipidic compound particularly for use as an additive in a lipidic cubic phase material, the lipidic compound being selected from the group consisting of the following compounds according to the Scheme found further below:
  • Y01 -21 , Y01 -23 (N-oleoyl-L-serine methyl ester), Y01 -17 (Dimethyl- N-oleoyl-L-glutamate), Y01 -72 (N-oleoyl-L-phenylalanine methyl ester), Y01 - 27 (Ethyl N-oleoyl-L-cysteinate);
  • cyclopropyl compounds SB008 (2,3-dihydroxypropyl-8-(2-octylcyclopropyl) octanoate), No. 235 (N,N-(8-(2-octylcyclopropyl)octanoyl) bis-acetic acid),
  • esters No. 146, No. 163 (3-amino-2-hydroxypropyl oleate);
  • the lipidic compounds are selected from the group consisting of the following compounds according to the Scheme:
  • amides Y01 -23 (N-oleoyl-L-serine methyl ester), Y01 -17 (Dimethyl-N- oleoyl-L-glutamate);
  • cyclopropyl compounds No. 236 (N-(8-(2-octylcyclopropyl)octanoyl) glutamic acid dimethyl ester), No. 238 (N-(8-(2-octylcyclopropyl)octanoyl) L-serine methyl ester), No. 240 (N-(8-(2-octylcyclopropyl)octanoyl) L-serine), No. 243 (N-(8-(2-octylcyclopropyl)octanoyl) glutamic acid);
  • guanidinium compounds Y01 -188, Y01 -190.
  • a lipidic cubic phase material comprising a hydrophilic component and a lipophilic component, said lipo- philic component comprising a major lipophilic constituent and at least one lipidic additive, which lipidic additive comprises a hydrophilic head group and a hydrophobic tail attached thereto.
  • lipidic additive comprises a hydrophilic head group and a hydrophobic tail attached thereto.
  • fatty acids alcohol derivatives from fatty acids, monoglycerides, diglycerides, lipids and their derivatives, preferably the corresponding compounds that have their acid group(s) replaced by a hydroxyl or thiol or ether or thioether group or ⁇ -hydroxyalkenes or their ethers or homologous thiols or thioethers; monoa- cylglycerols, preferably cis monounsatu- rated monoacylglycerols, more preferably monoolein (C18: c9), monopalmitolein (C16: c9) and monovacennin (C18: c7); medium-chain length alkyl glycosides; polyalkylenglycols, poly- ethylenglycols, diacylglycerophospholipids, monoacyl- glycerophospholipids and derivatives thereof; and/or polyketides, saccharide, fatty acids, alcohol derivatives from fatty acids
  • the hydrophobic tail comprises at least one cis double bond or cyclopropyl moiety (claim 4), which was found to be favorable with regard to LCP formation.
  • the lipidic additive comprises a photochennically activatable moiety, which is particularly advantageous in applications for controlled release vehicles.
  • Advantageous lipidic cubic phase materials are those having a lipidic additive as defined in claims 6 to 8.
  • the major lipophilic constitutent may be any amphiphilic compound that can form a LCP with water (see, e.g. Fontell, K. Colloid & Polymer Science 1990, 268, 264-285).
  • Advantageous embodiment regarding the major lipophilic constit- uent are defined in claims 9 to 12.
  • iso- prenoid-chained lipids are described, for example, in: Masakatsu Hato, Jun Yam- ashita and Manzo Shiono J. Phys. Chem. B, 2009, 1 13, 10196-10209.
  • the hydrophilic component com- prises an aqueous solution containing a predetermined active compound.
  • active compound shall be interpreted broadly, meaning, e.g. a drug, a prodrug or any other therapeutically or diagnostically useful compound. Accordingly, the lipidic cubic phase materials of the present invention are particularly advantageous for use in a therapeutic method (claim 14).
  • lipidic cubic phase material forming a lipidic cubic phase material according to claim 13 by mixing said lipophilic component and said hydrophilic component comprising an aqueous solution containing said predetermined active compound; placing said lipidic cubic phase material in a region of interest;
  • the active compound is relased in the region of interest, which will typically be a particular region in a patient's body.
  • the releasing step comprises applying a photochemical stimulus generated by ultraviolet irradiation, which will lead to a rearrangement or break-up of the arrangement enclosing the active compound.
  • the active compound is a DNA compound. If required, e.g. for tracking purposes, e.g. in scientific research or in diagnostics, the DNA compound may have a fluorescent or other marker.
  • the lipidic cubic phase material is used in the form of cubosomes, i.e. as a dispersion of small, submicron LCP particles, in which all the molecular properties of LCPs are retained. This is particularly useful, for example, for use as a vehicle for controlled delivery and/or release of drugs or other active components.
  • the invention concerns a novel class of designed, lipid-based, smart matrix materials which can incorporate (enclose) a broad range of guest molecules (organic, inorganic, biological) with various sizes and properties, retain them in their active state, and optionally deliver them at the required site, and at a selected, chosen time upon triggering.
  • the guest molecules can be pharmacologically, nutritionally or cosmetically active substances. Because of the special material properties of the host matrix materials, they can be applied in a wide range of biological compartments hitherto unavailable. A significant and unique material property of this class of materials is its transparency, thereby making it ideal candidates for ocular drug delivery.
  • These novel materials have the following set of properties: Biocompatible
  • Loadable can incorporate substantial amounts (mM range) of guest molecules with various polarities and charge such as hydrophobic and hydrophilic drugs, proteins, nucleic acids etc.
  • - Switchable Optionally have designed, built-in switches for the control of structure-function (e.g. binding and fast release)
  • PHY phytantriol
  • Figure 1 shows a monoolein (MO)/water phase diagram, depicting the exist- ence and structures of the various phases as function of composition and temperature (from: V. Cherezov, J. Clogston, M. Z. Papiz, M. Caf- frey, J. Mol. Biol. 357, 1605-1618 (2006)).
  • LCP structures The lower hydrated Ia3d, and the fully hydrated Pn3m phase, which can coexist with any amount of excess water.
  • Figure 2 shows photographs of LCP(s) with dyes, demonstrating their solid
  • Figure 4 shows the photochemistry of compound 48 (absorbance vs. time):
  • Figure 5 shows the following diffusion experiments (absorbance vs. time) of methylene green in 80% LCP of MO with 5% of compound 48 as additive, demonstrating complete release without irradiation (upper curve), and binding upon UV irradiation at 366 nm (middle curve), plus a com- parison with 5.0% oleic acid as additive (bottom curve). UV irradiation at 366 nm.
  • Figure 6 shows the following diffusion experiments (absorbance vs. time):
  • Figure 7 shows aborbance (at 260 nm, non-labelled DNA) vs. time courses:
  • Figure 8 shows aborbance (at 645 nm, fluorescently labelled DNA) vs. time courses: binding of DNA to LCP containing Y01 -190 (59.4% MO, 0.6% Y01 -190, 40% H 2 O)(lower trace, diamonds), and release of DNA from non-modified LCP (60% MO, 40% H 2 O) (upper trace, squares).
  • LCPs are ideal materials for the incorporation of various guest molecules with a wide range of properties. Diffusion in and out of hitherto known LCPs is passive, and there is no known, physiologically compatible method to trigger release from LCP. To overcome this drawback, we have synthesized a series of novel lipids that can be used as additives with designed functionalities. When mechanically mixed with the lipids that form LCPs (typically monoacylglycerols, and most commonly monoolein), they form novel LCPs. The lipids that form LCPs must have a propensity to form curved, self-assembled structures, most commonly bilayers.
  • Such lipids have one or more cis double bonds along their hydrophobic tail, or alternatively a cyclopropyl moiety.
  • the chain length can vary, and is typically C14 or longer.
  • Their headgroups may vary, the only requirement being that they are hydrophilic.
  • the additives are lipid molecules, i.e. molecules that are insoluble in water, but can be mixed with the host lipids to form a LCP.
  • Our novel additives have one or more cis double bond(s) along the chain, or alternatively a cyclopropyl moiety, with a total chain length that is typically between C14 and C22.
  • the linkage between the headgroup and the chain is variable, and can be an ester, thioester, amide, ether, etc.
  • a light activatable group (the "switch") is located either at the headgroup region or along the hydrophobic chain.
  • the switch can be any functional group that can be activated photochemically. Examples are: (a) Photolabile "caged” moieties of the substituted nitrobenzyl type; (b) azobenzene functionalities; etc.
  • LCPs Fabrication of LCPs is accomplished by vigorous mixing of the lipid(s) with the aqueous solution. Mixing can be by centrifugation or by any other means such as mechanical mixing, typically in special syringes.
  • the lipid composition is based on the phase diagram(s), and is typically in the range of 60-80 % (w/w).
  • the aque- ous composition is thus accordingly 20-40 % (w/w).
  • the additive is in the range of 1 -5% (w/w) with respect to the total lipid content.
  • Triggering can be accomplished by chemical means, preferably by photochemical means.
  • the active photochemical moiety (the "switch") undergoes well-defined structural changes upon light activation. Because the switch is covalently linked to the lipid additive, it affects the lipid's overall structure, and as a consequence alters the properties of the LCP's membrane. These structural changes thus control the binding and release properties of the host LCP.
  • LCPs can be considered as universal "encapsulators" for compounds with varied size, charge, and polarity.
  • LCPs have both hydrophobic and hydrophilic compartments. They can therefore be applied universally, and can be placed on and adhere to various surfaces. b) LCP are soft solid materials, therefore they can be shaped on any surface as needed. c) LCPs are biocompatible, therefore they can be applied in (bio)medical, pharmacological, cosmetics, or food contexts.
  • these novel materials that incorporate active agent can be implanted to any tissue and can also be used in transcutaneous applications. Most importantly, because of their transparency, they do not affect vision. This property makes them amenable to intraocular ap- plications: they can incorporate the active compounds (drugs) in the eye, and can deliver them at the chosen time and with a given dosage upon photo-triggering.
  • Y01 -17 (compound 25), Y01 -21 , Y01 -23 (compound 22), Y01 -25, Y01 -27, Y01 - 72, FK 121 .
  • FK121 All amides mentioned here, except FK121 , were synthesized according to general Method A (see below). FK121 was synthesized in a 3 step synthesis as fol- lows: Synthesis of FK121 (three step synthesis)
  • Cis-9,10-Methyleneoctadecanoyl chloride (297 mg, 0.89 mmol) in 0.1 ml pyridine was added to a solution of (2,2-dimethyl-1 ,3-dioxolan-4-yl)methanol (solketal) (133 mg, 126 ⁇ _, 1 .01 mmol, Acros 97 %) in pyridine (0.5 ml_, Fluka puriss) at 0°C.
  • the reaction mixture was stirred for 48 hours, poured into 10 ml DCM and 10 ml of sulfuric acid (0.25 mol/L).
  • SB034 was synthesized analogous to a known procedure (E.J. Harbon et al, J. Phys. Chem. B, 2004, 108, 18789-18792): A suspension of anhydrous potassium carbonate (3.46 g, 25.1 mmol), 4-phenylazophenol (0.99 g, 5 mmol, Alfa Aesar), SB033 (687 mg, 2.36 mmol) and dry acetone (15 ml) was refluxed for 24 h. The reaction mixture was brought to room temperature and filtered to remove salts, and the acetone was removed by rotary evaporation.
  • SB036 was obtained from SB034 as follows: A solution of KOH (0.79g, 20.4 mmol) in MeOH (6.8 ml) was added dropwise to a stirred solution of SB034 (0.7g, 1 .71 mmol) in MeOH (13 ml) at room temperature under argon. The reaction mixture was heated at 40°C for 1 h, followed by stirring overnight at room tempera- ture. The reaction mixture was poured into water, acidified with 2N HCI until pH 3 ⁇ 4 2, and extracted with Et 2 O (3 x 30 ml_). The combined organic layers were washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was purified by recrystallization in hexane at 60°C to yield 588 mg (87%) of SB036 Synthesis of SB040
  • SB031 was obtained from 4,5-dimethoxy-2-nitrobenzyl alcohol (180 mg, 0.85 mmol, Alfa Aesar 98%), N-oleoyl-sarcosine (300mg, 0.48 mmol), DCC (348 mg, 1 .68 mmol), DMAP (14 mg, 0.1 1 mmol) in dry DCM following general Method C (see below).
  • R f (hexane:EtOAc 60:40) 0.2.
  • PU258 was obtained from 5-amino-2-nitrobenzyl alcohol (60 mg, 0.35 mmol), oleic acid (100mg, 0.35 mmol, Aldrich tech 90 %), DCC (73 mg, 0.35 mmol, Fluka puriss), DMAP (43 mg, 0.35 mmol, Fluka puriss) in dry DCM (9 ml) following general Method C (see below).
  • R f (Et 2 O:hexane 60:40) 0.23.
  • PU252 was obtained from the respective ethyl ester PU251 (160 mg, 0.23 mmol), which was reacted with lithium hydroxide monohydrate (20 mg, 0.48 mmol) in EtOH/H 2 O according to general Method D (see below).
  • the crude product was purified by preparative thin layer (CH 2 CI 2 :MeOH 98:2 with 0.5% AcOH) to yield 59 mg (54%) of PU252.
  • R f (EtOAc :hexane 3:2 + 2% AcOH) 0.37.
  • PU259 was obtained from 5-amino-2-nitrobenzyl alcohol (30 mg, 0.18 mmol), ⁇ , ⁇ -bis-acetic acid oleamide (35 mg, 0.088 mmol), DCC (37 mg, 0.18 mmol, Fluka puriss), DMAP (22 mg, 0.18 mmol, Fluka puriss) in dry DCM (3.5 ml) following general Method C (see below).
  • Step 1 Synthesis of the tosylated monoolein 1 17
  • the guanidinylated lipid derivative Y01 -190 was prepared from the primary azide SB061 (readily available from 2-azidoethylamine and oleoyl chloride), which was reduced to the amine derivative SB062 under neutral conditions with PPh3 in
  • DCC Dicyclohexylcarbodiimide
  • PEI polyethyleneimine
  • Experiment 1 A solution containing 0.5 nmol of the 5'-TTTTTTTT-3' oligo DNA (non fluorescent) was added to the appropriate amount of MO/PEI mixture (99.5-0.5 w/w), and LCP was prepared using the standard mixing procedure. MW of PEI: V250.
  • Experiment 2 The analogous experiment was carried out with fluorescently- labeled 16-mer oligo DNA (Cy5-16mix) and with LCP formed with MO containing Y01 -190 as additive.
  • Binding and release profiles of oligonucleotides were established by using UV spectroscopic detection, using non-labelled (measured at 260 nm), and fluores- cently labelled oligonucleotides (cyanine dye Cy5, which exhibits absorption maximum of 645 nm in water).
  • fluores- cently labelled oligonucleotides cyanine dye Cy5 which exhibits absorption maximum of 645 nm in water.
  • 14 g of LCP material was placed in specially designed holder and overlaid with 1 ml of mQ water, and the respec- tive DNA absorption was measured in the overlay solution.
  • the DNA compound is bound toPEI-containing LCP whereas it is quickly released from non-modified LCT.
  • the DNA compound is very strongly bound to Y01 -190- containing LCP whereas it is quickly released from non-modified LCT.
  • MO Monoolein

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention porte sur de nouveaux composés, en particulier destinés à être utilisés comme additifs dans un matériau lipidique en phase cubique, et sur de nouveaux matériaux lipidiques en phase cubique. Ces matériaux sont biocompatibles, stables et transparents et permettent d'encapsuler des composés actifs tels que des médicaments et de les libérer à volonté par déclenchement chimique et/ou photochimique. L'invention porte également un procédé de libération contrôlée d'un composé actif prédéfini, comprenant les étapes consistant à : former un matériau lipidique en phase cubique par mélange d'un composant lipophile et d'un composant hydrophile comprenant une solution aqueuse contenant le composé actif ; placer le matériau lipidique en phase cubique dans une région recherchée ; et libérer le composé actif en soumettant le matériau lipidique en phase cubique à un stimulus chimique ou photochimique.
PCT/EP2013/070976 2012-10-08 2013-10-08 Biomatériaux lipidiques pour l'encapsulation et la libération déclenchée WO2014056939A1 (fr)

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CN107879945A (zh) * 2017-12-07 2018-04-06 深圳市大物科技有限责任公司 用地沟油或油脂制备重金属螯合剂的方法
WO2018132876A1 (fr) * 2017-01-19 2018-07-26 The University Of Sydney Nouveaux inhibiteurs de transport de glycine pour le traitement de la douleur
US20210238209A1 (en) * 2018-05-28 2021-08-05 Université de Bourgogne Oleic acid derivatives, pharmaceutical composition or food composition comprising said oleic acid derivatives, and their uses

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018132876A1 (fr) * 2017-01-19 2018-07-26 The University Of Sydney Nouveaux inhibiteurs de transport de glycine pour le traitement de la douleur
CN107879945A (zh) * 2017-12-07 2018-04-06 深圳市大物科技有限责任公司 用地沟油或油脂制备重金属螯合剂的方法
US20210238209A1 (en) * 2018-05-28 2021-08-05 Université de Bourgogne Oleic acid derivatives, pharmaceutical composition or food composition comprising said oleic acid derivatives, and their uses

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