AU2013269583B2 - Oil/water-emulsion-type topical compositions containing a retinoid - Google Patents
Oil/water-emulsion-type topical compositions containing a retinoid Download PDFInfo
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- AU2013269583B2 AU2013269583B2 AU2013269583A AU2013269583A AU2013269583B2 AU 2013269583 B2 AU2013269583 B2 AU 2013269583B2 AU 2013269583 A AU2013269583 A AU 2013269583A AU 2013269583 A AU2013269583 A AU 2013269583A AU 2013269583 B2 AU2013269583 B2 AU 2013269583B2
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- Prior art keywords
- hydrogen atom
- radical
- composition according
- cutaneous
- carbon atoms
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- 239000000203 mixture Substances 0.000 title claims abstract description 101
- 150000004492 retinoid derivatives Chemical class 0.000 title abstract description 5
- 230000000699 topical effect Effects 0.000 title description 5
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 58
- 125000004432 carbon atom Chemical group C* 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 35
- -1 alkyl radical Chemical class 0.000 claims description 25
- 239000004480 active ingredient Substances 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 239000012071 phase Substances 0.000 claims description 21
- 208000035475 disorder Diseases 0.000 claims description 20
- 210000002615 epidermis Anatomy 0.000 claims description 20
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 19
- 239000003921 oil Substances 0.000 claims description 19
- 235000019198 oils Nutrition 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 229920000642 polymer Polymers 0.000 claims description 16
- 229960005323 phenoxyethanol Drugs 0.000 claims description 13
- 210000003491 skin Anatomy 0.000 claims description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- GHHURQMJLARIDK-UHFFFAOYSA-N 2-hydroxypropyl octanoate Chemical compound CCCCCCCC(=O)OCC(C)O GHHURQMJLARIDK-UHFFFAOYSA-N 0.000 claims description 11
- 239000006184 cosolvent Substances 0.000 claims description 11
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 9
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- 230000002500 effect on skin Effects 0.000 claims description 8
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 6
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 6
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 6
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 claims description 5
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 claims description 5
- 229940043375 1,5-pentanediol Drugs 0.000 claims description 5
- ZQCIPRGNRQXXSK-UHFFFAOYSA-N 1-octadecoxypropan-2-ol Chemical compound CCCCCCCCCCCCCCCCCCOCC(C)O ZQCIPRGNRQXXSK-UHFFFAOYSA-N 0.000 claims description 5
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 claims description 5
- 241000196324 Embryophyta Species 0.000 claims description 5
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- 208000009621 actinic keratosis Diseases 0.000 claims description 5
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- 229940031578 diisopropyl adipate Drugs 0.000 claims description 5
- LLRANSBEYQZKFY-UHFFFAOYSA-N dodecanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCCCCCC(O)=O LLRANSBEYQZKFY-UHFFFAOYSA-N 0.000 claims description 5
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 claims description 5
- 230000035876 healing Effects 0.000 claims description 5
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- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 5
- 239000001814 pectin Substances 0.000 claims description 5
- 229920001277 pectin Polymers 0.000 claims description 5
- 235000010987 pectin Nutrition 0.000 claims description 5
- WCVRQHFDJLLWFE-UHFFFAOYSA-N pentane-1,2-diol Chemical compound CCCC(O)CO WCVRQHFDJLLWFE-UHFFFAOYSA-N 0.000 claims description 5
- 230000019612 pigmentation Effects 0.000 claims description 5
- 229940078491 ppg-15 stearyl ether Drugs 0.000 claims description 5
- 239000001944 prunus armeniaca kernel oil Substances 0.000 claims description 5
- 208000017520 skin disease Diseases 0.000 claims description 5
- 229960005078 sorbitan sesquioleate Drugs 0.000 claims description 5
- 150000003626 triacylglycerols Chemical class 0.000 claims description 5
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims description 4
- 244000144725 Amygdalus communis Species 0.000 claims description 4
- 235000011437 Amygdalus communis Nutrition 0.000 claims description 4
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 claims description 4
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 4
- 206010040925 Skin striae Diseases 0.000 claims description 4
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- 239000003246 corticosteroid Substances 0.000 claims description 4
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- 230000002538 fungal effect Effects 0.000 claims description 4
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- 229920005862 polyol Polymers 0.000 claims description 4
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- 239000004302 potassium sorbate Substances 0.000 claims description 4
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- 230000005855 radiation Effects 0.000 claims description 4
- 230000009885 systemic effect Effects 0.000 claims description 4
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- 239000005711 Benzoic acid Substances 0.000 claims description 3
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
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- 235000010493 xanthan gum Nutrition 0.000 claims description 3
- 229940082509 xanthan gum Drugs 0.000 claims description 3
- DWHIUNMOTRUVPG-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCO DWHIUNMOTRUVPG-UHFFFAOYSA-N 0.000 claims description 2
- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 claims description 2
- LVDKZNITIUWNER-UHFFFAOYSA-N Bronopol Chemical compound OCC(Br)(CO)[N+]([O-])=O LVDKZNITIUWNER-UHFFFAOYSA-N 0.000 claims description 2
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
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- SOROIESOUPGGFO-UHFFFAOYSA-N diazolidinylurea Chemical compound OCNC(=O)N(CO)C1N(CO)C(=O)N(CO)C1=O SOROIESOUPGGFO-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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Abstract
The invention relates to a composition in the form of an oil-in-water emulsion, preferably free of emulsifying agents, comprising, in a physiologically acceptable medium, at least one particular retinoid. The invention also relates to the method for preparing such a composition and to the cosmetic and dermatological use thereof.
Description
Oil/water-emulsion-type topical compositions containing a retinoid
The invention relates to a composition in the form of emulsion comprising, in a physiologically acceptable environment, at least one new retinoid with the general formula (I)
(I) where:
Ri is a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a -CF3 radical; R2 is a hydrogen atom, an alkyl or alkoxy radical of 1 to 4 carbon atoms or a chlorine atom; R3 is a hydrogen atom, or a linear or branched alkyl or alkoxy radical of 1 to 10 carbon atoms possibly substituted by a methoxy group; R4 is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms; R5 is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms; or R4 and R5 together form, with the -N-C(=Y)- bond, a ring of the pyrrolidine, pyrrolidinone, piperidine or piperidinone type; Y denotes two hydrogen atoms or a heteroatom such as oxygen or sulfur;
Ar denotes a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring; X denotes an oxygen atom, possibly substituted by an alkyl or alkylamine chain or a single C-C bond; A denotes a hydrogen atom or the following formula:
where o Q is an oxygen atom or the bond-NH-; o Rg denotes a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical of 3 to 6 carbon atoms, a -C(0)CH2 or -C(0)CH2CH3 radical; o R7 and R/ denote, independently of each other, a hydrogen atom or a hydroxyl group, on condition that R7 and R/ are not simultaneously a hydroxyl group; n is equal to 0,1, 2, 3, 4 or 5.
These compounds, described in patent EP1831149, are potent retinoids modulating the nuclear receptor of retinoic acid (RAR), more specifically of the gamma subtype of this receptor (RARy).
The receptors RARs activate the transcription by binding with elements of DNA sequences, called the RAR Element (RARE) response elements, in the form of a heterodimer with the X receptors of the retinoids (called RXRs).
Three subtypes of human RARs have been identified and described: RARa, RARp and RARy.
Since the gamma RAR receptors are located in the epidermis it is important for the compounds described in the general formula (I) to be released in this part of the skin to provide clinical efficacy.
The topical application of retinoids may result in irritation of the skin, dryness and erythema. Numerous articles describe this irritating effect, such as the articles by Stiicker & al. Skin Res Technol. 2002 May;8(2):133-40 or by Thielitz & al. Am J Clin Dermatol. 2008;9(6):369-81.
To obtain topical preparations for pharmaceutical use containing retinoids, numerous techniques are used, in particular emulsions such as those referred to in the patent EP-826366, which describes emulsions which may contain retinoids, or even patent EP-989846, which describes emulsions containing retinoids and at least one emulsifier.
Emulsifiers are molecules that belong to the chemical family of amphiphilic molecules, which are often irritating. Compositions without emulsifiers are in fact less irritating that those containing them.
The fact that emulsifiers are not used in the compositions containing retinoids would therefore enable cutaneous irritation due to the presence of this class of molecule to be limited.
The prior art describes O/W emulsions with or without emulsifier. We may cite, in particular, patent US 5,851,538, which describes formulations with or without emulsifier with porous microspheres containing a practically continuous network of pores open to the outside and comprising retinoids.
Nevertheless, although the compounds described by the general formula (I) exhibit interesting chemical and physical stability properties for preparations for pharmaceutical uses, they degrade chemically in many of their solvents.
There is therefore a need for stable, well tolerated pharmaceutical compositions containing compounds described by general formula (I). A first aspect relates to an oil-in-water emulsion-type composition comprising a fatty phase comprising: a compound with general formula (I)
where:
Ri is a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a -CF3 radical; R2 is a hydrogen atom, an alkyl or alkoxy radical of 1 to 4 carbon atoms or a chlorine atom; R3 is a hydrogen atom, or a linear or branched alkyl or alkoxy radical of 1 to 10 carbon atoms possibly substituted by a methoxy group; R4 is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms; R5 is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms; or R4 and R5 together form, with the -N-C(=Y)- bond, a ring of the pyrrolidine, pyrrolidinone, piperidine or piperidinone type; Y denotes two hydrogen atoms or a heteroatom such as oxygen or sulfur;
Ar denotes a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring; X denotes an oxygen atom, possibly substituted by an alkyl or alkylamine chain or a single C-C bond; A denotes a hydrogen atom or the following formula:
where: o Q is an oxygen atom or the bond-NH-; o R6 denotes a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical of 3 to 6 carbon atoms, a -C(0)CH2 or -C(0)CH2CH3 radical; o R7 and R/ denote, independently of each other, a hydrogen atom or a hydroxyl group, on condition that R7 and R7' are not simultaneously a hydroxyl group; n is equal to 0, 1, 2, 3, 4 or 5 ; at least one principal solvent of the compound (I) selected from among benzyl alcohol, laureth-4, phenoxyethanol, propylene glycol monocaprylate, pentylene glycol, dimethyl isosorbide and mixtures thereof, and at least one co-solvent oil of the compound (I) selected from among the caprylic/capric triglycerides, sweet almond oil, propylene glycol monocaprylate, propylene glycol laurate, sorbitan sesquioleate, diisopropyl adipate, PPG-15 stearyl ether, apricot kernel oil PEG-6 ester, and mixtures thereof, and an aqueous phase comprising at least one gelifying agent selected from polymers of plant origin, gums, pectins, cellulose and its derivatives, polymers of microbiological origin and gelifying polymers of synthetic origin. A second aspect relates to a composition such as described above for its use as a medicinal product. A third aspect relates to a composition as described above for its use in the treatment of pathologies such as: 1) dermatological complaints associated with a keratinisation disorder relating to cellular differentiation and proliferation, particularly for treating common acnes, comedonic acnes, polymorphic acnes, rosacea acnes, nodulocystic acnes, conglobata acne, senile acnes and secondary acnes such as solar, medicamentous or professional acne; 2) keratinisation disorders, in particular ichtyoses, ichtyosiform conditions, lamellar ichtyosis, Darrier's disease, palmoplantar keratodermias, leukoplasias, pityriasis rubra pilaris and leukoplasiform conditions, cutaneous or mucous (oral) lichen; 3) dermatological disorders with an inflammatory immune-allergic component, with or without cellular proliferation disorder, and in particular all forms of psoriasis, whether cutaneous, mucous or ungueal, and even psoriasic rheumatism, or atopical dermatitis and the different forms of eczema; 4) cutaneous disorders due to exposure to UV radiation, as well as to repair or control ageing of the skin, whether photo-induced or chronological, or to reduce pigmentations and actinic keratoses, or all pathologies associated with chronological or actinic ageing, such as xerosis, pigmentations and wrinkles; 5) any condition associated with benign dermal or epidermal proliferations, whether or not of viral origin, such as common warts, flat warts, molluscum contagiosum and verruciform epidermodysplasia, oral or florid papillomatoses; 6) dermatological complaints such as immune dermatoses such as erythematous lupus, bullous immune diseases and collagenic diseases such as sclerodermia; 7) stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy; 8) healing complaints, or to prevent or repair stretch marks, or else to promote healing; 9) any disorder of fungal origin in the cutaneous region, such as tinea pedis and tinea versicolor; 10) pigmentation disorders such as hyperpigmentation, melasma, hypopigmentation or vitiligo ; 11) cancerous or pre-cancerous, cutaneous or mucous conditions such as actinic keratoses, Bowen's disease, carcinomas in-situ, keratoacanthoma and skin cancers such as basocellular carcinoma (BCC), spinocellular carcinoma (SCC) and cutaneous lymphomas such as T lymphoma. A fourth aspect relates to a method for the treatment of cutaneous lymphomas comprising administering the composition as described above to a patient in need thereof. A fifth aspect relates to use of a fatty phase comprising: a compound with general formula (I)
where :
Ri is a hydrogen atom, an alkyl radical of 1 to 4 carbons or a -CF3 radical; R2 is a hydrogen atom, an alkyl or alkoxy radical of 1 to 4 carbon atoms or a chlorine atom; R3 is a hydrogen atom, or a linear or branched alkyl or alkoxy radical of 1 to 10 carbon atoms possibly substituted by a methoxy group; R4 is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms; R5 is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms; or R4 and R5 together form, with the -N-C(=Y)- bond, a ring of the pyrrolidine, pyrrolidinone, piperidine or piperidinone type; Y denotes two hydrogen atoms or a heteroatom;
Ar denotes a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring; X denotes an oxygen atom, possibly substituted by an alkyl or alkylamine chain or a single C-C bond; A denotes a hydrogen atom or the following formula:
where o Q is an oxygen atom or the bond -NH-; o R6 denotes a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical of 3 to 6 carbon atoms, a -C(0)CH2 or -C(0)CH2CH3 radical; o R7 and R/ denote, independently of each other, a hydrogen atom or a hydroxyl group, on condition that R7 and R/ are not simultaneously a hydroxyl group; n is equal to 0,1, 2,3, 4 or 5 ; at least one principal solvent of compound (I), selected from among benzyl alcohol, laureth-4, phenoxyethanol, propylene glycol monocaprylate, pentylene glycol, dimethyl isosorbide and mixtures thereof, and at least one co-solvent oil of compound (I), selected from among the caprylic/capric triglycerides, sweet almond oil, propylene glycol monocaprylate, propylene glycol laurate, sorbitan sesquioleate, diisopropyl adipate, PPG-15 stearyl ether, apricot kernel oil PEG-6 ester, and mixtures thereof, and an aqueous phase comprising at least one gelifying agent, selected from polymers of plant origin, gums, pectins, cellulose and its derivatives, polymers of microbiological origin and gelifying polymers of synthetic origin in the manufacture of an oil-in-water emulsion-type composition for the treatment of cutaneous lymphomas. A sixth aspect relates to a method for preparing an oil-in-water emulsion-type composition as described above and comprising the following stages: a) solubilisation of the hydrophilic excipients under agitation b) solubilisation under agitation of the retinoid in the principal solvent c) addition of the lipophilic excipients d) gelification of the aqueous phase by adding the gelifier e) addition of the oily phase, then the silicone oil. A seventh aspect relates to the compositions comprising a compound with general formula (I)
And at least one polyacrylamide gelifier, characterised in that the maximum quantity of active ingredient absorbed in the epidermis 16 hours after application is between 6 ng/cm2 and 19 ng/cm2.
An eighth aspect relates to the oil-in-water emulsion-type compositions comprising a compound with general formula (I)
And at least one polyacrylamide gelifier, characterised in that the maximum quantity of active ingredient absorbed in the epidermis is obtained between 3 and 10 hours after application and preferably between 5 and 7 hours after application.
The invention will be described in greater detail in the description and the examples which follow, and also in the appended figures in which:
Figure 1 presents the distribution profile in the various compartments of the skin of a composition according to the invention.
Figure 2 presents the kinetics of penetration into the epidermis of a composition according to the invention.
Figure 3 presents the results of a study of tolerance of a composition according to the invention, compared with a reference gel.
Detailed description of the invention
To facilitate the reading of this description reference will be made to general formula (I) and compound A in the remaining text, as being described thus:
General formula (I):
where:
Ri is a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a -CF3 radical; R2 is a hydrogen atom, an alkyl or alkoxy radical of 1 to 4 carbon atoms or a chlorine atom; R3 is a hydrogen atom, or a linear or branched alkyl or alkoxy radical of 1 to 10 carbon atoms optionally substituted by a methoxy group; R4 is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms; R5 is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms; or R4 and R5 together form, with the -N-C(=Y)- bond, a ring of the pyrrolidine, pyrrolidinone, piperidine or piperidinone type; Y denotes two hydrogen atoms or a heteroatom such as oxygen or sulfur;
Ar denotes a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring; X denotes an oxygen atom, possibly substituted by an alkyl or alkyamine chain or a single C-C bond; A denotes a hydrogen atom or the following formula:
where o Q is an oxygen atom or the bond-NH-; o R6 denotes a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical of 3 to 6 carbon atoms, a -C(0)CH2 or -C(0)CH2CH3 radical; o R7 and R7' denote, independently of each other, a hydrogen atom or a hydroxyl group, on condition that R7 and R/ are not simultaneously a hydroxyl group; n is equal to 0,1, 2, 3, 4 or 5.
Compound A: as being 3"-tert-butyl-4,-(2-hydroxy-ethoxy)-4"-pyrrolidin-l-yl-[l,l,;3,,l"]-terphenyl-4-carboxylic acid.
Due to the physico-chemical characteristics of the active ingredient, the Applicant has had to face a certain number of constraints in the use of the compounds described by general formula (I).
These compounds: -are soluble in few solvents normally used in the fatty phases of the topical emulsions - degrade chemically in many of their solvents - degrade chemically in the presence of numerous emulsifiers. A first subject according to this invention describes compositions containing at least one compound with general formula (I) in the form of emulsions of the type O/W (Oil in Water) and in which the active ingredient is solubilised in the fatty phase.
According to a particularly preferred embodiment, the composition according to the invention does not contain any emulsifier.
These emulsions exhibit good physical and chemical stability, a rapid rate of penetration and a high level of penetration in the epidermis and/or the dermis.
Emulsion is understood to mean a macroscopically homogeneous but microscopically heterogeneous mixture of two immiscible liquid substances that we shall call phases. An O/W (oil in water) emulsion consists of a fatty (or oily) phase dispersed in an aqueous phase.
In the invention the compositions contain the active ingredient described by general formula (I) at concentrations ranging from 0.00001% to 1% by weight, preferably from 0.0001 to 0.1 % by weight, and more preferably from 0.001 to 0.1 % by weight, relative to the total weight of the composition.
Preferably the active ingredient described by general formula (I) is compound A.
In the invention the compositions contain at least one gelifying agent.
The term "gelifying agent" is intended to mean a polymer compound capable of conferring on the composition the texture of a gel.
The gelifying agent (s) may in particular be selected from polymers of plant origin, gums, pectins, cellulose and its derivatives, polymers of microbiological origin, such as xanthan gum, and gelifying polymers of synthetic origin.
By way of non-exhaustive example of gelifiers that may enter into the compositions, mention may be made of Acrylates/C10-30 Alkyl Acrylate Crosspolymer, sold under the name of Pemulen TR-1 or Pemulen TR-2 by the company Lubrizol, gelifiers in the polyacrylamide family, such as the mixture of Sodium acrylamide/acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80, sold under the name of Simulgel 600PHA by the company SEPPIC, and the mixture of polyacrylamide/isoparaffin C13-14/laureth-7 sold under the name of Sepigel 305 by the company SEPPIC, the carbomers sold under the name of Ultrez 20®, Ultrez 10®, Carbopol 1382® or Carbopol ETD2020NF®, Carbopol 981 or even Carbopol 980 by the company Lubrizol, the polysaccharides with, by way of non-exhaustive examples, xanthan gum, such as Xanturall80® sold by the company Kelco, gellan gum sold under the name of Kelcogel by the company Kelco, guar gum, cellulose and its derivatives, such as microcrystalline cellulose and carboxymethyl cellulose of sodium sold under the name of Avicel CL-611 by the company FMC Biopolymer, hydroxypropylmethylcellulose, in particular the product sold under the name of Methocel E4M premium by the company Dow Chemical, or hydroxyethylcellulose, in particular the product sold under the name of Natrosol HHX 250® by the company Ashland, sodium carboxymethylcellulose, in particular Blanose cellulose gum 7F sold by the company Ashland, the family of aluminium magnesium silicates, such as Veegum K sold by the company Vanderbilt, the family of acrylic polymers coupled to hydrophobic chains such as PEG-150/decyl/SMDI copolymer sold under the name of Aculyn 44 (polycondensate, comprising, at least as elements, a polyethylene glycol with 150 or 180 mols of ethylene oxide, decyclic alcohol and methylene bis(4-cyclohexylisocyanate) (SMDI), at 35% by weight in a mixture of propylene glycol (39%) and water (26%)), the family of modified starches such as modified potato starch sold under the name of Structure Solanacee or their mixtures, the family of the carrageenans, particularly those distributed among four major families: κ, λ, β, ω, such as Viscarin® and the Gelcarin® marketed by the company IMCD.
Preferably a gelifying agent of the polyacrylamide type, such as Simulgel 600 PHA®, which has thickening and stabilising properties, is used in concentrations ranging from 0.005 to 5 % by weight, and preferably ranging from 1% to 4% by weight.
The person skilled in the art knows that for an emulsifier system the proportion of emulsifier required to emulsify a fatty phase in an oil in water emulsion is normally of the order of 1/5 of the % of the fatty phase. By way of non-exhaustive example a fatty phase representing at least 11% of the ingredients of the formulas would require a minimum of 2.2% of emulsifiers.
According to a preferred embodiment of the invention, no emulsifier is used. However, it is possible in spite of this that certain ingredients contain low percentages of emulsifier in their own composition. Because of the low percentage that may result from this in the composition according to the invention, they cannot have the function of an emulsifier in the composition (content preferably lower than 0.6% by weight, relative to the total weight of the composition).
In the invention the compositions contain a fatty phase that may consist of: - a principal solvent of an active ingredient described by general formula (I), which may be in particular benzyl alcohol, laureth-4, phenoxyethanol, propylene glycol monocaprylate, pentylene glycol or dimethyl isosorbide, and preferably phenoxyethanol sold, for example, under the name phenoxetol by Clariant.
When the principal solvent is phenoxyethanol, the amount of phenoxyethanol ranges from 0.2 to 5% by weight and preferably from 0.5 to 2% by weight relative to the total weight of the composition.
The term "principal solvent" is intended to mean a liquid which has the property of dissolving, diluting or extracting other substances without causing any chemical modification of these substances and without itself being modified.
According to the invention, a principal solvent is such a liquid, in which the compounds with the general formula (I) (and more preferably the compound A) have a solubility, at ambient temperature and atmospheric pressure, greater than or equal to 0.1% by weight. - one or more co-solvent oils of an active ingredient described by general formula (I), which may be, in preference, chosen from the following co-solvent oils: Caprylic/ capric triglycerides (Miglyol 812N) supplied by IMCD, Prunus Amygdalus Dulcis (Sweet Almond) oil supplied by SICTIA, Propylene glycol monocaprylate (Capryol 90) supplied by GATTEFOSSE, Propylene glycol laurate (Lauroglycol FCC) supplied by GATTEFOSSE, Sorbitan Sesquioleate (Arlacel 83VPharma) supplied by CRODA, Diisopropyl Adipate (Crodamol DA) supplied by CRODA, PPG-15 stearyl ether (Arlamol PS15E-LQ) supplied by CRODA, Apricot Kernel Oil PEG-6 Ester (Labrafil M1944CS) supplied by GATTEFOSSE in proportions which can range from 0.5 to 50% by weight and preferably from 4 to 30% by weight.
The term "co-solvent" is intended to mean a substance having the role of solvent in combination with another substance.
In the invention the compositions described above may also contain additives (among which mention may be made of the following categories, used alone or in combination): - One or more silicone oils that improve the properties of the formula on application, such as Cyclomethicone (St-Cyclomethicone 5NF) or Dimethicone (Q7 9120 silicon fluid, with a viscosity of 20 cst to 12500 cst from Dow Corning) between 0 and 10%, and preferably between 0 and 4%. - One or more preservatives such as methyl parabene, propyl parabene, benzalconium chloride, phenoxyethanol sold under the name of phenoxetol by Clariant, benzyl alcohol sold under the name benzyl alcohol by Merck, potassium sorbate sold under the name of potassium Sorbate by VWR, benzoic acid sold under the name Benzoic Acid by VWR, 2-Bromo-2-Nitropropane-l,3-Diol sold under the name of Bronopol by Jan Dekker International, Chlorohexidine sold under the name of Chlorohexidine digluconate 20% solution by Arnaud Pharmacie, chlorocresol and its derivatives, sodium benzoate sold under the name of Probenz SP by the company Unipex, ethyl alcohol and diazolidinyl urea. These preservatives may be used alone or in combination for effective protection of formulas against all bacterial contamination in contents ranging from 0% to 5% by weight, and preferably from 0.01 to 2% by weight.
The term "preservative" denotes any substance capable of opposing the modifications of chemical or microbiological origin of a product. - Ethanol, the quantity of which may be between 0 and 30% by weight and preferably between 0 and 10% by weight. - Moistening agents, preferably polyols and preferably selected from among propylene glycol, glycerine, diglycerine or sorbitol (Neosorb supplied by ROQUETTE, Parteck SI supplied by Merck, but also Sorbitol USP Powder supplied by LIPO CHEMICALS), whose quantity ranges from 0 to 40% by weight relative to the total weight of the composition, and preferably from 5 to 35%. -Chelating agents such as EDTA (ethylene diamine tetraacetic acid) and its derivatives or salts, dihydroglycerine, citric and tartaric acids, gluconolactone sold under the name glucono-delta-lactone SG by Jungbunzlauer or mixtures thereof. -Antioxidants such as vitamin E and its derivatives, such as DL alpha tocopherol or tocopherol acetate from Roche; vitamin C and its derivatives, such as Ascorbyl Palmitate from Roche, Butylhydroxy toluene sold under the name of Nipanox BHT by Clariant. -Palliatives and/or anti-irritants such as PPG-12/SMDI copolymer sold by Bertek Pharmaceuticals under the commercial name of Polyolprepolymer-2, glycyrrhetinic acid or its derivatives, for example Enoxolone sold by the company BASF, hyaluronic acid as such or in its form of sodium hyaluronate sold under the commercial name of HYAL. NA PWD PH 15-51-45 by the company Contipro, allantoin sold under the name of RONACARE ALLANTOINE by MERCK. - Any other additive normally used in the pharmaceutical and cosmetic fields enabling specific properties to be assigned to the said preparation. GENERAL COMPOSITION FOR ACNE:
When it is intended for the treatment of acne, the composition according to the invention advantageously contains the following ingredients, the percentages being expressed by weight in relation to the total weight of the composition of the oil in water emulsion type. from 0.00001% to 1% and preferably from 0.0001 to 0.1 % of compound with the general formula (I) from 0.005 to 10 % and preferably from 1 to 5% of gelifier from 0.2 to 5% and preferably from 0.5 to 2% of principal solvent of the compound with the general formula (I) from 0.5 to 50% and preferably from 4 to 15% of co-solvent oils of the compound with the general formula (I) from 0 to 20% and preferably from 0 to 5% of mineral oils from 0 to 50% and preferably from 5 to 35% of polyol from 0 to 10% and preferably from 0 to 4% of silicone oil from 0 to 5% and preferably from 0.01 to 2% of preservative system from 0 to 30% and preferably from 0 to 10% of ethanol from 0 to 15% and preferably from 0.1 to 10% of additives COMPOSITIONS SUITABLE FOR ICHTYOSIS, PALMOPLANTAR HYPERKERATOSIS OR PSORIASIS:
In this case, the composition according to the invention advantageously contains the following ingredients, the percentages being expressed by weight in relation to the total weight of the composition of the oil-in-water emulsion type. from 0.00001% to 1% and preferably from 0.0001 to 0.1% of compound with the general formula (I) from 0.005 to 10 % and preferably from 1 to 5% of gelifier from 0.2 to 5% and preferably from 0.5 to 2% of principal solvent of the compound with the general formula (I) from 0.5 to 50% and preferably from 10 to 30% of co-solvent oils of the compound with the general formula (I) from 1 to 50% and preferably from 10 to 30% of polyol from 0 to 10% and preferably from 0 to 4% of silicone oil from 0 to 5% and preferably from 0.01 to 2% of preservative system from 0 to 15% and preferably from 0.1 to 10% of additives
Another object according to the invention relates to a method of preparing a composition described as above and comprising the following stages: A) Preparation of the aqueous phase
Solubilisation of the hydrophilic excipients under agitation, if necessary under heat B) Preparation of the oily phase
In a suitable receptacle, solubilisation under agitation, of compound A in Phenoxyethanol, under heat if necessary.
Allow to return to ambient temperature and add the lipophilic excipients except the silicone oil (for example ST-cyclomethicone 5) when this is present. C) Mixing of the two phases.
At ambient temperature gelify the aqueous phase by adding the gelifier (for example Simulgel 600PHA), then add the oily phase then the silicone oil when this is present.
Examples
Example 1 - Pre-formulation
In order to obtain an oil in water emulsion containing a compound with the general formula (I) in the fat phase, pre-formulation studies have been conducted to identify the excipients allowing good solubilisation as well as good stability of the active ingredient. (1) List of fat phase excipients in which the maximum solubility has been determined by HPLC :
The limit below which the compounds with the general formula (I) are considered as being not solubilised is 0.1% by weight. (2) Stability of compound A in its principal solvents:
These stability studies of compound A in its principal solvents show that compound A degrades chemically in a number of its solvents.
These results have enabled us to select our principal solvent (phenoxyethanol) and our co-solvent oils from among the solvent oils which exhibit good stability results, with the aim of developing O/W emulsions in which compound A is solubilised in the oily phase.
(3) Stability of compound A in mixtures of excipients (solvent/surfactants) determined by HPLC :
Studies of stability of compound A solubilised in oils (in which it is stable) in the presence of surfactants have been conducted:
The limits fixed for high stability are 95%-105% as a percentage relative to TO.
These studies showed that compound A degrades chemically in the presence of numerous surfactants. Following these results we therefore decided to develop an O/W emulsion without emulsifier. EXAMPLE 2: Formulations
In the following examples the formulae are characterised at TO. The physical and chemical stability of the formulations is achieved after storage at ambient temperature (TA) and at +40°C after T+lMonth and/or T+2Months or T+3Months or T+6Months. The equipment and methods used for these characteristics are described below.
Compound A is defined as 3"-tert-butyl-4'-(2-hydroxy-ethoxy)-4"-pyrrolidin-l-yl-[l,l';3',l"]-terphenyl-4-carboxylic acid. -Chemical assaying of compound A:
-Equipment: HPLC -Expression of the results: the titre of the active ingredient is expressed as a % related to the initial % achieved at TO. The limits fixed for high stability are 95%-105%. -Macroscopic observation: - Macroscopic observation enables the physical integrity of the products at TO and after stability to be guaranteed. -Microscopic observation: - Microscopic observation enables good solubilisation of compound A from TO, nonrecrystallisation in the course of time, as well as the size of the globules in the oily phase to be evaluated. -Equipment: AXIO ZEISS Microscope fid: -Equipment: METTLER TOLEDO Seven Multi pH meter -Method : Measurements carried out at ambient temperature after 24h stabilisation in an enclosure at 25°C of all the samples. -Viscosity: -The measurement of the viscosity enables the consistency of the formulas produced to be evaluated. -Equipment: Brookfield RV DVII + Pro -Method: Measurements carried out at ambient temperature after 24h stabilisation in an enclosure at 25°C of all the samples. The value is read after 1 minute. The choice of spindle and speed will be described in each composition example. The values obtained are expressed in centipoises (Cps). -Centrifuging: -The centrifuging enables the resistance of the formulas to a mechanical stress to be evaluated.
-Equipment: Galaxy 14D VWR -Method: 30 minutes at 5000 rpm -A conforming result means that there is neither separation of phases nor exudate.
Formula 1
These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time.
Formula 2
These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time.
Formula 3
These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time.
Formula 4
These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time.
Formula 5
These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time.
Formula 6
These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time.
Formula 7
These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time.
Formula 8
These results demonstrate a good physical stability of the composition as a whole overtime.
Formula 9
These results demonstrate a good physical stability of the composition as a whole over time.
Formula 10
These results demonstrate a good physical stability of the composition as a whole overtime.
Formula 11
These results demonstrate a good physical stability of the composition as a whole overtime.
Formula 12
These results demonstrate a good physical stability of the composition as a whole overtime.
Formula 13
These results demonstrate a good physical stability of the composition as a whole over time.
Formula 14
These results demonstrate a good physical stability of the composition as a whole over time.
Formula 15
Formula 16
Formula 17
These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time.
Formula 18 (0298.0113)
These results demonstrate good physical and chemical stability of the active ingredient and of the composition as a whole over time.
Formula .19 ;.
Formula 20;
Formula 21:
Formula 22 :
Formula 23 :
These results demonstrate a good physical stability of the composition as a whole over time.
Example 3: Characterisation of the formulations by cutaneous penetration studies on human skin:
The cutaneous penetration studies enable the formulations to be characterised and the parameters peculiar to each of the formulations to be demonstrated.
Two types of cutaneous penetration studies were carried out ex vivo on human skin. In these studies compound A corresponds to 3"-tert-butyl-4,-(2-hydroxy-ethoxy)-4"-pyrrolidin-l-yl-[l,l,;3,,l"]-terphenyl-4-carboxylic acid.
The reference gel is described as follows:
1- "Single time" cutaneous penetration study:
In this study the formula is applied for 16 hours to the surface of the skin. After the application, compound A (COMPOUND A) is quantified in the different compartments of the skin: stratum corneum, epidermis, dermis and receiving liquid according to a validated bioanalysis method.
The details of the cutaneous application are given in the table below.
The bioanalysis was conducted by mass spectrometry in tandem by positive electrospray ionisation using a Xevo device (Waters). The limit of quantification for compound A is 1 ng/mL.
The conditions of LC/MS/MS developed enabled up to 0.1% of the dose applied in each of the compartments to be detected (unabsorbed dose, stratum, epidermis, dermis and receiving liquid).
The technical conditions are given in the table below.
In this type of "single point" study the parameters considered are: a. The distribution profile in the different compartments (qualitative data) b. The penetration in the epidermis + dermis compartment (numerical data) a-Distribution profile in the different compartments:
This profile is shown in Figure 1.
The distribution profile between the different compartments is of the same time for the 2 formulae evaluated: accumulation in the stratum corneum, lower rate of penetration in the epidermis, and very low penetration in the dermis. Compound A is not detected in the receiving liquid. b-Penetration values in the epidermis + dermis compartment:
The penetration values for the oil in water type emulsion without emulsifier, containing 100pg/g (0.01%) of compound A are between 6.8ng/cm2 and 10.6ng/cm2. The levels of penetration of compound A after application of the oil in water type emulsion without emulsifier tend to be higher than those obtained after application of the reference gel. 2- Penetration kinetics study:
In this type of study the penetration of the active ingredient is quantified in each compartment of the skin after 0.5 h, 1 h, 3 h, 6 h and 24 h of application. The penetration kinetics in each compartment are then determined and characterised.
The details of the cutaneous application are given in the table below:
The quantity of active ingredient in each compartment at each time was determined by LC/UV or by LC/MS. The bioanalysis method was validated so that at least 0.1% of the dose applied in each compartment could be detected.
In this type of study the parameters considered are: a. The penetration kinetics profile in the epidermis (qualitative data) b. The initial rate of penetration in the epidermis c. The maximum quantity that has penetrated the epidermis a. Penetration kinetics profile in the epidermis:
This is shown in Figure 2.
The release kinetics of compound A obtained for the oil in water type emulsion without emulsifier exhibit a high initial gradient followed by a ceiling during which the penetration of compound A no longer increases in the course of time. The reference formula (gel) shows the same kinetics with rapid release for the first few hours, after which a plateau is reached.
As seen in Section 1 ("Single time" cutaneous penetration study), these two formulae have different penetration levels at 16h, and the penetration of compound A in the epidermis after application of the oil in water emulsion without emulsifier tends to be higher than that obtained after application of the reference gel. b. Initial rate of the kinetics:
The initial value of the rate of the kinetics or gradient in the first 3 hours is 4.2ng/cm2/h. c. Maximum quantity in the epidermis:
The maximum quantity in the epidermis is 18.7ng/cm2.
Example 4 Tolerance study In this study: -10 subjects received 2 grams of gel (reference gel) applied to 1000 cm2 for 4 weeks. A reference gel is understood to mean a gel described as follows:
- 10 subjects received 2 grams of Cream B (oil in water emulsion without emulsifier-Formula 1) applied to 1000 cm2 for 4 weeks.
During the study the investigators had the opportunity of changing the area of application where irritation was excessive.
The results of the study are presented in the table below: The numerical values are the number of patients for whom a change of area was made (value N in the table), and the value in brackets is the percentage corresponding to N.
Development of the percentage of subjects for whom there is no change of area of application
Figure 3 shows the percentage of subjects for whom there was no change in the area of application as a function of the day of application.
For example, on day 5, for 90% of the subjects receiving Cream B, there was no need to change the area of application. In other words, 10% of the subjects who received Cream B suffered from an irritation requiring a change of area of application.
It is therefore established that the irritation occurs more quickly in the subjects who received the gel than in the subjects who received Cream B. A marked difference is observed from day 9 onwards.
It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.
In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.
Claims (19)
1. An oil-in-water emulsion-type composition comprising a fatty phase comprising: a compound with general formula (I)
where : Ri is a hydrogen atom, an alkyl radical of 1 to 4 carbons or a -CF3 radical; R2 is a hydrogen atom, an alkyl or alkoxy radical of 1 to 4 carbon atoms or a chlorine atom; R3 is a hydrogen atom, or a linear or branched alkyl or alkoxy radical of 1 to 10 carbon atoms possibly substituted by a methoxy group; R4 is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms; R5 is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms; or R4 and R5 together form, with the -N-C(=Y)- bond, a ring of the pyrrolidine, pyrrolidinone, piperidine or piperidinone type; Y denotes two hydrogen atoms or a heteroatom; Ar denotes a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring; X denotes an oxygen atom, possibly substituted by an alkyl or alkylamine chain or a single C-C bond; A denotes a hydrogen atom or the following formula: where
o Q is an oxygen atom or the bond-NH-; o R6 denotes a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical of 3 to 6 carbon atoms, a -C(0)CH2 or -C(0)CH2CH3 radical; o R7 and R7' denote, independently of each other, a hydrogen atom or a hydroxyl group, on condition that R7 and R/ are not simultaneously a hydroxyl group; n is equal to 0,1, 2,3, 4 or 5 ; at least one principal solvent of compound (I) selected from among benzyl alcohol, laureth-4, phenoxyethanol, propylene glycol monocaprylate, pentylene glycol, dimethyl isosorbide and mixtures thereof, and at least one co-solvent oil of compound (I) selected from among the caprylic/capric triglycerides, sweet almond oil, propylene glycol monocaprylate, propylene glycol laurate, sorbitan sesquioleate, diisopropyl adipate, PPG-15 stearyl ether, apricot kernel oil PEG-6 ester, and mixtures thereof, and an aqueous phase comprising at least one gelifying agent selected from polymers of plant origin, gums, pectins, cellulose and its derivatives, polymers of microbiological origin and gelifying polymers of synthetic origin.
2. The composition according to Claim 1, wherein the compound with general formula (I) is defined so that: Ri is a hydrogen atom, the t-butyl or i-propyl radical; R2 is a hydrogen atom, the t-butyl or i-propyl radical; R3 is a hydrogen atom or the ethyl radical; R4 and R5 are, independently from each other, the methyl or ethyl radical or together form a pyrrolidine ring; A is as previously defined, where R6 denotes a hydrogen atom, the i-propyl or t-butyl radical, a cycloalkyl radical of 3 to 6 carbon atoms, a -C(0)CH2 or -C(0)CH2CH3 radical.
3. The composition according to Claim 1, characterised in that the compound is 3"-tert-butyl-4'-(2-hydroxy-ethoxy)-4"-pyrrolidin-l-yl-[l,l';3',l"]-terphenyl-4-carboxylic acid.
4. The composition according to any one of the preceding claims, wherein it is deprived of an emulsifying agent.
5. The composition according to any one of the preceding claims, wherein the gelifying agent is selected from: - the Acrylates/C10-30 Alkyl Acrylate Crosspolymer sold under the name of Pemulen TR-1 or Pemulen TR-2, - the gelifiers in the family of polyacrylamides, - the mixture polyacrylamide/isoparaffin C13-14/laureth-7 sold under the name of Sepigel 305, - the carbomers sold under the name of Ultrez 20®, Ultrez 10®, Carbopol 1382® or Carbopol ETD2020NF®, Carbopol 981 or Carbopol 980, - the polysaccharides comprising xanthan gum, gellan gum sold under the name of Kelcogel, guar gum, cellulose and its derivatives, hydroxypropylmethylcellulose,hydroxyethylcellulose, or sodium carboxymethylcellulose, - the family of aluminium magnesium silicates, - the family of acrylic polymers linked to hydrophobic chains, - the family of modified starches or their mixtures, - the family of carrageenans.
6. The composition according to Claim 1, wherein the principal solvent is phenoxyethanol.
7. The composition according to any one of the preceding claims, wherein it also contains one or more additives selected from among: -one or more preserving agents selected from among methyl parabene, propyl parabene, benzalconium chloride, phenoxyethanol sold under the name of phenoxetol, benzyl alcohol sold under the name of benzyl alcohol, potassium sorbate sold under the name of potassium sorbate, benzoic acid, 2-bromo-2-nitropropane-l,3-diol sold under the name of Bronopol, chlorohexidine, chlorohexidine digluconate, chlorocresole and its derivatives, ethyl alcohol and diazolidinyl urea, -One or more chelating agents, - One or more antioxidants, - One or more palliatives and/or anti-irritants.
8. The composition according to any one of the preceding claims, wherein it also contains a mineral oil.
9. The composition according to any one of the preceding claims, wherein it also contains a moistening agent.
10. The composition according to any one of the preceding claims, wherein it also contains a silicone 011.
11. The composition according to any one of the preceding claims, wherein it also contains ethanol.
12. The composition according to any one of Claims 1 to 11, wherein it comprises the following ingredients: from 0.00001% to 1% by weight of compound of formula (I) from 0.005 to 10 % by weight of gelifying agent, as defined in claim 1, from 0.2 to 5% by weight of principal solvent, as defined in claim 1. from 0.5 to 50% by weight of co-solvent oil(s), as defined in claim 1, and optionally: from 0 to 20% by weight of mineral oil(s) from 0 to 50% by weight of polyol(s) from 0 to 10% by weight of silicone oil(s) from 0 to 5% by weight of preservative agent(s) from 0 to 30% by weight of ethanol from 0 to 15% by weight of additive(s).
13. The composition according to any one of the preceding claims, wherein the maximum quantity of active ingredient absorbed in the dermis and epidermis 16 hours after application is between 6 ng/cm2 and 19 ng/cm2.
14. The composition according to Claim 13, wherein the maximum quantity of active ingredient absorbed in the dermis and epidermis 16 hours after application is between 6.8 ng/cm2 and 10.6 ng/cm2.
15. The composition according to any one of the preceding claims, wherein the maximum quantity of active ingredient absorbed in the epidermis is obtained between 3 and 10 hours after application.
16. The composition according to any one of Claims 1 to 15 for use as a medicinal product.
17. The composition according to any one of Claims 1 to 16 for use for the treatment of one or more of the following pathologies: -dermatological complaints associated with a keratinisation disorder relating to cellular differentiation and proliferation; -keratinisation disorders; -dermatological disorders with an inflammatory immune-allergic component, with or without cellular proliferation disorder; -cutaneous disorders due to exposure to UV radiation, as well as to repair or control ageing of the skin, whether photo-induced or chronological, or to reduce pigmentations and actinic keratoses, or all pathologies associated with chronological or actinic ageing; -any condition associated with benign dermal or epidermal proliferations, whether or not of viral origin; -dermatological complaints; -stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy; -healing complaints, or to prevent or repair stretch marks, or even to promote healing; -any disorder of fungal origin in the cutaneous region; -pigmentation disorders; -cancerous or pre-cancerous, cutaneous or mucous conditions, skin cancers, and cutaneous lymphomas.
18. A method for the treatment of one or more of the following pathologies: -dermatological complaints associated with a keratinisation disorder relating to cellular differentiation and proliferation; -keratinisation disorders; -dermatological disorders with an inflammatory immune-allergic component, with or without cellular proliferation disorder; -cutaneous disorders due to exposure to UV radiation, as well as to repair or control ageing of the skin, whether photo-induced or chronological, or to reduce pigmentations and actinic keratoses, or all pathologies associated with chronological or actinic ageing; -any condition associated with benign dermal or epidermal proliferations, whether or not of viral origin; -dermatological complaints; -stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy; -healing complaints, or to prevent or repair stretch marks, or even to promote healing; -any disorder of fungal origin in the cutaneous region; -pigmentation disorders; -cancerous or pre-cancerous, cutaneous or mucous conditions, skin cancers, and cutaneous lymphomas; comprising administering the composition according to any one of claims 1 to 15 to a patient in need thereof.
19. Use of a fatty phase comprising: a compound with general formula (I)
where : - Rx is a hydrogen atom, an alkyl radical of 1 to 4 carbons or a -CF3 radical; - R2 is a hydrogen atom, an alkyl or alkoxy radical of 1 to 4 carbon atoms or a chlorine atom; - R3 is a hydrogen atom, or a linear or branched alkyl or alkoxy radical of 1 to 10 carbon atoms possibly substituted by a methoxy group; - R4 is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms; - R5 is a hydrogen atom or an alkyl radical of 1 to 3 carbon atoms; or R4 and R5 together form, with the -N-C(=Y)- bond, a ring of the pyrrolidine, pyrrolidinone, piperidine or piperidinone type; Y denotes two hydrogen atoms or a heteroatom; Ar denotes a 1,4-phenyl, 2,5-pyridyl, 5,2-pyridyl or 2,5-thiophenyl ring; X denotes an oxygen atom, possibly substituted by an alkyl or alkylamine chain or a single C-C bond; A denotes a hydrogen atom or the following formula:
where o Q is an oxygen atom or the bond-NH-; o R6 denotes a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, a cycloalkyl radical of 3 to 6 carbon atoms, a -C(0)CH2 or -C(0)CH2CH3 radical; o R7 and R7' denote, independently of each other, a hydrogen atom or a hydroxyl group, on condition that R7 and R7' are not simultaneously a hydroxyl group; n is equal to 0,1, 2,3, 4 or 5 ; at least one principal solvent of compound (I) selected from among benzyl alcohol, laureth-4, phenoxyethanol, propylene glycol monocaprylate, pentylene glycol, dimethyl isosorbide and mixtures thereof, and at least one co-solvent oil of compound (I) selected from among the caprylic/capric triglycerides, sweet almond oil, propylene glycol monocaprylate, propylene glycol laurate, sorbitan sesquioleate, diisopropyl adipate, PPG-15 stearyl ether, apricot kernel oil PEG-6 ester, and mixtures thereof, and an aqueous phase comprising at least one gelifying agent, selected from polymers of plant origin, gums, pectins, cellulose and its derivatives, polymers of microbiological origin and gelifying polymers of synthetic origin in the manufacture of an oil-in-water emulsion-type composition for the treatment of one or more of the following pathologies: -dermatological complaints associated with a keratinisation disorder relating to cellular differentiation and proliferation; -keratinisation disorders; -dermatological disorders with an inflammatory immune-allergic component, with or without cellular proliferation disorder; -cutaneous disorders due to exposure to UV radiation, as well as to repair or control ageing of the skin, whether photo-induced or chronological, or to reduce pigmentations and actinic keratoses, or all pathologies associated with chronological or actinic ageing; -any condition associated with benign dermal or epidermal proliferations, whether or not of viral origin; -dermatological complaints; -stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy; -healing complaints, or to prevent or repair stretch marks, or even to promote healing; -any disorder of fungal origin in the cutaneous region; -pigmentation disorders; -cancerous or pre-cancerous, cutaneous or mucous conditions, skin cancers, and cutaneous lymphomas.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261654729P | 2012-06-01 | 2012-06-01 | |
| FR1255094A FR2991177B1 (en) | 2012-06-01 | 2012-06-01 | TOPICAL COMPOSITIONS, CONTAINING RETINOID, EMULSION TYPE EMULSION IN WATER WITHOUT EMULSIFIER |
| US61/654,729 | 2012-06-01 | ||
| FR1255094 | 2012-06-01 | ||
| PCT/EP2013/061201 WO2013178760A1 (en) | 2012-06-01 | 2013-05-30 | Oil/water-emulsion-type topical compositions containing a retinoid |
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| AU2013269583A1 AU2013269583A1 (en) | 2015-01-15 |
| AU2013269583A8 AU2013269583A8 (en) | 2015-05-21 |
| AU2013269583B2 true AU2013269583B2 (en) | 2017-08-24 |
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| AU2013269583A Active AU2013269583B2 (en) | 2012-06-01 | 2013-05-30 | Oil/water-emulsion-type topical compositions containing a retinoid |
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| EP (1) | EP2854802B2 (en) |
| JP (1) | JP6271527B2 (en) |
| KR (1) | KR102127022B1 (en) |
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|---|---|---|---|---|
| CN106659646B (en) | 2014-07-16 | 2022-07-01 | 莱雅公司 | Sprayable sunscreen composition with oil droplets |
| CA3056766A1 (en) * | 2016-05-26 | 2017-11-30 | Dermala Inc. | Compositions and methods for treating acne vulgaris |
| WO2018042352A1 (en) * | 2016-08-31 | 2018-03-08 | Taro Pharmaceutical Industries | Fenoldopam topical formulations for treating skin disorders |
| KR20200092523A (en) | 2019-01-24 | 2020-08-04 | 삼성디스플레이 주식회사 | Backlight unit and liquid crystal display device including the same |
| JP7124234B2 (en) | 2019-03-08 | 2022-08-23 | タロー・ファーマシューティカル・インダストリーズ・リミテッド | Stable topical compositions of fenoldopam |
| CN112656695A (en) * | 2019-10-15 | 2021-04-16 | 嘉兴睿肤丽生物科技有限公司 | Preparation of retinol nano-emulsion with low irritation and high stability |
| CN114555033A (en) * | 2019-10-16 | 2022-05-27 | 莱雅公司 | Two-part composition for caring for keratin materials |
| CN110791390A (en) * | 2019-11-15 | 2020-02-14 | 南京魄力倍清洁科技有限公司 | Composite alkaline cleaning agent |
| CN114929678B (en) * | 2019-11-29 | 2023-08-15 | 石家庄迪斯凯威医药科技有限公司 | Substituted m-terphenyl compound, and pharmaceutical composition and application thereof |
| WO2024114789A1 (en) * | 2022-12-02 | 2024-06-06 | 南京迈诺威医药科技有限公司 | Pharmaceutical composition comprising trifarotene and use thereof |
Citations (2)
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|---|---|---|---|---|
| WO2006066978A1 (en) * | 2004-12-23 | 2006-06-29 | Galderma Research & Development | Novel ligands that modulate rar receptors, and use thereof in human medicine and in cosmetics |
| US20100143445A1 (en) * | 2007-05-04 | 2010-06-10 | Galderma Research & Development | Dermatological/cosmetic skin depigmenting compositions |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5851538A (en) | 1995-12-29 | 1998-12-22 | Advanced Polymer Systems, Inc. | Retinoid formulations in porous microspheres for reduced irritation and enhanced stability |
| US5690947A (en) | 1996-08-30 | 1997-11-25 | Chesebrough-Pond's Usa Co., Division Of Conopco, Inc. | Borage seed oil as an anti-irritant in compositions containing hydroxy acids or retinoids |
| US6017549A (en) | 1997-09-30 | 2000-01-25 | E-L Management Corp. | Non-irritating cosmetic and pharmaceutical compositions |
| US6531141B1 (en) | 2000-03-07 | 2003-03-11 | Ortho-Mcneil Pharmaceutical, Inc. | Oil-in-water emulsion containing tretinoin |
| US7820186B2 (en) | 2001-12-21 | 2010-10-26 | Galderma Research & Development | Gel composition for once-daily treatment of common acne comprising a combination of benzoyl peroxide and adapalene and/or adapalene salt |
| US20060110415A1 (en) | 2004-11-22 | 2006-05-25 | Bioderm Research | Topical Delivery System for Cosmetic and Pharmaceutical Agents |
| FR2916975B1 (en) † | 2007-06-11 | 2009-09-04 | Galderma Res & Dev | COMPOSITIONS COMPRISING AT LEAST ONE RETINOID COMPOUND, ANTI-IRRITANT COMPOUND AND BENZOYL PEROXIDE, AND USES THEREOF |
| EP2065032A1 (en) | 2007-11-27 | 2009-06-03 | Galderma Research & Development | A method for producing adapalene gels |
-
2012
- 2012-06-01 FR FR1255094A patent/FR2991177B1/en not_active Expired - Fee Related
-
2013
- 2013-05-30 SG SG11201408759XA patent/SG11201408759XA/en unknown
- 2013-05-30 CA CA2874474A patent/CA2874474C/en not_active Expired - Fee Related
- 2013-05-30 JP JP2015514509A patent/JP6271527B2/en active Active
- 2013-05-30 EP EP13726504.7A patent/EP2854802B2/en active Active
- 2013-05-30 NZ NZ702472A patent/NZ702472A/en unknown
- 2013-05-30 CN CN201380040780.6A patent/CN104507469B/en active Active
- 2013-05-30 AU AU2013269583A patent/AU2013269583B2/en active Active
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- 2013-05-30 WO PCT/EP2013/061201 patent/WO2013178760A1/en active Application Filing
- 2013-05-30 RU RU2014152998A patent/RU2637408C2/en active
- 2013-05-30 KR KR1020147036533A patent/KR102127022B1/en active Protection Beyond IP Right Term
- 2013-05-30 BR BR112014029885-8A patent/BR112014029885B1/en active IP Right Grant
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006066978A1 (en) * | 2004-12-23 | 2006-06-29 | Galderma Research & Development | Novel ligands that modulate rar receptors, and use thereof in human medicine and in cosmetics |
| US20100143445A1 (en) * | 2007-05-04 | 2010-06-10 | Galderma Research & Development | Dermatological/cosmetic skin depigmenting compositions |
Also Published As
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| BR112014029885A2 (en) | 2017-06-27 |
| WO2013178760A1 (en) | 2013-12-05 |
| CN104507469A (en) | 2015-04-08 |
| AU2013269583A8 (en) | 2015-05-21 |
| BR112014029885A8 (en) | 2023-01-10 |
| BR112014029885B1 (en) | 2023-01-17 |
| KR20150028252A (en) | 2015-03-13 |
| NZ702472A (en) | 2016-08-26 |
| KR102127022B1 (en) | 2020-06-25 |
| EP2854802B1 (en) | 2018-07-25 |
| RU2637408C2 (en) | 2017-12-04 |
| CA2874474A1 (en) | 2013-12-05 |
| JP2015523342A (en) | 2015-08-13 |
| CN104507469B (en) | 2018-01-02 |
| ES2691299T3 (en) | 2018-11-26 |
| FR2991177B1 (en) | 2014-12-19 |
| SG11201408759XA (en) | 2015-01-29 |
| ES2691299T5 (en) | 2022-11-22 |
| JP6271527B2 (en) | 2018-01-31 |
| CA2874474C (en) | 2020-10-27 |
| EP2854802B2 (en) | 2022-08-24 |
| FR2991177A1 (en) | 2013-12-06 |
| EP2854802A1 (en) | 2015-04-08 |
| RU2014152998A (en) | 2016-07-27 |
| AU2013269583A1 (en) | 2015-01-15 |
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