EP3606509A1 - Topical doxycycline composition - Google Patents
Topical doxycycline compositionInfo
- Publication number
- EP3606509A1 EP3606509A1 EP18714781.4A EP18714781A EP3606509A1 EP 3606509 A1 EP3606509 A1 EP 3606509A1 EP 18714781 A EP18714781 A EP 18714781A EP 3606509 A1 EP3606509 A1 EP 3606509A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- doxycycline
- composition according
- polyol
- solution
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 95
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 title claims abstract description 55
- 229960003722 doxycycline Drugs 0.000 title claims abstract description 49
- 230000000699 topical effect Effects 0.000 title claims abstract description 23
- 210000004400 mucous membrane Anatomy 0.000 claims abstract description 12
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 7
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 7
- 230000002209 hydrophobic effect Effects 0.000 claims description 49
- 239000000463 material Substances 0.000 claims description 44
- 229920005862 polyol Polymers 0.000 claims description 35
- 150000003077 polyols Chemical class 0.000 claims description 35
- HALQELOKLVRWRI-VDBOFHIQSA-N doxycycline hyclate Chemical compound O.[Cl-].[Cl-].CCO.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H]([NH+](C)C)[C@@H]1[C@H]2O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H]([NH+](C)C)[C@@H]1[C@H]2O HALQELOKLVRWRI-VDBOFHIQSA-N 0.000 claims description 29
- 229960001172 doxycycline hyclate Drugs 0.000 claims description 29
- 239000007787 solid Substances 0.000 claims description 27
- 229920000858 Cyclodextrin Polymers 0.000 claims description 23
- 239000007788 liquid Substances 0.000 claims description 21
- 239000000839 emulsion Substances 0.000 claims description 19
- 235000019271 petrolatum Nutrition 0.000 claims description 10
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 10
- 229940097362 cyclodextrins Drugs 0.000 claims description 8
- 208000015181 infectious disease Diseases 0.000 claims description 8
- 239000004264 Petrolatum Substances 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 7
- 229940066842 petrolatum Drugs 0.000 claims description 7
- 210000004877 mucosa Anatomy 0.000 claims description 6
- 239000004166 Lanolin Substances 0.000 claims description 5
- 230000015556 catabolic process Effects 0.000 claims description 5
- 238000006731 degradation reaction Methods 0.000 claims description 5
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 5
- 229930195729 fatty acid Natural products 0.000 claims description 5
- 239000000194 fatty acid Substances 0.000 claims description 5
- 229940039717 lanolin Drugs 0.000 claims description 5
- 235000019388 lanolin Nutrition 0.000 claims description 5
- 239000012188 paraffin wax Substances 0.000 claims description 5
- 150000005691 triesters Chemical class 0.000 claims description 5
- 230000002458 infectious effect Effects 0.000 claims description 4
- 230000003750 conditioning effect Effects 0.000 claims description 3
- 229960004434 doxycycline monohydrate Drugs 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 238000004321 preservation Methods 0.000 claims description 3
- 208000007244 Canaliculitis Diseases 0.000 claims description 2
- 206010010741 Conjunctivitis Diseases 0.000 claims description 2
- 206010022941 Iridocyclitis Diseases 0.000 claims description 2
- 241001303601 Rosacea Species 0.000 claims description 2
- 201000004612 anterior uveitis Diseases 0.000 claims description 2
- 208000010217 blepharitis Diseases 0.000 claims description 2
- 230000004064 dysfunction Effects 0.000 claims description 2
- 208000008025 hordeolum Diseases 0.000 claims description 2
- 201000004614 iritis Diseases 0.000 claims description 2
- 206010023332 keratitis Diseases 0.000 claims description 2
- 201000004700 rosacea Diseases 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229940021506 stye Drugs 0.000 claims description 2
- 210000004907 gland Anatomy 0.000 claims 1
- 210000000744 eyelid Anatomy 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 20
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 11
- 239000003755 preservative agent Substances 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 7
- PTNZGHXUZDHMIQ-CVHRZJFOSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O PTNZGHXUZDHMIQ-CVHRZJFOSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 229950011479 hyclate Drugs 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 5
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000001116 FEMA 4028 Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229960004853 betadex Drugs 0.000 description 3
- 238000011109 contamination Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 239000012049 topical pharmaceutical composition Substances 0.000 description 3
- 241000589291 Acinetobacter Species 0.000 description 2
- 241000186216 Corynebacterium Species 0.000 description 2
- 241000194032 Enterococcus faecalis Species 0.000 description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 description 2
- 241000588621 Moraxella Species 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- -1 Saturated fatty acid di- Chemical class 0.000 description 2
- 241000607715 Serratia marcescens Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 241000191963 Staphylococcus epidermidis Species 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 230000001143 conditioned effect Effects 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- CKFGINPQOCXMAZ-UHFFFAOYSA-N methanediol Chemical compound OCO CKFGINPQOCXMAZ-UHFFFAOYSA-N 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 1
- 229940073464 benzododecinium bromide Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- SXPWTBGAZSPLHA-UHFFFAOYSA-M cetalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SXPWTBGAZSPLHA-UHFFFAOYSA-M 0.000 description 1
- 229960000228 cetalkonium chloride Drugs 0.000 description 1
- 229960002798 cetrimide Drugs 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- SIYLLGKDQZGJHK-UHFFFAOYSA-N dimethyl-(phenylmethyl)-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethyl]ammonium Chemical compound C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 SIYLLGKDQZGJHK-UHFFFAOYSA-N 0.000 description 1
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019256 formaldehyde Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 208000021267 infertility disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 210000004175 meibomian gland Anatomy 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical class CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- RARSHUDCJQSEFJ-UHFFFAOYSA-N p-Hydroxypropiophenone Chemical compound CCC(=O)C1=CC=C(O)C=C1 RARSHUDCJQSEFJ-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 150000004072 triols Chemical class 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- 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
- A61K31/65—Tetracyclines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to a novel pharmaceutical composition comprising doxycycline for topical application, particularly to the eye and eyelids.
- the invention also relates to this topical composition for its use in the treatment of bacterial infections of the skin and mucous membranes.
- Doxycycline is an antibiotic of the tetracycline family which is essentially administered orally in pharmaceutical compositions adapted for such administration, essentially tablets of different forms with different dosages of doxycycline.
- a liquid form suitable for administration in the form of intravenous infusion is also a liquid form suitable for administration in the form of intravenous infusion.
- the active ingredient is used in the form of hyclate or monohydrate.
- compositions suitable for topical application must meet strict specifications for their storage, so that the product undergoes little damage (usually less than 5%) when stored for 6 months, or up to 2 years.
- doxycycline degrades on contact with water which renders it unfit for use in the form of usual topical formulations.
- compositions with doxycycline contents greater than 1% for the treatment of ulcers and burns in patients with leprosy The application US 2006/0172982 describes compositions with more than 10% doxycycline, up to 50%, for treating and preventing infections and inflammations (allergies, colds, etc.).
- CN 10653817 discloses compositions with greater than 2% doxycycline, up to more than 20%, in powder form with particle sizes of more than 70 ⁇ .
- the invention allows a novel treatment solution for bacterial infections of the mucous membranes and skin with a topical composition of doxycycline stable over time.
- anhydrous pharmaceutical composition for topical application of doxycycline characterized in that it comprises:
- anhydrous vehicle suitable for topical application which consists of a semisolid hydrophobic material a1) selected from petrolatum alone or supplemented with lanolin, optionally mixed with a liquid hydrophobic material a2) selected from paraffin, di- or tri-esters saturated with C6-C12 fatty acids, and b) doxycycline in a form adapted to its application on the skin or mucous membranes.
- the doxycycline in a form suitable for application to the skin or mucous membranes is a doxycycline salt selected from doxycycline hyclate and doxycycline monohydrate, preferably doxycycline hyclate.
- the doxycycline in particular hyclate or monohydrate, preferably hyclate, may be b1) in a pulverulent or micronized solid form or else in solution b2) in an anhydrous polyol, preferably in liquid form at room temperature (15 ° C - 25 ° C).
- ° C) selected from glycerol, propylene glycol, triethylene glycol, butylene glycol, methylene glycol and polyethylene glycols with a molecular weight ranging from 200 to 1500 and mixtures thereof.
- the concentration of doxycycline, in particular hyclate is between 0.001% and
- the invention also relates to this topical composition for its use in the treatment of bacterial infections of the mucous membranes and skin.
- Figure 1 shows a stability curve of doxycycline hyclate at 0.1% in aqueous solution as a function of time at 25 ° C and 40 ° C.
- Figure 2 shows a stability curve of 0.1% doxycycline hyclate in glycerol solution with or without cyclodextrin as a function of time at 25 ° C.
- Figure 3 shows a stability curve of an anhydrous formulation of 0.1% doxycycline hyclate in the presence of cyclodextrin as a function of time at 25 ° C.
- the composition according to the invention is a pharmaceutical composition, that is to say a composition intended to be administered to a human or to an animal, and, consequently, meets the sanitary requirements recognized worldwide for the design and the preparation of these compositions.
- Excipients in particular, their use as the methods of analysis are known to those skilled in the pharmaceutical field, and in particular in accordance with the requirements of the pharmacopoeia, such as the European Pharmacopoeia (Ph. Eur.), The US Pharmacopeial Convention (USP) and the Japanese Pharmacopoeia (JP) in effect.
- the composition according to the invention is an anhydrous composition so as to limit the risk of degradation of the active ingredient.
- the constituents of the composition are anhydrous, that is to say having a residual moisture content of less than 0.5%, preferably less than 0.2%, measured according to the method of determination indicated by the European Pharmacopoeia in force as the method of Karl Fisher for example.
- composition according to the invention is suitable for topical application, ie for direct application to the skin and / or the mucous membranes.
- the composition according to the invention is an ophthalmic composition, intended to be applied to the eye, to the ocular mucosa or even close to the eye, on the eyelids, where the product can migrate to the eye and the ocular mucosa.
- ophthalmic composition particular attention is paid to the choice of excipients, their qualities and the methods of preparation to eliminate the risks of microbial contaminations and / or side effects such as eye irritation due to the fragility of the eye and the ocular mucosa.
- composition according to the invention is also adapted to be packaged in conventional containers of topical pharmaceutical compositions, and in particular for ophthalmic compositions, in particular tubes or flasks.
- the packaging is suitable for single-dose or multi-dose uses, possibly with or without means for determining the quantities applied. After conditioning, the composition according to the invention can be stored for several months without substantial degradation of the doxycycline.
- the semisolid hydrophobic material a1) is advantageously chosen from petrolatum, also known under the name "petrolatum” or petroleum jelly, alone or with added lanolin in usual proportions known to those skilled in the art.
- petrolatum also known under the name "petrolatum” or petroleum jelly
- lanolin in usual proportions known to those skilled in the art.
- the petrolatum / lanolin mixture is also called lanovaseline, in which lanolin can represent up to 50% of the total weight of the mixture, generally of the order of 20 to 30%.
- the semisolid hydrophobic material a1) is petroleum jelly.
- the liquid hydrophobic material a2) is chosen from paraffin, di- or tri-esters of C6-C12 fatty acids, their mixtures and their derivatives. These products used in pharmacy are well known to those skilled in the art. Saturated fatty acid di-or triesters are esters of diols or triols for which hydroxyls are esterified with a fatty acid. In particular, medium chain triglycerides (or MCTs), such as Examples are triesters of glycerol and of capric and caprylic acids, especially marketed under the names Mygliol ® 810 or 812 or Labrafac ® Lipophilic. Others include synthetic products such as fatty acid esters of C6-C12 polyethylene oxide sold under the name Labrasol ®.
- the liquid hydrophobic material a2) is paraffin.
- the weight ratio liquid hydrophobic material / semi-solid hydrophobic material is preferably from 50/50 to 0/100.
- the content of liquid hydrophobic material a2) in the mixture will depend on the properties desired for the final composition, in particular its viscosity and its ease of use, depending on whether an application is sought on the skin or on the mucous membranes, for example or the time during which the composition is to be maintained in contact with the skin or mucous membranes.
- doxyclin is in the form of a doxycycline salt selected from doxycycline hyclate and doxycycline monohydrate, preferably doxycycline hyclate.
- the doxycycline in particular the doxycycline hyclate, is in the form of solid particles b1) of suitable size for ophthalmic ointments.
- the particle size is less than or equal to 20 ⁇ .
- This particle size is measured according to the usual particle analysis methods described in the current European Pharmacopoeia, such as the laser diffraction particle size distribution technique.
- the final concentration of particulate doxycycline in the composition, in particular hyclate is between 0.001% and 1% (w / w), preferably between 0.005% and 0.5% (w / w), more preferably between 0.01% and 0.1% (m / m).
- the anhydrous vehicle suitable for topical application will advantageously consist of a mixture of hydrophobic liquid material / semi-solid hydrophobic material whose mass ratio ranges from 50/50 to 10/90.
- the doxycycline in particular the doxycycline hyclate is in the form of a solution b2) in an anhydrous polyol.
- anhydrous polyols described in the pharmacopoeias are advantageously chosen from glycerol, propylene glycol, polyethylene glycols with a molecular weight ranging from 200 to 1500 and mixtures thereof.
- Polyethylene glycols with a molecular weight ranging from 200 to 1500 are advantageously chosen from Macrogols 400, 600 and 1500.
- the polyol is glycerol.
- the concentration of doxycycline, in particular of doxycycline hyclate in the polyol ranges from 0.001% to 3.0% by weight relative to the total mass of the solution.
- the doxycycline solution in particular doxycycline hyclate in the polyol may also comprise one or more cyclodextrins.
- Cyclodextrins in pharmacopoeias are well known to those skilled in the art. Mention may in particular be made of cyclodextrins, ⁇ -cyclodextrins and hydroxypropyl-3-cyclodextrins.
- the concentration of cyclodextrins in the polyol may advantageously range from 0.01% to 4.4% by weight relative to the total mass of the solution.
- the solution comprises:
- the total doxycycline, in particular doxycycline hyclate, cyclodextrin and polyol represents 100% by weight of the solution, that is to say that the solution consists solely of doxycycline, polyol and optionally cyclodextrin.
- Such a solution is prepared according to the usual methods of preparing solutions.
- the doxycycline in particular the doxycycline hyclate, is added to the polyol with magnetic stirring until complete dissolution.
- the resulting mixture is clear.
- cyclodextrin preparation in particular doxycycline hyclate and cyclodextrin, is prepared according to the following conditions:
- the cyclodextrin is added to the polyol and stirred magnetically between 1 to 5 hours, preferably between 2 and 4 hours,
- the doxycycline is then added to the mixture and stirred magnetically between 16 and 20 hours.
- the composition is a "hydrophilic in lipophilic (H / L)" type emulsion, the doxycycline (b) solution, in particular of doxycycline hyclate in the polyol forming globules. surrounded by the anhydrous vehicle (a).
- the globules of polyol solution advantageously have a size less than or equal to 50 ⁇ , advantageously between 20 and 30 ⁇ .
- the final concentration of doxycycline, in particular hyclate, in the form of a solution in an anhydrous polyol in the topical composition according to the invention, in particular in the form of an emulsion, is between 0.001% and 1% (m / m), preferably between 0.005% and 0.5% (w / w), more preferably between 0.01% and 0.1% (w / w).
- the present invention also relates to the solution of doxycycline in a polyol as defined previously as such, in particular as a pharmaceutical composition or as an intermediate composition for the preparation of a composition pharmaceutical, more particularly for the preparation of a topical composition in the form of H / L emulsion as described above and hereinafter.
- the composition according to the invention is a composition without preservatives.
- Preservative agents generally used in topical compositions (pharmaceutical, cosmetic, etc.) to prevent their contamination by germs are well known to those skilled in the art, such as quaternary ammoniums, in particular benzalkonium chloride, dimethylbenzylammonium, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzothonium chloride, cetalkonium chloride, mercurial preservatives, such as phenylmercuric nitrate / acetate / borate, thiomersal, alcoholic preservatives, such as ethanol, chlorobutanol, benzyl alcohol, phenylethanol, phenylethyl alcohol, carboxylic acids, such as sorbic acid, phenols, in particular methyl / propyl paraben, amidines, for example chlorhexidine digluconate and / or chel
- preservative-free is meant according to the invention a composition substantially free of such preservatives to meet a "no preservatives" indication. Its preservative content is less than or equal to 10 ppm, more particularly less than or equal to 1 ppm, preferably equal to 0 ppm, no preservative included in its composition.
- the composition In the absence of preservatives, the composition must undergo a particular treatment during its preparation and its conditioning so as to avoid and prevent contamination by microorganisms (such as Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Pneumococci, Streptococcus faecalis , Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, Moraxella, Corynebacterium, Acinetobacter, Escherichia coli, Haermophilus influenzae).
- microorganisms such as Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Pneumococci, Streptococcus faecalis , Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, Moraxella, Coryne
- composition without preservatives according to the invention differs from a simple composition comprising the same ingredients obtained without showing any particular precautions or describing steps of the process making it possible to obtain this characteristic sterility of the compositions according to the invention, in particular ophthalmic compositions.
- the invention particularly relates to the following topical compositions:
- compositions according to the invention are carried out according to the usual methods known to those skilled in the art, in particular with the precautions required to prepare sterile and preservative-free compositions and to condition them.
- the invention also relates to the use of a composition according to the invention for its packaging in a suitable pharmaceutical container to deliver the composition for its topical application and its preservation for several months without substantial degradation of the doxycycline.
- the invention relates to a composition as defined above, for its use in the treatment of bacterial infections of the mucous membranes or the skin, in particular the eyelids and / or the ocular mucosa.
- the invention also relates to a method for treating bacterial infections of the mucous membranes or of the skin, in particular the eyelids and / or the ocular mucosa, for which an amount of at least one infection is applied to the place of infection and / or in the vicinity thereof.
- appropriate composition according to the invention that is allowed to act. The application will be renewed as needed, advantageously until the disappearance of the symptoms of the infection.
- composition will advantageously be used or the method will be advantageously used for conditions due to bacteria sensitive to tetracyclines, such as Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Pneumococci, Streptococcus faecalis, Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, Moraxella, Corynebacterium, Acinetobacter, E coli, / - / aemophilus influenzae for diseases such as stye, infectious conjunctivitis, infectious keratitis, blepharitis, dysfunction of Meibomian glands, ulceris (anterior uveitis) , canaliculitis and rosacea.
- tetracyclines such as Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Pneumo
- the different formulations are made using a vacuum mixer equipped with a suitable dispersion system.
- hydrophobic ointment containing the dispersed solid active principle is carried out according to the following method:
- the liquid hydrophobic material / semi-solid hydrophobic material base is formulated by mixing in a water bath at 70 ° C. in order to render all the components miscible. The temperature of the mixture is lowered to 45 ° C and the hydrophobic base is transferred to the mixer whose temperature is 45 ° C.
- the doxycycline hyclate is added to the mixer and the whole is evacuated to 80%.
- the stirring of the formula is carried out for 30 minutes, at 700 rpm, at 45 ° C. and then the temperature of the whole mixture is lowered to 37 ° C.
- the ointment obtained is packaged and cooled to room temperature.
- phase A The liquid hydrophobic material / semi-solid hydrophobic material base (referred to as phase A) is formulated by mixing in a water bath at 75 ° C. so as to render all the components miscible.
- the semi-solid hydrophobic material is added directly into the mixer at 45 ° C.
- phase A The temperature of phase A is lowered to 45 ° C and then phase A is transferred to the mixer whose temperature is 45 ° C.
- phase B The doxycycline hyclate is added to the polyol (called phase B) and stirred magnetically until complete dissolution and the temperature of the solution is increased to 45 ° C.
- phase B is added to phase A with stirring to form an emulsion.
- the emulsion is stirred for 30 minutes at 700 rpm at 45 ° C. and then the temperature of the whole mixture is lowered to 37 ° C.
- the emulsion obtained is conditioned and cooled to room temperature.
- the preparation in the form of an H / L emulsion containing the active principle and the cyclodextrins in solution in the polyol is carried out according to the following method:
- phase A The liquid hydrophobic material / semi-solid hydrophobic material base (referred to as phase A) is formulated by mixing in a water bath at 75 ° C. so as to render all the components miscible.
- the semi-solid hydrophobic material is added directly into the mixer at 45 ° C.
- phase A The temperature of phase A is lowered to 45 ° C and then phase A is transferred to the mixer whose temperature is 45 ° C.
- phase B The cyclodextrin is added to the polyol (called phase B) and stirred magnetically then the doxycycline hyclate is added to phase B and stirred magnetically until complete dissolution of all the components, the temperature of the solution is increased until at 45 ° C.
- phase B is added to phase A with stirring to form an emulsion.
- the emulsion is stirred for 30 minutes at 700 rpm at 45 ° C. and the temperature of the whole mixture is lowered to 37 ° C.
- the emulsion obtained is conditioned and cooled to room temperature.
- the content of active ingredient is determined according to the following high performance liquid chromatography method:
- compositions according to the invention mark their high stability with little or no degradation of the doxycycline (taking into account the error margins of the measurements), as shown in FIG. shows figure 2.
- the semi-solid hydrophobic material used is petroleum jelly (petrolatum) and the liquid paraffin liquid hydrophobic material.
- Emulsion 1 Weighted mass
- Emulsion 5 Weighted mass
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Abstract
Description
COMPOSITION TOPIQUE DE DOXYCYCLINE TOPICAL COMPOSITION OF DOXYCYCLINE
DOMAINE DE L'INVENTION FIELD OF THE INVENTION
La présente invention concerne une nouvelle composition pharmaceutique comprenant de la doxycycline pour une application topique, en particulier sur l'œil et les paupières. L'invention concerne également cette composition topique pour son utilisation dans le traitement des infections bactériennes de la peau et des muqueuses. The present invention relates to a novel pharmaceutical composition comprising doxycycline for topical application, particularly to the eye and eyelids. The invention also relates to this topical composition for its use in the treatment of bacterial infections of the skin and mucous membranes.
ETAT DE LA TECHNIQUE STATE OF THE ART
La doxycycline est un antibiotique de la famille des tétracyclines qui est essentiellement administrée per os dans des compositions pharmaceutiques adaptées pour une telle administration, essentiellement des comprimés de différentes formes avec différents dosages en doxycycline. Il existe également une forme liquide adaptée à une administration sous forme de perfusion intra veineuse. Le principe actif est employé sous forme d'hyclate ou bien de monohydrate. Doxycycline is an antibiotic of the tetracycline family which is essentially administered orally in pharmaceutical compositions adapted for such administration, essentially tablets of different forms with different dosages of doxycycline. There is also a liquid form suitable for administration in the form of intravenous infusion. The active ingredient is used in the form of hyclate or monohydrate.
Il n'existe pas de formules commerciales adaptées à une administration topique du produit, essentiellement pour des problèmes de stabilité et de conservation du principe actif dans de telles compositions. En effet, les compositions pharmaceutiques appropriées pour une application topique doivent répondre à des cahiers des charges drastiques quant à leur conservation, de sorte que le produit subit peu de dégradations (moins de 5% habituellement) lorsque conservé pendant 6 mois, voire jusqu'à 2 ans. Or, la doxycycline se dégrade au contact de l'eau ce qui la rend inapte pour une exploitation sous forme de formulations topiques usuelles. There are no commercial formulas suitable for topical administration of the product, mainly for problems of stability and preservation of the active ingredient in such compositions. Indeed, pharmaceutical compositions suitable for topical application must meet strict specifications for their storage, so that the product undergoes little damage (usually less than 5%) when stored for 6 months, or up to 2 years. However, doxycycline degrades on contact with water which renders it unfit for use in the form of usual topical formulations.
Les seules applications topiques de doxycycline rapportées dans la littérature concernent des formes extemporanées comprenant de grandes quantités d'antibiotique pour des pathologies très particulières. Ainsi, la demande RU 2095065 décrit des compositions topiques extemporanées à teneurs en doxycycline supérieures à 1 % pour le traitement des ulcères et brûlures chez les patients atteints de lèpre. La demande US 2006/0172982 décrit des compositions à plus de 10% de doxycycline, jusqu'à 50%, pour traiter et prévenir les infections et les inflammations (allergies, rhumes,...). La demande CN 10653817 décrit des compositions avec plus de2% de doxycycyline, jusqu'à plus de 20%, sous forme de poudre avec des tailles de particules de plus de 70 μηι. Ces teneurs élevées correspondent bien à des formulations extemporanées, pour lesquelles la durée de conservation est courte, la forte teneur permettant de compenser la perte de principe actif. The only topical applications of doxycycline reported in the literature concern extemporaneous forms comprising large amounts of antibiotic for very particular pathologies. Thus, the application RU 2095065 describes topical extemporaneous compositions with doxycycline contents greater than 1% for the treatment of ulcers and burns in patients with leprosy. The application US 2006/0172982 describes compositions with more than 10% doxycycline, up to 50%, for treating and preventing infections and inflammations (allergies, colds, etc.). CN 10653817 discloses compositions with greater than 2% doxycycline, up to more than 20%, in powder form with particle sizes of more than 70 μηι. These high levels correspond well to extemporaneous formulations, for which the shelf life is short, the high content making it possible to compensate for the loss of active ingredient.
L'invention permet une nouvelle solution de traitement des infections bactériennes des muqueuses et de la peau avec une composition topique de doxycycline stable dans le temps. EXPOSE DE L'INVENTION The invention allows a novel treatment solution for bacterial infections of the mucous membranes and skin with a topical composition of doxycycline stable over time. SUMMARY OF THE INVENTION
Pour résoudre le problème de stabilité de la doxycycline, l'invention concerne une composition pharmaceutique anhydre pour une application topique de doxycycline, caractérisée en ce qu'elle comprend : To solve the problem of stability of doxycycline, the invention relates to an anhydrous pharmaceutical composition for topical application of doxycycline, characterized in that it comprises:
a) un véhicule anhydre approprié pour une application topique qui consiste en une matière hydrophobe semi-solide a1 ) choisie parmi le petrolatum seul ou additionné de lanoline, éventuellement en mélange avec une matière hydrophobe liquide a2) choisie parmi la paraffine, les di- ou tri-esters saturés d'acides gras en C6-C12, et b) la doxycycline sous une forme adaptée à son application sur la peau ou des muqueuses. a) an anhydrous vehicle suitable for topical application which consists of a semisolid hydrophobic material a1) selected from petrolatum alone or supplemented with lanolin, optionally mixed with a liquid hydrophobic material a2) selected from paraffin, di- or tri-esters saturated with C6-C12 fatty acids, and b) doxycycline in a form adapted to its application on the skin or mucous membranes.
De manière préférée, la doxycycline sous une forme adaptée à son application sur la peau ou des muqueuses est un sel de doxycycline choisi parmi l'hyclate de doxycycline et le monohydrate de doxycycline, de manière préférée l'hyclate de doxycycline. Preferably, the doxycycline in a form suitable for application to the skin or mucous membranes is a doxycycline salt selected from doxycycline hyclate and doxycycline monohydrate, preferably doxycycline hyclate.
La doxycycline, en particulier hyclate ou monohydrate, préférentiellement hyclate, peut être b1 ) sous une forme solide pulvérulente ou micronisée ou bien en solution b2) dans un polyol anhydre, de préférence se présentant sous forme liquide à température ambiante (15°C - 25°C) choisi parmi le glycérol, le propylène glycol, le triéthylène glycol, le butylène glycol, le méthylène glycol et les polyéthylèneglycols de poids moléculaire allant de 200 à 1500 et leurs mélanges. The doxycycline, in particular hyclate or monohydrate, preferably hyclate, may be b1) in a pulverulent or micronized solid form or else in solution b2) in an anhydrous polyol, preferably in liquid form at room temperature (15 ° C - 25 ° C). ° C) selected from glycerol, propylene glycol, triethylene glycol, butylene glycol, methylene glycol and polyethylene glycols with a molecular weight ranging from 200 to 1500 and mixtures thereof.
La concentration en doxycycline, en particulier hyclate, est comprise entre 0,001 % et The concentration of doxycycline, in particular hyclate, is between 0.001% and
1 % (m/m), de préférence entre 0,005% et 0,5% (m/m), plus préférentiellement entre 0,01 % et 0,1 % (m/m). 1% (w / w), preferably between 0.005% and 0.5% (w / w), more preferably between 0.01% and 0.1% (w / w).
L'invention concerne également cette composition topique pour son utilisation dans le traitement des infections bactériennes des muqueuses et de la peau. The invention also relates to this topical composition for its use in the treatment of bacterial infections of the mucous membranes and skin.
DESCRIPTION DES FIGURES DESCRIPTION OF THE FIGURES
La figure 1 représente une courbe de stabilité de l'hyclate de doxycycline à 0,1 % en solution aqueuse en fonction du temps à 25°C et à 40°C. Figure 1 shows a stability curve of doxycycline hyclate at 0.1% in aqueous solution as a function of time at 25 ° C and 40 ° C.
La figure 2 représente une courbe de stabilité de l'hyclate de doxycycline à 0,1 %, dans une solution de glycérol avec ou sans cyclodextrine, en fonction du temps à 25°C. Figure 2 shows a stability curve of 0.1% doxycycline hyclate in glycerol solution with or without cyclodextrin as a function of time at 25 ° C.
La figure 3 représente une courbe de stabilité d'une formulation anhydre d'hyclate de doxycycline à 0,1 % en présence de cyclodextrine en fonction du temps à 25°C. Figure 3 shows a stability curve of an anhydrous formulation of 0.1% doxycycline hyclate in the presence of cyclodextrin as a function of time at 25 ° C.
DESCRIPTION DETAILLEE DE L'INVENTION DETAILED DESCRIPTION OF THE INVENTION
La composition selon l'invention est une composition pharmaceutique, c'est-à-dire une composition destinée à être administrée à un humain ou à un animal, et, en conséquence, répond aux exigences sanitaires reconnues dans le monde entier pour la conception et la préparation de ces compositions. Les excipients en particulier, leur utilisation comme les méthodes d'analyse sont connus de l'homme du métier du domaine pharmaceutique, et notamment conforme aux exigences de la pharmacopée, comme la Pharmacopée Européenne (Ph. Eur.), l'U.S Pharmacopeial Convention (USP) et la Pharmacopée Japonaise (JP) en vigueur. The composition according to the invention is a pharmaceutical composition, that is to say a composition intended to be administered to a human or to an animal, and, consequently, meets the sanitary requirements recognized worldwide for the design and the preparation of these compositions. Excipients in particular, their use as the methods of analysis are known to those skilled in the pharmaceutical field, and in particular in accordance with the requirements of the pharmacopoeia, such as the European Pharmacopoeia (Ph. Eur.), The US Pharmacopeial Convention (USP) and the Japanese Pharmacopoeia (JP) in effect.
La composition selon l'invention est une composition anhydre de manière à limiter les risques de dégradation du principe actif. A cet effet, les constituants de la composition sont anhydres, c'est-à-dire ayant un taux d'humidité résiduelle inférieure à 0,5%, de préférence inférieure à 0,2% mesurée selon la méthode de dosage indiqué par la Pharmacopée Européenne en vigueur comme la méthode de Karl Fisher par exemple. The composition according to the invention is an anhydrous composition so as to limit the risk of degradation of the active ingredient. For this purpose, the constituents of the composition are anhydrous, that is to say having a residual moisture content of less than 0.5%, preferably less than 0.2%, measured according to the method of determination indicated by the European Pharmacopoeia in force as the method of Karl Fisher for example.
La composition selon l'invention est adaptée pour une application topique, c'est à dire pour une application directe sur la peau et/ou les muqueuses. En particulier, la composition selon l'invention est une composition ophtalmique, destinée à être appliquée sur l'œil, sur la muqueuse oculaire ou encore à proximité de l'œil, sur les paupières, où le produit peut migrer sur l'œil et la muqueuse oculaire. Pour une composition ophtalmique, une attention particulière est faite sur le choix des excipients, leurs qualités et les méthodes de préparation pour écarter les risques de contaminations microbiennes et/ou d'effets secondaires comme les irritations oculaires du fait de la fragilité de l'œil et de la muqueuse oculaire. The composition according to the invention is suitable for topical application, ie for direct application to the skin and / or the mucous membranes. In particular, the composition according to the invention is an ophthalmic composition, intended to be applied to the eye, to the ocular mucosa or even close to the eye, on the eyelids, where the product can migrate to the eye and the ocular mucosa. For an ophthalmic composition, particular attention is paid to the choice of excipients, their qualities and the methods of preparation to eliminate the risks of microbial contaminations and / or side effects such as eye irritation due to the fragility of the eye and the ocular mucosa.
La composition selon l'invention est également adaptée pour être conditionnée dans des contenants usuels de compositions pharmaceutiques topiques, et notamment pour des compositions ophtalmiques, en particulier des tubes ou des flacons. Le conditionnement est adapté pour des usages unidose ou multidoses, éventuellement avec ou sans moyens de dosage des quantités appliquées. Après conditionnement, la composition selon l'invention peut être conservée plusieurs mois sans dégradation substantielle de la doxycycline. The composition according to the invention is also adapted to be packaged in conventional containers of topical pharmaceutical compositions, and in particular for ophthalmic compositions, in particular tubes or flasks. The packaging is suitable for single-dose or multi-dose uses, possibly with or without means for determining the quantities applied. After conditioning, the composition according to the invention can be stored for several months without substantial degradation of the doxycycline.
La matière hydrophobe semi-solide a1 ) est avantageusement choisie parmi le petrolatum, également connu sous la dénomination « vaseline » ou encore gelée de pétrole, seul ou additionné de lanoline dans des proportions usuelles connues de l'homme du métier. Le mélange petrolatum / lanoline est également appelé lanovaseline, dans lequel la lanoline peut représenter jusqu'à 50% du poids total du mélange, généralement de l'ordre de 20 à 30%. The semisolid hydrophobic material a1) is advantageously chosen from petrolatum, also known under the name "petrolatum" or petroleum jelly, alone or with added lanolin in usual proportions known to those skilled in the art. The petrolatum / lanolin mixture is also called lanovaseline, in which lanolin can represent up to 50% of the total weight of the mixture, generally of the order of 20 to 30%.
Selon un mode préféré de réalisation de l'invention, la matière hydrophobe semi-solide a1 ) est de la vaseline. According to a preferred embodiment of the invention, the semisolid hydrophobic material a1) is petroleum jelly.
La matière hydrophobe liquide a2) est choisie parmi la paraffine, les di- ou tri-esters d'acides gras en C6-C12, leurs mélanges ainsi que leurs dérivés. Ces produits employés en pharmacie sont bien connus de l'homme du métier. Les di-ou triesters saturés d'acides gras sont des esters de diols ou de triols pour lesquels des hydroxyles sont estérifiés par un acide gras. On citera en particulier les triglycérides à chaînes moyennes (ou TCM) comme par exemple les triesters de glycérine et d'acides caprique et caprylique, notamment commercialisés sous les dénominations Mygliol® 810 ou 812ou de Labrafac® Lipophile. On citera aussi des produits de synthèse comme des esters d'acides gras en C6-C12 polyoxyéthylénés commercialisés sous la dénomination Labrasol®. The liquid hydrophobic material a2) is chosen from paraffin, di- or tri-esters of C6-C12 fatty acids, their mixtures and their derivatives. These products used in pharmacy are well known to those skilled in the art. Saturated fatty acid di-or triesters are esters of diols or triols for which hydroxyls are esterified with a fatty acid. In particular, medium chain triglycerides (or MCTs), such as Examples are triesters of glycerol and of capric and caprylic acids, especially marketed under the names Mygliol ® 810 or 812 or Labrafac ® Lipophilic. Others include synthetic products such as fatty acid esters of C6-C12 polyethylene oxide sold under the name Labrasol ®.
Selon un mode particulier de réalisation de l'invention, la matière hydrophobe liquide a2) est de la paraffine. According to a particular embodiment of the invention, the liquid hydrophobic material a2) is paraffin.
Le rapport massique matière hydrophobe liquide/matière hydrophobe semi-solide va de préférence de 50/50 à 0/100. La teneur en matière hydrophobe liquide a2) dans le mélange dépendra des propriétés recherchées pour la composition finale, notamment de sa viscosité et de sa facilité d'usage, selon que l'on cherchera une application sur la peau ou sur les muqueuses, par exemple, ou selon le temps durant lequel la composition doit être maintenue au contact de la peau ou des muqueuses. The weight ratio liquid hydrophobic material / semi-solid hydrophobic material is preferably from 50/50 to 0/100. The content of liquid hydrophobic material a2) in the mixture will depend on the properties desired for the final composition, in particular its viscosity and its ease of use, depending on whether an application is sought on the skin or on the mucous membranes, for example or the time during which the composition is to be maintained in contact with the skin or mucous membranes.
L'homme du métier saura déterminer cette teneur en matière hydrophobe liquide a2) en tenant compte également de la forme de doxycycline qui sera employée. De préférence, la doxycline est sous forme de sel de doxycycline choisi parmi l'hyclate de doxycycline et le monohydrate de doxycycline, de manière préférée l'hyclate de doxycycline. Those skilled in the art will be able to determine this content of liquid hydrophobic material a2), also taking into account the form of doxycycline that will be used. Preferably, doxyclin is in the form of a doxycycline salt selected from doxycycline hyclate and doxycycline monohydrate, preferably doxycycline hyclate.
Selon un premier mode de réalisation de l'invention, la doxycycline, en particulier l'hyclate de doxycycline est sous une forme de particules solides b1 ) de taille adaptée aux pommades ophtalmiques. Avantageusement, la taille des particules est inférieure ou égale à 20 μηη. Cette taille de particules est mesurée selon les méthodes usuelles d'analyse des particules décrites à la Pharmacopée Européenne en vigueur telles que la technique de granulométrie à diffraction laser. La concentration finale en doxycycline sous forme de particules dans la composition, en particulier hyclate, est comprise entre 0,001 % et 1 % (m/m), de préférence entre 0,005% et 0,5% (m/m), plus préférentiellement entre 0,01 % et 0,1 % (m/m). According to a first embodiment of the invention, the doxycycline, in particular the doxycycline hyclate, is in the form of solid particles b1) of suitable size for ophthalmic ointments. Advantageously, the particle size is less than or equal to 20 μηη. This particle size is measured according to the usual particle analysis methods described in the current European Pharmacopoeia, such as the laser diffraction particle size distribution technique. The final concentration of particulate doxycycline in the composition, in particular hyclate, is between 0.001% and 1% (w / w), preferably between 0.005% and 0.5% (w / w), more preferably between 0.01% and 0.1% (m / m).
Dans ce cas, le véhicule anhydre approprié pour une application topique sera avantageusement constitué d'un mélange matière hydrophobe liquide/matière hydrophobe semi-solide dont le rapport massique va de 50/50 à 10/90. In this case, the anhydrous vehicle suitable for topical application will advantageously consist of a mixture of hydrophobic liquid material / semi-solid hydrophobic material whose mass ratio ranges from 50/50 to 10/90.
Selon un deuxième mode de réalisation de l'invention, la doxycycline, en particulier l'hyclate de doxycycline est sous la forme d'une solution b2) dans un polyol anhydre. Ces polyols anhydres décrits dans les pharmacopées sont avantageusement choisis parmi le glycérol, le propylène glycol, les polyéthylèneglycols de poids moléculaire allant de 200 à 1500 et leurs mélanges. According to a second embodiment of the invention, the doxycycline, in particular the doxycycline hyclate is in the form of a solution b2) in an anhydrous polyol. These anhydrous polyols described in the pharmacopoeias are advantageously chosen from glycerol, propylene glycol, polyethylene glycols with a molecular weight ranging from 200 to 1500 and mixtures thereof.
Les polyéthylèneglycols de poids moléculaire allant de 200 à 1500 sont avantageusement choisis parmi les Macrogols 400, 600 et 1500. Polyethylene glycols with a molecular weight ranging from 200 to 1500 are advantageously chosen from Macrogols 400, 600 and 1500.
Selon un mode préféré de réalisation de l'invention, le polyol est le glycérol. According to a preferred embodiment of the invention, the polyol is glycerol.
De préférence, la concentration en doxycycline, en particulier en hyclate de doxycycline dans le polyol va de 0,001 % à 3,0% en masse par rapport à la masse totale de la solution.Preferably, the concentration of doxycycline, in particular of doxycycline hyclate in the polyol ranges from 0.001% to 3.0% by weight relative to the total mass of the solution.
La solution de doxycycline, en particulier d'hyclate de doxycycline dans le polyol peut également comprendre une ou des cyclodextrines. Les cyclodextrines dans les pharmacopées sont bien connues de l'homme du métier. On citera en particulier les o cyclodextrines, les β-cyclodextrines et les hydroxypropyl-3-cyclodextrines. The doxycycline solution, in particular doxycycline hyclate in the polyol may also comprise one or more cyclodextrins. Cyclodextrins in pharmacopoeias are well known to those skilled in the art. Mention may in particular be made of cyclodextrins, β-cyclodextrins and hydroxypropyl-3-cyclodextrins.
Dans ce cas, la concentration en cyclodextrines dans le polyol pourra avantageusement aller de 0,01 % à 4,4% en masse par rapport à la masse totale de la solution. In this case, the concentration of cyclodextrins in the polyol may advantageously range from 0.01% to 4.4% by weight relative to the total mass of the solution.
Selon un mode particulier de réalisation de l'invention, la solution comprend : According to a particular embodiment of the invention, the solution comprises:
- de 0,03% à 2,0% (m/m) de doxycycline, en particulier d'hyclate de doxycycline - from 0.03% to 2.0% (m / m) of doxycycline, in particular doxycycline hyclate
- de 0 à 4,4% (m/m) de cyclodextrine, et from 0 to 4.4% (m / m) of cyclodextrin, and
- de 93,6% à 99,97% (m/m) de polyol. from 93.6% to 99.97% (m / m) of polyol.
Plus particulièrement le total doxycycline, en particulier hyclate de doxycycline, cyclodextrine et polyol représente 100% en masse de la solution, c'est à dire que la solution est uniquement constituée de doxycycline, de polyol et le cas échéant de cyclodextrine. More particularly, the total doxycycline, in particular doxycycline hyclate, cyclodextrin and polyol represents 100% by weight of the solution, that is to say that the solution consists solely of doxycycline, polyol and optionally cyclodextrin.
Une telle solution est préparée selon les méthodes usuelles de préparation de solutions. Such a solution is prepared according to the usual methods of preparing solutions.
La doxycycline, en particulier l'hyclate de doxycycline est rajouté dans le polyol sous agitation magnétique jusqu'à dissolution complète. Le mélange obtenu est limpide. The doxycycline, in particular the doxycycline hyclate, is added to the polyol with magnetic stirring until complete dissolution. The resulting mixture is clear.
La préparation de cyclodextrine, en particulier d'hyclate de doxycycline et de cyclodextrine se fait selon les conditions suivantes : The cyclodextrin preparation, in particular doxycycline hyclate and cyclodextrin, is prepared according to the following conditions:
- la cyclodextrine est ajoutée au polyol et agitée magnétiquement entre 1 à 5 heures, de préférence entre 2 et 4 heures, the cyclodextrin is added to the polyol and stirred magnetically between 1 to 5 hours, preferably between 2 and 4 hours,
la doxycycline est ensuite ajoutée dans le mélange et mis sous agitation magnétique entre 16 et 20 heures. the doxycycline is then added to the mixture and stirred magnetically between 16 and 20 hours.
Le mélange obtenu est limpide. The resulting mixture is clear.
Selon un mode préféré de réalisation de l'invention, la composition est une émulsion de type « hydrophile dans lipophile (H/L) », la solution de doxycycline (b), en particulier d'hyclate de doxycycline dans le polyol formant des globules entourés du véhicule anhydre (a). Les globules de solution de polyol ont avantageusement une taille inférieure ou égale à 50 μηη, avantageusement entre 20 et 30 μηη. According to a preferred embodiment of the invention, the composition is a "hydrophilic in lipophilic (H / L)" type emulsion, the doxycycline (b) solution, in particular of doxycycline hyclate in the polyol forming globules. surrounded by the anhydrous vehicle (a). The globules of polyol solution advantageously have a size less than or equal to 50 μηη, advantageously between 20 and 30 μηη.
La concentration finale en doxycycline en particulier hyclate, sous forme de solution dans un polyol anhydre dans la composition topique selon l'invention, en particulier sous forme d'émulsion, est comprise entre 0,001 % et 1 % (m/m), de préférence entre 0,005% et 0,5% (m/m), plus préférentiellement entre 0,01 % et 0,1 % (m/m). La présente invention concerne également la solution de doxycyline dans un polyol telle que définie précédemment en tant que telle, en particulier comme composition pharmaceutique ou comme composition intermédiaire pour la préparation d'une composition pharmaceutique, plus particulièrement pour la préparation d'une composition topique sous forme d'émulsion H/L telle que décrite précédemment et ci-après. The final concentration of doxycycline, in particular hyclate, in the form of a solution in an anhydrous polyol in the topical composition according to the invention, in particular in the form of an emulsion, is between 0.001% and 1% (m / m), preferably between 0.005% and 0.5% (w / w), more preferably between 0.01% and 0.1% (w / w). The present invention also relates to the solution of doxycycline in a polyol as defined previously as such, in particular as a pharmaceutical composition or as an intermediate composition for the preparation of a composition pharmaceutical, more particularly for the preparation of a topical composition in the form of H / L emulsion as described above and hereinafter.
De manière avantageuse, la composition selon l'invention est une composition dépourvue de conservateurs. Les agents conservateurs généralement employés dans des compositions topiques (pharmaceutiques, cosmétiques, etc.) pour éviter leur contamination par des germes, sont bien connus de l'homme du métier, comme les ammoniums quaternaires, notamment le chlorure de benzaikonium, l'alkyl-diméthyl-benzylammonium, le cétrimide, le chlorure de cétylpyridinium, le bromure de benzododécinium, le chlorure de benzothonium, le chlorure de cetalkonium, les conservateurs mercuriels, comme le nitrate/acétate/borate phénylmercurique, le thiomersal, les conservateurs alcooliques, comme l'éthanol, le chlorobutanol, l'alcool benzylique, le phényléthanol, l'alcool phényléthylique, les acides carboxyliques, tels que l'acide sorbique, les phénols, en particulier méthyl/propyl parabène, les amidines, par exemple le chlorhexidine digluconate et/ou des agents chélateur comme l'EDTA en association avec au moins un autre conservateur. Advantageously, the composition according to the invention is a composition without preservatives. Preservative agents generally used in topical compositions (pharmaceutical, cosmetic, etc.) to prevent their contamination by germs, are well known to those skilled in the art, such as quaternary ammoniums, in particular benzalkonium chloride, dimethylbenzylammonium, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzothonium chloride, cetalkonium chloride, mercurial preservatives, such as phenylmercuric nitrate / acetate / borate, thiomersal, alcoholic preservatives, such as ethanol, chlorobutanol, benzyl alcohol, phenylethanol, phenylethyl alcohol, carboxylic acids, such as sorbic acid, phenols, in particular methyl / propyl paraben, amidines, for example chlorhexidine digluconate and / or chelating agents such as EDTA in combination with at least one other preservative.
Par « sans conservateurs », on entend selon l'invention une composition substantiellement dépourvue de tels conservateurs pour répondre à une indication « sans conservateurs ». Sa teneur en conservateurs est inférieure ou égale à 10 ppm, plus particulièrement inférieure ou égale à 1 ppm, préférentiellement égale à 0 ppm, aucun conservateur n'entrant dans sa composition. By "preservative-free" is meant according to the invention a composition substantially free of such preservatives to meet a "no preservatives" indication. Its preservative content is less than or equal to 10 ppm, more particularly less than or equal to 1 ppm, preferably equal to 0 ppm, no preservative included in its composition.
En l'absence de conservateurs, la composition doit subir un traitement particulier au cours de sa préparation et de son conditionnement de manière à éviter et prévenir la contamination par des microorganismes (tels que Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Pneumocoques, Streptococcus faecalis, Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, Moraxella, Corynebacterium, Acinetobacter, Escherichia coli, Haermophilus influenzae). Ces traitements et procédures sont bien connus de l'homme du métier. En ce sens, une composition sans conservateurs selon l'invention se distingue d'une simple composition comprenant les mêmes ingrédients obtenue sans montrer de précautions particulières ni décrivant d'étapes du procédé permettant d'obtenir cette stérilité caractéristique des compositions selon l'invention, en particulier des compositions ophtalmiques. In the absence of preservatives, the composition must undergo a particular treatment during its preparation and its conditioning so as to avoid and prevent contamination by microorganisms (such as Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Pneumococci, Streptococcus faecalis , Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, Moraxella, Corynebacterium, Acinetobacter, Escherichia coli, Haermophilus influenzae). These treatments and procedures are well known to those skilled in the art. In this sense, a composition without preservatives according to the invention differs from a simple composition comprising the same ingredients obtained without showing any particular precautions or describing steps of the process making it possible to obtain this characteristic sterility of the compositions according to the invention, in particular ophthalmic compositions.
L'invention concerne en particulier les compositions topiques suivantes : The invention particularly relates to the following topical compositions:
Pommade hydrophobe % masse totale de la composition Hydrophobic ointment% total mass of the composition
Véhicule Vehicle
Matière hydrophobe semi-solide* 50,000 - 90,000 % Semi-solid hydrophobic material * 50,000 - 90,000%
Matière hydrophobe liquide* 50,000 - 9,999 % Liquid hydrophobic material * 50,000 - 9,999%
Principe actif solide Doxycycline micronisée* 0,001 - 1 ,000 % Solid active principle Doxycycline micronized * 0.001 - 1, 000%
Tels que définis précédemment As previously defined
Emulsion H/L % masse totale de la composition Emulsion H / L% total mass of the composition
Phase hydrophobe Hydrophobic phase
Matière hydrophobe semi-solide* 84,500 - 94,999 % Semi-solid hydrophobic material * 84,500 - 94,999%
Matière hydrophobe liquide* 0,000 - 9,500 % Liquid hydrophobic material * 0.000 - 9.500%
Phase hydrophile Hydrophilic phase
Doxycycline* 0,001 - 1 ,000 % Doxycycline * 0.001 - 1, 000%
Polyol* 5,000 % Polyol * 5,000%
*Tels que définis précédemment * As previously defined
Emulsion H/L % masse totale de la composition Emulsion H / L% total mass of the composition
Phase hydrophobe Hydrophobic phase
Matière hydrophobe semi-solide* 83,560 - 89,998 % Semi-solid hydrophobic material * 83,560 - 89,998%
Matière hydrophobe liquide* 0,000 - 5,000 % Liquid hydrophobic material * 0.000 - 5.000%
Phase hydrophile Hydrophilic phase
Doxycycline* 0,001 - 1 ,000 % Doxycycline * 0.001 - 1, 000%
Cyclodextrines 0,001 - 0,440 % Cyclodextrins 0.001 - 0.440%
Polyol* 10,000 % Polyol * 10,000%
*Tels que définis précédemment * As previously defined
La préparation des compositions selon l'invention se fait selon les méthodes usuelles connues de l'homme du métier, en particulier avec les précautions requises pour préparer des compositions stériles et sans conservateurs et les conditionner. The preparation of the compositions according to the invention is carried out according to the usual methods known to those skilled in the art, in particular with the precautions required to prepare sterile and preservative-free compositions and to condition them.
L'invention concerne aussi l'utilisation d'une composition selon l'invention pour son conditionnement dans contenant pharmaceutique approprié délivrer la composition pour son application topique et sa conservation plusieurs mois sans dégradation substantielle de la doxycycline. The invention also relates to the use of a composition according to the invention for its packaging in a suitable pharmaceutical container to deliver the composition for its topical application and its preservation for several months without substantial degradation of the doxycycline.
L'invention concerne une composition telle que définie précédemment, pour son utilisation dans le traitement des infections bactériennes des muqueuses ou de la peau, en particulier des paupières et/ou de la muqueuse oculaire. The invention relates to a composition as defined above, for its use in the treatment of bacterial infections of the mucous membranes or the skin, in particular the eyelids and / or the ocular mucosa.
L'invention concerne aussi une méthode de traitement des infections bactériennes des muqueuses ou de la peau, en particulier des paupières et/ou de la muqueuse oculaire, pour laquelle on applique sur le lieu de l'infection et/ou à proximité, une quantité appropriée de composition selon l'invention que l'on laisse agir. L'application sera renouvelée en tant que besoin, avantageusement jusqu'à la disparition des symptômes de l'infection. The invention also relates to a method for treating bacterial infections of the mucous membranes or of the skin, in particular the eyelids and / or the ocular mucosa, for which an amount of at least one infection is applied to the place of infection and / or in the vicinity thereof. appropriate composition according to the invention that is allowed to act. The application will be renewed as needed, advantageously until the disappearance of the symptoms of the infection.
La composition sera avantageusement utilisée ou la méthode sera avantageusement mise en œuvre pour des affections dues à des bactéries sensibles aux tétracyclines, comme Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Pneumocoques, Streptococcus faecalis, Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, Moraxella, Corynebacterium, Acinetobacter, E coli, /-/aemophilus influenzae pour les pathologies comme l'orgelet, la conjonctivite infectieuse, la kératite infectieuse, la blépharite, le dysfonctionnement des glandes de Meibomius, l'iritis (uvéite antérieure), la canaliculite et la rosacée. The composition will advantageously be used or the method will be advantageously used for conditions due to bacteria sensitive to tetracyclines, such as Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Pneumococci, Streptococcus faecalis, Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, Moraxella, Corynebacterium, Acinetobacter, E coli, / - / aemophilus influenzae for diseases such as stye, infectious conjunctivitis, infectious keratitis, blepharitis, dysfunction of Meibomian glands, iritis (anterior uveitis) , canaliculitis and rosacea.
EXEMPLES EXAMPLES
Matériels et méthodes Materials and methods
Les différentes formulations sont réalisées à l'aide d'un mélangeur sous vide équipé d'un système de dispersion adapté. The different formulations are made using a vacuum mixer equipped with a suitable dispersion system.
La préparation sous forme de pommade hydrophobe contenant le principe actif solide dispersé est réalisée selon la méthode suivante : The preparation in the form of hydrophobic ointment containing the dispersed solid active principle is carried out according to the following method:
La base matière hydrophobe liquide/matière hydrophobe semi-solide est formulée par mélange dans un bain marie à 70°C afin de rendre l'ensemble des composants miscibles. La température du mélange est abaissée à 45°C et la base hydrophobe est transférée dans le mélangeur dont la température est de 45°C. The liquid hydrophobic material / semi-solid hydrophobic material base is formulated by mixing in a water bath at 70 ° C. in order to render all the components miscible. The temperature of the mixture is lowered to 45 ° C and the hydrophobic base is transferred to the mixer whose temperature is 45 ° C.
La doxycycline hyclate est ajoutée dans le mélangeur et l'ensemble est mis sous vide à 80%. The doxycycline hyclate is added to the mixer and the whole is evacuated to 80%.
L'agitation de la formule est effectuée pendant 30 minutes, à 700 rpm, à 45°C puis la température de l'ensemble du mélange est descendue à 37°C. The stirring of the formula is carried out for 30 minutes, at 700 rpm, at 45 ° C. and then the temperature of the whole mixture is lowered to 37 ° C.
- La pommade obtenue est conditionnée et refroidie jusqu'à température ambiante. - The ointment obtained is packaged and cooled to room temperature.
La préparation sous forme d'émulsion H/L contenant le principe actif en solution dans le polyol est réalisée selon la méthode suivante : The preparation in the form of an H / L emulsion containing the active ingredient in solution in the polyol is carried out according to the following method:
La base matière hydrophobe liquide/matière hydrophobe semi-solide (appelée phase A) est formulée par mélange dans un bain marie à 75°C afin de rendre l'ensemble des composants miscibles. Pour le ratio massique matière hydrophobe liquide/matière hydrophobe semi-solide 0/100, la matière hydrophobe semi-solide est ajoutée directement dans le mélangeur à 45°C. The liquid hydrophobic material / semi-solid hydrophobic material base (referred to as phase A) is formulated by mixing in a water bath at 75 ° C. so as to render all the components miscible. For the liquid hydrophobic material mass ratio / 0/100 semi-solid hydrophobic material, the semi-solid hydrophobic material is added directly into the mixer at 45 ° C.
La température de la phase A est abaissée à 45°C puis la phase A est transférée dans le mélangeur dont la température est de 45°C. The temperature of phase A is lowered to 45 ° C and then phase A is transferred to the mixer whose temperature is 45 ° C.
- L'hyclate de doxycyline est ajouté au polyol (appelé phase B) et agité magnétiquement jusqu'à dissolution complète puis la température de la solution est augmentée jusqu'à 45°C. The doxycycline hyclate is added to the polyol (called phase B) and stirred magnetically until complete dissolution and the temperature of the solution is increased to 45 ° C.
Lorsque les phases A et B sont à même température, la phase B est ajoutée à la phase A sous agitation pour former une émulsion. When phases A and B are at the same temperature, phase B is added to phase A with stirring to form an emulsion.
- L'émulsion est agitée pendant 30 minutes, à 700 rpm, à 45°C puis la température de l'ensemble du mélange est abaissée à 37°C. The emulsion is stirred for 30 minutes at 700 rpm at 45 ° C. and then the temperature of the whole mixture is lowered to 37 ° C.
L'émulsion obtenue est conditionnée et refroidie jusqu'à température ambiante. La préparation sous forme d'émulsion H/L contenant le principe actif et les cyclodextrines en solution dans le polyol est réalisée selon la méthode suivante : The emulsion obtained is conditioned and cooled to room temperature. The preparation in the form of an H / L emulsion containing the active principle and the cyclodextrins in solution in the polyol is carried out according to the following method:
La base matière hydrophobe liquide/matière hydrophobe semi-solide (appelée phase A) est formulée par mélange dans un bain marie à 75°C afin de rendre l'ensemble des composants miscibles. Pour le ratio massique matière hydrophobe liquide/matière hydrophobe semi-solide 0/100, la matière hydrophobe semi-solide est ajoutée directement dans le mélangeur à 45°C. The liquid hydrophobic material / semi-solid hydrophobic material base (referred to as phase A) is formulated by mixing in a water bath at 75 ° C. so as to render all the components miscible. For the liquid hydrophobic material mass ratio / 0/100 semi-solid hydrophobic material, the semi-solid hydrophobic material is added directly into the mixer at 45 ° C.
La température de la phase A est abaissée à 45°C puis la phase A est transférée dans le mélangeur dont la température est de 45°C. The temperature of phase A is lowered to 45 ° C and then phase A is transferred to the mixer whose temperature is 45 ° C.
La cyclodextrine est ajoutée au polyol (appelé phase B) et agitée magnétiquement puis l'hyclate de doxycyline est ajouté à la phase B et agitée magnétiquement jusqu'à dissolution complète de l'ensemble des composants, la température de la solution est augmentée jusqu'à 45°C. The cyclodextrin is added to the polyol (called phase B) and stirred magnetically then the doxycycline hyclate is added to phase B and stirred magnetically until complete dissolution of all the components, the temperature of the solution is increased until at 45 ° C.
- Lorsque les phases A et B sont à même température, la phase B est ajoutée à la phase A sous agitation pour former une émulsion. - When phases A and B are at the same temperature, phase B is added to phase A with stirring to form an emulsion.
L'émulsion est agitée pendant 30 minutes, à 700 rpm, à 45°C puis la température de l'ensemble du mélange est abaissée à 37°C. The emulsion is stirred for 30 minutes at 700 rpm at 45 ° C. and the temperature of the whole mixture is lowered to 37 ° C.
L'émulsion obtenue est conditionnée et refroidie jusqu'à température ambiante. The emulsion obtained is conditioned and cooled to room temperature.
Afin d'effectuer le dosage du principe actif dans la formulation, l'extraction suivante est réalisée : In order to perform the dosage of the active ingredient in the formulation, the following extraction is carried out:
1 ,0 g de formule est dilué dans 10,0 g d'eau et agité à l'aide d'un système d'agitation adapté pendant 30 minutes à 45°C 1.0 g of the formula is diluted in 10.0 g of water and stirred with a suitable stirring system for 30 minutes at 45 ° C.
- Après filtration avec un filtre nylon à 0,45 μηη, une dilution dans la phase mobile est effectuée pour un dosage par chromatographie en phase liquide à haute performance. After filtration with a 0.45 μηη nylon filter, a dilution in the mobile phase is carried out for a high performance liquid chromatography assay.
La teneur en principe actif est déterminée selon la méthode par chromatographie en phase liquide à haute performance suivante : The content of active ingredient is determined according to the following high performance liquid chromatography method:
- Colonne : XTerra® RP 8 5μηι 4.6x250 mm - Column: XTerra® RP 8 5μηι 4.6x250 mm
Phase mobile : Mobile phase:
o 65% d'eau contenant de l'acide oxalique à 0,13% o 65% water containing 0.13% oxalic acid
o 22 % d'acétonitrile o 22% acetonitrile
o 13% de méthanol o 13% methanol
- Débit : 1 ,0 mL/min Tests de stabilité - Flow rate: 1, 0 mL / min Stability tests
Des tests de stabilité sont réalisés aux températures de 25°C et 40°C : Stability tests are carried out at temperatures of 25 ° C and 40 ° C:
En solution aqueuse à 0,1 %, la doxycycline est rapidement dégradée comme le montre la figure 1 . In 0.1% aqueous solution, the doxycycline is rapidly degraded as shown in FIG.
Dans le glycérol (doxycycline hyclate à 0.1 %) avec et sans β-cyclodextrines, les compositions selon l'invention marquent leur grande stabilité avec pas ou peu de dégradation de la doxycycline (tenant compte des marges d'erreurs des mesures), comme le montre la figure 2. In glycerol (doxycycline hyclate 0.1%) with and without β-cyclodextrins, the compositions according to the invention mark their high stability with little or no degradation of the doxycycline (taking into account the error margins of the measurements), as shown in FIG. shows figure 2.
Dans la formulation topique à 25°C selon l'invention, une formulation anhydre à 0, 1 % en doxycycline hyclate, comme le montre la figure 3. In the topical formulation at 25 ° C according to the invention, an anhydrous formulation at 0, 1% doxycycline hyclate, as shown in Figure 3.
Compositions particulières Special compositions
Pour la préparation des compositions ci-dessous, on emploie comme matière hydrophobe semi-solide la vaseline blanche (petrolatum) et comme matière hydrophobe liquide la paraffine liquide. For the preparation of the compositions below, the semi-solid hydrophobic material used is petroleum jelly (petrolatum) and the liquid paraffin liquid hydrophobic material.
% masse totale de la% total mass of the
Pommade hydrophobe Masse pesée Hydrophobic ointment Weighted mass
composition composition
Véhicule Vehicle
Matière hydrophobe semi- Semi-hydrophobic material
450,000 g 70,000 % 450,000 g 70,000%
solide solid
Matière hydrophobe liquide 49,900 g 29,900 % Liquid hydrophobic material 49.900 g 29.900%
Principe actif solide Solid active principle
dispersé scattered
Hyclate de doxycycline Doxycycline hyclate
0,500 g 0,100 % 0.500 g 0.100%
micronisé micronized
% masse totale de la% total mass of the
Emulsion 1 Masse pesée Emulsion 1 Weighted mass
composition composition
Phase hydrophobe Hydrophobic phase
Matière hydrophobe semi- Semi-hydrophobic material
427,000 g 85,400 % 427,000 g 85.400%
solide solid
Matière hydrophobe liquide 47,500 g 9,500 % Liquid hydrophobic material 47,500 g 9,500%
Phase hydrophile Hydrophilic phase
Hyclate de doxycycline 0,500 g 0,100 % Doxycycline hyclate 0.500 g 0.100%
Polyol 25,000 g 5,000 % % masse totale de laPolyol 25,000 g 5,000% % total mass of the
Emulsion 2 Masse pesée Emulsion 2 Weighted mass
composition composition
Phase hydrophobe Hydrophobic phase
Matière hydrophobe semi- Semi-hydrophobic material
474,500 g 94,900 % solide 474,500 g 94.900% solid
Phase hydrophile Hydrophilic phase
Hyclate de doxycycline 0,500 g 0,100 % Doxycycline hyclate 0.500 g 0.100%
Polyol 25,000 g 5,000 % Polyol 25,000 g 5,000%
% masse totale de la% total mass of the
Emulsion 3 Masse pesée Emulsion 3 Weighted mass
composition composition
Phase hydrophobe Hydrophobic phase
Matière hydrophobe semi- Semi-hydrophobic material
448,200 g 89,640 % solide 448,200 g 89,640% solid
Phase hydrophile Hydrophilic phase
Hyclate de doxycycline 0,150 g 0,030 % Doxycycline hyclate 0.150 g 0.030%
β-cyclodextrine 1 ,650 g 0,330 % β-cyclodextrin 1, 650 g 0.330%
Polyol 50,000 g 10,000 % Polyol 50,000 g 10,000%
% masse totale de la% total mass of the
Emulsion 4 Masse pesée Emulsion 4 Weighted mass
composition composition
Phase hydrophobe Hydrophobic phase
Matière hydrophobe semi- Semi-hydrophobic material
448,400 g 89,680 % solide 448.400 g 89.680% solid
Phase hydrophile Hydrophilic phase
Hyclate de doxycycline 0,500 g 0,100 % Doxycycline hyclate 0.500 g 0.100%
β-cyclodextrine 1 ,100 g 0,220 % β-cyclodextrin 1, 100 g 0.220%
Polyol 50,000 g 10,000 % Polyol 50,000 g 10,000%
% masse totale de la% total mass of the
Emulsion 5 Masse pesée Emulsion 5 Weighted mass
composition composition
Phase hydrophobe Hydrophobic phase
Matière hydrophobe semi- Semi-hydrophobic material
447,300 g 89,460 % solide 447.300 g 89.460% solid
Phase hydrophile Hydrophilic phase
Hyclate de doxycycline 0,500 g 0,100 % β-cyclodextrine 2,200 g 0,440 %Doxycycline hyclate 0.500 g 0.100% β-cyclodextrin 2,200 g 0.440%
Polyol 50,000 g 10,000 % Polyol 50,000 g 10,000%
Claims
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1752853A FR3064482B1 (en) | 2017-04-03 | 2017-04-03 | TOPICAL COMPOSITION OF DOXYCYCLINE |
| PCT/EP2018/058447 WO2018185078A1 (en) | 2017-04-03 | 2018-04-03 | Topical doxycycline composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP3606509A1 true EP3606509A1 (en) | 2020-02-12 |
Family
ID=59153076
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP18714781.4A Pending EP3606509A1 (en) | 2017-04-03 | 2018-04-03 | Topical doxycycline composition |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US11229597B2 (en) |
| EP (1) | EP3606509A1 (en) |
| JP (1) | JP2020512997A (en) |
| CA (1) | CA3058035A1 (en) |
| FR (1) | FR3064482B1 (en) |
| WO (1) | WO2018185078A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4618949A1 (en) * | 2022-11-17 | 2025-09-24 | Martin Coffey | Semifluorinated alkane antibiotic combination compositions for treatment of ocular disorders |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016154232A2 (en) * | 2015-03-23 | 2016-09-29 | BioPharmX, Inc. | Pharmaceutical tetracycline composition for dermatological use |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2095065C1 (en) * | 1995-04-06 | 1997-11-10 | Научно-исследовательский институт по изучению лепры Минздравмедпрома РФ | Agent for treatment of trophic ulcer and burn in leprosy patients |
| EP0960887B1 (en) * | 1996-06-14 | 2007-04-25 | Meiji Dairies Corporation | T cell epitope peptides |
| DE69940227D1 (en) * | 1998-05-08 | 2009-02-12 | Univ Miami | Use of sub-antimicrobial tetracyclines for the treatment of ocular rosacea |
| EP1494681A4 (en) * | 2002-04-16 | 2008-08-06 | Collagenex Pharm Inc | Methods of simultaneously treating ocular rosacea and acne rosacea |
| US20060172982A1 (en) * | 2005-01-28 | 2006-08-03 | Gardner Wallace J | Formulation comprising tetracycline or derivative and method of treating or preventing infections and inflammatory conditions |
| CN104519834B (en) * | 2012-08-02 | 2016-10-12 | 波利皮得有限公司 | For treating compositions and the method in bone space and open fracture |
| PT106679B (en) * | 2012-11-27 | 2015-03-25 | Hovione Farmaciencia Sa | TOPICAL FORMULATIONS OF TETRACYCLINES, THEIR PREPARATION AND USES |
| EP3199163A4 (en) * | 2014-09-23 | 2018-06-20 | Agencia Pública Empresarial Sanitaria Hospital Alto Guadalquivir | Composition of doxycycline in liposomes for the prevention, improvement and/or treatment of ocular pathologies |
| CA2997220A1 (en) * | 2015-09-03 | 2017-03-09 | Delivra Inc. | Transdermal formulations for delivery of doxycycline, and their use in the treatment of doxycycline-responsive diseases and conditions |
| CN106539817A (en) * | 2016-11-16 | 2017-03-29 | 杜光彦 | For treating ointment, the preparation method and its usage of acne |
-
2017
- 2017-04-03 FR FR1752853A patent/FR3064482B1/en active Active
-
2018
- 2018-04-03 WO PCT/EP2018/058447 patent/WO2018185078A1/en not_active Ceased
- 2018-04-03 US US16/498,323 patent/US11229597B2/en active Active
- 2018-04-03 JP JP2019554631A patent/JP2020512997A/en active Pending
- 2018-04-03 EP EP18714781.4A patent/EP3606509A1/en active Pending
- 2018-04-03 CA CA3058035A patent/CA3058035A1/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016154232A2 (en) * | 2015-03-23 | 2016-09-29 | BioPharmX, Inc. | Pharmaceutical tetracycline composition for dermatological use |
Also Published As
| Publication number | Publication date |
|---|---|
| FR3064482B1 (en) | 2020-11-13 |
| US11229597B2 (en) | 2022-01-25 |
| CA3058035A1 (en) | 2018-10-11 |
| FR3064482A1 (en) | 2018-10-05 |
| JP2020512997A (en) | 2020-04-30 |
| US20210100739A1 (en) | 2021-04-08 |
| WO2018185078A1 (en) | 2018-10-11 |
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