CN101478951A - 包含聚丙烯酸衍生物、纤维素醚和崩解剂的亲水性基质制备用于治疗女性生殖道疾病的药物的用途 - Google Patents
包含聚丙烯酸衍生物、纤维素醚和崩解剂的亲水性基质制备用于治疗女性生殖道疾病的药物的用途 Download PDFInfo
- Publication number
- CN101478951A CN101478951A CNA2007800239858A CN200780023985A CN101478951A CN 101478951 A CN101478951 A CN 101478951A CN A2007800239858 A CNA2007800239858 A CN A2007800239858A CN 200780023985 A CN200780023985 A CN 200780023985A CN 101478951 A CN101478951 A CN 101478951A
- Authority
- CN
- China
- Prior art keywords
- application
- cellulose
- polyacrylic acid
- tablet
- vaginal
- 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
- 239000011159 matrix material Substances 0.000 title claims abstract description 22
- 229920002125 Sokalan® Polymers 0.000 title claims abstract description 20
- 229920003086 cellulose ether Polymers 0.000 title claims abstract description 15
- 239000004584 polyacrylic acid Substances 0.000 title claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 239000007884 disintegrant Substances 0.000 title abstract 2
- 239000003814 drug Substances 0.000 title description 53
- 208000017443 reproductive system disease Diseases 0.000 title description 2
- 239000007787 solid Substances 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims description 26
- 235000002639 sodium chloride Nutrition 0.000 claims description 24
- 239000000758 substrate Substances 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 20
- 210000001215 vagina Anatomy 0.000 claims description 17
- 230000000843 anti-fungal effect Effects 0.000 claims description 15
- 229940121375 antifungal agent Drugs 0.000 claims description 15
- -1 hydroxypropyl Chemical group 0.000 claims description 13
- 230000003115 biocidal effect Effects 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 239000004599 antimicrobial Substances 0.000 claims description 10
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 10
- 229920002472 Starch Polymers 0.000 claims description 7
- 229940032147 starch Drugs 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- MBRHNTMUYWQHMR-UHFFFAOYSA-N 2-aminoethanol;6-cyclohexyl-1-hydroxy-4-methylpyridin-2-one Chemical compound NCCO.ON1C(=O)C=C(C)C=C1C1CCCCC1 MBRHNTMUYWQHMR-UHFFFAOYSA-N 0.000 claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- 241001597008 Nomeidae Species 0.000 claims description 6
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 230000002421 anti-septic effect Effects 0.000 claims description 6
- 229960003749 ciclopirox Drugs 0.000 claims description 6
- SCKYRAXSEDYPSA-UHFFFAOYSA-N ciclopirox Chemical compound ON1C(=O)C=C(C)C=C1C1CCCCC1 SCKYRAXSEDYPSA-UHFFFAOYSA-N 0.000 claims description 6
- 229960004375 ciclopirox olamine Drugs 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 230000000842 anti-protozoal effect Effects 0.000 claims description 5
- 239000003904 antiprotozoal agent Substances 0.000 claims description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 239000004310 lactic acid Substances 0.000 claims description 5
- 235000014655 lactic acid Nutrition 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 229920000148 Polycarbophil calcium Polymers 0.000 claims description 4
- 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 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 229960001631 carbomer Drugs 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 238000004132 cross linking Methods 0.000 claims description 4
- 229940088597 hormone Drugs 0.000 claims description 4
- 239000005556 hormone Substances 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 235000019426 modified starch Nutrition 0.000 claims description 4
- 229950005134 polycarbophil Drugs 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- RWBRUCCWZPSBFC-RXRZZTMXSA-N (20S)-20-hydroxypregn-4-en-3-one Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](O)C)[C@@]1(C)CC2 RWBRUCCWZPSBFC-RXRZZTMXSA-N 0.000 claims description 3
- 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 claims description 3
- 229920000856 Amylose Polymers 0.000 claims description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- 239000004098 Tetracycline Substances 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- 235000010980 cellulose Nutrition 0.000 claims description 3
- 229920002678 cellulose Polymers 0.000 claims description 3
- 239000001913 cellulose Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 229960005309 estradiol Drugs 0.000 claims description 3
- 229930182833 estradiol Natural products 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 229960002867 griseofulvin Drugs 0.000 claims description 3
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 239000000186 progesterone Substances 0.000 claims description 3
- 229960003387 progesterone Drugs 0.000 claims description 3
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 claims description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 claims description 2
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 0.000 claims description 2
- 229930186147 Cephalosporin Chemical class 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 claims description 2
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 208000016908 Female Genital disease Diseases 0.000 claims description 2
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 239000004368 Modified starch Substances 0.000 claims description 2
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 claims description 2
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 claims description 2
- 229930182555 Penicillin Natural products 0.000 claims description 2
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 claims description 2
- 206010046914 Vaginal infection Diseases 0.000 claims description 2
- 229960004150 aciclovir Drugs 0.000 claims description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
- 229960001126 alginic acid Drugs 0.000 claims description 2
- 150000004781 alginic acids Chemical class 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 229940126575 aminoglycoside Drugs 0.000 claims description 2
- 239000003782 beta lactam antibiotic agent Chemical class 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 229940124587 cephalosporin Drugs 0.000 claims description 2
- 150000001780 cephalosporins Chemical class 0.000 claims description 2
- 229960002227 clindamycin Drugs 0.000 claims description 2
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 claims description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 claims description 2
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 claims description 2
- 229960001348 estriol Drugs 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 229960002568 ethinylestradiol Drugs 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229960004413 flucytosine Drugs 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- 229960002899 hydroxyprogesterone Drugs 0.000 claims description 2
- 229960002751 imiquimod Drugs 0.000 claims description 2
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 claims description 2
- 229960004616 medroxyprogesterone Drugs 0.000 claims description 2
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 claims description 2
- UXYRZJKIQKRJCF-TZPFWLJSSA-N mesterolone Chemical compound C1C[C@@H]2[C@@]3(C)[C@@H](C)CC(=O)C[C@@H]3CC[C@H]2[C@@H]2CC[C@H](O)[C@]21C UXYRZJKIQKRJCF-TZPFWLJSSA-N 0.000 claims description 2
- 229960005272 mesterolone Drugs 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 229960000282 metronidazole Drugs 0.000 claims description 2
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 claims description 2
- 150000002780 morpholines Chemical class 0.000 claims description 2
- 229960002136 nifuratel Drugs 0.000 claims description 2
- SRQKTCXJCCHINN-NYYWCZLTSA-N nifuratel Chemical compound O=C1OC(CSC)CN1\N=C\C1=CC=C([N+]([O-])=O)O1 SRQKTCXJCCHINN-NYYWCZLTSA-N 0.000 claims description 2
- KZUIYQJTUIACIG-YBZCJVABSA-N nomegestrol Chemical compound C1=C(C)C2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 KZUIYQJTUIACIG-YBZCJVABSA-N 0.000 claims description 2
- 229960004911 nomegestrol Drugs 0.000 claims description 2
- 229940053934 norethindrone Drugs 0.000 claims description 2
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 claims description 2
- 229960001179 penciclovir Drugs 0.000 claims description 2
- 239000003075 phytoestrogen Substances 0.000 claims description 2
- 229960001237 podophyllotoxin Drugs 0.000 claims description 2
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 claims description 2
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 claims description 2
- 229920001592 potato starch Polymers 0.000 claims description 2
- 229960002847 prasterone Drugs 0.000 claims description 2
- 229960004765 promestriene Drugs 0.000 claims description 2
- IUWKNLFTJBHTSD-AANPDWTMSA-N promestriene Chemical compound C1C[C@]2(C)[C@@H](OC)CC[C@H]2[C@@H]2CCC3=CC(OCCC)=CC=C3[C@H]21 IUWKNLFTJBHTSD-AANPDWTMSA-N 0.000 claims description 2
- 239000002423 protozoacide Substances 0.000 claims description 2
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical class NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 229940080313 sodium starch Drugs 0.000 claims description 2
- 229940124530 sulfonamide Drugs 0.000 claims description 2
- 150000003456 sulfonamides Chemical class 0.000 claims description 2
- 229960003604 testosterone Drugs 0.000 claims description 2
- 235000019364 tetracycline Nutrition 0.000 claims description 2
- 150000003522 tetracyclines Chemical class 0.000 claims description 2
- 229940040944 tetracyclines Drugs 0.000 claims description 2
- WZDGZWOAQTVYBX-XOINTXKNSA-N tibolone Chemical compound C([C@@H]12)C[C@]3(C)[C@@](C#C)(O)CC[C@H]3[C@@H]1[C@H](C)CC1=C2CCC(=O)C1 WZDGZWOAQTVYBX-XOINTXKNSA-N 0.000 claims description 2
- 229960001023 tibolone Drugs 0.000 claims description 2
- 229960005053 tinidazole Drugs 0.000 claims description 2
- 239000002132 β-lactam antibiotic Chemical class 0.000 claims description 2
- 229940124586 β-lactam antibiotics Drugs 0.000 claims description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims 3
- 229920013820 alkyl cellulose Polymers 0.000 claims 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical class NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 claims 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims 1
- 241000233866 Fungi Species 0.000 claims 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 claims 1
- 241000700605 Viruses Species 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 claims 1
- 239000003364 biologic glue Substances 0.000 claims 1
- 150000001720 carbohydrates Chemical class 0.000 claims 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims 1
- 210000003679 cervix uteri Anatomy 0.000 claims 1
- 239000003405 delayed action preparation Substances 0.000 claims 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims 1
- 210000004392 genitalia Anatomy 0.000 claims 1
- 229960004716 idoxuridine Drugs 0.000 claims 1
- 150000004291 polyenes Chemical class 0.000 claims 1
- GGOZGYRTNQBSSA-UHFFFAOYSA-N pyridine-2,3-diol Chemical class OC1=CC=CN=C1O GGOZGYRTNQBSSA-UHFFFAOYSA-N 0.000 claims 1
- 150000007660 quinolones Chemical class 0.000 claims 1
- 150000005846 sugar alcohols Polymers 0.000 claims 1
- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 claims 1
- 229960004880 tolnaftate Drugs 0.000 claims 1
- 150000003852 triazoles Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 41
- 239000000227 bioadhesive Substances 0.000 abstract description 21
- 238000013270 controlled release Methods 0.000 abstract description 16
- 238000009472 formulation Methods 0.000 abstract description 5
- 208000004926 Bacterial Vaginosis Diseases 0.000 abstract description 3
- 208000037009 Vaginitis bacterial Diseases 0.000 abstract description 3
- 208000005448 Trichomonas Infections Diseases 0.000 abstract description 2
- 206010044620 Trichomoniasis Diseases 0.000 abstract description 2
- 201000007096 Vulvovaginal Candidiasis Diseases 0.000 abstract description 2
- 208000013464 vaginal disease Diseases 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 38
- 229940079593 drug Drugs 0.000 description 21
- 230000008961 swelling Effects 0.000 description 15
- 229940044977 vaginal tablet Drugs 0.000 description 15
- 239000000003 vaginal tablet Substances 0.000 description 15
- 239000000499 gel Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 230000035587 bioadhesion Effects 0.000 description 12
- 239000000523 sample Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 210000004877 mucosa Anatomy 0.000 description 10
- 229920000642 polymer Polymers 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 239000012530 fluid Substances 0.000 description 8
- 230000008901 benefit Effects 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 238000012916 structural analysis Methods 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 210000003756 cervix mucus Anatomy 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 210000000981 epithelium Anatomy 0.000 description 6
- 229910000831 Steel Inorganic materials 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- 230000005284 excitation Effects 0.000 description 5
- 239000003292 glue Substances 0.000 description 5
- 230000003232 mucoadhesive effect Effects 0.000 description 5
- 239000010959 steel Substances 0.000 description 5
- 239000000872 buffer Substances 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 230000036571 hydration Effects 0.000 description 4
- 238000006703 hydration reaction Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000007909 solid dosage form Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 244000237986 Melia azadirachta Species 0.000 description 3
- 235000013500 Melia azadirachta Nutrition 0.000 description 3
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 230000009245 menopause Effects 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000008299 semisolid dosage form Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 239000006216 vaginal suppository Substances 0.000 description 3
- 229940120293 vaginal suppository Drugs 0.000 description 3
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- SNUSZUYTMHKCPM-UHFFFAOYSA-N 1-hydroxypyridin-2-one Chemical class ON1C=CC=CC1=O SNUSZUYTMHKCPM-UHFFFAOYSA-N 0.000 description 2
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 description 2
- 238000012935 Averaging Methods 0.000 description 2
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 244000178870 Lavandula angustifolia Species 0.000 description 2
- 235000010663 Lavandula angustifolia Nutrition 0.000 description 2
- MVTQIFVKRXBCHS-SMMNFGSLSA-N N-[(3S,6S,12R,15S,16R,19S,22S)-3-benzyl-12-ethyl-4,16-dimethyl-2,5,11,14,18,21,24-heptaoxo-19-phenyl-17-oxa-1,4,10,13,20-pentazatricyclo[20.4.0.06,10]hexacosan-15-yl]-3-hydroxypyridine-2-carboxamide (10R,11R,12E,17E,19E,21S)-21-hydroxy-11,19-dimethyl-10-propan-2-yl-9,26-dioxa-3,15,28-triazatricyclo[23.2.1.03,7]octacosa-1(27),6,12,17,19,25(28)-hexaene-2,8,14,23-tetrone Chemical compound CC(C)[C@H]1OC(=O)C2=CCCN2C(=O)c2coc(CC(=O)C[C@H](O)\C=C(/C)\C=C\CNC(=O)\C=C\[C@H]1C)n2.CC[C@H]1NC(=O)[C@@H](NC(=O)c2ncccc2O)[C@@H](C)OC(=O)[C@@H](NC(=O)[C@@H]2CC(=O)CCN2C(=O)[C@H](Cc2ccccc2)N(C)C(=O)[C@@H]2CCCN2C1=O)c1ccccc1 MVTQIFVKRXBCHS-SMMNFGSLSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 229920006243 acrylic copolymer Polymers 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 2
- 229960003644 aztreonam Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- CNBGNNVCVSKAQZ-UHFFFAOYSA-N benzydamine Chemical compound C12=CC=CC=C2C(OCCCN(C)C)=NN1CC1=CC=CC=C1 CNBGNNVCVSKAQZ-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- KHAVLLBUVKBTBG-UHFFFAOYSA-N caproleic acid Natural products OC(=O)CCCCCCCC=C KHAVLLBUVKBTBG-UHFFFAOYSA-N 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229920001477 hydrophilic polymer Polymers 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000001524 infective effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000000171 lavandula angustifolia l. flower oil Substances 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000003488 releasing hormone Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000010677 tea tree oil Substances 0.000 description 2
- 229940111630 tea tree oil Drugs 0.000 description 2
- 229960000580 terconazole Drugs 0.000 description 2
- 229960002703 undecylenic acid Drugs 0.000 description 2
- 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
- MQHLMHIZUIDKOO-OKZBNKHCSA-N (2R,6S)-2,6-dimethyl-4-[(2S)-2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl]morpholine Chemical compound C1=CC(C(C)(C)CC)=CC=C1C[C@H](C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-OKZBNKHCSA-N 0.000 description 1
- XIYOPDCBBDCGOE-IWVLMIASSA-N (4s,4ar,5s,5ar,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methylidene-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C=C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1[C@H](O)[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O XIYOPDCBBDCGOE-IWVLMIASSA-N 0.000 description 1
- RNIADBXQDMCFEN-IWVLMIASSA-N (4s,4ar,5s,5ar,12ar)-7-chloro-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methylidene-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C=C1C2=C(Cl)C=CC(O)=C2C(O)=C2[C@@H]1[C@H](O)[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O RNIADBXQDMCFEN-IWVLMIASSA-N 0.000 description 1
- SGKRLCUYIXIAHR-AKNGSSGZSA-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 Chemical compound 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 SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- IMLJLCJZQLGHJS-JEKSYDDFSA-N (4s,4ar,5s,5ar,6s,12ar)-4-(dimethylamino)-1,5,6,10,11,12a-hexahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;dihydrate Chemical compound O.O.C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O IMLJLCJZQLGHJS-JEKSYDDFSA-N 0.000 description 1
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 1
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[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 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 1
- MPIPASJGOJYODL-SFHVURJKSA-N (R)-isoconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@@H](OCC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 MPIPASJGOJYODL-SFHVURJKSA-N 0.000 description 1
- QKDHBVNJCZBTMR-LLVKDONJSA-N (R)-temafloxacin Chemical compound C1CN[C@H](C)CN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1F QKDHBVNJCZBTMR-LLVKDONJSA-N 0.000 description 1
- ZCJYUTQZBAIHBS-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)benzyl]oxy}ethyl]imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C=CC(SC=2C=CC=CC=2)=CC=1)CN1C=NC=C1 ZCJYUTQZBAIHBS-UHFFFAOYSA-N 0.000 description 1
- OCAPBUJLXMYKEJ-UHFFFAOYSA-N 1-[biphenyl-4-yl(phenyl)methyl]imidazole Chemical compound C1=NC=CN1C(C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OCAPBUJLXMYKEJ-UHFFFAOYSA-N 0.000 description 1
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 description 1
- QXHHHPZILQDDPS-UHFFFAOYSA-N 1-{2-[(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound S1C=CC(COC(CN2C=NC=C2)C=2C(=CC(Cl)=CC=2)Cl)=C1Cl QXHHHPZILQDDPS-UHFFFAOYSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- ACTOXUHEUCPTEW-BWHGAVFKSA-N 2-[(4r,5s,6s,7r,9r,10r,11e,13e,16r)-6-[(2s,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2s,5s,6r)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-o Chemical compound O([C@H]1/C=C/C=C/C[C@@H](C)OC(=O)C[C@@H](O)[C@@H]([C@H]([C@@H](CC=O)C[C@H]1C)O[C@H]1[C@@H]([C@H]([C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1)N(C)C)O)OC)[C@@H]1CC[C@H](N(C)C)[C@@H](C)O1 ACTOXUHEUCPTEW-BWHGAVFKSA-N 0.000 description 1
- UDYUIWXQUBNDHC-UHFFFAOYSA-N 6-[[4-(4-chlorophenoxy)phenoxy]methyl]-1-hydroxy-4-methylpyridin-2-one Chemical compound ON1C(=O)C=C(C)C=C1COC(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 UDYUIWXQUBNDHC-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 241000589220 Acetobacter Species 0.000 description 1
- 241001270131 Agaricus moelleri Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229930183010 Amphotericin Natural products 0.000 description 1
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 description 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- 239000004099 Chlortetracycline Substances 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RBNPOMFGQQGHHO-UWTATZPHSA-N D-glyceric acid Chemical class OC[C@@H](O)C(O)=O RBNPOMFGQQGHHO-UWTATZPHSA-N 0.000 description 1
- 108010000437 Deamino Arginine Vasopressin Proteins 0.000 description 1
- 208000034423 Delivery Diseases 0.000 description 1
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ASXBYYWOLISCLQ-UHFFFAOYSA-N Dihydrostreptomycin Natural products O1C(CO)C(O)C(O)C(NC)C1OC1C(CO)(O)C(C)OC1OC1C(N=C(N)N)C(O)C(N=C(N)N)C(O)C1O ASXBYYWOLISCLQ-UHFFFAOYSA-N 0.000 description 1
- 102000009025 Endorphins Human genes 0.000 description 1
- 108010049140 Endorphins Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010701 Lavanda vera Nutrition 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000378467 Melaleuca Species 0.000 description 1
- 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 1
- DMUAPQTXSSNEDD-QALJCMCCSA-N Midecamycin Chemical compound C1[C@](O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C DMUAPQTXSSNEDD-QALJCMCCSA-N 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 239000004104 Oleandomycin Substances 0.000 description 1
- RZPAKFUAFGMUPI-UHFFFAOYSA-N Oleandomycin Natural products O1C(C)C(O)C(OC)CC1OC1C(C)C(=O)OC(C)C(C)C(O)C(C)C(=O)C2(OC2)CC(C)C(OC2C(C(CC(C)O2)N(C)C)O)C1C RZPAKFUAFGMUPI-UHFFFAOYSA-N 0.000 description 1
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 108010079780 Pristinamycin Proteins 0.000 description 1
- RLNUPSVMIYRZSM-UHFFFAOYSA-N Pristinamycin Natural products CC1OC(=O)C(C=2C=CC=CC=2)NC(=O)C2CC(=O)CCN2C(=O)C(CC=2C=CC(=CC=2)N(C)C)CCN(C)C(=O)C2CCCN2C(=O)C(CC)NC(=O)C1NC(=O)C1=NC=CC=C1O RLNUPSVMIYRZSM-UHFFFAOYSA-N 0.000 description 1
- URWAJWIAIPFPJE-UHFFFAOYSA-N Rickamicin Natural products O1CC(O)(C)C(NC)C(O)C1OC1C(O)C(OC2C(CC=C(CN)O2)N)C(N)CC1N URWAJWIAIPFPJE-UHFFFAOYSA-N 0.000 description 1
- VYWWNRMSAPEJLS-MDWYKHENSA-N Rokitamycin Chemical compound C1[C@](OC(=O)CC)(C)[C@@H](OC(=O)CCC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](O)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C VYWWNRMSAPEJLS-MDWYKHENSA-N 0.000 description 1
- NJCJBUHJQLFDSW-UHFFFAOYSA-N Rufloxacin Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 NJCJBUHJQLFDSW-UHFFFAOYSA-N 0.000 description 1
- 229930192786 Sisomicin Natural products 0.000 description 1
- 239000004187 Spiramycin Substances 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 239000004182 Tylosin Substances 0.000 description 1
- 229930194936 Tylosin Natural products 0.000 description 1
- 239000004188 Virginiamycin Substances 0.000 description 1
- 108010080702 Virginiamycin Proteins 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- ZCMBQLPNFWBVQG-UHFFFAOYSA-J [Ca+2].[Ca+2].O.[PH2](=O)[O-].[PH2](=O)[O-].[PH2](=O)[O-].[PH2](=O)[O-] Chemical compound [Ca+2].[Ca+2].O.[PH2](=O)[O-].[PH2](=O)[O-].[PH2](=O)[O-].[PH2](=O)[O-] ZCMBQLPNFWBVQG-UHFFFAOYSA-J 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229960004821 amikacin Drugs 0.000 description 1
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 1
- 229960003204 amorolfine Drugs 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229940009444 amphotericin Drugs 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002460 anti-migrenic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229950006334 apramycin Drugs 0.000 description 1
- XZNUGFQTQHRASN-XQENGBIVSA-N apramycin Chemical compound O([C@H]1O[C@@H]2[C@H](O)[C@@H]([C@H](O[C@H]2C[C@H]1N)O[C@@H]1[C@@H]([C@@H](O)[C@H](N)[C@@H](CO)O1)O)NC)[C@@H]1[C@@H](N)C[C@@H](N)[C@H](O)[C@H]1O XZNUGFQTQHRASN-XQENGBIVSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960005397 arbekacin Drugs 0.000 description 1
- MKKYBZZTJQGVCD-XTCKQBCOSA-N arbekacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)CC[C@H]1N MKKYBZZTJQGVCD-XTCKQBCOSA-N 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[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 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- PFOLLRNADZZWEX-FFGRCDKISA-N bacampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OC(C)OC(=O)OCC)=CC=CC=C1 PFOLLRNADZZWEX-FFGRCDKISA-N 0.000 description 1
- 229960002699 bacampicillin Drugs 0.000 description 1
- 229940098166 bactrim Drugs 0.000 description 1
- 229960000333 benzydamine Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229960002206 bifonazole Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 229960005074 butoconazole Drugs 0.000 description 1
- SWLMUYACZKCSHZ-UHFFFAOYSA-N butoconazole Chemical compound C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 SWLMUYACZKCSHZ-UHFFFAOYSA-N 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 239000001527 calcium lactate Substances 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical class C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 description 1
- 229960003669 carbenicillin Drugs 0.000 description 1
- CZTQZXZIADLWOZ-CRAIPNDOSA-N cefaloridine Chemical compound O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-CRAIPNDOSA-N 0.000 description 1
- 229960003866 cefaloridine Drugs 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 1
- 229960005090 cefpodoxime Drugs 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960003260 chlorhexidine Drugs 0.000 description 1
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 1
- 229960004475 chlortetracycline Drugs 0.000 description 1
- 235000019365 chlortetracycline Nutrition 0.000 description 1
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229940069078 citric acid / sodium citrate Drugs 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin 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)([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
- 238000004140 cleaning Methods 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
- 229960003326 cloxacillin Drugs 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 229960002615 dalfopristin Drugs 0.000 description 1
- 108700028430 dalfopristin Proteins 0.000 description 1
- SUYRLXYYZQTJHF-VMBLUXKRSA-N dalfopristin Chemical compound O=C([C@@H]1N(C2=O)CC[C@H]1S(=O)(=O)CCN(CC)CC)O[C@H](C(C)C)[C@H](C)\C=C\C(=O)NC\C=C\C(\C)=C\[C@@H](O)CC(=O)CC1=NC2=CO1 SUYRLXYYZQTJHF-VMBLUXKRSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229960002398 demeclocycline Drugs 0.000 description 1
- 229960004281 desmopressin Drugs 0.000 description 1
- NFLWUMRGJYTJIN-NXBWRCJVSA-N desmopressin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 NFLWUMRGJYTJIN-NXBWRCJVSA-N 0.000 description 1
- 229960003807 dibekacin Drugs 0.000 description 1
- JJCQSGDBDPYCEO-XVZSLQNASA-N dibekacin Chemical compound O1[C@H](CN)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N JJCQSGDBDPYCEO-XVZSLQNASA-N 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 description 1
- 229960001585 dicloxacillin Drugs 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 229950001733 difloxacin Drugs 0.000 description 1
- NOCJXYPHIIZEHN-UHFFFAOYSA-N difloxacin Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1 NOCJXYPHIIZEHN-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 229960002222 dihydrostreptomycin Drugs 0.000 description 1
- ASXBYYWOLISCLQ-HZYVHMACSA-N dihydrostreptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](CO)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O ASXBYYWOLISCLQ-HZYVHMACSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 229960004100 dirithromycin Drugs 0.000 description 1
- WLOHNSSYAXHWNR-NXPDYKKBSA-N dirithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H]2O[C@H](COCCOC)N[C@H]([C@@H]2C)[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 WLOHNSSYAXHWNR-NXPDYKKBSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229960003913 econazole Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960001274 fenticonazole Drugs 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 229960004273 floxacillin Drugs 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960001398 flurithromycin Drugs 0.000 description 1
- XOEUHCONYHZURQ-HNUBZJOYSA-N flurithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@@](C)(F)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 XOEUHCONYHZURQ-HNUBZJOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 239000012052 hydrophilic carrier Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 239000013010 irrigating solution Substances 0.000 description 1
- 229960004849 isoconazole Drugs 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 229960004144 josamycin Drugs 0.000 description 1
- XJSFLOJWULLJQS-NGVXBBESSA-N josamycin Chemical compound CO[C@H]1[C@H](OC(C)=O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](OC(=O)CC(C)C)[C@](C)(O)C2)[C@@H](C)O1 XJSFLOJWULLJQS-NGVXBBESSA-N 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 229940083668 ketek Drugs 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 229950007634 kitasamycin Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000018219 lavender Nutrition 0.000 description 1
- XYJOGTQLTFNMQG-KJHBSLKPSA-N leucomycin V Chemical compound CO[C@H]1[C@H](O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1 XYJOGTQLTFNMQG-KJHBSLKPSA-N 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000036445 liquid secretion Effects 0.000 description 1
- 229960002422 lomefloxacin Drugs 0.000 description 1
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229960004196 lymecycline Drugs 0.000 description 1
- AHEVKYYGXVEWNO-UEPZRUIBSA-N lymecycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(=O)NCNCCCC[C@H](N)C(O)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O AHEVKYYGXVEWNO-UEPZRUIBSA-N 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 229960000826 meclocycline Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229940042016 methacycline Drugs 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 229960002757 midecamycin Drugs 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229960003255 natamycin Drugs 0.000 description 1
- 239000004311 natamycin Substances 0.000 description 1
- 235000010298 natamycin Nutrition 0.000 description 1
- NCXMLFZGDNKEPB-FFPOYIOWSA-N natamycin Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C[C@@H](C)OC(=O)/C=C/[C@H]2O[C@@H]2C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 NCXMLFZGDNKEPB-FFPOYIOWSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 229960000808 netilmicin Drugs 0.000 description 1
- ZBGPYVZLYBDXKO-HILBYHGXSA-N netilmycin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@]([C@H](NC)[C@@H](O)CO1)(C)O)NCC)[C@H]1OC(CN)=CC[C@H]1N ZBGPYVZLYBDXKO-HILBYHGXSA-N 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229960002351 oleandomycin Drugs 0.000 description 1
- 235000019367 oleandomycin Nutrition 0.000 description 1
- RZPAKFUAFGMUPI-KGIGTXTPSA-N oleandomycin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C RZPAKFUAFGMUPI-KGIGTXTPSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940026778 other chemotherapeutics in atc Drugs 0.000 description 1
- 230000027758 ovulation cycle Effects 0.000 description 1
- 229960003483 oxiconazole Drugs 0.000 description 1
- QRJJEGAJXVEBNE-MOHJPFBDSA-N oxiconazole Chemical compound ClC1=CC(Cl)=CC=C1CO\N=C(C=1C(=CC(Cl)=CC=1)Cl)\CN1C=NC=C1 QRJJEGAJXVEBNE-MOHJPFBDSA-N 0.000 description 1
- 229960000321 oxolinic acid Drugs 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 229960004236 pefloxacin Drugs 0.000 description 1
- FHFYDNQZQSQIAI-UHFFFAOYSA-N pefloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 FHFYDNQZQSQIAI-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008342 pharmaceutical dispersion Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229960001732 pipemidic acid Drugs 0.000 description 1
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 1
- OIQJEQLSYJSNDS-UHFFFAOYSA-N piroctone Chemical compound CC(C)(C)CC(C)CC1=CC(C)=CC(=O)N1O OIQJEQLSYJSNDS-UHFFFAOYSA-N 0.000 description 1
- 229950001046 piroctone Drugs 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960003961 pristinamycin Drugs 0.000 description 1
- DAIKHDNSXMZDCU-OUDXUNEISA-N pristinamycin-IIA Natural products CC(C)[C@H]1OC(=O)C2=CCCN2C(=O)c3coc(CC(=O)C[C@H](O)C=C(C)C=CCNC(=O)C=C[C@@H]1C)n3 DAIKHDNSXMZDCU-OUDXUNEISA-N 0.000 description 1
- JOOMGSFOCRDAHL-XKCHLWDXSA-N pristinamycin-IIB Natural products CC(C)[C@@H]1OC(=O)[C@H]2CCCN2C(=O)c3coc(CC(=O)C[C@@H](O)C=C(C)C=CCNC(=O)C=C[C@H]1C)n3 JOOMGSFOCRDAHL-XKCHLWDXSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229950006862 rilopirox Drugs 0.000 description 1
- 229960001170 rokitamycin Drugs 0.000 description 1
- 229960005009 rolitetracycline Drugs 0.000 description 1
- HMEYVGGHISAPJR-IAHYZSEUSA-N rolitetracycline Chemical compound O=C([C@@]1(O)C(O)=C2[C@@H]([C@](C3=CC=CC(O)=C3C2=O)(C)O)C[C@H]1[C@@H](C=1O)N(C)C)C=1C(=O)NCN1CCCC1 HMEYVGGHISAPJR-IAHYZSEUSA-N 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- 229960004062 rufloxacin Drugs 0.000 description 1
- 235000021003 saturated fats Nutrition 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 229960005456 sisomicin Drugs 0.000 description 1
- URWAJWIAIPFPJE-YFMIWBNJSA-N sisomycin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(CN)O2)N)[C@@H](N)C[C@H]1N URWAJWIAIPFPJE-YFMIWBNJSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 229960001294 spiramycin Drugs 0.000 description 1
- 235000019372 spiramycin Nutrition 0.000 description 1
- 229930191512 spiramycin Natural products 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 1
- 229960004576 temafloxacin Drugs 0.000 description 1
- 229960002722 terbinafine Drugs 0.000 description 1
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960000223 tilmicosin Drugs 0.000 description 1
- JTSDBFGMPLKDCD-XVFHVFLVSA-N tilmicosin Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1C[C@H](C)C[C@H](C)C1)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O JTSDBFGMPLKDCD-XVFHVFLVSA-N 0.000 description 1
- 229960004214 tioconazole Drugs 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229960005041 troleandomycin Drugs 0.000 description 1
- LQCLVBQBTUVCEQ-QTFUVMRISA-N troleandomycin Chemical compound O1[C@@H](C)[C@H](OC(C)=O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](OC(C)=O)[C@@H](C)C(=O)[C@@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)OC(C)=O)[C@H]1C LQCLVBQBTUVCEQ-QTFUVMRISA-N 0.000 description 1
- 229960004059 tylosin Drugs 0.000 description 1
- 235000019375 tylosin Nutrition 0.000 description 1
- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000009677 vaginal delivery Effects 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 235000019373 virginiamycin Nutrition 0.000 description 1
- 229960003842 virginiamycin Drugs 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
- A61K9/0039—Devices retained in the uterus for a prolonged period, e.g. intrauterine devices for contraception
-
- 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
- A61K9/20—Pills, tablets, discs, rods
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- 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
-
- 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
- A61P31/02—Local antiseptics
-
- 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
-
- 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
- A61P31/10—Antimycotics
-
- 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
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Gynecology & Obstetrics (AREA)
- Urology & Nephrology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Inorganic Chemistry (AREA)
- Virology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
披露了亲水性基质,其包括:a)优选用量0.5-40%的至少一种聚丙烯酸衍生物,b)优选用量30-90%的至少一种纤维素醚,和c)优选用量2-50%的至少一种崩解剂,各用量以该基质的重量为基准。该基质用于与至少一种可药用的活性成分组合用于制备治疗阴道疾病的固体生物粘附性控释制剂,所述疾病诸如外阴阴道念珠菌病,细菌性阴道病或滴虫病。该基质在固体制剂中的使用量约占制剂重量的5-60%,优选20-40%,并且所述活性成分的使用量约占制剂重量的2-70%优选5-50%。
Description
发明领域
本发明涉及用于治疗女性生殖器疾病的阴道递药生物粘附性控释片。
发明背景
阴道递送为对局部和全身疾病给药的重要途径。然而,尽管这种给药途径有许多优点,诸如自我插入和避免首过效应,但是因影响某些生理学因素,如pH和存在根据年龄和月经周期不同而改变的有限阴道分泌物的广泛个体间变异性而尚未得到广泛利用。
此外,认为商品化形式,诸如霜剂,泡沫,凝胶,灌洗液,片剂通过阴道的自洁作用而居留于阴道腔内的时间期限相对短并且通常需要每日多次剂量来确保所需的治疗作用。
为了延长在阴道腔内的停留时间,已经研发了半固体和固体剂型形式的生物粘附性治疗系统。
生物粘附性半固体试剂,诸如霜剂,泡沫,凝胶具有即使在没有生理分泌物存在下也促进药物在阴道腔内释放的优点。
这是因为药物细分散于或溶于构成剂型的液体媒介物(水或油相或其混合物)。这类在半固体剂型中的涉及低浓度的高度药物分散体由此因其铺散于阴道上皮的大部分表面而导致对粘膜的局部刺激现象发生率较低。作为结果,通常满足了良好的患者依从性。
然而,一般还没有将这些系统设计成可确保药物的任何有效控释,这类药物完全可利用于在阴道腔内的即刻释放。
相反,基于水的系统不能与水敏感性药物一起使用,基于油的系统表现出较低的患者依从性且水包油型或油包水型乳剂通常存在较差的物理稳定性,从而产生分离现象。
最后,但并非最不重要的是,这些系统还存在需要使用涂药器来引入阴道的缺点。
与半固体形式相比涉及稳定性降低问题的生物粘附型固体剂型,诸如片剂,锭剂,栓剂(阴道插入剂)已知较易于给药。
相反,它们因阴道腔内的生理流体的量有限而表现出较差的药物扩散模式。它们还导致局部刺激现象,从而影响与药物在其中高度浓缩的小部分片剂或锭剂表面紧密接触的阴道粘膜。此外,不同于传统的半固体,这些系统在被生理流体操作活化时使其内含物在极窄的阴道上皮表面铺展,从而导致局部作用下降。
解决在阴道分泌物中释放差的一种可能的方式在于配制在阴道腔内熔化的阴道栓剂形式的药物。然而,这些递送系统不能在属于气候带III和IV中的温度通常超过30℃的国家销售。
在阴道递送领域中重要的改善以创建了具有控释特性的生物粘附型固体剂型为代表。这类剂型最大的优点在于其在阴道腔内停留延长的时间期限,包括全天和全夜,从而确保了预定的药物释放控制且由此能够减少给药频率。
令人遗憾的是,每日产生的极少的阴道流体,据估计约每日6g,严重地限制了药物从按照本领域目前状态制备的控释片中的扩散现象。
因此,对基于生物粘附性控释片的新治疗阴道递送系统存在需求,以便延长在阴道腔内的停留时间并且减少因药物溶出控制导致的给药频率。
理想的情况是,这些剂型应结合仅与单一施用的片剂和半固体相关的所有优点,即:易于制备,易于给药,生物粘附,有效药物控释,化学和物理稳定性,避免局部刺激现象,减少给药次数,冻胶稠度和在阴道腔内广泛面积上的高度药物分散。
与这些需要相匹配的一种可能方式在于制备包括由亲水性聚合物构成的速率控制赋形剂的基质片。这项技术广泛被利用于在需要在预定时间期限内精确药物释放速率的口服递送领域。此外,已经发现了基质片因经济和可靠性而非广泛有效研发每日一次口服剂型的原因的大规模工业化应用。
这项技术由使用可溶性或不溶性亲水性聚合物分散的混合制剂+压缩佐剂制备组成。然后将该混合物制粒或直接压片得到最终的控释剂型。
药物释放因构成基质的聚合物的溶胀特性而发生,所述基质在有含水介质存在下水化,由此发挥药物释放控制作用。
根据药物溶解度的不同,释放机制基于通过溶胀基质扩散或通过聚合物侵蚀或其组合。
药物释放动力学由此受到几个因素控制,即药物溶解度,聚合物水化速率,聚合物粘度和填充剂载荷,类型和用量。
然而,操纵药物释放控制的分散量含水介质的需求使基质片限于通常在胃肠道中可利用大量生理分泌物的口服递送领域。
在消化道内状态中,胃肠道进行强烈的机械活动,或称作蠕动波,与存在的食物和消化分泌液一起,这种现象极大地改变了溶胀基质在胃肠道输送过程中执行药物释放控制的能力,从而导致该片剂发生机械破碎,即刻释放药物(剂量突释效应)。
口服基质片由此应具有在溶胀状态保持其完整性的合适的机械结构,以确保由溶出动力学控制的时间吸收特性。
令人遗憾的是,就生物粘附性控释阴道递送的具体情况而言,每日的少量阴道分泌物不足以水化常规的基质片。这意味着未达到溶胀状态的基质片在实施中阻止或减缓药物扩散过程。由此预计治疗作用降低和发生影响保持与该片剂长时间紧密接触的阴道粘膜的局部刺激现象。在这些情况中,来自身体运动的低剪切力无法实现固体-凝胶转变,从而导致片剂长期停留在阴道腔中,而不执行任何药物释放。
US 6,416,779 B1中披露了治疗阴道疾病的含药装置,方法和组合物。
装置可以为棉塞,棉塞类装置,环,阴道栓,杯,海绵状物。
这类装置包括配制成霜剂,洗剂,泡沫,软膏剂或凝胶的掺入药物的制剂。这些装置不溶并且保持在阴道腔内就位以确保药物按照定时方式释放(2-24h)。还可以将装置设计成可吸收入血流。
掺入装置的优选制剂由0.1-10%重量的药物,60-90%重量的亲脂性或亲水性载体(即分别为饱和脂肪酸载体的半合成甘油酸酯类或聚乙二醇),5-25%重量的粘膜粘着剂(即纤维素衍生物)和任选的5-20%重量的吸附促进剂(即乙氧基二甘醇)。
通过需要取出的插入式管将装置放入阴道腔。
用粘膜粘着剂确保从装置中释放的药物与阴道壁粘附。
将生物粘附性片剂提及为具有棉塞或栓剂形状的另一种可能的递药装置,以确保阴道壁与片剂表面的最大接触。一旦被放入适当的制剂,这些包括羟丙基纤维素和聚丙烯酸的生物粘附系统就能够释放药物达5天。
WO 2006/017238涉及用于跨粘膜递送抗偏头痛药和/或抗恶心药的涂敷的阴道装置。涂层以掺入了包括药物和粘膜粘着剂的流体不能渗透的材料为代表。流体不能渗透性涂层的范围在于防止药物一旦从粘膜粘着性组合物释放入装置就吸收。结果,药物被完全递送至最接近子宫的上阴道壁和/或全身循环。
发明内容
令人意外的是,已经发现在由一种或多种纤维素醚和一种或多种聚丙烯酸衍生物制成的亲水性基质中包含崩解剂甚至在有限量阴道分泌物存在下也促进了溶胀状态的快速实现,由此导致控释凝胶在大部分阴道上皮中铺展开。
存在崩解剂加速了片剂的水化速率,在有身体运动引起的剪切力存在下导致快速固体-凝胶转变,由此导致即刻生物粘附。不同于口服递送的常规基质片,由此将生物粘附性控释阴道片设计成快速粘附阴道上皮并且失去其形状/完整性,以便生成在整个阴道粘膜中执行药物释放控制的生物粘附凝胶。
这些特征赋予了本发明控释生物粘附性阴道片的独特性,这是因为在被阴道分泌物活化后,它们合并了属于固体和半固体剂型的相对优点和与易于给药相关的患者依从性和生产成本控制方面的益处。
通过由崩解剂执行的对溶胀亲水性基质网状结构的进行性破坏确保快速固体-凝胶转变。最初从片剂的外部水化层发生的这种现象也快速影响在水化前分离的内部干燥层,由此保持较高的表面任意溶胀,甚至在存在含水介质量减少情况下亦如此。
更深一步说,由于崩解剂与亲水性基质中的其它成分,即纤维素醚和聚丙烯酸共聚物相比表现出较高的水化速率而获得快速固体-凝胶转变。
崩解剂的这种较高水化速率导致片剂的干燥层进行性鳞落,从而生成新的表面,这加速了构成基质的聚合物溶胀,促进了胶胨态快速形成,从而缩短了粘附阴道上皮所需的时间。
本发明的阴道片剂物质由此能够确保快速起效和在诸如阴道腔这类仅可利用有限量液体分泌物的环境中延长的治疗作用。释放机制基于扩散药物通过溶胀聚合物和凝胶基质的进行性浸蚀/溶出。
可以将相对现有固体和半固体形式的主要优点概括如下:
低生产成本,避免使用含水或有机溶剂,易于自我给药而无需使用涂药器,活化态时类似于凝胶的稠度,避免局部刺激现象,快速生物粘着,与控制药物递送相关的延迟滞留时间,延长的给药间隔,改善的化学和物理稳定性。
阴道生物粘附控释基质片的生产方法由下列步骤组成:制备基质混合物(i),所述基质混合物(i)包括下列可药用的赋形剂:
一种或多种纤维素醚,一种或多种崩解剂,一种或多种聚丙烯酸共聚物。
然后将基质(i)与混合物(ii)混合,所述混合物(ii)由一种或多种药物和功能赋形剂制成,所述功能赋形剂诸如填充剂,缓冲剂,表面活性剂,粘合剂,助流剂,抗氧化剂,螯合剂,润滑剂。由此获得最终混合物(iii)。
然后将最终混合物(iii)制粒或直接压制以获得最终的生物粘附性控释阴道片。有利的是可以将润滑剂作为压制前最后的成分加入到最终混合物(iii)中。
常用制粒法可以用于改善基质(i),药物-赋形剂混合物(ii)或最终混合物(iii)的流变性和可压缩性。
用称作卡波姆的基于聚丙烯酸的聚合物确保生物粘附性。可以使用许多不同等级的商购卡波姆。它们在分子量,交联结构程度或残留成分方面不同。在聚丙烯酸聚合物中,优选聚卡波非,即与二乙烯基二醇交联的聚丙烯酸。这种水不溶性聚合物具有约4.5的表观pKa并且可以吸收其重量60-100倍的水。
这些聚丙烯酸聚合物的详尽描述可以在R.C.Rowe等编辑的Handbook of Pharmaceutical Excipients,fourth ed.,Pharmaceutical Press and American Pharmaceutical Association2003中找到。
控释特性由纤维素醚类,诸如羟丙基甲基纤维素,羟丙基纤维素,羟乙基纤维素,甲基纤维素,乙基纤维素,乙酸纤维素,其衍生物及其混合物确保。这些醚类以许多具有不同表观粘度和取代度的不同等级市售。
优选纤维素醚具有在15cP-100,000cP(2%水溶液,20℃)范围内改变的表观粘度。优选的纤维素醚类为羟丙基甲基纤维素,羟丙基纤维素和甲基纤维素。
适用于本发明的崩解剂可以选自不同类型或其混合物,将其概括在下文中。
改性的纤维素,诸如交联羧甲基纤维素钠,交联聚乙烯吡咯烷酮,诸如交聚维酮,天然淀粉,诸如玉米淀粉,马铃薯淀粉,直接可压缩淀粉,诸如淀粉1500,改性淀粉,诸如羧甲基淀粉和羟基乙酸淀粉钠,淀粉衍生物,诸如直链淀粉,藻酸和藻酸钠,微晶纤维素。
交联羧甲基纤维素钠和交聚维酮为优选的崩解剂。
在第一优选的组中,亲水性基质组合物(i)由纤维素醚类30-90%w/w;聚丙烯酸衍生物0.5-40%,崩解剂2-50%组成,而基质组合物(i)和药物分别占片剂重量的约5-60%和约2-70%。
在另一优选的组中,亲水性基质组合物(i)由纤维素醚类40-80%w/w;聚丙烯酸衍生物2-40%(优选2-30%,甚至更优选1-20%),崩解剂5-40%组成,而基质组合物(i)和药物分别占片剂重量的约20-40%和约5-50%。
阴道片的控释特性可以通过在剂型中存在可溶和不溶性填充剂及其重量比来改变。
不溶性赋形剂可以选自微晶纤维素,磷酸钙,磷酸氢钙,硫酸钙和磷酸二钙。优选无水或水合磷酸二钙。
可溶性赋形剂可以选自乳糖,山梨醇,木糖醇,甘露糖醇,直链淀粉,葡萄糖,富马酸,柠檬酸,酒石酸,乳酸,苹果酸,抗坏血酸,琥珀酸,各种分子量的聚乙二醇类,可溶性羟基烷基纤维素,聚乙烯吡咯烷酮类,明胶,碳酸钠,碳酸氢钠。
为了抗衡绝经前和绝经后女性阴道分泌物的广泛pH变化,有利的是剂型还可以包含一种或多种缓冲剂以确保更可再现的药物释放特性。
在缓冲剂种类中,系统乳酸钙/乳酸,柠檬酸/柠檬酸钠和无水磷酸二氢钠,磷酸二氢钠一水合物或二水化物因其产生接近绝经前健康女性生理阴道分泌物范围的水pH的能力而为优选的。
此外,缓冲剂确保的另一个更有利的优点在于确保所用生物粘附性聚合物(卡波姆)的体内粘度的更可再现性,所述聚合物在溶胀状态下明显降低pH值至低于3.0。
通过按照实验部分中所述方法的结构分析评价本发明亲水性基质片的生物粘附和溶胀程度。
可以使用USP XXVIII或EP第5版中所述溶出仪器之一有利地进行体外药物释放试验。
本发明适用于可通过阴道途径递送的任何可接受的药物。
有利的是,可药用的表面活性剂可以为制剂的组成部分以便提高在含水介质中表现出低溶解度的活性成分的溶出率。
在可以掺入本发明主题的控释生物粘附性阴道片的药物种类中有用于治疗外阴阴道念珠菌病的抗霉菌药,这种疾病为影响约75%女性在其生命过程中至少一次的白色假丝酵母(Candida Albicans)感染。抗霉菌药可以选自任何公知的合成或天然来源的抗霉菌药。活性剂可以为游离形式,即为游离酸或碱或为其盐的形式。实例包括:-1-羟基-2-吡啶酮化合物及其盐,例如环吡酮,利洛吡司,吡罗克酮,环吡酮胺和披露在US-A-4,957,730中的1-羟基-2-吡啶酮化合物;-咪唑衍生物及其盐,例如布康唑,克霉唑,益康唑,异康唑,酮康唑,咪康唑,噻康唑,联苯苄唑,芬替康唑和奥昔康唑;-聚烯衍生物及其盐,例如制霉菌素,那他霉素和两性霉素;-烯丙胺衍生物及其盐,例如Naphtifine和特比萘芬;-三唑衍生物及其盐,例如氟康唑,伊曲康唑,特康唑和伏立康唑;-吗啉衍生物及其盐,例如披露在US-A-5,120,530中的阿莫罗芬和吗啉类;-灰黄霉素和相关化合物,例如灰黄霉素;-酸性化合物,例如十一烯酸及其盐,特别是十一烯酸的锌盐和钙盐;-tolnaphtate及其盐;和-氟胞嘧啶及其盐。
抗霉菌药优选选自1-羟基2-吡啶酮化合物及其盐。
抗霉菌药还可以优选选自天然来源,特别是植物提取物。这些提取物的实例包括茶树油(Melaleuca attemifolia),熏衣草油(药用熏衣草(Lavandula officinalis chaix))和印度楝树(Azadirachtaindica)叶的提取物。
抗霉菌药可以单独使用或与其它抗霉菌药联用。特别地,如果抗霉菌药为天然来源,那么优选使用其组合。优选的混合物为茶树油,熏衣草油和印度楝树的叶提取物的组合。
抗霉菌药的量根据其结构及其抗微生物活性以及从片剂中的释放速率的不同而改变。一般而言,可以在本发明的组合物中使用抗霉菌药的有效量,即有效杀灭感染性微生物的用量,它一般大于平均抑制浓度(MIC)几倍到几十倍到数百倍。因此,优选抗霉菌药的用量在1-1000mg,更优选5-500mg,最优选10-250mg的单位剂量。
可以掺入本发明主题的控释生物粘附性阴道片的其它活性药物为抗生素以及其它治疗细菌性阴道病,滴虫病或其它外阴-阴道感染的抗微生物药。
抗生素可以选自任意已知的抗生素。抗生素可以为游离形式,即为游离酸或碱,或为其盐的形式。实例包括:-氨基糖苷类及其盐,例如阿米卡星,安普霉素,阿贝卡星,地贝卡星,庆大霉素,卡那霉素,新霉素,奈替米星,西索米星,链霉素,二氢链霉素,妥布霉素;-四环素类及其盐,例如金霉素,地美环素,多西环素,赖甲环素,甲氯环素,美他环素,米诺环素,土霉素,罗利环素,四环素;-大环内酯类及其盐,例如阿奇霉素,Cetromycin,克拉霉素(Claritromycin),地红霉素,红霉素,氟红霉素,交沙霉素,吉他霉素,麦迪霉素,竹桃霉素,普那霉素,达福普汀,罗他霉素,罗红霉素,螺旋霉素,泰利霉素,替米考星,醋竹桃霉素(Troleandomycoin),泰洛星,维吉霉素;-喹诺酮类及其盐,例如环丙沙星,二氟沙星,依诺沙星,左氧氟沙星,洛美沙星,莫西沙星,萘啶酸,诺氟沙星,氧氟沙星,奥索利酸,培氟沙星,吡哌酸,芦氟沙星,替马沙星;-单独使用或与二氨基吡啶联用的磺胺类及其盐,例如复方新诺明;青霉素化合物及其盐,例如氨苄西林,苯唑西林,氯唑西林,双氯西林,氟氯西林,阿莫西林,羧苄西林,巴氨西林;头孢菌素类和其它β-内酰胺抗生素及其盐,例如头孢氨苄,头孢噻啶,头孢孟多,头孢泊肟,碳青霉烯衍生物,如亚胺培南,单酰胺菌素,如氨曲南(aztreonan);林可胺类及其盐,例如克林霉素和林可霉素。
其它抗微生物药可以选自:抗原生动物(antiprotozoarian),抗菌药及其盐,包括甲硝唑,替硝唑,硝呋拉太;或选自防腐药,包括苄达明,氯己定等。
抗生素可以单独使用或与其它抗生素和/或抗原生动物药和/或抗菌药和/或防腐药和/或抗霉菌药联用。
抗生素和/或抗原生动物药和/或抗菌药和/或防腐药的量根据其结构及其抗微生物活性以及从片剂中的释放速率的不同而改变。一般而言,可以在本发明的组合物中使用抗生素或抗原生动物药或抗菌药或防腐药的有效量,即有效杀灭感染性微生物的用量,其一般大于平均抑制浓度(MIC)几倍到几十倍到数百倍。因此,优选抗生素或抗原生动物药或抗菌药或防腐药的用量在1-1000mg,更优选5-500mg,最优选10-250mg的单位剂量。
由于细菌性阴道病与阴道菌群和阴道腔天然pH的改变(从典型的健康绝经前女性的4-5的值升至7)相关,所以阴道剂型在维持基于每日的酸性pH的能力进一步产生了不利于微生物生长的环境,从而促进了天然生理条件的重建。
因此还设计了本发明控释生物粘附性阴道片以便单独或与一种或多种药物一起递送药物有机酸,诸如乳酸,苹果酸,柠檬酸,抗坏血酸,琥珀酸,酒石酸及其混合物。
可以掺入本发明主题的控释生物粘附性阴道片的其它活性药物为:药理活性肽或蛋白质物质,包括降钙素,胰岛素,去氨加压素,干扰素,内啡肽及其衍生物或片段;释放因子和释放激素,其它肽激素,其它激素,包括雌二醇和衍生物,和合成或天然来源的孕酮和衍生物,抗病毒药和其它化疗剂;抗病毒药优选选自阿昔洛韦,喷昔洛韦等,鬼臼毒素和咪喹莫特;激素优选选自雌二醇,炔雌醇,雌三醇,普罗雌烯,羟孕酮,孕酮,甲羟孕酮,二氢孕酮(dihydrogesterone),诺美孕酮,炔诺酮,替勃龙,睾酮,普拉睾酮,美睾酮或任意的植物雌激素。
具有慢性或复发性疾病的女性可能需要使用药物活性剂治疗延长的时间期限。然而,口服使用某些药物通常可能因副作用,较低的吸收率或较差的依从性而不可接受。此外,商购局部用剂型,诸如霜剂,凝胶,泡沫,阴道栓剂和片剂限于其在阴道腔内的滞留时间简短,从而需要多次给药而导致患者的依从性差。
生物粘附性控释阴道片因其特性而由此为通过局部递送抵抗大部分药物的口服副作用的正确选择,从而确保了延长给药间隔。
进一步通过下列非限制性实施例例证本发明。
实验部分
实施例1(对比例)
按照本领域公知的条件生产批号为P06-037的环吡酮胺100mg控释生物粘附性阴道片。
定性-定量配方如表I中所示。
表I
组分 | 用量(mg/片) |
1.环吡酮胺2.羟丙基甲基纤维素4,000cps3.聚卡波非4.微晶纤维素5.无水磷酸二钙6.甘露糖醇7.二氧化硅8.硬脂酸镁 | 100.00157.1452.38125.7152.38261.905.245.24 |
总计 | 760.00 |
该方法由掺合成分1-8,随后使用旋转式压片机(OfficineRonchi)直接压制组成。获得具有201N硬度的重量为760mg的片剂。2号和3号组分为亲水性基质(i)中的成分。
实施例2
按照本发明的教导生产批号为P06-038的环吡酮胺100mg控释生物粘附性阴道片。
按照实施例1中所述制备片剂。
定性-定量配方如表II中所示。
表II
组分 | 量(mg/片) |
1.环吡酮胺2.羟丙基甲基纤维素4,000cps3.聚卡波非4.羧甲基纤维素钠XL5.微晶纤维素6.无水磷酸二钙7.甘露糖醇8.二氧化硅9.硬脂酸镁 | 100.0139.0546.3576.00111.2446.35231.754.634.63 |
总计 | 760.00 |
2号,3号和4号组分为亲水性基质(i)中的成分。
获得具有248N硬度的重量为760mg的片剂。
实施例3
对实施例1(批号P-06-037)和实施例2(批号P-06-038)中所述片剂进行结构分析测定以便评估其生物粘附性能及其溶胀程度。通过单向ANOVA进行平均值之间显著性差异的测试。将在P<0.05水平的差异视为显著性的。
通过结构分析仪评价生物粘附特性[1]并且将猪阴道粘膜用作生物底物以便模拟阴道应用。
将软件控制的-具有5daN测力计的动力仪(AG/MC Acquati)用于测量分离力。
样品制备
阴道粘膜
使用外科剪刀从获自屠宰场的阴道粘膜上剥离结缔组织并且储存在-20℃下至使用为止。在实验应用前融化粘膜并且通过视觉谨慎检查任何缺陷,此后用腈基丙烯酸盐胶将其固定在张力仪底部上的钢板上。为了维持样品水化,将粘膜支持在浸渗去离子水的滤纸上并且使用1mL去离子水水化5min。
测试材料
通过安装了平冲头(11.28mm直径)的水压机(Glenrothes,UK)施加10吨的压力30秒获得170mg的制剂压紧物。
用腈基丙烯酸盐胶使测试材料压紧物粘附活动钢冲。
在压紧物与阴道粘膜之间构成接触时,施加1.3N恒力10min。测定粘膜粘着剂在以0.1mm/秒的恒定速率伸长10mm时使生物粘附压紧物与粘膜分离所需的分离力(最大分离力)方面的性能。还测定了分离力与伸长关系曲线下的面积以表示分离两种底物所需的功或能量。将不锈钢冲头用作阴性对照。
将实验数据概括在图1中。
图1中所示的数据表示制剂批号P-06-037和P-06-038具有良好的生物粘附特性。特别地,按照本发明教导制备的批号P06-038确保了最高生物粘附性。与批号P-06-037之间的实验差异具有统计学显著性(P<0.05)。
根据结构分析特性描述来评价亲水性生物粘附性阴道片的溶胀程度。
测试材料
用腈基丙烯酸盐胶使片剂与玻璃板粘固。在室温下将样品放入充入200ml阴道流体模拟物(VFS)的烧杯中。通过改变Owen和Katz[2]提出的处方制备VFS。VFS由下列组分组成(g):NaCl,3.51;KOH,1.40;Ca(OH)2,0.222;乳酸,2.00;乙酸,1.00,甘油,0.16;脲,0.4;葡萄糖,5.0。使用HCl将该溶液调整至pH为4.2。
在预定间隔,取出溶胀压紧物用于结构特性描述和测定凝胶层厚度和应力-应变关系曲线。
通过软件控制的安装了50daN池的结构分析仪(AG/MC1,Acquati,I)测定水向前透入的运动和凝胶层厚度的增加。结构分析仪为微处理控制动力仪,它记录了试验中材料的应力-应变关系曲线的完整分布。探头与分析仪内力传感器(force traducer)连接,它用于测定试验过程中探头遇到的阻力。
在本试验过程中,使样品位于测试平台中心。在本研究中使用直径为5mm的平顶圆钢探头。探头速度为10mm/min,直到基质表面检测到0.2N力值(阈值),此时探头以10mm/min的速度透入溶胀基质。一旦检测到预定的力,探头就以10mm/min被自动拉出。
将实验数据概括在图2中。
图2中所示的数据表明代表本发明主题的批号P-06-038片剂在VFS中15分钟水化后表现出较高溶胀程度,如所需透入功所示的。特别地,与批号P-06-037之间的差异具有统计学显著性(P<0.05)。
这类由批号P-06-038片剂表现出的较高溶胀程度表明了更快速的生物粘附。此外,认为来源于批号P-06-037片剂的那些中的约1/4的标准偏差(SD)下降确保了片剂在阴道腔内正确位移后的体内溶胀性能更可靠。
通过比较图1和2,显然批号P-06-038的片剂在统计学上表现出优良的与主要溶胀程度相关的生物粘附特性,生物粘附特性产生了对阴道上皮更快速的粘附。
实施例4
按照本发明的教导生产批号为P-07-022;P-07-039;P-07-049的环吡酮100mg控释生物粘附性阴道片。
通过下文详细描述的熔化制粒法获得环吡酮颗粒。
将286.65g环吡酮USP,52.50g PEG 6000,10.50g滑石粉,0.35g二氧化硅载入高剪切混合器(Rotolab Zanchetta-I)。将粉末在20℃下以800rpm混合5分钟,然后在约30分钟内以800rpm使产物T逐步升至65℃。
然后卸载产物,放在托盘上,使其在约40℃下冷却并且通过630μm孔筛析。
然后将获得的环吡酮颗粒(效率81.9%)与功能赋形剂混合并且按照实施例1中所述方法将该混合物压片。
定性-定量配方如表III上所示。
表III
获得具有315N(批号P-07-022),314N(批号P-07-039)和265N(批号P-07-049)硬度的重量为760mg的片剂。2号,3号和4号组分为亲水性基质(i)中的成分。
实施例5
使实施例4中所述片剂(批号P-07-022,P-07-039;P-07-049)进行溶出分析以便评价其改进的释放特性。所用的溶出方法为:USP溶出仪2,800mL磷酸盐缓冲液pH4.5,37℃,50rpm,n=6,UV297nm。将实验数据概括在图3中。
所有批号均表现出改进的释放特性。其计算的T80%(相当于80%药物释放的时间点)的结果是141min(批号P-07-039),274min(批号P-07-022),781min(批号P-07-049)。
实施例6
使实施例4中所述片剂(批号P-07-022,P-07-039;P-07-049)进行结构分析测定以便评价其生物粘附性能。通过单向ANOVA进行平均值之间的显著性差异测试。将P<0.05水平的差异视为显著性。
按照实施例3概括的方法评价生物粘附特性。
将实验数据概括在图4中。
图4中所示的数据表示所有制剂批号P-07-022;P-07-039和P-07-049均具有生物粘附特性,显然如其与对照组(不锈钢探头)相比的分离功所示。与对照组的差异具有统计学显著性(P<0.05)。
参考文献
Cilurzo F.,Minghetti P.,Selmin F.,CasiraghiA.,Montanari L.Polymethacryla salts as new low-swellable mucoadhesivematerials,J.Control.rel.,88(1):43-53,2004
[2]Owen D.H.和Katz D.F.,A Vaginal Fluid Simulant.Contraception,59:91-95,1999
Claims (24)
1.亲水性基质和至少一种可药用的活性成分在制备用于治疗女性生殖疾病的制剂中的应用,所述亲水性基质包括:
a)占该基质重量0.5-40%用量的至少一种聚丙烯酸衍生物;
b)至少一种纤维素醚;和
c)至少一种崩解剂。
2.权利要求1的应用,其特征在于所述至少一种聚丙烯酸衍生物的存在量占所述基质重量的2-40%,优选2-30%,所述至少一种纤维素醚的存在量占所述基质重量的30-90%且所述至少一种崩解剂的存在量占所述基质重量的2-50%。
3.权利要求1的应用,其特征在于所述至少一种聚丙烯酸衍生物存在量占所述基质重量的1-20%,所述至少一种纤维素醚存在量占所述基质重量的40-80%且所述至少一种崩解剂存在量占所述基质重量的5-40%。
4.权利要求1的应用,其特征在于所述至少一种聚丙烯酸衍生物为与糖类的聚烯基醚类或聚醇类交联的聚丙烯酸,优选卡波姆。
5.权利要求1的应用,其特征在于所述至少一种聚丙烯酸衍生物为与二乙烯基乙二醇交联的聚丙烯酸,优选聚卡波非。
6.权利要求1的应用,其特征在于所述至少一种纤维素醚选自羟基烷基纤维素,烷基纤维素,羧甲基纤维素或其盐。
7.权利要求1的应用,其特征在于所述羟基烷基纤维素选自羟丙基甲基纤维素,羟丙基纤维素和羟乙基纤维素;和/或所述烷基纤维素选自甲基纤维素和乙基纤维素。
8.权利要求1的应用,其特征在于所述至少一种崩解剂选自改性纤维素,诸如交联羧甲基纤维素钠,交联聚乙烯吡咯烷酮,诸如交聚维酮;天然淀粉诸如玉米淀粉,马铃薯淀粉,直接可压缩淀粉,改性淀粉,诸如羧甲基淀粉和羟基乙酸淀粉钠,淀粉衍生物,诸如直链淀粉,藻酸和藻酸钠,微晶纤维素。
9.权利要求1的应用,其特征在于所述制剂为固体。
10.权利要求9的固体制剂,其特征在于所述基质的存在量占该制剂重量的约5-60%,优选20-40%,并且所述至少一种活性成分的存在量占该制剂重量的约2-70%,优选5-50%。
11.权利要求9的应用,其特征在于包括可药用的填充剂,赋形剂和/或佐剂。
12.权利要求9的应用,其特征在于所述至少一种活性成分选自抗霉菌药,抗生素,抗病毒药,抗微生物药或化疗剂和激素。
13.权利要求12的应用,其特征在于所述抗霉菌药选自羟基-2-吡啶酮化合物,咪唑衍生物,聚烯衍生物,烯丙胺衍生物,三唑衍生物,吗啉衍生物,灰黄霉素化合物,酸性化合物,托萘酯,氟胞嘧啶及其盐。
14.权利要求12的应用,其特征在于所述抗霉菌药为环吡酮或环吡酮胺。
15.权利要求12的应用,其特征在于所述抗生素或其它抗微生物药选自单独的或与二氨基吡啶类,青霉素类化合物,头孢菌素类和其它β-内酰胺抗生素类,林可胺类,抗原生动物药,抗菌药,防腐剂及其盐联用的氨基糖苷类,四环素类,大环内酯类,喹诺酮类,磺胺类。
16.权利要求12的应用,其特征在于所述抗生素选自硝呋拉太,甲硝唑,替硝唑,克林霉素。
17.权利要求12的应用,其特征在于所述抗病毒药选自碘苷,阿昔洛韦,喷昔洛韦,鬼臼毒素或咪喹莫特。
18.权利要求12的应用,其特征在于所述激素选自雌二醇,炔雌醇,雌三醇,普罗雌烯,羟孕酮,孕酮,甲羟孕酮,二氢孕酮,诺美孕酮,炔诺酮,替勃龙,睾酮,普拉睾酮,美睾酮或任意的植物雌激素。
19.权利要求11的应用,其特征在于所述赋形剂选自抗坏血酸,乳酸及其盐。
20.权利要求9的应用,其特征在于所述固体制剂为片剂,优选为生物粘附片。
21.权利要求9的应用,其特征在于所述固体制剂为控释制剂。
22.权利要求9的应用,其特征在于在阴道腔内施用所述固体制剂。
23.权利要求1的应用,其特征在于所述女性生殖器疾病为因真菌,细菌,原生动物或病毒导致的宫颈和/或阴道感染。
24.权利要求1的应用,其特征在于所述女性生殖疾病为生殖器发育障碍,生殖器萎缩,生殖器弹性丧失或阴道干燥。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06116269.9 | 2006-06-29 | ||
EP06116269A EP1872775A1 (en) | 2006-06-29 | 2006-06-29 | Use of a hydrophilic matrix comprising a polyacrylic acid derivative, a cellulose ether and a disintegrant for the manufacture of a medicament for treating female genital disorders |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2013100083584A Division CN103071157A (zh) | 2006-06-29 | 2007-06-21 | 含聚丙烯酸衍生物、纤维素醚和崩解剂的亲水性基质制备治疗女性生殖器疾病的药物的用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101478951A true CN101478951A (zh) | 2009-07-08 |
Family
ID=37433668
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2013100083584A Pending CN103071157A (zh) | 2006-06-29 | 2007-06-21 | 含聚丙烯酸衍生物、纤维素醚和崩解剂的亲水性基质制备治疗女性生殖器疾病的药物的用途 |
CNA2007800239858A Pending CN101478951A (zh) | 2006-06-29 | 2007-06-21 | 包含聚丙烯酸衍生物、纤维素醚和崩解剂的亲水性基质制备用于治疗女性生殖道疾病的药物的用途 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2013100083584A Pending CN103071157A (zh) | 2006-06-29 | 2007-06-21 | 含聚丙烯酸衍生物、纤维素醚和崩解剂的亲水性基质制备治疗女性生殖器疾病的药物的用途 |
Country Status (25)
Country | Link |
---|---|
US (1) | US8865201B2 (zh) |
EP (2) | EP1872775A1 (zh) |
JP (1) | JP5205374B2 (zh) |
KR (1) | KR101443149B1 (zh) |
CN (2) | CN103071157A (zh) |
AR (1) | AR061771A1 (zh) |
AT (1) | ATE455534T1 (zh) |
BR (1) | BRPI0713298A2 (zh) |
CA (1) | CA2652226C (zh) |
CO (1) | CO6140022A2 (zh) |
CY (1) | CY1109910T1 (zh) |
DE (1) | DE602007004486D1 (zh) |
DK (1) | DK2032123T3 (zh) |
EA (1) | EA018257B1 (zh) |
ES (1) | ES2339069T3 (zh) |
HK (1) | HK1128587A1 (zh) |
HR (1) | HRP20100159T1 (zh) |
MA (1) | MA30597B1 (zh) |
MX (1) | MX2008016508A (zh) |
NO (1) | NO20090095L (zh) |
PL (1) | PL2032123T3 (zh) |
PT (1) | PT2032123E (zh) |
RS (1) | RS51279B (zh) |
SI (1) | SI2032123T1 (zh) |
WO (1) | WO2008000683A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109010320A (zh) * | 2018-09-18 | 2018-12-18 | 浙江汇能生物股份有限公司 | 一种双释型聚卡波非钙颗粒剂及制备方法和畜禽中的应用 |
CN114129530A (zh) * | 2021-12-08 | 2022-03-04 | 南京康川济医药科技有限公司 | 一种黄体酮缓释组合物及其制备方法 |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2344673B1 (es) | 2008-08-07 | 2011-05-03 | Italfarmaco, S.A. | Uso de estriol en la preparacion de una formulacion farmaceutica parael tratamiento de atrofia vaginal en mujeres con riesgo de potologiatumoral. |
EP2163240A1 (en) * | 2008-09-12 | 2010-03-17 | Universita' Degli Studi Di Genova | A method for the production of bioadhesive compact matrices |
JP5608167B2 (ja) * | 2008-10-23 | 2014-10-15 | ヘンケル コーポレイション | 加工デンプンを含む医薬ペレット、およびそれの治療への応用 |
ES2344675B1 (es) * | 2008-12-19 | 2011-04-28 | Italfarmaco, S.A. | Uso de estriol en la preparacion de una formulacion farrmaceutica para el tratamiento de atrofia vaginal en mujeres con riesgo de patologiacardiovascular. |
EP2243482A1 (en) * | 2009-04-20 | 2010-10-27 | Polichem SA | Use of nifuratel to treat infections caused by atopobium species |
US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
PT2782584T (pt) | 2011-11-23 | 2021-09-02 | Therapeuticsmd Inc | Preparações e terapias de substituição para hormonoterapias naturais combinadas |
US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
RU2713888C2 (ru) * | 2013-10-10 | 2020-02-10 | Терапьютиксмд, Инк. | Фармацевтические составы и способы на основе эстрадиола для интравагинального введения |
AR100562A1 (es) | 2014-05-22 | 2016-10-12 | Therapeuticsmd Inc | Composición farmacéutica de estradiol y progesterona para terapia de reemplazo hormonal |
CN105796520A (zh) * | 2014-12-29 | 2016-07-27 | 四川滇虹医药开发有限公司 | 一种缓释型硝酸布康唑直压片剂及其制备方法 |
JP6579529B2 (ja) | 2015-01-23 | 2019-09-25 | バイオシディウム アイピー ホルコ カンパニー | 抗菌組成物 |
US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
BR112018070199A2 (pt) | 2016-04-01 | 2019-01-29 | Therapeuticsmd Inc | composição farmacêutica de hormônio esteroide |
WO2017173044A1 (en) | 2016-04-01 | 2017-10-05 | Therapeuticsmd Inc. | Steroid hormone compositions in medium chain oils |
CN110267652A (zh) * | 2016-10-13 | 2019-09-20 | 康特伦英国斯温顿捷迪斯有限公司 | 用于阴道递送的冻干药物组合物 |
GB201808567D0 (en) * | 2018-05-24 | 2018-07-11 | Douglas Pharmaceuticals Ltd | Pharmaceutical compositions |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2096744A (en) * | 1932-10-27 | 1937-10-26 | Schering Corp | Hydrogenation products of follicle hormones and method of producing same |
US2232438A (en) * | 1934-08-04 | 1941-02-18 | Schering Corp | Unsaturated pregnanolones and pregnandiones and a method of producing the same |
US2243887A (en) * | 1935-11-09 | 1941-06-03 | Schering Corp | Tertiary carbinols of the cyclopentano-polyhydrophenanthrene series and a method of producing the same |
US2251939A (en) * | 1935-11-22 | 1941-08-12 | Schering Corp | Tertiary alcohols of the cyclopentano polyhydro phenanthrene series and a method of producing the same |
US2379832A (en) * | 1936-06-02 | 1945-07-03 | Schering Corp | Process for the manufacture of unsaturated ketones of the cyclopentano polyhydro phenanthrene series |
CH202847A (de) * | 1937-06-26 | 1939-02-15 | Chem Ind Basel | Verfahren zur Darstellung von Acetylen-Derivaten der Cyclopentanopolyhydrophenanthren-Reihe. |
US2265976A (en) * | 1937-10-25 | 1941-12-09 | Schering Corp | Tertiary alcohols of the estrane series and their derivatives and a process for their manufacture |
US2314185A (en) * | 1939-09-01 | 1943-03-16 | Zondek Bernhard | Process for the manufacture of progesterone |
BE665514A (zh) * | 1964-06-16 | |||
NL146838B (nl) * | 1966-06-24 | 1975-08-15 | Organon Nv | Werkwijze voor het bereiden van (delta)5(10)-3- keto-19-norsteroiden. |
JPS5562012A (en) * | 1978-11-06 | 1980-05-10 | Teijin Ltd | Slow-releasing preparation |
US7744916B2 (en) * | 1997-06-11 | 2010-06-29 | Umd, Inc. | Coated vaginal device for delivery of anti-migraine and anti-nausea drugs |
US6416779B1 (en) * | 1997-06-11 | 2002-07-09 | Umd, Inc. | Device and method for intravaginal or transvaginal treatment of fungal, bacterial, viral or parasitic infections |
US6248358B1 (en) * | 1998-08-25 | 2001-06-19 | Columbia Laboratories, Inc. | Bioadhesive progressive hydration tablets and methods of making and using the same |
UA74168C2 (uk) | 1999-10-05 | 2005-11-15 | Коламбіа Леборетеріс (Бермуда) Лімітед | Лікування ендометріозу або безпліддя, або покращення плідності та застосування бета-адренергічного агоніста для виробництва лікарського засобу |
IL153497A0 (en) | 2000-06-23 | 2003-07-06 | Teva Pharma | Rapidly expanding composition for gastric retention and controlled release of therapeutic agents, and dosage forms including the composition |
FR2813865B1 (fr) | 2000-09-08 | 2002-12-20 | Rexam Sofab | Dispositif a buse unique pour la distribution selective de deux produits |
EP1318790A4 (en) * | 2000-09-19 | 2006-02-01 | Cima Labs Inc | PHARMACEUTICAL COMPOSITIONS FOR RECTAL AND VAGINAL ADMINISTRATION |
IL157771A0 (en) * | 2001-03-27 | 2004-03-28 | Galen Chemicals Ltd | Intravaginal drug delivery devices for the administration of an antimicrobial agent |
US6899890B2 (en) * | 2002-03-20 | 2005-05-31 | Kv Pharmaceutical Company | Bioadhesive drug delivery system |
CN1302764C (zh) * | 2005-01-10 | 2007-03-07 | 凌沛学 | 一种妇科用药阴道凝胶片 |
-
2006
- 2006-06-29 EP EP06116269A patent/EP1872775A1/en not_active Withdrawn
-
2007
- 2007-06-21 RS RSP-2010/0045A patent/RS51279B/sr unknown
- 2007-06-21 PL PL07730288T patent/PL2032123T3/pl unknown
- 2007-06-21 CA CA2652226A patent/CA2652226C/en not_active Expired - Fee Related
- 2007-06-21 US US12/308,786 patent/US8865201B2/en not_active Expired - Fee Related
- 2007-06-21 EA EA200900087A patent/EA018257B1/ru not_active IP Right Cessation
- 2007-06-21 EP EP07730288A patent/EP2032123B1/en active Active
- 2007-06-21 MX MX2008016508A patent/MX2008016508A/es active IP Right Grant
- 2007-06-21 PT PT07730288T patent/PT2032123E/pt unknown
- 2007-06-21 JP JP2009517127A patent/JP5205374B2/ja not_active Expired - Fee Related
- 2007-06-21 DK DK07730288.3T patent/DK2032123T3/da active
- 2007-06-21 AT AT07730288T patent/ATE455534T1/de active
- 2007-06-21 SI SI200730193T patent/SI2032123T1/sl unknown
- 2007-06-21 CN CN2013100083584A patent/CN103071157A/zh active Pending
- 2007-06-21 KR KR1020087032076A patent/KR101443149B1/ko not_active IP Right Cessation
- 2007-06-21 DE DE602007004486T patent/DE602007004486D1/de active Active
- 2007-06-21 BR BRPI0713298-0A patent/BRPI0713298A2/pt not_active IP Right Cessation
- 2007-06-21 CN CNA2007800239858A patent/CN101478951A/zh active Pending
- 2007-06-21 WO PCT/EP2007/056185 patent/WO2008000683A1/en active Application Filing
- 2007-06-21 ES ES07730288T patent/ES2339069T3/es active Active
- 2007-06-29 AR ARP070102948A patent/AR061771A1/es unknown
-
2008
- 2008-12-24 CO CO08136879A patent/CO6140022A2/es unknown
-
2009
- 2009-01-07 NO NO20090095A patent/NO20090095L/no not_active Application Discontinuation
- 2009-01-22 MA MA31583A patent/MA30597B1/fr unknown
- 2009-05-05 HK HK09104134.0A patent/HK1128587A1/xx not_active IP Right Cessation
-
2010
- 2010-03-18 HR HR20100159T patent/HRP20100159T1/hr unknown
- 2010-03-19 CY CY20101100256T patent/CY1109910T1/el unknown
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109010320A (zh) * | 2018-09-18 | 2018-12-18 | 浙江汇能生物股份有限公司 | 一种双释型聚卡波非钙颗粒剂及制备方法和畜禽中的应用 |
CN109010320B (zh) * | 2018-09-18 | 2021-09-14 | 浙江汇能生物股份有限公司 | 一种双释型聚卡波非钙颗粒剂及制备方法和畜禽中的应用 |
CN114129530A (zh) * | 2021-12-08 | 2022-03-04 | 南京康川济医药科技有限公司 | 一种黄体酮缓释组合物及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
JP5205374B2 (ja) | 2013-06-05 |
EP2032123B1 (en) | 2010-01-20 |
SI2032123T1 (sl) | 2010-04-30 |
HK1128587A1 (en) | 2009-10-30 |
NO20090095L (no) | 2009-01-07 |
EA018257B1 (ru) | 2013-06-28 |
KR20090033341A (ko) | 2009-04-02 |
ES2339069T3 (es) | 2010-05-14 |
AR061771A1 (es) | 2008-09-17 |
CY1109910T1 (el) | 2014-09-10 |
CA2652226A1 (en) | 2008-01-03 |
MX2008016508A (es) | 2009-04-22 |
PT2032123E (pt) | 2010-04-07 |
RS51279B (sr) | 2010-12-31 |
JP2009541419A (ja) | 2009-11-26 |
US8865201B2 (en) | 2014-10-21 |
MA30597B1 (fr) | 2009-07-01 |
DE602007004486D1 (de) | 2010-03-11 |
EA200900087A1 (ru) | 2009-06-30 |
KR101443149B1 (ko) | 2014-09-23 |
ATE455534T1 (de) | 2010-02-15 |
US20110091555A1 (en) | 2011-04-21 |
CA2652226C (en) | 2014-08-12 |
EP2032123A1 (en) | 2009-03-11 |
CN103071157A (zh) | 2013-05-01 |
EP1872775A1 (en) | 2008-01-02 |
BRPI0713298A2 (pt) | 2012-04-17 |
HRP20100159T1 (hr) | 2010-05-31 |
DK2032123T3 (da) | 2010-03-08 |
WO2008000683A1 (en) | 2008-01-03 |
PL2032123T3 (pl) | 2010-06-30 |
CO6140022A2 (es) | 2010-03-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101478951A (zh) | 包含聚丙烯酸衍生物、纤维素醚和崩解剂的亲水性基质制备用于治疗女性生殖道疾病的药物的用途 | |
US10548839B2 (en) | Process of manufacturing a lyophilized fast dissolving, multi-phasic dosage form | |
US20100184785A1 (en) | Pharmaceutical formulation for the production of chewable tablets and lozenges | |
JPH05194188A (ja) | 制御放出薬学組成物 | |
CN100593398C (zh) | 用于活性物质释放的可崩解的薄膜形制剂及其制备方法 | |
CN110267652A (zh) | 用于阴道递送的冻干药物组合物 | |
WO2013038402A1 (en) | Vaginal danazol combined with non steroidal anti inflammatory drugs (nsaids) compositions | |
US20050255157A1 (en) | Sustained release, mucoadhesive vaginal pharmaceutical compositions | |
KR20210054137A (ko) | 레바미피드 또는 이의 약학적으로 허용가능한 염을 포함하는 경구투여용 서방성 약학 조성물 | |
CN101099730A (zh) | 含盐酸氨溴索与愈创木酚甘油醚活性成分的口服固体制剂 | |
CN100421666C (zh) | 爱普列特缓释制剂 | |
US7456207B2 (en) | Vaginal pharmaceutical compositions and methods for preparing them | |
US20070071814A1 (en) | Vaginal tablets comprising misoprostol and methods of making and using the same | |
Hani et al. | Novel vaginal drug delivery systems: a review | |
US20050118231A1 (en) | Solid dosage form for the ocular administration of an active principle, a soluble, solid ophthalmic insert and the production method thereof | |
JP2016503767A (ja) | 改良された許容性および良好な保存安定性を有する錠剤 | |
US20110091536A1 (en) | Compositions comprising euphorbia prostrata and process of preparation thereof | |
US20060182803A1 (en) | Oral sustained-release pharmaceutical composition of indapamide, production and use thereof | |
EP3964201A1 (en) | Brivaracetam pharmaceutical composition, preparation method therefor and application thereof | |
JP2011511823A (ja) | エストラジオール含有薬物の送達システム | |
AU2003259854A1 (en) | Optimal volume of intra-vaginal semisolid dosage forms for treating vaginal infections | |
WO2019083483A2 (en) | VAGINAL IMPLANT | |
WO2022056238A1 (en) | Solid dispersion formulations of an fxr agonist | |
CN102125527A (zh) | 口感改善的替米沙坦口崩片 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C12 | Rejection of a patent application after its publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20090708 |