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WO2009016663A1 - Conjugués de dextrine amphiphiles et leur utilisation dans des formulations pharmaceutiques en tant qu'agents complexants pour des médicaments hydrophobes pour améliorer la solubilité aqueuse et par conséquent l'efficacité thérapeutique de médicaments complexés - Google Patents

Conjugués de dextrine amphiphiles et leur utilisation dans des formulations pharmaceutiques en tant qu'agents complexants pour des médicaments hydrophobes pour améliorer la solubilité aqueuse et par conséquent l'efficacité thérapeutique de médicaments complexés Download PDF

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WO2009016663A1
WO2009016663A1 PCT/IT2007/000552 IT2007000552W WO2009016663A1 WO 2009016663 A1 WO2009016663 A1 WO 2009016663A1 IT 2007000552 W IT2007000552 W IT 2007000552W WO 2009016663 A1 WO2009016663 A1 WO 2009016663A1
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dextrin
hydrophobic
amphiphilic
conjugates
per
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PCT/IT2007/000552
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English (en)
Inventor
Isabella Orienti
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Istituto Giannina Gaslini
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin

Definitions

  • amphiphilic dextrin conjugates and their use in pharmaceutical formulations as complexing agents for hydrophobic drugs to improve the aqueous solubility and consequently the therapeutic efficacy of the complexed drugs Field of the invention.
  • the invention relates to water-soluble amphiphilic dextrins linked (conjugated) to hydrophobic acyl or alkyl chains with an average glucose polymerization degree of 5 to 600 and acyl or alkyl chains having 6 to 30 carbon atoms, saturated or unsaturated, linear or branched, preferably a C 18 monounsaturated oleyl acyl chain, wherein the average degree of substitution is between 0.01 to 0.5 moles of substituent per mole of glucose and is adjusted, depending on the average molecular weight of the dextrin and the chain length of the hydrophobic chain used, to obtain amphiphilic dextrin conjugates soluble in water at room temperature and self-assembling with formation of nano-aggregates containing hydrophobic inner cores able to complex hydropho
  • the dextrins may be linked to the hydrophobic chains also by means of poly (ethylene glycol) spacers whose polymerization degree may range between 2 to 1000. Morevoer the invention refers to processes for preparation of amphiphilic dextrin conjugates, processes for preparation of complexes between the amphiphilic dextrin conjugates and hydrophobic drugs or hydrophobic cosmetic substances, pharmaceutical or cosmetic preparations containing complexes between the amphiphilic dextrin conjugates and drugs or cosmetic substances or containing the amphiphilic dextrin conjugates as solubilizers of drugs or cosmetic substances sparingly soluble in water or as emulsifiers in oil-in- water or water-in-oil emulsions or as stabilizers in emulsions or suspensions, use of the pharmaceutical formulations containing the amphiphilic dextrin conjugates or the complexes to improve the bioavailability and consequently the therapeutic efficacy of the complexed drugs.
  • poly (ethylene glycol) spacers whose
  • the therapeutic response obtained by these studies is thus underestimated as referred to the total dose of drug solubilized in the organic solvent whereas, really, it depends on the small dose fraction remained in solution after dilution in the aqueous medium. From this emerges the importance to increase the aqueous solubility of hydrophobic drugs to improve bioavailability and consequently their therapeutic efficacy.
  • the approaches currently used to raise the aqueous solubility of hydrophobic drugs mainly rely on the use of solubilizing excipients such as surfactants, cyclodextrins, liposomes or organic solvents.
  • the non-polymeric surfactants such as Cremophor, polysorbates, Solutol, etc.
  • CMC critical micellar concentration
  • the dilution in the body fluids after administration of the pharmaceutical form causes a drop in the surfactant concentration below its CMC with a consequent micelle destabilization and precipitation of the drug previously solubilyzed in the micelles.
  • the polymeric surfactants such as poloxamers, polyacrilic acid esters, polyvinylalcohol or dextran substituted with hydrophobic chains [I. Oienti et al.
  • Liposomes may solubilyze hydrophobic drugs in their double phospholipidic sheet but this favours their aggregation and hinder the drug partition towards the aqueous body fluids thus decreasing drug bioavailability.
  • the ideal solubilizing agent must be characterized by structural flexibility in order to provide in water plastic amphiphilic aggregates easily changing conformation, to solubilize, by complexation, different molecules.
  • amphiphilic aggregates must be characterized by multiple intermolecular interactions stabilizing the self-assembled structure toward dilution, in this case high molecular weight solubilizing agents are needed.
  • polysaccharides appears to be particularly suitable to this aim as may be endowed with different degrees of structural flexibility depending on the glucosidic bond type in their polymeric backbone.
  • Polysaccharides may be rigid and water insoluble such as cellulose, characterized by ⁇ 1-4 glucosidic bonds or flexible water soluble such as dextrins, characterized by a ⁇ 1-4 and ⁇ 1-6 glucosidic bonds.
  • Dextrans even if water soluble, are less flexible than dextrins as contains ⁇ 1-3 and ⁇ 1-6 glucosidic bonds.
  • the ⁇ 1-3 bonds rigidify the polymeric backbone and slow down its degradation rate in vivo.
  • Dextran fatty acid esters are described in the Patent US 5 750 678 as solubilizers of substances which are sparingly soluble in water, however their solubilization ability does not exceed that of other commercially available solubilizers such as Solutol.
  • Dextrins at contrary, due to the flexibility of their polymeric backbone allow preparation of amphiphilic derivates, by conjugation with hydrophobic chains that, in aqueous environment, provide plastic aggregates able to easily change conformation to complex different type of hydrophobic molecules.
  • Dextrins moreover, are highly biocompatible and easily biodegradable, so they are particularly suitable to be used both in oral and injectable formulations.
  • Dextrin esters of fatty acids have been jet reported as gelling agents for liquid oils at substitution degree ranging from 1 to 3 fatty acid moles per glucose mole (Patent US 5 840 883) or as emulsifying agents for water-in-oil emulsions (Patent JP 8/283303) also in combination with hydrophilic gelling agents (Patent EP 1 166 770) to further stabilize the emulsion.
  • the substitution degree, higher than 1 fatty acid mole per glucose mole, provided derivatives slightly soluble or insoluble in water thus only suitable in lipophilic formulations such as lipogels or water-in-oil emulsions but not suitable as complexing agents aimed at increasing the solubility of hydrophobic substances in water.
  • the decrease in substitution degree under 1 fatty acid mole per glucose mole increases the solubility of the dextrin derivatives in water, moreover the suitable balancer ⁇ ent between the molecular weight of the dextrin and the hydrophobic chain provide completely soluble derivatives able to self-assemble in water with formation of nano-aggregates containing hydrophobic inner cores allowing complexation of hydrophobic molecules so increasing their aqueous solubility.
  • the present invention provides a polymer conjugated with hydrophobic acyl or alkyl chains, water soluble and amphiphilic, in which the polymer is the polysaccharide dextrin.
  • the dextrin-hydrophobic chains conjugate may be one in which the dextrin is linked directly to the hydrophobic chains or one in which the dextrin is linked indirectly to the hydrophobic chains by means of poly (ethylene glycol) spacers to which both the hydrophobic chain and the dextrin are linked.
  • the dextrin is preferably a non-cyclic dextrin.
  • hydrophobic chains with dextrins allows preparation of biocompatible, biodegradable and water soluble amphiphilic conjugates able to self-assemble in aqueous environment in nano-aggregates containing hydrophobic inner cores which easily complex hydrophobic drugs due to the structural flexibility of the amphiphilic molecules.
  • Dextrin is a glucose polymer which is produced by the hydrolysis of starch and consists of glucose units linked together by means mainly of ⁇ 1-4 linkages. In addition to ⁇ 1-4 linkages, there may be a proportion of ⁇ 1-6 linkages, the amount depending on the starch starting material of the dextrin.
  • the average molecular weight of the dextrin may range from about 500 to 110.000 preferably from 1.000 to 2.000.
  • the average polymerization degree of the dextrin is in the range from 5 to 600 preferably from 5 to 12.
  • the hydrophobic acyl or alkyl chains linked to the dextrin have 6 to 30 carbon atoms, saturated or unsaturated, linear or branched, preferably Cis monounsaturated oleyl acyl chains.
  • the dextrin is linked to the hydrophobic chains directly or through spacers, preferably directly.
  • the dextrin is linked to the hydrophobic chains by ester or ether or carbonate bonds, preferably ester bonds.
  • the average substitution degree of the amphiphilic dextrins is between 0.01 and 0.5 moles of substituent per mole of glucose, preferably 0.1.
  • the present invention provides methods for preparation of amphiphilic dextrin conjugates by dextrin linkage with hydrophobic chains where the degree of substitution is adjusted between 0.01 and 0.5 moles of substituent per mole of glucose depending on the average molecular weight of the dextrin and the chain-length of the hydrophobic chains used to obtain final amphiphilic products soluble in water at room temperature.
  • dextrin is dissolved in N-methylpyrrolidone, a C 1 S monounsaturated acyl halide, preferably oleyl chloride, is added in an amount such that the final product has preferably an.average degree of substitution of oleyl chains per glucose unit 0.1, in the presence of polyvinylpyridine in stoichimoetric amount with the halide.
  • the mixture is stirred at room temperature at least twenty-four hours, filtered to eliminate the undissolved material and then the dextrin-oleyl chain conjugate is precipitated from the mixture by addition of diethyl ether in excess.
  • the precipitate is separated preferably by centrifugation, dissolved in water and dialyzed against water at least twenty-four hours to remove traces of organic solvents.
  • the undissolved material, eventually present, is eliminated by filtration and the solution is preferably freeze-dried.
  • the present invention provides methods for preparing water soluble complexes of hydrophobic drugs with the amphiphilic dextrins to be used in pharmaceutical formulations or water soluble complexes of hydrophobic cosmetic active substances suitable for cosmetic formulations.
  • the dextrin linked to oleyl chains at 0.1 substitution degree (oleyl chains moles per glucose mole) is dissolved in the minimum volume of N-methylpyrrolidone to obtain a viscous solution.
  • the hydrophobic substance (drug or cosmetic active) is added to the viscous phase in amount such that the weight ratio between the' dextrin conjugate and the hydrophobic substance is between 1 and 200, preferably 50.
  • the suspension so obtained is kneaded to omogeneity and subsequently diluted with excess water under stirring at room temperature until a fluid phase is .obtained which is then dialyzed against water, at least twenty-four hours, to remove the organic solvent.
  • the undissolved material is removed preferably by filtration and the clear solution obtained is preferably freeze-dried.
  • hydrophobic drugs and/or cosmetic active substances particularly suitable to be complexed with the amphophilic dextrin conjugates thus increasing their aqueous solubility are: fenretinide, retinoic acid and other retinoids, paclitaxel, docetaxel, etoposide, teniposide, camptothecin, topotecan, irinotecan and other hydrophobic chemotherapeutic agents, cephalosporins and other hydrophobic antibiotics, hydrophobic vitamins, UV-A and UV-B filters.
  • the pharmaceutical formulations containing hydrophobic drugs complexed with the conjugates according to the present invention may be presented in a form suitable for parenteral, oral, topical rectal or intra-vaginal administration for humans or animals.
  • the pharmaceutical or cosmetic preparations according to the present invention may contain additional pharmaceutically or cosmetically acceptable auxiliary agents and/or diluents.
  • the present invention demonstrates that the enhancement of the aqueous solubility of hydrophobic drugs also enhances their therapeutic efficacy by increasing their bioavailability in the body fluids preferably the efficacy of fenretinide has been greatly enhanced in vivo by the amphophilic dextrin conjugates.
  • sheet 1 is view of the general structure of the dextrin- hydrophobic chains conjugates where R 1 , Ra, and R 3 may be hydrogen atoms or acyl or alkyl chains linked directly to the dextrin or through poly (ethylene glycol) spacers.
  • sheet 2 figure 2 is 1 H-NMR spectrum of DX-OLi 0 (600 MHz; D 2 O).
  • figure 3 is diagram of solubilization of fenretinide (HPR), etoposide (ETO), paclitaxel (PX), camptothecin (CPT) in water in the presence of dextrin with average polymerization degree 9-10, average molecular weight 1670, substituted with Cig mono ⁇ nsaturated oleyl acyl chains with degree of substitution 0.1 moles substituent per glucose mole (DX-OL 1 O).
  • HPR fenretinide
  • ETO etoposide
  • PX paclitaxel
  • CPT camptothecin
  • figure 4 is diagram of the mean size of DX-OLi 0 and the complexes of DX-OLio with fenretinide (HPR), etoposide (ETO) 5 paclit ⁇ sel (PX), camptothecin (CPT) prepared with kneading method (al) in water at different concentrations.
  • sheet 5 figure 5 is diagram of the release of fenretinide (HPR), etoposide (ETO), paclitaxel (PX), camptothecin (CPT) from the DX-OL 1O complexes prepared by the kneading method (al) in water at 37°C.
  • figure 6 is diagram with time course of the cytotoxic properties and growth inhibition effect of free fenretinide (HPR) and DX-OL 1O complexed HPR at concentrations of 2 ⁇ M (a), 3 ⁇ M (b), 4 ⁇ M (c) and 5 ⁇ M (d) and pure DX-OLio (25 ⁇ M) on neuroblastoma human cells HTLA-230.
  • HPR free fenretinide
  • DX-OL 1O complexed HPR at concentrations of 2 ⁇ M (a), 3 ⁇ M (b), 4 ⁇ M (c) and 5 ⁇ M (d) and pure DX-OLio (25 ⁇ M) on neuroblastoma human cells HTLA-230.
  • white columns state control black columns state pure DX-OLio
  • figure 7 is diagram with time course of the citytoxic properties and growth inhibition effect of free fenretinide (HPR) and DX-OL 1 O complexed HfR at 6 ⁇ M and pure DX-OLio (25 ⁇ M) on cells of human neuroblastoma LAN 5.
  • HPR free fenretinide
  • DX-OL 1 O complexed HfR at 6 ⁇ M and pure DX-OLio (25 ⁇ M) on cells of human neuroblastoma LAN 5.
  • white columns state control black columns state pure DX-OLio
  • grey columns state free HPR strip columns state HPR complexed.
  • sheet 8 figure 8 is diagram with time course of the citytoxic properties and growth inhibition effect of free fenretinide (HPR) and DX-OLio complexed HPR at 6 ⁇ M and pure DX-OLio (25 ⁇ M) on human neuroblastoma cells IMR 32.
  • figure 9 is diagram of the effect on cellular viability of free fenretinide (HPR) and DX-OL 10 complexed HPR on human melanoma cells MZ2-MEL.
  • sheet 10 figure 10 is diagram of the effect on cellular viability of free fenretinide (HPR) and DX-OLi 0 complexed HPR on human melanoma cells RPMI-7932.
  • figure 11 is diagram of the survival profiles of nude mice engrafted with HTLA-230 treated with pure DX- OLio, free fenretinide (HPR) and DX-OL 10 complexed HPR. Brief description as example of the preferred embodiments. The present invention will hereinafter be described hi more detailed way by means of examples that give preferred and detailed embodiments not exclusive.
  • Dextrin with an average glucose polymerization degree of 5 to 600 is dissolved in N-methylpyrrolidone, an acyl or alkyl halide is then added consisting of a hydrocarbon chain saturated or unsaturated, linear or " branched, the length of which may range between C 6 and C 3 o, said halide is added to the solution in amount such that the final product has an average degree of substitution between 0.01 to 0.5 moles of hydrocarbon chains per mole of glucose in the presence of a base such as pyridine, polyvinylpyridine, dimemylaminopyridine, DBU: 1,8- Diazabicyclo[5.4.0]undec-7-ene, DBN:1.5-Diazabicyclo[4.3.0]non-5-ene etc.
  • a base such as pyridine, polyvinylpyridine, dimemylaminopyridine, DBU: 1,8- Diazabicyclo[5.4.0]undec-7-ene, DBN:1.5-Diazabicyclo[
  • Method (b) Dextrin with an average glucose polymerization degree of 5 to 600 is dissolved hi dimethyl sulphoxide, an acyl or alkyl halide is then added consisting of a hydrocarbon chain saturated or unsaturated, linear or branched, the length of which may range between C 6 and C 30 , said halide is added to the solution in amount such that the final product has an average degree of substitution between 0,01 to 0.5 moles of hydrophobic chains per mole of glucose in the presence of a base such as pyridine, polyvinylpyridine, dimethylan ⁇ iopyridine, DBU: 1,8- Diazabicyclo [5.4.0]undec-7-ene, DBN:1,5-Diazabicyclo [4.3.0]non-5-ene etc.
  • a base such as pyridine, polyvinylpyridine, dimethylan ⁇ iopyridine, DBU: 1,8- Diazabicyclo [5.4.0]undec-7-ene, DBN:1,5-Diaz
  • Method (c) Dextrin with an average glucose polymerization degree of 5 to 600 is dissolved in a mixture of N-methylpyrrolidone and dimethyl sulphoxide, an acyl or alkyl halide is then added consisting of a hydrocarbon chain saturated or unsaturated, linear or branched, the length of which may range between Ce and C 30 , said halide is added to the solution in amount such that the final product has an average degree of substitution between 0.01 to 0.5 moles of hydrophobic chains per mole of glucose in the presence of a base such as pyridine, polyv ⁇ iylpyridine, dimethylaminopyridine, DBU:l,8-Diazabicyclo[5.4.0]undec-7- ene, DBN:l,5-Diazabicyclo[4.3.0]non-5-ene etc in stoichiometric amount with respect to the halide.
  • a base such as pyridine, polyv ⁇ iylpyridine, dimethylaminopyr
  • the hydrophobic chains are previously linked to the spacers following different procedures such as procedure (a), procedure (b), procedure (c) and procedure (d).
  • a C 6 to C 30 acyl halide is linked to a poly (ethylene glycol) chain (PEG) by reaction with a poly (ethylene glycol) mono halide where the acyl halide and the poly (ethylene glycol) mono halide in molar ratio 1:1 are dissolved in N-methylpyrrolidone or dimethyl sulphoxide or a mixture of the two solvents in the presence of a base. The mixture is stirred at room temperature for at least one hour. The resulting mono halide contains a PEG-C 6, C 3 o ester linkage.
  • Said mono halide is linked to the dextrin by (a) or (b) or (c) or (d) method where the said mono halide stands in for the acyl or alkyl halide in the (a) or (b) or (c) or (d) method.
  • the final product is a dextrin linked to the C 6 , C 30 acyl chain through a poly (ethylene glycol) spacer.
  • a C 6 to C30 alkyl .halide is linked to a poly (ethylene glycol) chain (PEG) by reaction with a poly (ethylene glycol) mono halide where the alkyl halide and the poly (ethylene glycol) mono halide in molar ratio 1:1 are dissolved in N-methylpyrrolidone or dimethyl sulphoxide or a mixture of the two solvents in the presence of a base. The mixture is stirred at room temperature for at least one hour. The resulting mono halide contains a PEG-C 6 , C30 ether linkage.
  • Said mono halide is linked to the dextrin by (a) or (b) or (c) or (d) method where the said mono halide stands in for the acyl or alkyl halide in the (a) or (b) or (c) or (d) method.
  • the final product is a dextrin linked to the C 6 , C3 0 alkyl chain through a poly (ethylene glycol) spacer.
  • a C 6 to C 30 fatty alcohol is linked to a poly (ethylene glycol) chain (PEG) by reaction with a poly (ethylene glycol) dihalide where the fatty alcohol and the poly (ethylene glycol) dihalide in molar ratio 1:1 are dissolved in N- methylpyrro ⁇ idone or dimethyl sulphoxide or a mixture of the two solvents in the presence of a base. The mixture is stirred at room temperature for at least one hour. The resulting mono halide contains a PEG-C 6 , C30 ether linkage.
  • Said mono halide is linked to the dextrin by (a) or (b) or (c) or (d) method where the said mono halide stands in for the acyl or alkyl halide in the (a) or (b) or (c) or (d) method.
  • the final product is a dextrin linked to the C 6 , C 30 fatty alcohol through a poly (ethylene glycol) spacer.
  • a C 6 to C 30 fatty alcohol is linked to a poly (ethylene glycol) chain (PEG) by reaction with a poly (ethylene glycol) dichloroformate where the fatty alcohol and the poly (ethylene glycol) dichloroformate in molar ratio 1:1 are dissolved in N-methylpyrrolidone or dimethyl sulphoxide or a mixture of the two solvents in the presence of a base. The mixture is stirred at room temperature for at least one hour. The resulting monochloroformate contains a PEG-C 6 , C 30 carbonate linkage.
  • Said monochloroformate is linked to the dextrin by (a) or (b) or (c) or (d) method where the said monochloroformate stands in for the acyl or alkyl halide in the (a) or (b) or (c) or (d) method.
  • the final product is a dextrin linked to the Ce, C30 fatty alcohol through a poly (ethylene glycol) spacer.
  • the amphiphilic dextrin conjugates obtained on the base of the above described methods are purified by dialysjs to remove traces of the organic solvents used, filtered sterile and freeze dried or spray-dried.
  • the dextrin conjugates are characterized as described in the under reported verifications (a), (b), (c) and (d). Verification (a).
  • the substitution degree of the amphiphilic dextrin conjugates has been obtained by 1 H-NMR (600 MHz; D 2 O and DMSO-de) by comparing the peak integral of the terminal methyl protons of the hydrophobic chains linked to the dextrin at 0.80 ppm with the peak integral of the Ci glucose proton at 5.20 ppm (figure 2).
  • the best preparative method is the method (a) as in this case the substitution takes place with the highest efficiency being near unity the ratio between the moles of substituent per glucose mole in the final product and in the preparative mixture (Table 1- page 22).
  • the aqueous solubility of the dextrin conjugates is evaluated by dissolving increasing amounts of the substituted dextrins in water at 25 or 37°C and checking the set up of saturation both microscopically by the appearance of solid formations and spectrophotometrically by the absorption increase at 260 nm up to a plateau.
  • the aqueous solubility increases with the temperature, decreases with increasing the molecular weight of the starting dextrin and with increasing the substitution degree and the molecular weight of the hydrophobic chains linked to the dextrin.
  • the derivatives most soluble are those obtained by dextrins of molecular weight lower than 2000, substituted without spacers with acyl chains in the range C 12 , C 1S at substitution degree 0.1 mole substituent per mole of glucose (Table 2 - page 22). The unsaturation in the acyl chains further raises solubility. Verification (c). The amphophilic dextrin conjugates in water form aggregates whose mean size depend on their concentration, molecular weight and physico- chemical characteristic of the substituents. The mean size of the aggregates is evaluated in water by dynamic light scattering measurements obtained by a Brookhaven 90-PLUS instrument equipped with a 50 mW He-Ne laser (532 nm) and thermo regulated at 25 or 37°C.
  • the scattering angle is fixed at 90°.
  • the measures indicate that the mean size of the aggregates increases with increasing the molecular weight of both tfie dextrin and the hydrophobic chains linked. It also increases with the increase of the substitution degree and the molecular • weight of the poly (ethylene glycol) spacers if present.
  • the derivatives obtained by dextrins of molecular weight under 2000 without spacers and with substitution degrees ranging from 0.01 to 0.1 mole substituent per mole glucose and hydrophobic chains length lower than C2 0 make aggregates in water characterized by low dimensions (300-350nm), narrow polydispersity. (0.35-0.41) and high stability as neither the increase in concentration nor the temperature increase appreciably change their size and polydispersity indicating their suitability in pharmaceutical and cosmetic formulations where concentration decrease, following dilution in the biological structures, and temperature increase occur after administration.
  • Solubilization ability of the ampbiphilic dextrin conjugates toward hydrophobic drugs depends on the ability of the self-assembled structures, formed in water after dissolution of the dextrin conjugates, to complex the drugs in their hydrophobic inner core. Said solubilization ability is evaluated by adding excess drug amounts to aqueous phases containing increasing concentrations of the dextrin conjugates. The obtained suspensions are stirred twenty-four hours at room temperature, subsequently filtered to eliminate the undissolved drug and analyzed by spectrophotometric measures and HPLC to determine the drug content in solution.
  • the spectophotometric measures are carried out directly on the aqueous solutions, the HPLC measures (C 1 S, methanol, UV-VIS) after precipitation of the dextrin conjugates by ethanol. Reporting the concentration of the solubilized drug as a function of the dextrin conjugate concentration an increasing trend is obtained until a plateau corresponding to the water saturation with the dextrin conjugate (figure 3).
  • the increase in drug solubilization with the increase of the amphiphilic dextrin concentration is proportional to the solubilization ability of the amphiphilic dextrin toward the hydrophobic drug and the plateau provides the maximum solubility of each amphiphilic dextrin-drug system.
  • the maximum solubility of fenretinide in the presence of DX-OL 10 has been compared with that of commercially available.
  • solubilizers Labrasol, Pluronic F68, ⁇ -cyclodextrin each representing a different class of solubilizers currently used in pharmaceutical and cosmetic formulations (Table 3 - page 23). The results indicate that the solubility of fenretinide in the presence of DX-OL 1O is always higher than that obtained in the presence of the commercially available solubilizers analyzed.
  • kneading method (a) Complexation of hydrophobic drugs with the amphiphilic dextrin conjugates. To obtain the said complexation are considered the methods under described such as kneading method (a), cosolubilization method (b) and coprecipitation method (c).
  • the kneading method (a) may provide two proceedings:
  • the amphiphilic dextrin conjugate is dissolved in the minimum volume of N- methylpyrrolidone or dimethyl sulphoxide or a mixture of the two solvents to obtain a viscous solution.
  • the hydrophobic substance drug or cosmetic active substance
  • the mixture so obtained is kneaded to omogeneity and subsequently diluted with an excess of water under stirring at room temperature until a fluid phase is obtained, then dialyzed against water to completely remove the organic solvents.
  • the undissolved material is removed by filtration or centrifugation and the aqueous solution obtained is freeze-dried or spray-dried.
  • (a2) The amphiphilic dextrin conjugate is dissolved in the minimum volume of N- methylpyrrolidone or dimethyl sulphoxide or a mixture of the two solvents to obtain a viscous solution. Diethyl ether or ethanol is subsequently added in excess to the solution to induce precipitation of the dextrin conjugate in the form of a semisolid phase which is separated by centrifugation of filtration.
  • the hydrophobic substance drug or cosmetic active substance
  • the weight ratio is changed depending on the physico-chemical characteristics of the substance to be complexed.
  • the mixture so obtained is kneaded to omogeneity and subsequently diluted with an excess of water under stirring at room temperature until a fluid phase is obtained, then dialyzed against water to completely remove the organic solvents.
  • the undissolved material is removed by filtration or centrifugation and the aqueous solution obtained is freeze-dried or spray-dried.
  • the cosolubilization method (b) may provide two proceedings: (bl)
  • the amphiphilic dextrin conjugate is dissolved in water, the hydrophobic substance (drug or cosmetic active substance) is added in amount such that the weight ratio between the dextrin conjugate and the hydrophobic substance is between 1 and 200.
  • the weight ratio is changed depending on the physico- chemical characteristics of the substance to be complexed.
  • the suspension so obtained is stirred at room temperature for at least twenty-four hours and then the undissolved material is removed by filtration or centrifugation and the aqueous solution obtained is freeze-dried or spray-dried.
  • the amphiphilic dextrin conjugate is dissolved in water containing mixable organic solvents such as N-methylpyrrolidone, dimethyl sulphoxide or ethanol favouring the dissolution in water of the hydrophobic substance to be complexed.
  • the hydrophobic substance drug or cosmetic active substance
  • the weight ratio is changed depending on the physico-chemical characteristics of the substance to be complexed.
  • the suspension obtained is stirred for at least twenty-four hours at room temperature and then dialyzed against water to completely remove the organic solvents.
  • the coprecipitation method (c) may provide two proceedings: (cl) The amphiphilic dextrin conjugate is dissolved in N-methylpyrrolidone or dimethyl sulphoxide or a mixture of the two solvents in the presence of the hydrophobic substance to be complexed (drug or cosmetic active substance) in amount such that the weight ratio between the dextrin conjugate and the hydrophobic substance is between 1 and 200. The weight ratio is changed depending on the physico-chemical characteristics of the substance to be complexed.
  • the amphiphilic dextrin conjugate is dissolved in water in the presence of the hydrophobic substance to be complexed (drug or cosmetic active substance) in amount such that the weight ratio between the dextrin conjugate and the hydrophobic substance is between 1 and 200.
  • the weight ratio is changed depending on the physico-chemical characteristics of the substance to be complexed, ethanol or acetone are subsequently added in excess to the solution to induce coprecipitation of the dextrin conjugate and the hydrophobic substance into the precipitated dextrin.
  • the coprecipitate is separated by filtration or centrifugation and then dissolved in water and dialyzed against water to completely remove the organic solvents.
  • the undissolved material is removed by filtration or centrifiigation and the aqueous solution obtained is freeze-dried or spray-dried.
  • the complexes are analyzed by 1 H-NMR (600 MHz; D 2 O) and spectrophotometry to evaluate the mode of interaction between drug and dextrin conjugate in the complexes preparated by the different methods.
  • 1 H-NMR spectra recorded in D 2 O the disappearance of the peaks characteristics of the complexed drugs is indicative of .the drug inclusion into the complexing structure.
  • the 1 H-NMR spectra of the complexes prepared by the kneading method are always characterized by disappearance of the peaks at 6-7.5 ppm characteristics of the aromatic protons of the analyzed drugs: fenretinide, etoposide, paclitaxel, camptotechine, indicating that in this case complexation takes place by drug inclusion into the hydrophobic inner core of the aggregates.
  • the complexes obtained by the other methods at contrary, do not show complete disappearance of any peak characteristic of the complexed drugs indicating that in these cases the complexation is not exclusively due to drug inclusion but other interactions are present in the complex such as drug absorption at the hydrophobic/hydrophilic interface of the dextrin aggregates.
  • the spectrophotometric data confirm these observations as the UV spectra show a single peak characteristic of the complexed drug in the case of the complexes obtained by the kneading method, indicative of a single interaction mode, and multiple peaks in the case of the complexes obtained by the other methods, indicative of multiple interactions (Table 4 - page 24).
  • the aqueous solubility of the complexes is obtained by adding increasing amounts of solid complexes to 50 ml of water and, after stirring at 25 or 37 0 C for twenty-four hours, evaluating microscopically the presence of undissolved material indicative of water saturation with the complex, or spectrophotometrically analyzing the aqueous solution at the wavelength of the maximum absorbtion of the complexed drug up to a plateau of the absorbance increase with concentration indicative of water saturation with the complex.
  • the study indicates that the complex solubility depends more on the nature of the dextrin conjugate that the characteristics of the complexed drug and increases with temperature. In particular the complex solubility increases by decreasing the molecular weight of the dextrin backbone and its substitution degree.
  • the complexation method also influences the complex solubility.
  • the (al) kneading method provides the most soluble complexes (Table 5 - page 25 ).
  • the complex drug loading is the ratio between the amount of drug and dextrin conjugate in the complex, it provides an evaluation of the complex efficiency in raising the aqueous drug solubility in the presence of the smaller amount pf complexing agent.
  • the complex drag loading is evaluated by 1 H-NMR 3 capillary electrophoresis (CE), and HPLC methods.
  • the completes prepared by the kneading method show lower size than the complexes prepared by the other methods due to the inclusion of the drug into the hydrophobic inner core of the aggregates which strictly tight together both the dextrin conjugate and the complexed drug.
  • the DX- OL 1 O complexes prepared by the kneading method are characterized by very low average size (150-260 nm) and narrow polydispersity (0.21-0.28) being therefore particularly suitable for intravenous administration of drugs and drug targeting to solid tumours where the discontinuity of the blood vessels favours extravasation and accumulation of particulate systems with size lower than 300 nm.
  • the low size may promote, moreover, the adsorption of the complexes through the intestinal Peyer's patches after oral administration, avoiding, in this way, the hepatic metabolism of the drug.
  • Transdermal absorption of the complexes may also be favoured by their nanometric dimensions.
  • a complex should provide the free drug or the cosmetic substance after the pharmaceutical or cosmetic formulation has been administered by the suitable route.
  • the release rate of the substance from the complex should be sufficiently high to make the drug or the cosmetic substance bioavailable in time periods compatible with the presence of the complex in the body fluids before clearance in the case of intravenous pharmaceutical formulations or with the permanence of the formulation in the site of administration in the case of the other administration routes.
  • Release studies of the complexed drugs are carried out by placing saturated aqueous solutions of the complexes in a releasing compartment in contact with a dialysis membrane, allowing diffusion only to the free drug and not to the complex.
  • the membrane separates the realeasing from a receiving compartment containing an aqueous phase and an organic solvent such as chloroform which extract the hydrophobic diffusing drug.
  • the organic solvent is periodically withdrawn and evaporated.
  • the residue obtained by evaporation is analyzed by HPLC (C 1S , methanol, UV-VIS detector) for its drug content.
  • HPLC C 1S , methanol, UV-VIS detector
  • the release studies indicate that the complexes are able to progressively release the free drug in an aqueous phase.
  • the release rate increases by decreasing the molecular weight of the dextrins and in the presence of acyl chains directly linked tqihe dextrin without a spacer.
  • the highest release rates are obtained from the DX-OL 1O complexes obtained by the (al) kneading method (figure 5).
  • the adrenergic MYCN amplified neuroblastoma cell line HTLA-230 was used.
  • Cells were maintained in DMEM growth medium containing 10% fetal bovine serum, L-glutarnmine 2mM, 100 ng/mL each penicillin and streptomycin at 37°C in a humidified 95% air/5% CO 2 atmosphere. Experiments were performed during the logarithmic phase of cell growth. Cells were seeded in 12-well plates (4 x 10 4 cells/well) as triplicates. After seventy-two hours the cells where left untreated or treated with growth medium containing the dextrin conjugates at concentrations ranging from 50 ⁇ g/ml to 300 ⁇ g/ml. Toxicity was not observed at any concentration tested for all the dextrin conjugates analyzed until seventy-two hours after the treatment.
  • the DX-OL 1O was also tested in vivo to evaluate its acute toxicity.
  • DX-OL 1 O was injected in CDl nude/nude mice intravenously at the dose of 250 mg/Kg for sixteen days. No toxic effects were observed on the animals neither during the treatment nor for three months after the beginning of the experiment.
  • In vitro biological evaluation of the DX-OLin_ complex with fenretinide The DX-OLio complex with fenretinide obtained by the method (al) has been evaluated for its activity in vitro. The studies have been carried out to evaluate the activity of the complexed vs free fenretinide.
  • the cells were left untreated or treated with growth medium containing 2, 3, 4, 5 or 6 ⁇ M free fenretinide (previously dissolved in ethanol); 2, 3, 4, 5 or 6 ⁇ M complexed fenretinide (dissolved in PBS) or an excess (25 ⁇ M) of pure DX-OL 1 O.
  • the effects of free and complexed fenretinide were determined by cell count and the trypan blue dye exclusion method. Cells maintained in medium alone and treated with pure DX-OL 1O were used as controls. The results were statistically evaluated and analyzed using two tailed unpaired t test with Welch's correction with confidence intervals set at 99%.
  • mice Twenty-four hours after the tumour cell inoculation, the animals were treated with complexed fenretmide (60 ⁇ g/mouse or 120 ⁇ g/mouse), free fenretinide (60 ⁇ g/mouse), pure DX-OL 1O (5mg/mouse) or vehicle alone (PBS) 5 given slowly through the tail vein in a volume of 200 ⁇ L. The treatment was repeated for sixteen days. The statistical significance of differential survival between experimental groups of mice was determined by Kaplan-Meier curves and long-rank (Peto) test by the use of StatDirect statistical software. Three times a week, mice were monitored for their body weight, general physical and performance status, as well as for externally visible tumour mass or ascites formation.
  • complexed fenretmide 60 ⁇ g/mouse or 120 ⁇ g/mouse
  • free fenretinide 60 ⁇ g/mouse
  • pure DX-OL 1O 5mg/mouse
  • PBS
  • Figure 11 shows the survival profile of treated versus control mice. A highly significant increase in mean survival time may be observed in mice that received the complexed fenretinide. Moreover, while control mice underwent rapid and extensive metastatic tumour growth, involving mainly adrenal gland, kidney, ovary, liver, spleen and bone marrow, in treated mice these events took place more slowly and in a less extensive amount.

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Abstract

L'invention porte sur un système amphiphile soluble dans l'eau améliorant la solubilité aqueuse de médicaments hydrophobes par complexation. Ledit système consiste en une dextrine conjuguée avec des chaînes acyles ou alkyles hydrophobes. Le conjugué de dextrine chaînes hydrophobes peut être un conjugué dans lequel la dextrine est indirectement liée aux chaînes hydrophobes ou un conjugué dans lequel la dextrine est indirectement liée aux chaînes hydrophobes par des espaceurs. La dextrine est, de préférence, une dextrine non cyclique.
PCT/IT2007/000552 2007-07-31 2007-07-31 Conjugués de dextrine amphiphiles et leur utilisation dans des formulations pharmaceutiques en tant qu'agents complexants pour des médicaments hydrophobes pour améliorer la solubilité aqueuse et par conséquent l'efficacité thérapeutique de médicaments complexés WO2009016663A1 (fr)

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WO2011070529A2 (fr) 2009-12-10 2011-06-16 Universidade Do Minho Hydrogel de dextrine pour applications biomédicales
US8258250B2 (en) 2009-10-07 2012-09-04 Johnson & Johnson Consumer Companies, Inc. Compositions comprising superhydrophilic amphiphilic copolymers and methods of use thereof
US8399590B2 (en) 2009-10-07 2013-03-19 Akzo Nobel Chemicals International B.V. Superhydrophilic amphiphilic copolymers and processes for making the same
WO2015103005A1 (fr) * 2014-01-03 2015-07-09 Research Institute At Nationwide Children's Hospital Composés amines amphiphiles et leur utilisation en tant qu'agents thérapeutiques et nanosupports
WO2016038534A1 (fr) * 2014-09-10 2016-03-17 Istituti Fisioterapici Ospitalieri (Ifo) - Istituto Regina Elena Per Lo Studio E La Cura Dei Tumori Complexes de fenrétinide
CN105884917A (zh) * 2016-05-20 2016-08-24 江南大学 一种直链糊精基脂质体及其制备方法
AU2015292212B2 (en) * 2014-07-25 2019-03-14 Laurent Pharmaceuticals Solid oral formulation of fenretinide
US10406127B2 (en) 2014-07-25 2019-09-10 Laurent Pharmaceuticals Solid oral formulation of fenretinide
US11173106B2 (en) 2009-10-07 2021-11-16 Johnson & Johnson Consumer Inc. Compositions comprising a superhydrophilic amphiphilic copolymer and a micellar thickener

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8258250B2 (en) 2009-10-07 2012-09-04 Johnson & Johnson Consumer Companies, Inc. Compositions comprising superhydrophilic amphiphilic copolymers and methods of use thereof
US8399590B2 (en) 2009-10-07 2013-03-19 Akzo Nobel Chemicals International B.V. Superhydrophilic amphiphilic copolymers and processes for making the same
US9114154B2 (en) 2009-10-07 2015-08-25 Johnson & Johnson Consumer Inc. Compositions comprising superhydrophilic amphiphilic copolymers and methods of use thereof
US9243074B2 (en) 2009-10-07 2016-01-26 Akzo Nobel Chemicals International B.V. Superhydrophilic amphiphilic copolymers and processes for making the same
US11173106B2 (en) 2009-10-07 2021-11-16 Johnson & Johnson Consumer Inc. Compositions comprising a superhydrophilic amphiphilic copolymer and a micellar thickener
WO2011070529A2 (fr) 2009-12-10 2011-06-16 Universidade Do Minho Hydrogel de dextrine pour applications biomédicales
WO2015103005A1 (fr) * 2014-01-03 2015-07-09 Research Institute At Nationwide Children's Hospital Composés amines amphiphiles et leur utilisation en tant qu'agents thérapeutiques et nanosupports
AU2015292212B2 (en) * 2014-07-25 2019-03-14 Laurent Pharmaceuticals Solid oral formulation of fenretinide
US10406127B2 (en) 2014-07-25 2019-09-10 Laurent Pharmaceuticals Solid oral formulation of fenretinide
US10512619B2 (en) 2014-07-25 2019-12-24 Laurent Pharmaceuticals Solid oral formulation of fenretinide
WO2016038534A1 (fr) * 2014-09-10 2016-03-17 Istituti Fisioterapici Ospitalieri (Ifo) - Istituto Regina Elena Per Lo Studio E La Cura Dei Tumori Complexes de fenrétinide
CN105884917A (zh) * 2016-05-20 2016-08-24 江南大学 一种直链糊精基脂质体及其制备方法

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