WO2021240099A1 - Conjugue terpenique de couplage - Google Patents
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- WO2021240099A1 WO2021240099A1 PCT/FR2021/050905 FR2021050905W WO2021240099A1 WO 2021240099 A1 WO2021240099 A1 WO 2021240099A1 FR 2021050905 W FR2021050905 W FR 2021050905W WO 2021240099 A1 WO2021240099 A1 WO 2021240099A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/07—Retinol compounds, e.g. vitamin A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
- A61K38/446—Superoxide dismutase (1.15)
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- 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
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- 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
- A61K47/6921—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/34—Alcohols
- A61K8/342—Alcohols having more than seven atoms in an unbroken chain
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- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
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- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/94—Involves covalent bonding to the substrate
Definitions
- the present invention relates to a coupling conjugate via a biodegradable bond between a particular terpene and a molecule of interest making it possible to obtain nanoparticles for, for example, the administration of active molecules.
- the class of terpenes is known for the formation of nanoparticles and can be coupled with molecules of interest, such as molecules for pharmaceutical purposes, to improve, or even allow, their bioavailability.
- WO2015 / 173367 discloses a conjugate of oxazaphosphorine and geranyl of formula (I) as described in this document, which can self-assemble into nanoparticles.
- WO2014 / 091436 discloses nanoparticles comprising at least one macromolecule of glycosaminoglycan type (such as fondaparinux or derivative) coupled non-covalently to at least one cationic hydrocarbon molecule of squalenic nature.
- FR2988092 discloses a complex of 5- (1,2-dihydroxy-ethyl) -3,4-dihydroxy-5H-furan-2-one (vitamin C) or derivative covalently linked to at least one hydrocarbon radical, such as squalene, famesol, geraniol, ... of formula (A) as described in this document. It is disclosed in particular in FR2988092 that the products self-assemble into nanoparticles in the aqueous phase.
- WO2010 / 049899 relates to a complex formed from at least one beta-lactam molecule covalently coupled to at least one hydrocarbon radical comprising 18 carbon atoms and containing at least one 2-methyl-buta-2-ene unit (more specifically of squalenic nature), nanoparticles of these complexes and their preparation process. It can be seen (for example in claim 1 of this document) that the complex comprises at least one statin.
- WO2010 / 049900 relates to a complex formed from at least one statin molecule covalently coupled to at least one hydrocarbon radical comprising 18 carbon atoms and containing at least one 2-methyl-buta-2-ene unit (more specifically of squalenic nature), nanoparticles of these complexes and their preparation process. It can be seen (for example in claim 1 of this document) that the complex comprises at least 3 double bonds.
- WO2009 / 150344 relates to a complex formed from at least one nucleic acid molecule comprising between 10 and 40 nucleotides, covalently coupled to at least one hydrocarbon compound which is at least one C1 8 hydrocarbon compound, having a structure of squalene or a structure similar to it.
- WO2009 / 071850 relates to a water-dispersible derivative of a therapeutic agent having low solubility in water, which comprises at least one molecule of said agent covalently linked to at least one molecule of a hydrocarbon derivative having a squalene structure or the like.
- FR2874016 relates to nanoparticles of Gemcitabine derivatives, more particularly 2,2'-difluoro-2'-deoxycytidine derivatives of formula (I) as described in this document.
- the substituent groups in this formula I can be C 18 hydrocarbon-based acyl radicals, and more particularly squalenoyl radicals.
- the function of squalenoyl is also given in this document: to retain its ability to compact or to cause a significant reduction in surface tension or even a rapid drop in surface tension when it is placed in the presence of a solvent. polar.
- FR 2608988 and FR2608942 relate to the preparation of dispersible colloidal systems of substances in the form of nanoparticles.
- nanoparticles comprising terpenes with several double bonds, giving them their ability to be compacted or even to cause a significant decrease in surface tension or a rapid drop in density. surface tension when placed in the presence of a polar solvent. Enrichment in unsaturated bonds (eg polarizable) allows this effect.
- unsaturated bonds eg polarizable
- the present invention relates to a conjugate formed capable of spontaneously self-assembling in water into nano-objects having a size ranging from a few tens to a few hundred nanometers, which allows the protection of the molecule of pharmaceutical, veterinary, phytosanitary or cosmetic interest from an early biodegradation.
- the degradation in a biological medium of the bond between the phytol (or other terpene) makes it possible to release the molecule of interest.
- the invention therefore allows an improvement in the bioavailability and / or the pharmacokinetic characteristics of the molecule of interest.
- the object of the present invention relates to a self-assembly agent of formula (I): X (-Spacer-Y -T erpene) p
- Y is a bond or a molecular fragment with a biodegradable bond
- Spacer is a bond or a fragment comprising at least one carbon atom
- X is a molecular fragment comprising at least one biodegradable bond
- p is between 0, 1 and 4, preferably p is an integer equal to 1 or 2;
- the “-Spacer-Y -” group can optionally be a link.
- the object of the present invention relates to a conjugate endowed with self-assembly properties of formula (II):
- AA is a self-assembly agent as defined herein;
- MA is a biologically active molecule
- K is between 0, 1 and 6, preferably k is an integer equal to 1 or 2; as well as those pharmaceutically or cosmetically acceptable salts and / or solvates.
- the object of the present invention also relates to a conjugate as described herein, characterized in that MA is an agent having cosmetic activity, such as an anti-wrinkle agent, an agent modifying the color of the skin, an agent for controlling the hair growth of the skin, a surface anti-acne agent, a skin firming agent, an anti-acne agent, an anti-microbial agent, an anti-oxidant agent, an anti-wrinkle agent, an anti-seborrheic agent, a soothing agent, an astringent agent, an activating agent of the microcirculation, a moisturizing agent, an agent promoting wound healing, an agent modifying the color of the skin, a perfuming agent, an agent for controlling the hair and hair growth, a firming agent, a regenerating agent, or a plumping agent.
- an agent having cosmetic activity such as an anti-wrinkle agent, an agent modifying the color of the skin, an agent for controlling the hair growth of the skin, a surface anti-acne
- the object of the present invention also relates to a self-assembly process in an aqueous medium, in which a conjugate according to formula (II) above (1) in solution in a water-miscible solvent SI , is (2) nano-precipitated in water, then (3) the solvent SI at least is evaporated off under reduced pressure.
- the subject of the present invention also relates to a self-assembly process in nano or microparticle in aqueous media of a conjugate as described presently characterized in that it comprises the following successive steps:
- the subject of the present invention also relates to a process for self-assembly in nano or microparticle in aqueous media of a conjugate as described here, characterized in that it comprises the following successive steps:
- (b2) a step of reducing the size of the oil droplets using a high pressure homogenizer.
- the object of the present invention also relates to a self-assembly process as described herein in which step (b2) is repeated at least once.
- the object of the present invention also relates to a nano or microparticle that can be obtained according to a process as described here.
- the object of the present invention also relates to a nano or microparticle comprising a conjugate as described herein.
- the subject of the present invention also relates to a pharmaceutical, veterinary and / or cosmetic formulation comprising a self-assembly agent of formula (I) as described above.
- the object of the present invention also relates to a pharmaceutical, veterinary and / or cosmetic formulation comprising a self-assembly conjugate of formula (II) as described above.
- the object of the present invention relates in particular to a cosmetic formulation as described presently, comprising a self-assembly conjugate of formula (II) as described above, characterized in that MA is an agent having an cosmetic activity, such as an anti-wrinkle agent, an agent modifying the color of the skin, an agent for controlling the hair growth of the skin, an anti-acne surface agent, a skin firming agent, an anti -acneic, an anti-microbial agent, an anti-oxidant, an anti-wrinkle agent, an anti-seborrheic agent, a soothing agent, an astringent agent, a microcirculation activating agent, a moisturizing agent, an agent promoting the cicatrization, an agent modifying the coloring of the skin, a perfuming agent, an agent making it possible to control hair and hair growth, a firming agent, a regenerating agent, or even a plumping agent.
- an agent having an cosmetic activity such as an anti-wrinkle agent
- branched linear terpene a hydrocarbon whose number of carbons is a multiple of five, comprising a linear chain of carbons, optionally branched by C1 to C4 alkyl groups.
- the C1-C4 alkyl groups include methyl, ethyl, propyl and butyl groups, preferably methyl and ethyl groups.
- the term “unsaturation” is understood to mean a double bond between two atoms, such as two carbon atoms in the case of an alkene for example.
- “self-assembly” it is understood that the molecules spontaneously assemble into particles when said particles are stimulated or conditioned to do so (for example in the presence of water). Depending on the size of the particles thus formed, it will be a question of nanoparticles (whose sizes are of the order of one nanometer to one or two hundred nanometers), or microparticles (whose sizes are of the order of one micrometer to about five hundred micrometers).
- self-assembly agent an agent, that is to say a molecular fragment allowing self-assembly as defined above.
- biodegradable bond it is understood a chemical bond (covalent or electrostatic, eg ionic, or by affinity) which can be broken by a biological means, that is to say from of a biological system, for example an enzyme or an acid.
- a biological means that is to say from of a biological system, for example an enzyme or an acid.
- the breaking of the bond can involve at least one water molecule; it will then be a question of hydrolysis.
- biologically active molecule is understood to mean any molecule having a biological effect, which may have a more general physiological effect on the biological entity considered.
- a “biological effect” can be identified by a comparison between at least one treated biological entity and at least one identical or similar biological entity without treatment.
- nanoprecipitation it is understood a self-assembly of molecules as defined above causing the formation and separation of the liquid in which it was dissolved in the form of a particle ( s) of nanometric size.
- the term “pharmaceutically acceptable” refers to compositions, compounds, salts and the like which are, in the context of sound medical judgment, suitable for contact with the tissues of the subject. , or which can be administered to the subject, without excessive toxicity or other complications commensurate with a reasonable benefit / risk ratio.
- pharmaceutically acceptable salt can refer to non-toxic salts, which can generally be prepared by contacting the compound of the invention with an appropriate organic or inorganic acid.
- pharmaceutical salts can be, but are not limited to, acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, bromides, butyrates, carbonates, chlorides, citrates, diphosphates, fumarates, iodides, lactates, laurates, malates, maleates, mandelates, mesylates, oleates, oxalates, palmitates, phosphates, propionates, succinates, sulphates, tartrates and similar compounds.
- solvate or the expression “pharmaceutically acceptable solvate” refers to a solvate formed from the association of one or more molecules of compounds of the invention with one or more solvent molecules.
- solvates includes hydrates such as hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and the like.
- the object of the present invention relates to the use as described herein, characterized in that the terpene comprises between 15 and 25 carbon atoms.
- the object of the present invention relates more particularly to the use as described here, characterized in that the terpene is bio-sourced.
- bio-sourced it is understood in the context of the present invention that the compounds which can be provided in a few steps (extraction, treatment with an acid, treatment not with a base, precipitation, etc.) are obtained from the biomass.
- an organic synthesis product is produced from chemicals and / or petrochemicals.
- the present invention relates to the use as described herein characterized in that the terpene is phytol or a phytol derivative such as isophytol.
- derivative can denote in the context of the present invention an isomer of the product concerned.
- a phytol derivative can be isophytol, or even phytantriol.
- a derivative can also relate to the product concerned with a grafted substituent chosen from halogen, -OH, -NH2, -CH3, -C (0) 0H, or even -C (0) 0R where R is independently a C1- alkyl. C4.
- the object of the present invention relates to the self-assembly agent of formula (I) as described above.
- an "aryl” group refers to an unsubstituted or substituted aromatic ring.
- the aryl group is a phenyl group optionally substituted by one or more groups such as C1-C4 alkyl, C1-C4 alkyloxy, OH or halogen atoms.
- heteroaryl refers to an aromatic ring system in which one or more aromatic atoms are a heteroatom such as N, O or S.
- the heteroaryl group can be substituted or unsubstituted and preferably comprises 4 to 6 ring atoms.
- heteroaryl groups include, without limitation, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl or oxazolyl.
- an "aliphatic heterocycle” refers to a non-aromatic ring system in which one or more aromatic atoms are a heteroatom such as N, O or S.
- the heteroaryl group may or may not be substituted. substituted and preferably comprises from 4 to 6 ring atoms.
- Examples of aliphatic heterocycles are, but are not limited to, morpholine, piperazine, pyrrolidine, dioxane, piperidine, tetrahydrofuran and the like.
- the spacer can comprise a polyether group, such as polyethylene glycol or polypropylene glycol, preferably comprising from 2 to 6 monomers.
- a polyether group such as polyethylene glycol or polypropylene glycol, preferably comprising from 2 to 6 monomers.
- the spacer is chosen from amino acids, dipeptides and their derivatives.
- the spacer can be based on citrulline, lysine, omithine, alanine, phenylalanine, cysteine, glycine, valine, leucine and their dipeptides.
- the spacer can be chosen from the following fragments: - NH-, -O-, -S-, -NR-, -ONH-, -ONR-, -0C (0) 0-, -OC (S) S-, -N (R) C (S) S-, and combinations thereof, wherein R is independently alkyl, preferably C1-C3 alkyl, optionally with polyether groups, such as polyethylene glycol or polypropylene glycol, preferably comprising from 2 to 6 monomers on one side or the other of said fragments.
- the spacer can be Yl- (CH2) m-Y2 with m being an integer of 1 to 8 or Yl- (CH2-CH2-0) q-CH2-CH2-Y2 with q being an integer of 1 to 5, where Y1 and Y2 are independently selected from -O-, -NH-, -S-, -OC (O) -, -C (0) NR-, -C (0) NH- , -NHC (O) -, -0-C (S) -S-, -NR-, -ONH-, -ONR-, -0C (0) -0-, NRC (S) S- and -C ( 0) 0-, R independently being alkyl, preferably C1-C3 alkyl.
- the spacer can be Yl- (CH2) m-Y2 where m is an integer from 1 to 6, preferably from 1 to 4 and Y1 and Y2 are independently selected from -O-, -NH -, -S-, -C (0) NH-, -NHC (O) -, -OC (O) - and -C (0) 0- [60]
- p can advantageously be between 0.5 and 3.5, between 0.7 and 3, or between 0.9 and 2.5.
- p is a substantially integer number chosen from among 1, 2, 3 and 4. By “substantially” it is here understood a variation of plus or minus 0, 1.
- the present invention relates to a self-assembly agent of formula (I) as described above characterized in that the spacer comprises, or consists of, one of any fragments following: in which “n” are independently whole numbers between 0 and 6, preferably between 1 and 4.
- the present invention relates to a self-assembly agent of formula (I) as described above characterized in that in that said biodegradable bond of "X" comprises at least one bond ionic and / or the biodegradable bond of "Y" is a covalent bond.
- R is independently an alkyl, preferably a C1-C3 alkyl, optionally with polyether groups, such
- the present invention relates to a self-assembly agent of formula (I) as described above, characterized in that “Y” and / or “X” comprise at least one ionic fragment , for example -NH3 + , -CO2, -PO4, -SO3, -SO4 2 and / or -NR3 + , where R is independently C1-C4 alkyl.
- the present invention relates to a self-assembly agent of formula (I) as described above, characterized in that “Y” and / or “X” comprise at least one trivalent fragment , such as -C (-0-) 2, -B (-0-) 2, and / or -0-P0 (-0-) 2.
- the fragment has the ability to bind to three other functions.
- the active molecule can comprise one or more binding functions.
- Y and / or “X” comprise at least one trivalent fragment, such as -C (-0-) 2, -B (-0-) 2, and / or -0-P0 (-0-) 2
- the ratio between the fragment "Y” (and / or "X"), and MA may be 1: 1 and / or 1: 2.
- two fragments of active molecules "MA” and one fragment "- Spacer-Y-Terpene ", or two fragments" -Spacer-Y-Terpene "and a fragment of active molecule" MA ".
- the fragments with 2 bonds represent acetals and boron acetals and these functions describe a bond to the same molecule, ie a 1: 1 complex between the terpene (ie the fragment of formula (I) comprising Y and / or X) and MA.
- the present invention relates to a self-assembly agent of formula (I) as described above characterized in that "Y" and / or "X" comprise, or consist of, any of the following fragments: wherein :
- - "u" are independently whole numbers between 0 and 6, preferably between 0 and 1.
- R is a hydrogen atom, a C1-C6 alkyl group, a C4-C8 aromatic group or a monocyclic or polycyclic (Cl-C6) -aryl (C4-C8) alkyl group, for example R can represent a hydrogen atom, a methyl, ethyl, propyl, butyl, phenyl, or else a benzyl group.
- the object of the present invention relates to the conjugate endowed with self-assembly properties of formula (II) as described above.
- the bond between MA and AA in the conjugate with self-assembly properties of formula (II) may be covalent (referred to herein as “covalent form”) or ionic (referred to herein as “ionic form”).
- the object of the present invention may thus relate to a conjugate endowed with self-assembly properties of formula (II) comprising an active ingredient MA, such as for example a drug, known to have a low bioavailability such as paclitaxel.
- an active ingredient MA such as for example a drug, known to have a low bioavailability such as paclitaxel.
- AD active pharmaceutical ingredient
- examples of active pharmaceutical ingredient (AD) include antimicrobial agents, anti-acne agents, anti-inflammatory agents, analgesic agents, anesthetic agents, antihistamine agents, antiseptic agents, immunosuppressants, antihemorrhagic agents, vasodilators, wound healing agents, anti-biofilm agents and mixtures thereof.
- the subject of the present invention can thus relate to a conjugate endowed with self-assembly properties of formula (II) comprising an active principle MA, such as for example a cosmetic ingredient.
- cosmetic ingredients (MA) include 4-nBu-resorcinol, 6-nHex-resorcinol, caffeic acid, ferulic acid, kojic acid, biotin, adenosine mono- phosphate, adenosine tri-phosphate, aescin, arbutin, retinol, bakuchiol, bisabolole, boldine, caffeine, cannabidiol, Coenzyme A, Coenzyme Q10, dihydroxy acetone, D- panthenol, glabridin, idebenone, L-carnitine, licochalchone A, N-acetyl-tetrapeptide-2, N-acetyl-tetrapeptide-9; niacinamide
- the subject of the present invention may thus relate to a conjugate endowed with self-assembly properties of formula (II) comprising an active ingredient MA, such as for example a phytosanitary ingredient.
- phytosanitary (MA) ingredients include: benzoic acid, benalaxyl, bromoxynil, captan, carbendazim, carfentrazone, carvone, daminozide, dicamba, difenoconazole, epoxiconazole, fenhexamid, flazasulfuron, fludioxonyl, goprodotoprodotoplyphosidione, iisprodotoplyphosidione, isoplyprodotophosid , imazalil, MCPA, mecoprop, etconazol, propiconazole, sulfosulfuron, warfarin and structural peptides YDPAPPPPPP, TDVDHVFLRF-amide, SD VDHVFLRF - amide,
- active molecule MA amlodipine, gallopamil, verapamil, bamidipine, felodipine, isradipine, lacidipine, verapamil, quinidine, amiodarone, reversine, matairesinol , sipholenol and cyclosporine, lercanidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine or diltiazem.
- the present invention relates to a conjugate of formula (II) as described above, characterized in that MA is chosen from ibuprofen, paracetamol, 4-nBu-resorcinol, 6 -nHex-resorcinol, azelaic acid, caffeic acid, ferulic acid, glycyrrhizic acid, hyaluronic acid, kojic acid, linoleic acid, lipoic acid, biotin, di -phosphate, adenosine mono-phosphate, adenosine tri-phosphate, aescine, arbutin, bakuchiol, bis- (Et) -Hexyl-dihydroxymethoxybenzyl-malonate, bisabolole, boldine, caffeine, cannabidiol, coenzyme A, coenzyme Q10, dihydroxy acetone, dihydroxymethylchromonyl palmitate, D-panthenol
- the present invention relates to a conjugate of formula (II) as described above, characterized in that MA is chosen from the following active ingredients: methylprednisolone, dexamethasone, cortisone, ibuprofen, naproxen, flurbiprofen , ketoprofen, vitamin C, camosic acid, astaxanthin, vitamin B1, vitamin B6, vitamin B12, b-carotene derivatives, lutein, allantoin, vitamin A, folic acid, vancomycin, rifampicin, quaternary ammonium salts and chlorhexidine.
- MA is chosen from the following active ingredients: methylprednisolone, dexamethasone, cortisone, ibuprofen, naproxen, flurbiprofen , ketoprofen, vitamin C, camosic acid, astaxanthin, vitamin B1, vitamin B6, vitamin B12, b-carotene derivatives, lutein, allantoin,
- the present invention relates to a conjugate of formula (II) as described above, characterized in that MA is of a size less than 20 kDa, preferably less than 15 kDa, more preferably less at 10 kDa, even more preferably less than 5 kDa, such as less than 3 kDa or less than 2 kDa.
- the present invention relates to a conjugate of formula (II) as described above, characterized in that MA is an antimicrobial agent chosen from the following active principles: penicillins and related drugs, carbapenems, cephalosporins aminoglycosides and related drugs, erythromycin, bacitracin, mupirocin, chloramphenicol, thiamphenicol, sodium fusidate, lincomycin, clindamycin, macrolides, novobiocin, tancomycin, tancomycin, les streptogramins, anti-folate agents including sulfonamides, trimethoprim and its combinations and pyrimethamine, synthetic antibacterials including nitrofurans, methazolamide, methazolamide mandelate and hippurate, nitroimidazoles, quinolones, fluoroquinolones, isoniazid, pyrazinmbutamide acid, pyrazinmbutamide aminos
- the present invention relates to a conjugate of formula (II) as described above, characterized in that MA is a topical anti-acne agent chosen from the following active ingredients: adapalene, l azelaic acid, clindamycin (eg, clindamycin phosphate), doxycycline (eg, doxycycline monohydrate), erythromycin, keratolytics such as salicylic acid and retinoic acid (Retin-A ”) , norgestimate, organic peroxides, retinoids such as isotretinoin and tretinoin, sodium sulfacetamide, tazarotene and acetretin.
- MA is a topical anti-acne agent chosen from the following active ingredients: adapalene, l azelaic acid, clindamycin (eg, clindamycin phosphate), doxycycline (eg, doxycycline monohydrate), erythro
- the present invention relates to a conjugate of formula (II) as described above, characterized in that MA is an antihistamine agent chosen from the following active ingredients: diphenhydramine hydrochloride, salicylate diphenhydramine, diphenhydramine, chlorpheniramine hydrochloride, isothipendyl chlorpheniramine maleate hydrochloride, tripelennamine hydrochloride, promethazine hydrochloride, methdilazine hydrochloride and the like.
- MA is an antihistamine agent chosen from the following active ingredients: diphenhydramine hydrochloride, salicylate diphenhydramine, diphenhydramine, chlorpheniramine hydrochloride, isothipendyl chlorpheniramine maleate hydrochloride, tripelennamine hydrochloride, promethazine hydrochloride, methdilazine hydrochloride and the like.
- Examples of local anesthetic agents which can be used as the "MA" group in the conjugate of formula (II) as described above include dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, l p-Butylaminobenzoic acid 2- (di-ethylamino) ethyl ester hydrochloride, procame hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride, pipyclonocycline hydrochloride and diene .
- the present invention relates to a conjugate of formula (II) as described above, characterized in that MA is an antiseptic agent chosen from the following active principles: alcohols, ammonium compounds quaternary, boric acid, chlorhexidine and chlorhexidine derivatives, phenols, terpenes, bactericides, disinfectants, including thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine , cetylpyridolium chloride, and trimethylammonium bromide.
- MA is an antiseptic agent chosen from the following active principles: alcohols, ammonium compounds quaternary, boric acid, chlorhexidine and chlorhexidine derivatives, phenols, terpenes, bactericides, disinfectants, including thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine , cetylpyridolium chloride,
- the present invention relates to a conjugate of formula (II) as described above, characterized in that MA is an anti-inflammatory agent chosen from the following active principles: non-steroidal anti-inflammatory agents (NSAIDs); propionic acid derivatives such as ibuprofen and naproxen; acetic acid derivatives such as indomethacin; enolic acid derivatives such as meloxicam, acetaminophen; methyl salicylate; monoglycol salicylate; aspirin; mefenamic acid; flufenamic acid; diclofenac; alclofenac; diclofenac sodium; ibuprofen; ketoprofen; naproxen; pranoprofen; fenoprofen; sulindac; fenclofenac; clidanac; flurbiprofen; fentiazac; bufexamac; piroxicam; oxyphenbutazone; pentazocine; t
- NSAIDs
- the present invention relates to a conjugate of formula (II) as described above, characterized in that MA is an analgesic agent chosen from the following active ingredients: alfentanil, benzocaine, buprenoiphine, butorphanol, butamben, capsaicin, clonidine, codeine, dibucaine, enkephalin, fentanyl, hydrocodone, hydromorphone, indomethacin, lidocaine, levorphanol, meperidine, methadone , morphine, oxomophine, nicomorphine, oxymorphone, pentazocine, pramoxine, proparacaine, propoxyphene, proxymetacaine, sufentanil, tetracaine and tramadol.
- an analgesic agent chosen from the following active ingredients: alfentanil, benzocaine, buprenoiphine, butorphanol, butamben, capsaicin, clonidine,
- the present invention relates to a conjugate of formula (II) as described above, characterized in that MA is anesthetic agent chosen from the following active principles: phenol; chloroxylenol; dyclonine; ketamine; menthol; pramoxine; resorcinol; procame-based drugs such as benzocaine, bupivacaine, chloroprocaine; cinchocaine; cocaine; dexivacaine; diamocaine; dibucaine; etidocaine; hexylcaine; levobupivacaine; lidocaine; mepivacaine; oxethaza ⁇ ne; prilocaine; procaine; proparacaine; propoxycaine; pyrrocaine; risocaine; rodocaine; ropivacaine; tetracaine; and derivatives, such as pharmaceutically acceptable salts and esters, including bupivacaine HCl, chlor
- the present invention relates to a conjugate of formula (II) as described above, characterized in that MA is an antihemorrhagic agent chosen from the following active principles: protamine sulfate, acid aminocaproic acid, tranexamic acid, carbazochrome, sodium sulfanate, carbazochrome, ratine and hesperidin.
- MA is an antihemorrhagic agent chosen from the following active principles: protamine sulfate, acid aminocaproic acid, tranexamic acid, carbazochrome, sodium sulfanate, carbazochrome, ratine and hesperidin.
- the present invention relates to a conjugate of formula (II) as described above characterized in that MA is an agent having a cosmetic activity, such as an anti-wrinkle agent, an agent modifying the skin coloring, an agent for controlling hair growth in the skin, an anti-acne surface agent, a skin tightening agent, an anti-acne agent, an anti-microbial agent, an anti-oxidant agent , an anti-wrinkle agent, an anti-seborrheic agent, a soothing agent, an astringent agent, a microcirculation activating agent, a moisturizing agent, an agent promoting wound healing, an agent modifying the color of the skin, a perfuming agent, an agent making it possible to control hair and hair growth, a firming agent, a regenerating agent, or else a plumping agent.
- a cosmetic activity such as an anti-wrinkle agent, an agent modifying the skin coloring, an agent for controlling hair growth in the skin, an anti-acne surface agent,
- MA can be an agent with a cosmetic activity chosen from retinol, hyaluronic acid, an amino acid, chosen for example from alanine, arginine, cysteine, glycine, sericin or tyrosine, caffeic acid, cinnamic acid, ellagic acid, gallic acid, propyl gallate, oleic acid, linoleic acid, linolenic acid, hyaluronic acid, acid nicotinic, salicylic acid, adenosine, allantoin, bakuchiol, beta-carotene, caffeine, cannabidiol, ceramides, cholesterol, glabridine, niacinamide, panthenol, prasterone, acetyl hexapeptide -8, tripeptide-3, heptapeptide-15 palmitate, proxeratin, resveratrol, retinol,
- Another object of the invention is a nanoparticle comprising a compound of the invention. More precisely, a compound of the invention is present as a constituent, more preferably as a main component of the nanoparticle, which means that the compound of the invention (ie a conjugate of formula (I) or (II) ) may be more than 50% by weight, e.g. more than 60%, 70%, 80%, 90%, 95%, 98%, 99% or 99.5% by weight of the total weight of the nanoparticle.
- the nanoparticle is formed by a compound of the invention. In other words, the nanoparticle results from the self-organization of the molecules of the compound of the invention.
- One embodiment of the present invention relates to a nanoparticulate system based on the formation of ion pairs between charged linear terpene molecules (positive or negative) according to formula (I) of the present invention (such as phytol or derivatives) and active MA molecules charged (negative or positive respectively) without the need for covalent coupling. It is thus possible to adjust the quantity of charged linear terpene molecules (positive or negative) according to formula (I) according to the present invention relative to the active molecules according to the present invention to obtain the nanoparticles.
- the ratio that is to say the index "k” in formula II) between molecules of charged linear terpenes (positive or negative) according to formula (I) of the present invention relative to the active molecules MA can vary. between 0.1 and 6.
- k is between 0.5 and 5.5, between 0, 7 and 5, between 1 and 4, between 1.5 and 3, or alternatively between 2 and 3. From preferably, k is a substantially whole number chosen from among 1, 2, 3, 4, 5 and 6. By “substantially”, it is here understood a variation of plus or minus 0, 1.
- conjugated molecule (s) of active principle (s) can simply be covalently linked directly or via a spacer to a linear terpene according to the present invention (such as phytol or a derivative of phytol).
- the average diameter of said nanoparticles is within a range from 10 nm to 800 nm, more preferably from 50 nm to 400 nm, and more preferably from 100 nm to 200 nm.
- the mean hydrodynamic diameter of the nanoparticle of the invention is typically 10 to 800 nm, preferably 30 to 500 nm and in particular 50 to 400 nm.
- the nanoparticles can have an average hydrodynamic diameter of 70 nm to 200 nm, for example 100 nm to 250 nm.
- the mean hydrodynamic diameter is preferably determined by dynamic light scattering at 20 ° C, more preferably at 25 ° C.
- mono-dispersed colloidal suspensions of particles having an average diameter ranging from 10 to 800 nm, in particular from 75 to 500 nm, and more preferably from 100 nm to 200 nm.
- Particle size is an important parameter determining the in vivo fate of nanoparticles after oral administration and, as a general rule for example, sizes less than 500 nm are considered to facilitate interactions with epithelia.
- patent application WO2012 / 076824 discloses methods of synthesizing these nanoparticles.
- the compounds according to the invention are capable of self-organizing into nanoparticles.
- nanoprecipitation is a common technique that combines the advantages of one-step preparation, easy scaling, and the use of less toxic solvents compared to other manufacturing methods.
- the formation of nanoparticles can increase the biological activity of the compound and improve the delivery of these active molecules to cells.
- the compound of the invention in the form of nanoparticles can have improved storage stability compared to its free form.
- the compounds of the invention according to formulas (I) and (II) can be provided in the form of nanoparticles or in formulations intended to produce nanoparticles, that is to say intended to be placed in aqueous solution.
- the nanoparticles of the compound of formula (I) and / or (II) can be obtained by dissolving the compound in an organic solvent such as acetone or ethanol, then adding this mixture in a phase aqueous with stirring leading to the formation of nanoparticles with or without surfactant (s).
- surfactants include, for example, polyoxyethylene-polyoxypropylene copolymers, sodium lauryl sulfate, phospholipid derivatives and lipophilic derivatives of polyethylene glycol.
- the invention also relates to a colloidal system containing the particles of the invention, preferably in an aqueous medium.
- solubilizers such as products aiding in solubilization
- solubilizers are polyglycerols (such as polyglyceryl laurate), phospholipid derivatives (such as hydrogenated lecithin), sugar esters (such as sucrose stearate), sugar alcohols (such as those of glucoside type, such as decyl glucoside), amino acid derivatives (such as sodium stearoyl glutamate), potassium cetyl phosphate, sorbitan palmitate, glyceryl stearate inulin lauryl carbamate, benzoate of C12-C15 alkyls, coco-caprylate, coco-caprate, isoamyl laurate, dicaprylyl carbonate, dicaprylyl maleate, or also triethyl citrate.
- the nanoparticles according to the present invention can be obtained by a process comprising at least the steps consisting in: providing a solution of a compound of formula (II) as defined above in a water-soluble organic solvent, pouring said organic solution into an aqueous phase which, with stirring, instantly forms the expected nanoparticles in suspension in said aqueous phase, and where appropriate, isolating said nanoparticles.
- the subject of the present invention also relates to a method of self-assembly in nano or microparticle in aqueous media of a conjugate as described presently characterized in that it comprises the following successive steps
- (b2) a step of reducing the size of the oil droplets using a high pressure homogenizer.
- step (a2) of preparing an oil-in-water emulsion comprises the preparation of an aqueous solution. with water, hydrogenated lecithin and optionally a C2- O, alkyl-diol such as propanediol.
- step (a2) of preparing an oil-in-water emulsion comprises the preparation of an oily phase. composed of a solubilizer, retinyl -phytolate and butylated hydroxytoluene (BHT).
- BHT butylated hydroxytoluene
- step (a2) of preparing an oil-in-water emulsion comprises an introduction of an oily phase into an oil-in-water emulsion.
- aqueous phase for example with stirring of the rotor / stator type at a temperature between 40 and 60 ° C and / or at a speed between 1000 and 3000 rpm, for example 2000 rpm, for 5 to 10 minutes.
- the object of the present invention also relates to a self-assembly process as described here in which step (b2) of introducing the emulsion obtained in step (a2) into a high homogenizer pressure, for example under temperature conditions between 20 and 30 ° C and at pressures between 1500 and 2500 bars, such as 2000 bars.
- a high homogenizer pressure for example under temperature conditions between 20 and 30 ° C and at pressures between 1500 and 2500 bars, such as 2000 bars.
- the present invention further relates to a compound according to formulas (I) or (II) according to the present invention or to a pharmaceutical composition according to the present invention for its use as a medicament intended for treating cancer, especially skin allergies.
- inflammatory reactions especially inflammatory reactions of the skin such as dermatitis, eczema, psoriasis, vitiligo, erythema, inflammatory alopecia, viral infections, infections bacterial, respiratory diseases, such as asthma, skin conditions such as acne, autoimmune diseases, pain, neurodegenerative diseases, myopathies, osteopathies, hepatitis, renal insufficiency, urinary diseases -genital, eye disease, digestive tract disease, COVID 19, and / or blood disease.
- the present invention also relates to said composition for its use as a medicament for the treatment and / or prevention of the aforementioned diseases and / or conditions.
- the invention therefore relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) or a salt or solvate thereof, a nanoparticle of the invention as well as any particular compound described here and an excipient. pharmaceutically acceptable.
- the compound or the nanoparticle of the invention is present as an active ingredient in said pharmaceutical composition.
- the pharmaceutical composition of the invention can comprise: from 0.01 to 90% by weight of a compound or of a nanoparticle of the invention, and from 10% to 99.99% by weight of excipient (S) pharmaceutically acceptable (s), the percentage being expressed relative to the total weight of the composition.
- the pharmaceutical composition can comprise: from 0.1% to 50% by weight of a compound or of a nanoparticle of the invention, and from 50% to 99.9% by weight of pharmaceutically acceptable excipients.
- the invention also relates to a method of treating or preventing a disease in a subject, said method comprising administering the subject with a therapeutically effective amount of a compound of formula (I) or of a nanoparticle. as defined above.
- a therapeutically effective amount or dose an amount of the compound of the invention which prevents, eliminates, slows down the disease under consideration or reduces or delays one or more symptoms or disorders. caused by or associated with said disease in the subject, preferably a human.
- the effective amount, and more generally the dosage regimen, of the compound of the invention and of its pharmaceutical compositions can be determined and adapted by those skilled in the art. An effective dose can be determined using conventional techniques and observing the results obtained under like circumstances.
- the therapeutically effective dose of the compound of the invention will vary depending on the disease to be treated or to be prevented, its severity, the route of administration, any co-therapy involved, the age of the patient, his weight, his state of health. general, medical history, etc.
- the amount of the compound to be administered to a patient may range from about 0.01 mg / kg to 500 mg / kg body weight, preferably 0.1 mg / kg to 300 mg / kg body weight, per example from 25 to 300 mg / kg.
- the compound or nanoparticle of the invention can be administered to the subject daily for several consecutive days, for example for 2 to 10 consecutive days, preferably 3 to 6 consecutive days. This treatment can be repeated every two or three weeks or every one, two or three months. Alternatively, the compound or the nanoparticle of the invention can be administered in a single dose once a week, once every two weeks or once a month. The treatment can be repeated one or more times a year.
- the approach envisaged according to the ionic form of the invention, or by affinity (by lipophilicity / hydrophilicity), makes it possible to avoid: i) tedious synthesis; ii) the risk of losing the activity of the drug by chemical modification; and iii) the need to break the covalent bonds between the active compounds and the self-assembly agents in order to release the active compounds.
- composition comprising the compounds according to the present invention can be administered systemically (eg orally) or locally (eg topically).
- the compound of the invention (for example in the form of a pharmaceutical, dermatological or cosmetic composition) can be administered by any conventional route comprising, but not limited to, oral, buccal, sublingual, rectal, intravenous, intramuscular, subcutaneous, intraosseous, dermal, transdermal, mucosa, transmucosal, intra-articular, intra-cardiac, intra-cerebral, intra-peritoneal, intranasal , pulmonary, intraocular, vaginal or transdermal.
- the route of administration of the compound of the invention may vary depending on the disease to be treated and on the organ or tissue of the patient suffering from the disease.
- the compound of the invention is administered intravenously or orally.
- the subject or patient is preferably a human.
- another object of the present invention may relate to the use of a conjugate according to the present invention as a cosmetic agent for combating intrinsic aging of the skin.
- Another subject of the present invention may relate to a composition for topical administration, characterized in that it contains at least one conjugate according to the present invention.
- Another object of the present invention may relate to a cometic use of a conjugate according to the present invention or of a composition containing this conjugate for its cosmetic action, such as an anti-wrinkle action, for example with retinol or l. 'one of its derivatives.
- the nanoparticles of the invention can be administered intravenously in the form of an aqueous suspension and are therefore compatible with vascular microcirculation.
- the present invention is aimed at nanoparticles as defined above, optionally in the form of a lyophilizate, for the preparation of a pharmaceutical composition in particular applicable to mucous membranes such as the oropharyngeal mucosa, the oral mucosa, the pulmonary mucosa, the vaginal mucosa, the nasal mucosa, and the gastrointestinal mucosa.
- the pharmaceutical composition can be a lyophilizate or a lyophilized powder. Said powder can be dissolved or suspended in a suitable vehicle just before being administered to the patient, for example intravenously or orally.
- the present invention also relates to a lyophilizate comprising at least the nanoparticles as described above.
- this lyophilizate further comprises at least one cryoprotectant, in particular trehalose, glycerol and glucose, and more preferably trehalose.
- the present invention is thus aimed at dosages in solid forms intended for oral administration containing at least nanoparticles according to the invention, optionally in the form of a lyophilizate, or preparations intended for reconstituting the nanoparticles.
- This dosage in solid form can advantageously be a dosage in solid form with delayed release, such as, for example, enteric coated tablets or capsules, the surface coating of which ensures the delayed release.
- the claimed nanoparticles may also be suitable for administration other than by the oral route, for example by the topical route or by the subcutaneous route.
- the nanoparticles according to the present invention are particularly advantageous with respect to a highly improved skin penetration of the product according to the present invention of formulas (I) or (II) due to the size and the nature of the nanoparticles (hydrocarbon chain).
- the pharmaceutical composition can be of any type. More precisely, but by way of example, the pharmaceutical formulations compatible with the nanoparticles according to the invention can be: intravenous injections or infusions; saline solutions or purified water solutions; compositions for inhalation; creams, ointments, lotions, gels; capsules, sugar-coated tablets, cachets and syrups incorporating in particular as a vehicle, water, calcium phosphate, sugars such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and / or gelatin.
- the pharmaceutical formulations compatible with the nanoparticles according to the invention can be: intravenous injections or infusions; saline solutions or purified water solutions; compositions for inhalation; creams, ointments, lotions, gels; capsules, sugar-coated tablets, cachets and syrups incorporating in particular as a vehicle, water, calcium phosphate, sugars such as lacto
- the pharmaceutical composition can be a solid oral dosage form, a liquid dosage form, a suspension, for example for intravenous route, a dosage form for topical application such as a cream, an ointment. , a gel and the like, a transdermal patch, mucoadhesive patch or tablet, in particular an adhesive bandage or dressing, suppository, aerosol for intranasal or pulmonary administration.
- the formulation of the active therapeutic compounds considered according to the present invention in the form of nanoparticles according to the present invention, constitutes an advantageous alternative compared to the formulations which already exist, in several respects.
- the present invention thus relates to a pharmaceutical or dermatological composition, in particular a medicament, comprising at least one nanoparticle, optionally in the form of a lyophilizate, as described above, in association with at least one pharmaceutically acceptable vehicle.
- composition of the invention can be obtained by mixing a compound of formula (I) as described above or a nanoparticle thereof with at least one pharmaceutical excipient.
- nanoparticles When used in dispersion in an aqueous solution, they can be combined with excipients such as sequestering or chelating agents, antioxidants, pH regulators and / or buffering agents.
- solid dosage forms resistant to pH are particularly useful for improving the absolute bioavailability of the nanoparticles of the invention relative to the acidic pH of the stomach.
- excipients include, but are not limited to, solvents such as water or water / ethanol mixtures, fillers, carriers, diluents, binders, anti-caking agents, plasticizers , disintegrants, lubricants, flavors, buffering agents, stabilizers, colorants, antioxidants, non-stick agents, softeners, preservatives, surfactants, waxes, emulsifiers, wetting agents and slip agents.
- diluents include, but are not limited to, microcrystalline cellulose, starch, modified starch, calcium phosphate dibasic dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, mono- or disaccharides such as lactose, dextrose, sucrose, mannitol, galactose and sorbitol, xylitol and their combinations.
- binders include, but are not limited to, starches, eg, potato starch, wheat starch, corn starch; gums, such as gum tragacanth, acacia gum and gelatin; hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose; polyvinylpyrrolidone, copovidone, polyethylene glycol and their combinations.
- lubricants include, but are not limited to, fatty acids and their derivatives such as calcium stearate, glyceryl monostearate, acrylates, glyceryl palmitostearate, magnesium stearate, zinc stearate or stearic acid, or polyalkylene glycols such as PEG.
- the slip can be selected from colloidal silica, silicon dioxide, talc and the like.
- disintegrants include, but are not limited to, crospovidone, croscarmellose salts such as croscarmellose sodium, starches and their derivatives.
- surfactants include, but are not limited to, simethicone, triethanolamine, polysorbates and their derivatives such as tween® 20 or tween® 40, poloxamers, fatty alcohols such as lauryl alcohol, l cetyl alcohol and alkyl sulfate such as sodium dodecyl sulfate (SDS).
- emulsifiers include, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, polyethylene glycol and sorbitan fatty acid esters or mixtures thereof.
- liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, polyethylene glycol, xanthan gum and fatty acid esters of sorbitan or mixtures of these substances, and the like.
- the composition can also include adjuvants, such as wetting agents, emulsifying agents, suspending agents, antioxidants, buffers, pH modifiers and the like.
- Suspensions in addition to the compound or nanoparticle of the invention, may contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxide. aluminum, bentonite, agar-agar and the like.
- suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxide. aluminum, bentonite, agar-agar and the like.
- Vaginal or rectal suppositories can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ordinary temperatures but liquid at temperature. body and, therefore, melted into the rectum or vaginal cavity and release the active component.
- Ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc and zinc oxide, or mixtures thereof.
- excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc and zinc oxide, or mixtures thereof.
- the excipient (s) to be combined with the active compound of the invention can vary according to (i) the physicochemical properties, in particular the stability of said active compound, (ii) the desired pharmacokinetic profile for said active ingredient. (iii) the dosage form and (iv) the route of administration.
- Oral solid dosage forms include, but are not limited to, tablets, capsules, pills, and granules.
- said oral solid forms can be prepared with coatings and shells, such as enteric coatings or other suitable coatings or shells.
- coatings and shells are well known in the art. Examples of coating compositions which can be used are polymeric substances and waxes.
- Liquid dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs
- FIG. 1 is a graph representing the stability of nanoparticulate suspensions over time for conjugates 3 (dashed line) and conjugates 4 (solid line).
- FIG. 2 is a graph representing the stability of the nanoparticulate suspensions over time for the conjugates 7 (line in large spaced dashes), conjugates 8 (solid line) and conjugates 9 (line in small closely spaced dashes).
- FIG. 3 is a histogram representing the Variation of areas as a function of time for conjugate 9 (black column) and retinol (gray column), at 0, 1 and 2 days.
- Figure 4 is a bar graph showing the change in retinol and retinyl phytolate content in the dark.
- Figure 5 is a bar graph showing the change in retinol and retinyl phytolate content in light.
- Figure 6 is a bar graph showing the change in retinol and retinyl phytolate content at 4 ° C.
- Figure 7 is a histogram showing the change in the content of retinol and retinyl phytolate at 45 ° C
- FIG. 8 is a histogram representing the cumulative amount of retinyl phytolate (pg / cm 2 ) in the skin layers with the PhtoVec
- FIG. 9 is a histogram representing the cumulative amount of retinol and retinyl phytolate (pg / cm 2 ) in the skin layers obtained from gels C, D, E.
- Ep Epidermis
- FZ Franz type diffusion cell
- PBS Phosphate buffered saline solution (pH 7.4)
- the average particle sizes were measured by the so-called “Dynamic Light Scattering” (DLS) method on a Malvern-Panalytical Nano-Sizer ZS® at 25 ° C with a detection angle of 173 ° and a length of 633 nm wave. The reported sizes are determined by the average of three measurements. The measurements were carried out in polystyrene cuvettes.
- DLS Dynamic Light Scattering
- Example 1 Products synthesized.
- reaction medium is hydrolyzed with NH 4 CI aq. saturated, then transferred to a separating funnel and the organic phase is separated.
- the aqueous phase is extracted with EtOAc (3 x 50 mL).
- the organic extracts are combined, washed with HCl aq. (0.1 N), dried over MgSCL, filtered and concentrated under reduced pressure.
- the concentrate is then purified by chromatography on silica gel (EtOAc / CyH - 30:70 to 50:50) to provide the expected compound (12.84 g, 32.42 mmol, 96%) in the form of a yellow oil.
- reaction medium is hydrolyzed with NH4Cl aq. saturated then transferred to a separating funnel and the organic phase is separated.
- the aqueous phase is extracted with EtOAc (3 x 30 mL).
- EtOAc 3 x 30 mL
- the organic extracts are combined, washed with NaCl aq. saturated (2 x 30 mL), dried over MgSCL, filtered and concentrated under reduced pressure.
- reaction medium is hydrolyzed with NH4Cl aq. then transferred to a separating funnel and the organic phase is separated.
- the aqueous phase is extracted with EtOAc (3 x 30 mL).
- EtOAc 3 x 30 mL
- the organic extracts are combined, washed with NaCl aq. saturated (2 x 30 mL), dried over MgSC, filtered and concentrated under reduced pressure.
- reaction medium is hydrolyzed with HCl aq. (1 N, 10 mL). then extracted with CH2Cl2 (3 x 20 mL). The organic phases are combined, washed with aq NaCl. saturated (2 x 20 mL) then dried over Na2SC> 4, filtered and concentrated under reduced pressure.
- Example 2 examples of self-assembly
- the prepared nanoobjects have been characterized and generally have the following characteristics:
- surfactants such as coconut amidopropyl betaine, sodium laureth sulfate, sorbitan palmitate, lauryl glucoside, fatty alcohols, acids and their mixture, phospholipids, phosphatidyl choline, polyglyceryls, sucroesters have also been used. and are currently under study for their stabilizing effect on conjugate suspensions
- the samples are prepared as follows: 40 ⁇ L of the residual suspension is dissolved in 500 ⁇ L of FLO MiliQ.
- Vitamin A (retinol) is known to be sensitive to oxygen and UV radiation. The phytolization process stabilizes retinol. This protection was demonstrated by HPLC monitoring of a nanoparticulate suspension of the conjugate 9 at 20 ° C. in comparison with a solution of retinol under the same conditions.
- Solutions of retinol and conjugate 9 in nanoparticulate form (6 mg / L in a mixture
- ThO / ZPrOH 1 1) were stored at 21 ° C in ambient light and analyzed by HPLC over time (24 and 48h).
- Table 5 Variation of areas as a function of time.
- CCL Retinol breaks down twice as quickly when in free form.
- the face cream was prepared as follows:
- Table 7 Composition of a face cream.
- Aqueous gel [299] Aqueous gel:
- conjugate 9 in a cosmetic gel was carried out as follows: [301] Procedure: Homogenize phase A (see Table 7) with vigorous stirring (1500 revolutions / min) for 20 minutes. Then, introduce phase B (see Table 7) and homogenize until the powders have completely dissolved. Prepare the phase C premix (see Table 7) then introduce it into the mixture and homogenize with vigorous stirring for 15 minutes. Introduce phase D (see Table 7) then homogenize until the powders have completely dissolved. Finally, adjust to pH at 5.0-5.5 with phase E. [302] Table 6: Composition of an aqueous gel.
- the objective of this study is to evaluate ex vivo, on skin explants of human origin, the promoting effect of transdermal passage of an innovative skin delivery system according to the present invention.
- the tracer used to compare the 2 formulations is retinol.
- F 1 Retinol ((0.9% retinol equivalent) vectorized with phytol in nanoparticulate form
- F2 Retinol (0.9% retinol equivalent) in free form with a propenetrating agent (transcutol to
- NB The use of trancutol is regulated and limited to 2.6% for leave-in body applications.
- the human skin samples are obtained from a plastic surgery department of a clinic in Tours (France), after an abdominoplasty operation. Following the operation, the skin is placed in an enclosure at a temperature of 4 ° C and then transferred to our establishment.
- the hypodermis Upon receipt, the hypodermis is gently removed and the skin sample is recorded with an encrypted identification number and then stored at -20 ° C. According to OECD guidelines (Test No. 428), the skin can be stored at this temperature for up to one year without changing its permeability.
- a sample of human skin is divided into 10 skin explants of dimension 3 ⁇ 3 cm.
- the explants are thawed at room temperature for 10 minutes then cleaned with PBS.
- the integrity of the skin barrier of each explant is checked by measuring the insensible water loss (IWL). PIE values measured for the 10 skin explants being between 5.2 and 7.6 gm 2 .h _1, skin explants are considered suitable for experimentation. The thickness of each explant is measured at five different places.
- IWL insensible water loss
- the receiving compartments are filled with receiving liquid. Particular care is taken to avoid the formation of air bubbles under the skin explants.
- the diffusion cells are placed on a magnetic plate to keep the receiving liquid in agitation, and the whole is placed in an oven making it possible to obtain a temperature at the surface of the skin of 32 ° C. and a humidity level of 50%.
- the speed of agitation of the receiving liquid during the duration of the experiment is fixed at 400 rpm.
- the formulations are in the form of an emulsion, the applications are therefore carried out with a positive displacement pipette.
- the amount deposited on the surface of the skin is 500 mg.
- the epidermis and dermis are separated by lightly scraping the surface or if necessary by heating to 65 ° C for 15 seconds.
- Table 13 Average quantity of retinol (pg / cm 2 ) in the skin layers (24 hours of extraction).
- the amount of retinol measured in the dermis is of the same order as that of the control ( ⁇ 0.2 pg / cm 2 ).
- the three formulas do not seem to allow the diffusion of retinol into the dermis.
- formulation F2 is the one which is the least effective in allowing transdermal diffusion of retinol.
- Formulation F1 shows the most interesting results in terms of the amount of retinol transported to the stratum corneum and epidermis regardless of the condition.
- PhytoVec are emulsions prepared from compounds with self-assembly properties.
- these emulsions called PhytoVec-retinol, are made from retinyl phytolate as follows:
- Preparation of the aqueous phase composed of demineralized water and which may include a surfactant and propanediol Preparation of the oily phase composed of a solubilizer, retinyl phytolate and BHT (butyl hydroxytoluene)
- aqueous phase composed of demineralized water, hydrogenated lecithin and which may include propanediol
- the graph of FIG. 5 represents the results of the tests in light (20 ° C).
- the graph of FIG. 6 represents the results of the tests at 4 ° C.
- the active content for the liposomes decreases quite rapidly, while that for VR_20ER_014_ B and VR_20ER_026_ A remain high for the first 7 days. Then (7 to 30 days), the levels of active for VR_20ER_014_ B and VR_20ER_026_ A decrease, while remaining higher than that of liposomes to finally reach significantly the level of retinol liposomes at 90 days.
- the objective of this study is to evaluate ex vivo, on skin explants of human origin, the promoting effect of the transdermal passage of the PhytoVec system according to the present invention.
- Each formulation is applied to a skin explant. At the end of the contact period (24 hours), the total concentration of retinyl phytolate is measured in the different skin layers (corneal layer, epidermis and dermis) and a diffusion kinetics on 4 points is carried out.
- a sample of human skin is divided into 15 skin explants of dimension 3x3 cm. The explants are thawed at room temperature for 10 minutes then cleaned with PBS.
- the receiving compartments are filled with receiving liquid (no air bubbles under the skin explants).
- the diffusion cells are placed on a magnetic plate to keep the receiving liquid in agitation, and the whole is placed in an oven making it possible to obtain a temperature at the surface of the skin of 32 ° C. and a humidity level of 50%.
- the speed of agitation of the receiving liquid during the duration of the experiment is fixed at 400 rpm 1 .
- the amount deposited on the surface of the skin is 500 mg.
- All of the receiving liquid is placed in a 15 mL “Falcon®” tube and then frozen.
- the epidermis and dermis are separated by lightly scraping the surface or if necessary by heating to 65 ° C for 15 seconds.
- the epidermis and dermis are placed individually in a 15 mL "Falcon®” tube, weighed and finally frozen.
- retinyl phytolate The greatest proportion of retinyl phytolate (approximately 75%) is found in the stratum corneum with an average cumulative amount of 8 pg / cm 2 .
- the epidermis represents the skin layer where 20% of the total retinyl phytolate measured in the skin is found.
- the average cumulative quantity of retinyl phytolate is 2 ⁇ g / cm 2
- the formulation VR 20ER 026 A makes it possible to obtain the best result.
- retinyl phytolate is found at a proportion of 2% compared to the previous layers, which represents on average 0.2pg / cm 2 .
- the average cumulative quantity of retinyl phytolate measured is 200 times greater than that found in retinol in the case of gel C. This result indicates that these formulations allow the stratum corneum to be loaded with retinol.
- retinyl phytolate is found in proportions twice as high as that measured in retinol in the case of gel C
- the cumulative amount of retinyl phytolate obtained with gels D and E is comparable to that obtained for retinol in gel C.
- the gel E including VR 20ER 026 A allows an average total administration of retinyl phytolate which is greater than that obtained with the gel D including VR_20ER_014_B.
- the transdermal distribution of retinyl phytolate is greater compared to gel formulations.
- PhytoVec formulations mainly allow the stratum corneum to be loaded with retinyl phytolate, thus forming a reservoir providing release of the molecule in the underlying layers.
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Abstract
Description
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Priority Applications (7)
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IL297711A IL297711A (en) | 2020-05-20 | 2021-05-20 | A conjugate containing a conjugated terpene |
CN202180035599.0A CN115916142A (zh) | 2020-05-20 | 2021-05-20 | 偶联萜烯缀合物 |
CA3176403A CA3176403A1 (fr) | 2020-05-20 | 2021-05-20 | Conjugue terpenique de couplage |
EP21733848.2A EP4153322A1 (fr) | 2020-05-20 | 2021-05-20 | Conjugue terpenique de couplage |
KR1020227043023A KR20230013044A (ko) | 2020-05-20 | 2021-05-20 | 커플링된 테르펜 컨쥬게이트 |
AU2021281592A AU2021281592A1 (en) | 2020-05-20 | 2021-05-20 | Coupled terpene conjugate |
JP2022566069A JP2023526904A (ja) | 2020-05-20 | 2021-05-20 | カップリングテルペンコンジュゲート |
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FR2005150A FR3110427B1 (fr) | 2020-05-20 | 2020-05-20 | Conjugué terpenique de couplage |
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CN (1) | CN115916142A (fr) |
AU (1) | AU2021281592A1 (fr) |
CA (1) | CA3176403A1 (fr) |
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2020
- 2020-05-20 FR FR2005150A patent/FR3110427B1/fr active Active
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2021
- 2021-05-19 US US17/324,615 patent/US20210361771A1/en active Pending
- 2021-05-20 JP JP2022566069A patent/JP2023526904A/ja active Pending
- 2021-05-20 IL IL297711A patent/IL297711A/en unknown
- 2021-05-20 EP EP21733848.2A patent/EP4153322A1/fr active Pending
- 2021-05-20 KR KR1020227043023A patent/KR20230013044A/ko unknown
- 2021-05-20 CA CA3176403A patent/CA3176403A1/fr active Pending
- 2021-05-20 WO PCT/FR2021/050905 patent/WO2021240099A1/fr active Application Filing
- 2021-05-20 CN CN202180035599.0A patent/CN115916142A/zh active Pending
- 2021-05-20 AU AU2021281592A patent/AU2021281592A1/en active Pending
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FR3110427A1 (fr) | 2021-11-26 |
EP4153322A1 (fr) | 2023-03-29 |
KR20230013044A (ko) | 2023-01-26 |
CN115916142A (zh) | 2023-04-04 |
JP2023526904A (ja) | 2023-06-26 |
AU2021281592A1 (en) | 2022-11-17 |
FR3110427B1 (fr) | 2023-07-14 |
CA3176403A1 (fr) | 2021-12-02 |
IL297711A (en) | 2022-12-01 |
US20210361771A1 (en) | 2021-11-25 |
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