SK18652000A3 - PHARMACEUTICAL COMPOSITION ON THE BASIS OF ERYTHROMYCIN FATTYì (54) ACID SALTS FOR THE TOPICAL TREATMENT OF SKIN DISEASES - Google Patents
PHARMACEUTICAL COMPOSITION ON THE BASIS OF ERYTHROMYCIN FATTYì (54) ACID SALTS FOR THE TOPICAL TREATMENT OF SKIN DISEASES Download PDFInfo
- Publication number
- SK18652000A3 SK18652000A3 SK1865-2000A SK18652000A SK18652000A3 SK 18652000 A3 SK18652000 A3 SK 18652000A3 SK 18652000 A SK18652000 A SK 18652000A SK 18652000 A3 SK18652000 A3 SK 18652000A3
- Authority
- SK
- Slovakia
- Prior art keywords
- erythromycin
- pharmaceutical composition
- fatty acid
- skin
- acne
- Prior art date
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 title claims abstract description 91
- 229960003276 erythromycin Drugs 0.000 title claims abstract description 40
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- 230000000699 topical effect Effects 0.000 title claims abstract description 12
- 208000017520 skin disease Diseases 0.000 title claims abstract description 9
- 239000002253 acid Substances 0.000 title 1
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 32
- 239000000194 fatty acid Substances 0.000 claims abstract description 32
- 229930195729 fatty acid Natural products 0.000 claims abstract description 32
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 27
- 208000002874 Acne Vulgaris Diseases 0.000 claims abstract description 22
- 206010000496 acne Diseases 0.000 claims abstract description 22
- -1 erythromycin fatty acid salt Chemical class 0.000 claims abstract description 10
- 239000007788 liquid Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 30
- 239000006071 cream Substances 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000000839 emulsion Substances 0.000 claims description 13
- YAVZHCFFUATPRK-YZPBMOCRSA-N Erythromycin stearate Chemical group CCCCCCCCCCCCCCCCCC(O)=O.O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 YAVZHCFFUATPRK-YZPBMOCRSA-N 0.000 claims description 6
- 229960004142 erythromycin stearate Drugs 0.000 claims description 6
- 239000000499 gel Substances 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 2
- 230000035515 penetration Effects 0.000 abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 3
- 239000000546 pharmaceutical excipient Substances 0.000 abstract 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 14
- 239000003755 preservative agent Substances 0.000 description 11
- 230000002335 preservative effect Effects 0.000 description 10
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 7
- 229960000541 cetyl alcohol Drugs 0.000 description 7
- XJNUECKWDBNFJV-UHFFFAOYSA-N hexadecyl 2-ethylhexanoate Chemical compound CCCCCCCCCCCCCCCCOC(=O)C(CC)CCCC XJNUECKWDBNFJV-UHFFFAOYSA-N 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 235000021355 Stearic acid Nutrition 0.000 description 6
- 230000001476 alcoholic effect Effects 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 6
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 6
- 239000008117 stearic acid Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 239000003925 fat Substances 0.000 description 5
- 235000004213 low-fat Nutrition 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 210000001732 sebaceous gland Anatomy 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 description 3
- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 description 3
- 229960002916 adapalene Drugs 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 229940057204 dimethicone 100 Drugs 0.000 description 3
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 3
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229960003500 triclosan Drugs 0.000 description 3
- 241000186427 Cutibacterium acnes Species 0.000 description 2
- 239000004367 Lipase Substances 0.000 description 2
- 102000004882 Lipase Human genes 0.000 description 2
- 108090001060 Lipase Proteins 0.000 description 2
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 235000021588 free fatty acids Nutrition 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 235000019421 lipase Nutrition 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940057917 medium chain triglycerides Drugs 0.000 description 2
- 229960002509 miconazole Drugs 0.000 description 2
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
- 230000000149 penetrating effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229940055019 propionibacterium acne Drugs 0.000 description 2
- 210000002374 sebum Anatomy 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- AKSNFBZYFYUEGF-UHFFFAOYSA-N (2-aminoacetyl) octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(=O)CN AKSNFBZYFYUEGF-UHFFFAOYSA-N 0.000 description 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- JOLQKTGDSGKSKJ-UHFFFAOYSA-N 1-ethoxypropan-2-ol Chemical compound CCOCC(C)O JOLQKTGDSGKSKJ-UHFFFAOYSA-N 0.000 description 1
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- HDIFHQMREAYYJW-FMIVXFBMSA-N 2,3-dihydroxypropyl (e)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C\CCCCCCCC(=O)OCC(O)CO HDIFHQMREAYYJW-FMIVXFBMSA-N 0.000 description 1
- FLPJVCMIKUWSDR-UHFFFAOYSA-N 2-(4-formylphenoxy)acetamide Chemical compound NC(=O)COC1=CC=C(C=O)C=C1 FLPJVCMIKUWSDR-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 239000004604 Blowing Agent Substances 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- WHPAGCJNPTUGGD-UHFFFAOYSA-N Croconazole Chemical compound ClC1=CC=CC(COC=2C(=CC=CC=2)C(=C)N2C=NC=C2)=C1 WHPAGCJNPTUGGD-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 241001430197 Mollicutes Species 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 239000004164 Wax ester Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 229960003473 androstanolone Drugs 0.000 description 1
- 230000003255 anti-acne Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 229960002255 azelaic acid Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 229940074979 cetyl palmitate Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960002042 croconazole Drugs 0.000 description 1
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 1
- 229960000978 cyproterone acetate Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- SASYSVUEVMOWPL-NXVVXOECSA-N decyl oleate Chemical compound CCCCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC SASYSVUEVMOWPL-NXVVXOECSA-N 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 229940050781 erythromycin / isotretinoin Drugs 0.000 description 1
- 229940050580 erythromycin / tretinoin Drugs 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- ACGUYXCXAPNIKK-UHFFFAOYSA-N hexachlorophene Chemical compound OC1=C(Cl)C=C(Cl)C(Cl)=C1CC1=C(O)C(Cl)=CC(Cl)=C1Cl ACGUYXCXAPNIKK-UHFFFAOYSA-N 0.000 description 1
- 229960004068 hexachlorophene Drugs 0.000 description 1
- PXDJXZJSCPSGGI-UHFFFAOYSA-N hexadecanoic acid hexadecyl ester Natural products CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 230000011268 leukocyte chemotaxis Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- DWZFNULJNZJRLM-UHFFFAOYSA-N methoxy-dimethyl-trimethylsilylsilane Chemical compound CO[Si](C)(C)[Si](C)(C)C DWZFNULJNZJRLM-UHFFFAOYSA-N 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000003784 poor nutrition Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 231100000046 skin rash Toxicity 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 235000019386 wax ester Nutrition 0.000 description 1
- 150000003751 zinc Chemical class 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
- A61P17/10—Anti-acne agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Oblasť technikyTechnical field
Vynález sa týka farmaceutickej kompozície na báze erytromycínových solí mastných kyselín s 12 až 22 atómmi uhlíka vo zvyšku mastnej kyseliny, ako aj použitia týchto erytromycínových soli mastných kyselín na topické liečenie kožných ochorení.The invention relates to a pharmaceutical composition based on erythromycin fatty acid salts of 12 to 22 carbon atoms in the fatty acid residue, as well as the use of these erythromycin fatty acid salts for the topical treatment of skin diseases.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Ku kožným ochoreniam, rozšíreným najmä u mladistvých, patri akné. Akné sa vyznačuje hnisavými kožnými vyrážkami, ktoré sa objavujú prevažne na tvári, na šiji a na hrudi. Je spôsobené infekciou zväčšených mazových žliaz kože baktériami Propionibacterium acnes, ktoré sú prítomné na povrchu kože. Tým dochádza k tvorbe hnisom naplnených pľuzgierikov v oblasti mazových žliaz kože (Herder, Lexikón der Biológie, Spektrum Akademischer Verlag, Heidelberg 1994, str. 87). Podstatným aspektom vzniku a zachovania akné je tvorba voľných mastných kyselín vo folikule mazovej žľazy, ktorá je vyvolaná lipázou z Propionibacterium acnes. Príčiny vzniku akné su mnohoraké. Pri často sa vyskytujúcom Acne vulgaris napríklad androgény stimulujú sekréciu mazu a tým podporujú jeho vznik. Pritom v koži chorých na akné zjavne dochádza k zvýšenej premene testosterônu na fakticky účinný dihydrotestosterón. Ďalej pri vzniku akné hrajú úlohu bakteriálne sekundárne infekcie, dedičné a psychogénne takiory, ako aj nesprávna výživa. (Pschyrembel Klinisches Wôrterbuch, Walter de Gruyter, Berlín 1986, str. 13).Skin diseases, especially in adolescents, include acne. Acne is characterized by purulent skin rashes that appear predominantly on the face, neck, and chest. It is caused by infection of the enlarged sebaceous glands of the skin with Propionibacterium acnes, which are present on the skin surface. This leads to the formation of pus-filled blisters in the area of the sebaceous glands of the skin (Herder, Lexicon of Biology, Spektrum Akademischer Verlag, Heidelberg 1994, p. 87). An essential aspect of the formation and maintenance of acne is the formation of free fatty acids in the sebaceous gland follicle, which is induced by Propionibacterium acnes lipase. The causes of acne are many. In the case of the frequently occurring Acne vulgaris, for example, androgens stimulate sebum secretion and thereby promote the production of sebum. In the skin of acne patients, there appears to be an increased conversion of testosterone to actually effective dihydrotestosterone. Furthermore, bacterial secondary infections, hereditary and psychogenic diseases, as well as poor nutrition play a role in the development of acne. (Pschyrembel Klinisches Worterbuch, Walter de Gruyter, Berlin 1986, p. 13).
Pretože baktérie zohrávajú pri uvoľňovaní dráždivých mastných kyselín podstatnú úlohu a tým sa podstatne podieľajú na vytvorení akné, navrhlo sa použiť pri liečení antibiotika. Najmä je známe použitie erytromycinu. Eiytromycin je popri malej toxicite široko účinný proti mnohým grampozitívnym baktériám, napríklad Streptococcus a Staphylococcus, ako aj niektorým gramnegativnym baktériám, napríklad Neisseria a Haemophilus, ako aj proti mykoplazmám (Rômpp Chemie-Lexikon, Georg Thieme ·· ·· ·· · ·· ··· ··· · · · • · ··· · · · · · · • · · · · · · ···· · · ·Since bacteria play an essential role in the release of irritating fatty acids and thus contribute substantially to the formation of acne, it has been suggested to be used in the treatment of antibiotics. In particular, the use of erythromycin is known. Eiytromycin, in addition to its low toxicity, is broadly effective against many Gram positive bacteria such as Streptococcus and Staphylococcus, as well as some Gram negative bacteria such as Neisseria and Haemophilus as well as against mycoplasmas (Rômpp Chemie-Lexikon, Georg Thieme) ·· ·· ·· ·· ··· ·························
-2Verlag, Stuttgart 1997, str. 1210). Hlavnou indikáciou erytromycínu je papulopustulózne akne (Niedner, Ziegenmayer, Dermatika, Wissenschaftliche Verlagsgesellschaft 1992, str. 94). Pod vplyvom erytromycínu dochádza k zníženiu množstva vytvorených voľných mastných kyselín. Po prvé sa v dôsledku antibakteriálnej účinnosti erytromycínu zmenši množstvo baktérií, po druhé sa ale dá dokázať aj priamy účinok na lipázu, pričom sú nevyhnutne koncentrácie erytromycínu, ktoré sú pod minimálnou inhibičnou koncentráciou (MHK). Naviac dochádza aj k zníženiu chemotaxie leukocytov, čo vedie k utlmeniu zápalu.-2Verlag, Stuttgart 1997, p. 1210). The main indication of erythromycin is papulopustular acne (Niedner, Ziegenmayer, Dermatika, Wissenschaftliche Verlagsgesellschaft 1992, p. 94). Under the influence of erythromycin, the amount of free fatty acids formed is reduced. Firstly, due to the antibacterial activity of erythromycin, the amount of bacteria is reduced, but secondly, a direct effect on lipase can also be demonstrated, with concentrations of erythromycin below the minimum inhibitory concentration (MHK) being inevitable. In addition, there is a reduction in leukocyte chemotaxis leading to a reduction in inflammation.
Liečenie antibiotikami a špeciálne erytromycínom sa dá rozdeliť po prvé na orálne a po druhé na vonkajšie podávanie. Tak erytromycin, ako aj erytromycinstearát sa nachádzajú na trhu v povolených liekoch na orálne podávanie na liečenie akné a infekcií kože. Hoci sa orálnym podávaním dosahuje v boji proti akné dobrá účinnosť, systematické podávanie má nevýhodu, že je zaťažený celý organizmus. Ďalej sa pri tomto použití účinná látka nevyhnutne rozriedi po celom tele.Treatment with antibiotics and especially erythromycin can be divided first into oral and second into external administration. Both erythromycin and erythromycin stearate are marketed in authorized oral formulations for the treatment of acne and skin infections. Although oral efficacy has good efficacy in combating acne, systemic administration has the disadvantage that the entire organism is burdened. Furthermore, in this use, the active ingredient is necessarily diluted throughout the body.
Pretože pri vonkajšej terapii, t. j. pri topickom použití erytromycínu, sa antibiotikum aplikuje lokálne, dá sa vyššie uvedeným nevýhodám orálneho podávania zabrániť. Po vonkajšom použití erytromycínu dôjde k odlišnej penetrácii do mazovej žľazy, pričom iipofílna báza penetruje lepšie než vo vode rozpustné soli. Problémom pri liečbe erytromycínom bolo doteraz udržanie stability prípravku pri súčasne dobrej penetrácii produktu. Stabilita topických erytromycinových prípravkov bola predmetom rozličných výskumov. Tak sa v GB-A-1 152 644 navrhuje stabilná kompozícia erytromycínu v oleji, pričom olej ma 6 až 18 atómov uhlíka a jódové číslo?? menšie než 42. Pri týchto kompozíciách na lipofilnej báze je erytromycin pomerne stabilný, avšak použitie mastných nosných látok pri terapeutickom liečení akné nie je zvlášť žiaduce, pretože tieto kompozície neumožňujú primerané uvoľňovanie antibiotika. Okrem toho tato kompozícia nevnikne ihneď do kože. Pretože koža pacientov s akné je od prírody mastná, zložky s obsahom oleja nepredstavujú primerané nosné látky. Koža pacienta s akné vyžaduje skôr prípravky s malým obsahom tuku.Because in external therapy, i. j. in the topical use of erythromycin, the antibiotic is administered topically, the above mentioned disadvantages of oral administration can be avoided. After external application of erythromycin, different penetration into the sebaceous gland occurs, with the iipophilic base penetrating better than the water-soluble salts. The problem with the treatment of erythromycin has so far been to maintain the stability of the formulation while at the same time penetrating the product well. The stability of topical erythromycin formulations has been the subject of various investigations. Thus GB-A-1 152 644 proposes a stable composition of erythromycin in oil, wherein the oil has 6 to 18 carbon atoms and an iodine number. In these lipophilic-based compositions, erythromycin is relatively stable, but the use of fatty carriers in the therapeutic treatment of acne is not particularly desirable as these compositions do not allow adequate antibiotic release. In addition, the composition does not enter the skin immediately. Because the skin of patients with acne is naturally oily, oil-containing ingredients do not constitute adequate carriers. Rather, the skin of an acne patient requires low fat preparations.
Výhodným vehikulom pre účinné látky pri terapii akné sú O/V (olej-vo-vode) krémy alebo emulzie, ktoré majú len malý podiel tuku, ale vysoký podiel vody. V dôsledkuO / V (oil-in-water) creams or emulsions having a low fat content but a high water content are preferred vehicles for acne therapy. Due to the
koži primeraných vlastností týchto formulácií môže koža antibiotiká dobre prijať, a preto su pri terapii akne zvlášť účinné. Pri vyšetreniach sa však zistilo, že účinnosť erytromycinu v emulziách s vysokým podielom vody klesla pri skladovaní pri 25 °C po dobu jedného mesiaca až o 60 % východiskovej hodnoty (International Journal of Pharmaceutics 67, 195-199, 1991). V dôsledku tejto nestability vodných prípravkov na báze erytromycinu a tym zmenšenej trvanlivosti produktu nie je priemyselná výroba a predaj O/V-krému alebo emulzií na báze erytromycinu možná.the skin of the appropriate properties of these formulations can be well absorbed by the skin of the antibiotic and are therefore particularly effective in the treatment of acne. However, investigations revealed that the efficacy of erythromycin in high water emulsions decreased by up to 60% of the baseline value at 25 ° C for one month (International Journal of Pharmaceutics 67, 195-199, 1991). Due to this instability of the aqueous erythromycin-based formulations and the reduced product shelf life, the industrial manufacture and sale of O / W-cream or erythromycin-based emulsions is not possible.
Z týchto výskumov d'alej vyplýva, že V/O (voda-v-oleji) emulzie si pri skladovaní po dobu 12 týždňov zachovávajú účinnosť vyššiu než 90 % východiskovej hodnoty. Alkoholické roztoky a alkoholické gély vykázali mierne zníženú trvanlivosť, pričom pri skladovaní vždy pri 25 °C sa zaznamenala pre alkoholický roztok strata 10 % počas prvých troch týždňov a pre alkoholický gél strata 20 % po dvoch mesiacoch. Ďalej sa zistilo, že erytromycín je v alkalickej oblasti zvlášť aktívny, avšak nastavenie pH hodnoty na S,5 malo škodlivý vplyv na aktivitu účinnej látky. Preto sa ponúkajú lieky na báze erytromycinu na topické použitie takmer výhradne v alkoholických nosičoch.These investigations further show that the V / O (water-in-oil) emulsions retain an efficacy of greater than 90% of the initial value when stored for 12 weeks. Alcoholic solutions and alcoholic gels showed a slightly reduced shelf life, with a 10% loss in alcoholic solution for the first three weeks and a 20% loss in alcoholic gel after two months when stored at 25 ° C each. Furthermore, erythromycin was found to be particularly active in the alkaline region, but adjusting the pH to 0.5 had a detrimental effect on the activity of the active ingredient. Therefore, erythromycin-based drugs are offered for topical use almost exclusively in alcoholic carriers.
US-A-4 000 263 opisuje roztok na báze erytromycinu s dobrou stabilitou pri skladovaní, pričom erytromycín je rozpustený v nosiči, ktorý pozostáva z propylénglykolu, etylalkoholu a polyoxyetylén-lauiylalkoholu.US-A-4 000 263 discloses an erythromycin-based solution with good storage stability, wherein the erythromycin is dissolved in a carrier consisting of propylene glycol, ethyl alcohol and polyoxyethylene-lauyl alcohol.
V US-A-4 469 684 sa navrhuje pri skladovaní stabilná kompozícia, v ktorej sa erytromycín nachádza vo forme jeho zinkovej soli v t-butanole.US-A-4 469 684 proposes a storage-stable composition in which erythromycin is in the form of its zinc salt in t-butanol.
DE-A-37 12 758 opisuje stabilnú anti-akné-kompozíciu na báze erytromycinu, v ktorej sa erytromycín nachádza vo farmaceutický prijateľnom nosiči, ktorý obsahuje 20 až 99,5 hmotn. % monoetyléteru propylénglykolu alebo dipropylénglykolu.DE-A-37 12 758 discloses a stable erythromycin-based anti-acne composition in which erythromycin is present in a pharmaceutically acceptable carrier comprising 20 to 99.5 wt. % of propylene glycol monoethylether or dipropylene glycol.
Ďalšie kompozície sú opísané v FR-A-7707785, FR-A-7732761, ako aj v EP-A8020929, v ktorých sa eiytromycín taktiež nachádza v nosiči z polyolu, vyššieho alifatického alkoholu alebo esteru mastnej kyseliny.Other compositions are described in FR-A-7707785, FR-A-7732761 as well as in EP-A8020929, in which eiytromycin is also present in a carrier of a polyol, a higher aliphatic alcohol or a fatty acid ester.
Všetky tieto priemyselne vyrobené topické erytromycínové prípravky preto pozostávajú prevažne z alkoholu, resp. alkoholických zmesi alebo bezvodých masťových základov. Takto sú síce tieto prípravky dostatočne stabilné, ale nemajú žiaducu, kožiAll of these industrially manufactured topical erythromycin formulations therefore consist mainly of alcohol, respectively. alcoholic mixtures or anhydrous ointment bases. Thus, although these preparations are sufficiently stable, they have no desirable skin
-4·· ·· ·· · ·· ··· ······ • · ··· · · · ·· · • · · · · · · ···· · · · ···· ····· ·· ·· ·· · ·· · primeranú vlastnosť krémov alebo emulzií s malým obsahom tuku, ktoré sú zvlášť vhodné na terapiu akne.-4 ···························································· The appropriate property of low-fat creams or emulsions, which are particularly suitable for the treatment of acne.
Preto je úlohou predloženého vynálezu pripraviť farmaceutickú kompozíciu na liečenie kožných ochorení, najmä akné, pričom táto kompozícia zostane stabilnou aj pri dlhodobejšom skladovaní a vykazuje vysokú účinnosť, dobrú penetráciu do kože, ako aj vysokú znášanlivosť kožou. Aby sa zabránilo príslušným známym nevýhodám orálneho podávania antibiotík, táto kompozícia by sa mala s výhodou používať topicky.It is therefore an object of the present invention to provide a pharmaceutical composition for the treatment of skin diseases, in particular acne, which composition remains stable even after prolonged storage and exhibits high efficacy, good skin penetration as well as high skin tolerance. In order to avoid the known known disadvantages of oral administration of antibiotics, this composition should preferably be used topically.
Podstata vynálezuSUMMARY OF THE INVENTION
Táto úloha je podľa tohto vynálezu vyriešená farmaceutickou kompozíciou, ktorá obsahuje prinajmenšom jednu erytromycínovú soľ mastnej kyseliny s 12 až 22 atómmi uhlíka vo zvyšku mastnej kyseliny a tekutý alebo viskózny nosič.This object is solved according to the invention by a pharmaceutical composition comprising at least one erythromycin salt of a C 12 -C 22 fatty acid in the fatty acid residue and a liquid or viscous carrier.
Predložený vynález sa ďalej týka použitia erytromycínových solí mastných kyselín s 12 až 22 atómami uhlíka vo zvyšku mastnej kyseliny na topické liečenie kožných ochorení.The present invention further relates to the use of erythromycin salts of C 12 -C 22 fatty acids in the fatty acid residue for the topical treatment of skin diseases.
Prekvapujúco sa zistilo, že podľa tohto vynálezu použitá erytromycinová soľ C1222-mastnej kyseliny sa dá použiť namiesto bežne používaného erytromycínu ako voľná zásada na topické liečenie.Surprisingly, it has been found that the erythromycin salt of C1222 fatty acid used according to the invention can be used instead of the commonly used erythromycin as a free base for topical treatment.
Erytromycínový derivát vo forme soli Ci2-22-mastnej kyseliny, ktorá sa použije podľa tohto vynálezu, môže obsahovať nasýtené alebo nenasýtené, ako aj rozvetvené alebo nerozvetvené mastné kyseliny a ich zmesi. Výhodnými príkladmi použiteľných mastných kyselín sú kyselina myristová, kyselina palmitová, kyselina laurová a kyselina stearová. Zvlášť výhodne sa vo farmaceutickej kompozícii podľa tohto vynálezu ako účinná látka použije erytromycinstearát.Clarithromycin salt C 2 -22 fatty acid, which is used according to the invention may comprise a saturated or unsaturated, and branched or unbranched fatty acids, and mixtures thereof. Preferred examples of useful fatty acids are myristic acid, palmitic acid, lauric acid and stearic acid. Especially preferably, erythromycin stearate is used as the active ingredient in the pharmaceutical composition of the invention.
Erytromycínové soli Ci2-22-mastných kyselín sa dajú pripraviť bežnými postupmi spôsobom, ktorý je ako taký známy. Z roztokov kultúry Streptomyces erythreus izolovaná erytromycinová báza sa napríklad dá rozpustiť v organickom rozpúšťadle, ako je acetón. Následne sa získaný roztok zmieša s mastnou kyselinou alebo zmesou mastných kyselín. Pritom vypadne prakticky čistá erytromycinová soľ mastnej kyseliny.Erythromycin salts of C 12-22 fatty acids can be prepared by conventional procedures in a manner known per se. For example, the erythromycin base isolated from Streptomyces erythreus culture can be dissolved in an organic solvent such as acetone. Subsequently, the solution obtained is mixed with a fatty acid or a mixture of fatty acids. A virtually pure fatty acid erythromycin salt precipitates.
-5·· ·· ·· · ·· • · φ ··· · · · • · ··· · · · · · · • ·· ··· ······· · ···· · · · · · ·· ·· ·· · ·· ·-5 ··································· · · · · · · · · · · ·
Farmaceutická kompozícia obsahuje erytromycínovú soľ Ci2-22-mastnej kyseliny vo farmaceutický účinnom množstve. Najmä sa erytromycinová soľ Ci2-22-mastnej kyseliny s výhodou použije v množstve od 0,5 do 10 hmotn. %, ešte výhodnejšie od 1 do 5 hmotn. %, vzťahované na celkové množstvo farmaceutickej kompozície. Ako sa prekvapujúco zistilo, účinnosť erytromycínovej soli Ci2-22-mastnej kyseliny je v množstve, zvýšenom o podiel mastnej kyseliny, presne taká ako aktivita erytromycinu ako voľnej bázy v rovnakom nosiči. Použitie tohto derivátu preto nevedie k strate účinnosti pri terapii akné.The pharmaceutical composition comprises a erythromycin salt of a C 12-22 fatty acid in a pharmaceutically effective amount. In particular, the erythromycin salt of the C 12-22 fatty acid is preferably used in an amount of from 0.5 to 10 wt. %, even more preferably from 1 to 5 wt. %, based on the total amount of the pharmaceutical composition. As was surprisingly found, the effectiveness of the erythromycin salt of a C 2 -22 fatty acid in an amount, increased the proportion of a fatty acid, such that exactly one of erythromycin free base in the same vehicle. Therefore, the use of this derivative does not lead to a loss of efficacy in the treatment of acne.
Farmaceutická kompozícia ďalej popri účinnej látke, erytromycínovej soli C12.22mastnej kyseliny, obsahuje tekutý alebo viskózny nosič, ktorý sa dá zvoliť z bežných farmaceutických nosičov. S výhodou sa nosič zvoli tak, aby získaná kompozicia bola vhodná na topickú aplikáciu. Je zvlášť výhodné, keď tento nosič existuje vo forme emulzie, suspenzie, krému alebo gélu, aby sa umožnilo bezproblémové nanesenie kompozície na kožu. Zvlášť výhodné je, keď má nosič veľmi malý podiel tuku a vysoký podiel vody. Najmä sa uprednostňujú krémy alebo emulzie s malým obsahom tuku, ako O/V-krémy alebo emulzie, ale aj aplikačné formy s extrémne vysokým podielom vody, ako su gély. Podiel vody je obyčajne najmenej asi 40 %, ale pre čisto vodné nosiče je možný podiel vody takmer 100 %. Najmä je zvlášť výhodný podiel vody od 60 do takmer 100 %, pretože prípravok týmto spôsobom koža zvlášť dobre prijima.In addition to the active ingredient, the erythromycin salt of the C12.22 fatty acid, the pharmaceutical composition comprises a liquid or viscous carrier which can be selected from conventional pharmaceutical carriers. Preferably, the carrier is selected such that the composition obtained is suitable for topical application. It is particularly preferred that the carrier exists in the form of an emulsion, suspension, cream or gel to allow problem-free application of the composition to the skin. It is particularly preferred that the carrier has a very low fat content and a high water content. Particularly preferred are low fat creams or emulsions, such as O / W-creams or emulsions, but also dosage forms with extremely high water content, such as gels. The proportion of water is usually at least about 40%, but for pure aqueous carriers a proportion of water of almost 100% is possible. Particularly preferred is a water content of from 60 to almost 100%, since the composition in this way particularly absorbs the skin.
Ako ďalšie nosné komponenty sa v kompozícii podľa tohto vynálezu môžu nachádzať tuky, napríklad oleje a vosky, ako aj alkoholy. Ak sa použije O/V krém alebo emulzia, lipidová zložka sa môže zvoliť z cetearyloktanoátu, decyloleátu, triglyceridov so strednou dĺžkou reťazcov, glycerylmonostearátu, kyseliny stearovej, cetylalkoholu, tekutých esterov vosku, izopropylmyristátu a cetylpalmitátu. Zvlášť výhodne sa použijú cetearyloktanoát, glyceíylmonostearát, cetylalkohol a triglyceridy so strednou dĺžkou reťazcov.Fats such as oils and waxes as well as alcohols may be present as further carrier components in the composition of the invention. When an O / V cream or emulsion is used, the lipid component may be selected from cetearyl octanoate, decyl oleate, medium chain triglycerides, glyceryl monostearate, stearic acid, cetyl alcohol, liquid wax esters, isopropyl myristate and cetyl palmitate. Particular preference is given to using cetearyl octanoate, glycyl monostearate, cetyl alcohol and medium chain triglycerides.
Táto farmaceutická kompozícia môže mať na jednej strane krémový, resp. pastovitý charakter, ale tiež môže vykazovať tekutú, gélovitú konzistenciu. Umožňuje s výhodou rýchlu penetráciu do kože a do mazových žliaz.The pharmaceutical composition may, on the one hand, be creamy and / or creamy. paste-like character, but may also have a liquid, gel-like consistency. It preferably allows rapid penetration into the skin and sebaceous glands.
Popri uvedených zložkách môže prípravok obsahovať ďalšie farmaceutický prijateľné prísady, ako sú konzervačné prostriedky, aromatické látky, antioxidanty,In addition to the ingredients, the formulation may contain other pharmaceutically acceptable ingredients such as preservatives, flavoring agents, antioxidants,
-6·· ·· ·· · ·· ··· · · · ·· • · ··· · · · · · · • · · · · · · ···· · · * ···· ·· · ·· ·· ·· ·· · ·· puŕŕovacie látky, farbivá a/alebo pigmenty. Tak nosič, ako aj ďalšie prísady však nie sú špeciálne obmedzene, pokiaľ neovplyvňujú účinok erytromycinovej soli Ci2-22-mastnej kyseliny.-6 ···································· Blowing agents, dyes and / or pigments. However, both the carrier and the other ingredients are not particularly limited as long as they do not affect the effect of the erythromycin salt of the C 12-22 fatty acid.
Farmaceutická kompozícia môže popri erytromycinovej soli Ci2.22-mastnej kyseliny obsahovať ďalšie účinné látky, ktoré sú vhodné na liečenie kožných ochorení. Príklady týchto účinných látok nie sú zvlášť obmedzené, pokiaľ neovplyvňujú účinok erytromycinovej soli Ci2-22-mastnej kyseliny. Ako ďalšie účinné látky môže kompozícia podľa tohto vynálezu obsahovať napríklad adapalén, izotretinoín, tretinoin, metronidazol, benzoylperoxid, triklosan, hexachlorofén, estradiol, klotrimazol, ketokonazol, mikonazol, krokonazol, kyselinu azelaovú, spironolaktón, cyproterónacetát, chlórmadinónacetát, cyoktol a ich zmesi.The pharmaceutical composition may contain, in addition to the erythromycin salt of the C 12,22 fatty acid, other active substances which are suitable for the treatment of skin diseases. Examples of these active ingredients are not particularly limited insofar as they do not affect the effect of the erythromycin salt of a C 12-22 fatty acid. As further active ingredients, the composition according to the invention may contain, for example, adapalene, isotretinoin, tretinoin, metronidazole, benzoyl peroxide, triclosan, hexachlorophene, estradiol, clotrimazole, ketoconazole, miconazole, croconazole, azelaic acid, spironolactone, cyproterone acetate, chlormadoketol acetate.
Farmaceutická kompozícia podľa tohto vynálezu sa dá pripraviť bežným spôsobom. Podľa druhu prípravku (napríklad tekutá emulzia, krém, gél) sa pritom jednotlivé zložky, najmä tekutý nosič a účinná látka, navzájom naviažu. Ak sa použijú lipidové zložky, tieto sa obyčajne pridajú k zložkám vodnej íazy. Aby sa zlepšilo zmiešanie oboch fáz, tuková fáza alebo vodná fáza sa môžu zahriať. Zvlášť výhodne sa pred spojením zahrejú obe fázy. Teplota závisí od príslušných zložiek, obyčajne však je 30 °C až 90 °C, s výhodou 40 °C až 80 °C. Ďalej je výhodné, keď sa tuková fáza za miešania alebo homogenizovania pomaly pridáva do vodnej fázy. Erytromycínová soľ €12-22mastnej kyseliny sa môže zapracovať po spojení tukovej a vodnej fäzy. Pred pridaním účinnej látky sa získaná zmes obyčajne ochladí na teplotu 20 °C až 40 °C, s výhodou 25 cCaž35 °C.The pharmaceutical composition of the invention may be prepared in a conventional manner. Depending on the type of preparation (e.g. liquid emulsion, cream, gel), the individual components, in particular the liquid carrier and the active substance, are bonded to one another. If lipid components are used, these are usually added to the aqueous phase components. In order to improve the mixing of the two phases, the fat phase or the aqueous phase may be heated. Both phases are particularly preferably heated prior to coupling. The temperature depends on the ingredients, but is usually 30 ° C to 90 ° C, preferably 40 ° C to 80 ° C. It is further preferred that the fat phase is slowly added to the aqueous phase with stirring or homogenization. The erythromycin salt of C 12-22 fatty acid may be incorporated after the combination of the fatty and aqueous soybean. Before addition of the active ingredient, the mixture is typically cooled to a temperature of 20 DEG C. to 40 DEG C., preferably 25 DEG C. c Caž35.
Erytromycínové soli Ci2-22-mastných kyselín sa môžu podľa tohto vynálezu použiť na topické liečenie kožných ochorení, najmä akné.Erythromycin salt of a C 2 -22 fatty acids may be used according to the invention for topical treatment of skin disorders, in particular acne.
Vynález bližšie objasníme pomocou nasledujúcich príkladov. Nemá sa však na ne obmedziť.The invention is illustrated by the following examples. However, it should not be limited to them.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
1. Príklady kompozícieExamples of compositions
Príklad 1:Example 1:
Príklad 2:Example 2:
Príklad 3:Example 3:
···· • ·· • ···· • · ·· · ········ · ··· · ···· · ··· · ····
voda ad 100,0 gwater to 100.0 g
·· · • ·· • ·· · • ····· • · • ·· •· • ·· ·· ·············································
glycerín vodaglycerin water
3,0 g ad 100,0 g3.0 g and 100.0 g
voda ad 100,0 gwater to 100.0 g
Príklad 5: Erytromycín/triklosanový krém erytromycinstearatExample 5: Erythromycin / triclosan cream erythromycinstearate
4,0 g triklosan4.0 g triclosan
0,5 g0.5 g
Príklad 6: Erytromycín/mikonazolový krémExample 6: Erythromycin / miconazole cream
Príklad 8: Erytromycín/izotretinoínový krémExample 8: Erythromycin / isotretinoin cream
- 10konzervačný prostriedok q. s.- 10 Preservative q. with.
voda ad 100,0 gwater to 100.0 g
Príklad 9: Erytromycín/tretinoínový krémExample 9: Erythromycin / tretinoin cream
konzervačný prostriedokpreservative
q.s.qs
voda ad 100,0 gwater to 100.0 g
2, Príprava prípravku2, Preparation of the preparation
Prípravok, ktorý obsahuje zložky podľa príkladu 3 (erytromycínový krém), sa pripravil nasledujúcim spôsobom.A formulation containing the ingredients of Example 3 (erythromycin cream) was prepared as follows.
Látky tukovej fázy, t. j. glycerolmonostearát, neutrálny olej, kyselina stearová, giycerylmonoricinoleját a glycerín, sa spolu navážili a zahriali na 75 °C. Zložky vodnej fázy, t. j. voda a konzervačný prostriedok, sa taktiež zahriali na 75 °C. Keď obe fázy dosiahli túto teplotu, tuková fáza sa za miešania alebo homogenizovania pomaly pridávala do vodnej fázy. Získaná emulzia sa za miešania ochladila. Pri teplote asi 30 °C sa zapracoval erytromycinstearát, aby sa získal erytromycínový krém.Fat phase substances, e.g. j. glycerol monostearate, neutral oil, stearic acid, giyceryl monoricin oleate and glycerin were weighed together and heated to 75 ° C. The components of the aqueous phase, i. j. water and preservative were also heated to 75 ° C. When both phases reached this temperature, the fat phase was slowly added to the aqueous phase with stirring or homogenization. The resulting emulsion was cooled with stirring. At about 30 ° C, erythromycin stearate was incorporated to obtain an erythromycin cream.
-11·«·· • ·· • ···· • · ·· · • · ·· ···· ·· · • ·· • ·· · • 99999-11 «· · 99 99 99 99 99 99 99 99 99 99 99 99 99
9999
999 ··999 ··
9999
9999
999999
3. Skúšky stability3. Stability tests
Podľa príkladu 1 pripravený prípravok so 6,12 hmotn. % erytromycinstearátu (zodpovedajúce 4,0 hmotn. % erytromycínovej bázy) v O/V-kréme sa 6 mesiacov skladoval pri 25 °C. Ako vidieť z tabuľky 1, nedošlo k žiadnemu významnému poklesu obsahu a tým účinnosti.A formulation of 6.12 wt. % of erythromycin stearate (corresponding to 4.0 wt% erythromycin base) in the O / W-cream was stored at 25 ° C for 6 months. As can be seen from Table 1, there was no significant decrease in content and thus efficiency.
Tabuľka 1 (počítané ako erytromycínová báza)Table 1 (calculated as erythromycin base)
Claims (8)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19917548A DE19917548A1 (en) | 1999-04-19 | 1999-04-19 | Stable topical pharmaceutical composition for treating skin diseases, especially acne, contains erythromycin higher fatty acid salt in liquid or viscous carrier |
| PCT/EP2000/002950 WO2000062784A1 (en) | 1999-04-19 | 2000-04-03 | Pharmaceutical composition on the basis of erythromycin fatty acid salts for the topical treatment of skin diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| SK18652000A3 true SK18652000A3 (en) | 2001-08-06 |
Family
ID=7905021
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SK1865-2000A SK18652000A3 (en) | 1999-04-19 | 2000-04-03 | PHARMACEUTICAL COMPOSITION ON THE BASIS OF ERYTHROMYCIN FATTYì (54) ACID SALTS FOR THE TOPICAL TREATMENT OF SKIN DISEASES |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP1085883A1 (en) |
| AU (1) | AU4115100A (en) |
| BG (1) | BG105093A (en) |
| DE (1) | DE19917548A1 (en) |
| EE (1) | EE200000727A (en) |
| HR (1) | HRP20000884A2 (en) |
| HU (1) | HUP0102702A3 (en) |
| NO (1) | NO20006260L (en) |
| PL (1) | PL344988A1 (en) |
| SK (1) | SK18652000A3 (en) |
| WO (1) | WO2000062784A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114632139B (en) * | 2022-04-02 | 2023-04-07 | 北京双吉制药有限公司 | Erythromycin ointment and preparation method thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2383667A1 (en) * | 1977-03-16 | 1978-10-13 | Desjonqueres Stephane | Topical erythromycin compsns. - for treating acne, in hydrating or oily excipient |
| US4299826A (en) * | 1979-10-12 | 1981-11-10 | The Procter & Gamble Company | Anti-acne composition |
| IT1210608B (en) * | 1980-12-08 | 1989-09-14 | Rorer Int Overseas | COMPOSITION FOR TOPICAL ACNE TREATMENT |
| EP0109102B1 (en) * | 1982-10-15 | 1988-01-20 | THE PROCTER & GAMBLE COMPANY | Storage stable topical pharmaceutical composition including nitrogen-containing stabilizers |
| JPS6021831A (en) * | 1983-07-11 | 1985-02-04 | コ−ニング・グラス・ワ−クス | Glass for cathode ray tube face plate |
| LU86945A1 (en) * | 1987-07-17 | 1989-03-08 | Oreal | PHARMACEUTICAL AND COSMETIC COMPOSITIONS BASED ON PYRIDONES AND ANTIBACTERIAL AGENTS |
| DE19706979A1 (en) * | 1997-02-21 | 1998-08-27 | Lindopharm Gmbh | Combination preparation for oral erythromycins |
-
1999
- 1999-04-19 DE DE19917548A patent/DE19917548A1/en not_active Ceased
-
2000
- 2000-04-03 HU HU0102702A patent/HUP0102702A3/en unknown
- 2000-04-03 SK SK1865-2000A patent/SK18652000A3/en unknown
- 2000-04-03 AU AU41151/00A patent/AU4115100A/en not_active Abandoned
- 2000-04-03 EE EEP200000727A patent/EE200000727A/en unknown
- 2000-04-03 HR HR20000884A patent/HRP20000884A2/en not_active Application Discontinuation
- 2000-04-03 WO PCT/EP2000/002950 patent/WO2000062784A1/en not_active Ceased
- 2000-04-03 PL PL00344988A patent/PL344988A1/en not_active Application Discontinuation
- 2000-04-03 EP EP00920654A patent/EP1085883A1/en not_active Withdrawn
- 2000-12-08 NO NO20006260A patent/NO20006260L/en not_active Application Discontinuation
- 2000-12-27 BG BG105093A patent/BG105093A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EE200000727A (en) | 2002-04-15 |
| NO20006260L (en) | 2001-02-19 |
| DE19917548A1 (en) | 2000-10-26 |
| WO2000062784A1 (en) | 2000-10-26 |
| AU4115100A (en) | 2000-11-02 |
| HUP0102702A3 (en) | 2003-02-28 |
| PL344988A1 (en) | 2001-11-19 |
| HRP20000884A2 (en) | 2001-10-31 |
| HUP0102702A2 (en) | 2001-12-28 |
| BG105093A (en) | 2001-07-31 |
| EP1085883A1 (en) | 2001-03-28 |
| NO20006260D0 (en) | 2000-12-08 |
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