CN1486185A - 含有金属氧化物颜料的稳定的溴夫定局部制剂 - Google Patents
含有金属氧化物颜料的稳定的溴夫定局部制剂 Download PDFInfo
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- CN1486185A CN1486185A CNA028037448A CN02803744A CN1486185A CN 1486185 A CN1486185 A CN 1486185A CN A028037448 A CNA028037448 A CN A028037448A CN 02803744 A CN02803744 A CN 02803744A CN 1486185 A CN1486185 A CN 1486185A
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- Prior art keywords
- brivudine
- iron oxide
- titanium dioxide
- oxide
- pharmaceutical composition
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- 229960001169 brivudine Drugs 0.000 title claims abstract description 61
- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 title claims abstract description 61
- 239000000049 pigment Substances 0.000 title claims abstract description 19
- 229910044991 metal oxide Inorganic materials 0.000 title claims abstract description 10
- 150000004706 metal oxides Chemical class 0.000 title claims abstract description 9
- 239000012049 topical pharmaceutical composition Substances 0.000 title claims description 5
- 239000000203 mixture Substances 0.000 claims abstract description 25
- 230000000699 topical effect Effects 0.000 claims abstract description 9
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 67
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 66
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 56
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 42
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 36
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 36
- 239000004408 titanium dioxide Substances 0.000 claims description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 28
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 22
- -1 polyoxyethylene monostearate Polymers 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 239000005662 Paraffin oil Substances 0.000 claims description 17
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000000377 silicon dioxide Substances 0.000 claims description 14
- 235000012239 silicon dioxide Nutrition 0.000 claims description 14
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims description 12
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 11
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims description 11
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 11
- 239000011787 zinc oxide Substances 0.000 claims description 11
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 10
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 9
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 9
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims description 8
- 229940084106 spermaceti Drugs 0.000 claims description 8
- 239000012177 spermaceti Substances 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 239000007765 cera alba Substances 0.000 claims description 7
- 125000005456 glyceride group Chemical group 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000000194 fatty acid Substances 0.000 claims description 6
- 239000000499 gel Substances 0.000 claims description 6
- 239000000017 hydrogel Substances 0.000 claims description 6
- 239000004611 light stabiliser Substances 0.000 claims description 6
- 239000000473 propyl gallate Substances 0.000 claims description 6
- 229940075579 propyl gallate Drugs 0.000 claims description 6
- 235000010388 propyl gallate Nutrition 0.000 claims description 6
- 208000009889 Herpes Simplex Diseases 0.000 claims description 5
- 241000701085 Human alphaherpesvirus 3 Species 0.000 claims description 5
- 239000000839 emulsion Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 4
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 4
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 4
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 4
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 4
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 claims description 3
- 229940008099 dimethicone Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 2
- 239000004147 Sorbitan trioleate Substances 0.000 claims description 2
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 claims description 2
- 208000036142 Viral infection Diseases 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 2
- 229940057995 liquid paraffin Drugs 0.000 claims description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 2
- 235000019337 sorbitan trioleate Nutrition 0.000 claims description 2
- 229960000391 sorbitan trioleate Drugs 0.000 claims description 2
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims 1
- 230000006641 stabilisation Effects 0.000 claims 1
- 239000008117 stearic acid Substances 0.000 claims 1
- 239000003381 stabilizer Substances 0.000 abstract description 3
- 238000001782 photodegradation Methods 0.000 abstract 1
- 235000010215 titanium dioxide Nutrition 0.000 description 21
- 229960004150 aciclovir Drugs 0.000 description 11
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 8
- 239000003443 antiviral agent Substances 0.000 description 7
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 6
- 229960001179 penciclovir Drugs 0.000 description 6
- 208000004898 Herpes Labialis Diseases 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 206010067152 Oral herpes Diseases 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 108020005202 Viral DNA Proteins 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 241001529453 unidentified herpesvirus Species 0.000 description 3
- JGUMTYWKIBJSTN-UHFFFAOYSA-N 2-ethylhexyl 4-[[4,6-bis[4-(2-ethylhexoxycarbonyl)anilino]-1,3,5-triazin-2-yl]amino]benzoate Chemical compound C1=CC(C(=O)OCC(CC)CCCC)=CC=C1NC1=NC(NC=2C=CC(=CC=2)C(=O)OCC(CC)CCCC)=NC(NC=2C=CC(=CC=2)C(=O)OCC(CC)CCCC)=N1 JGUMTYWKIBJSTN-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012829 chemotherapy agent Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 229960004396 famciclovir Drugs 0.000 description 2
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 208000029433 Herpesviridae infectious disease Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 210000003711 chorioallantoic membrane Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
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- 230000002045 lasting effect Effects 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- VYQNWZOUAUKGHI-UHFFFAOYSA-N monobenzone Chemical compound C1=CC(O)=CC=C1OCC1=CC=CC=C1 VYQNWZOUAUKGHI-UHFFFAOYSA-N 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
本发明公开了金属氧化物颜料作为光稳定剂用于含有溴夫定的局部药物组合物的用途。
Description
本发明涉及稳定的含有抗病毒剂溴夫定的药物组合物及其在局部治疗疱疹病毒感染中的用途。人类疱疹病毒感染可由不同的疱疹病毒引起，最常见的是单纯疱疹病毒和水痘带状疱疹病毒。此外还存在着很多动物疱疹病毒。
1型单纯疱疹病毒可导致口腔皮肤粘膜感染，导致潜伏病毒的持续存在和唇疱疹(感冒疮)的反复发作。尽管多数唇疱疹的发作是轻微的，但却经常引起心理上的痛苦和身体上的不适，并且在严重的病例中会导致毁容。由于唇疱疹还具有传染的危险性，因此需要一种针对该疾病的有效的抗病毒治疗方法。
现有很多的抗病毒剂，诸如阿昔洛韦、泛昔洛韦、喷昔洛韦、溴夫定等，它们都具有治疗人类疱疹病毒感染的活性。当发生的是局部性的病毒感染时，优选采用局部治疗法。
最具活性的抗病毒剂，即，阿昔洛韦、喷昔洛韦、泛昔洛韦、溴夫定等，都显示相似的化学特性；事实上，它们的结构与构成核酸的嘌呤和嘧啶碱基相似。这些核苷类似物的抗病毒活性是以抑制病毒DNA合成为基础的。它们在感染的细胞中被病毒编码的酶磷酸化，并作为“错误嵌段”嵌入到病毒DNA中或直接抑制病毒DNA。
溴夫定，即(E)-5-(2-溴乙烯基)-2′-脱氧尿苷是强效的治疗水痘带状疱疹病毒(VZV)和1型单纯疱疹病毒(HSV-1)感染的抗病毒剂。它的体外抗VZV效能优于阿昔洛韦和喷昔洛韦[在13个临床VZV毒株中的平均IC50是0.001μg/ml(溴夫定)，0.2μg/ml(阿昔洛韦)，0.91μg/ml(喷昔洛韦)](AndreiG.，Snoeck R.，Reymen D.欧洲临床微生物感染杂志(Eur.J.Clin.Microbiol.Infect.)；14；318-319；1995)。
此外，溴夫定是HSV-1复制的强效抑制剂，并较之阿昔洛韦和喷昔洛韦具有更好的体外效能：在23个临床HSV-1毒株中，证实溴夫定的效力几乎是阿昔洛韦的两倍[平均IC50：0.52μg/ml(溴夫定)，0.92μg/ml(阿昔洛韦)](Andrei G.，Snoeck R.，Goubau P.欧洲临床微生物感染杂志(Eur.J.Clin.Microbiol.Infect.)；11；143-151；1992)。在20个临床分离物中进行的两项相似的试验中，喷昔洛韦的平均IC50是0.6μg/ml和0.8μg/ml(Weinberg A.，Bate B.J.，Masters H.B.抗微生物化疗试剂(Antimicrob.Agents Chemother.)；36；2037-2038；1992)。
早期的主要在HSV-1实验室毒株中进行的研究证实了溴夫定具有更低的IC50，在0.004μg/ml和0.2μg/ml之间(根据病毒毒株和细胞系统的不同而不同)(De Clercq E.，Descamps J.，Verhelst G.，传染病杂志(J.Infect.Dis.)；141；563-574；1980；De Clercq E.，抗微生物化疗试剂(Antimicrob.Agents Chemother.)；21；661-663；1982)。
许多专利教导了如何制备含抗病毒剂的药物组合物：
GB1,523,865描述了可用于通过口服、胃肠外、眼用或局部途径等不同给药途径施用阿昔洛韦的一些药物组合物的实例；
EP44543特别涉及经皮给药途径，并记载了几种适于以水性乳膏形式，或者尤其是油/水乳液形式对皮肤应用的阿昔洛韦制剂；
EP948332公开了适于通过局部涂药器给药的用于治疗唇疱疹的药物组合物，其中只含有阿昔洛韦或还含有维生素A；
EP809498公开了含有抗病毒剂的药物组合物，其中含有阿昔洛韦或溴夫定，以及一种抗炎糖皮质激素；
DE3706421公开了用于局部治疗疱疹病毒的药物组合物，其中含有5-乙基-2′-脱氧尿苷和尿素；
EP72137特别涉及用于治疗单纯疱疹或水痘带状疱疹的3-甲基-5-卤代乙烯基-脱氧尿的衍生物；
EP104066、EP95292、EP95294公开了用于局部及全身性治疗病毒的2′-脱氧尿苷衍生物；
GB 1601020首次要求了溴夫定及其合成以及通过不同途径治疗单纯疱疹的用途。
从这些已知的药物组合物中无法获得任何有助于制备用于局部给药的含有溴夫定的稳定药物组合物的信息。
事实上，溴夫定在平常用于局部制剂的条件下表现得特别不稳定。在这些条件下，人们发现溴夫定会发生很大程度上的光降解，从而使活性物质的浓度下降，使治疗的最终效果下降并产生显著的局部刺激，导致人们无法使用该药物组合物。溴夫定的降解是根据ICH(国际协调会议International Conference on Harmonization)的指南CPMP/ICH/279/95进行研究的。将不含有任何稳定剂的未包装的溴夫定样品在49.5W/m2强度下照射9.6小时(剂量：475Wh/m2)。照射后溴夫定的含量从约100％降至约70％。同时样品中已知和未知的杂质升至约30％。
适宜的光稳定剂除了能预防活性物质降解外，还应具有其它重要的性质，例如在所用浓度范围内没有毒性、没有不希望的生物活性、价格低、适于工业处理的物化性质、与制剂中的其它组分没有化学相互作用。
许多光稳定剂在稳定溴夫定的局部制剂中没有作用。此外，从与溴夫定相似的抗病毒剂的制剂中获得的知识也被证明对于解决局部药物组合物中溴夫定的光降解问题没有任何帮助。
我们惊奇地发现，相同的问题可以通过使用适宜量的金属氧化物类型的颜料来解决。
将活性成分包合在环糊精-复合物(如，α-、β-、γ-环糊精-复合物)中或者向其中加入不同的稳定剂来进行光稳定性研究。使用已知的光稳定剂，如抗氧化剂(如，没食子酸丙酯、α-脂酮酸)，化学紫外线过滤器(如，辛基三嗪酮)和颜料(二氧化钛、氧化锌、氧化铁黄)。
通过测定用紫外线灯照射2小时后(剂量为1MED [最小红斑量]，24.8Wh/m2，UVA-光)的溴夫定含量来确定光稳定效果。将UVA-光直接照射到不含原始包装的乳膏上。照射后未发生变化的溴夫定的含量越高，则光稳定性越好。
照射后，不含光稳定剂的溴夫定含量降低至最初浓度的约40％(100％相当于被测试制剂中5％w/w的溴夫定浓度)。将溴夫定包合于环糊精-复合物、加入抗氧化剂(没食子酸丙酯，0.02％w/w)或化学紫外线过滤器(辛基三嗪酮，5％w/w)可使溴夫定含量保持在最初浓度的30％和60％之间。加入颜料诸如二氧化钛、氧化铁或氧化锌将会获得意想不到的更为优良的结果。使用20％w/w浓度的二氧化钛所得的溴夫定最终含量约为85％。使用20％w/w浓度的颜料氧化铁黄也能获得约85％的溴夫定含量。
从以上结果中可以得出这样的结论：金属氧化物型光稳定剂可明显更有效的防止溴夫定光降解。
因此，本发明的发明目的是：通过加入金属氧化物型颜料来获得对光降解稳定的溴夫定局部组合物。
适宜的金属氧化物的例子是二氧化钛、氧化铁和氧化锌。
优选颜料二氧化钛和氧化铁。二氧化钛是白色的，而氧化铁黄可产生黄色的乳膏。氧化铁也可成功的用作含-钛白色乳膏的着色剂。这些颜料可单独或组合使用。
可产生光-稳定作用的颜料浓度可以在组合物重量的10％至50％之间变化，优选从15至35％、更优选从20至30％w/w间变化。溴夫定的含量通常为0.3至8％，优选从0.5至5％w/w。
在鸡蛋上进行尿囊绒膜测试(HET/CAM测试)以测定含市售二氧化钛(25％w/w)制剂可能有的刺激性。用紫外线灯以5MED(124Wh/m2，UVA-光)照射2小时后进行该测试。将UVA-光直接照射到不含原始包装的乳膏上。在此项耐受性测试中，不含颜料的乳膏评分为“中度刺激性”，含有颜料的评分为“轻度刺激性”。该结果出乎意料的证实了二氧化钛不仅能增加光-稳定性，而且还能降低潜在的刺激性。
根据本发明，优选的局部组合物是O/W或W/O乳膏、脂凝胶、水凝胶或唇膏形式的。
通常，用于局部给药的含有溴夫定的药物组合物可以根据已知方法制备，如按照Remington′s制药科学(Remington′s Pharmaceutical Science)，第17版，Mack出版公司，Easton，PA(1985)中记载的方法制备。例如，O/W乳膏可以按照以下三步操作制备，包括：乳化、加入颜料、加入活性成分。
实施例：
实施例1：O/W乳膏：
| 成分 | 量[g]，每100g |
| 溴夫定 | 1 |
| 二氧化钛 | 25 |
| 氧化铝 | 1.6 |
| 二氧化硅 | 0.1 |
| 甘油 | 0.4 |
| 二甲基硅油 | 0.5 |
| 半液体石蜡油 | 5 |
| 丙二醇 | 15 |
| Vasilinum album | 9 |
| 聚氧乙烯单硬脂酸酯 | 2 |
| 鲸蜡/硬脂醇 | 1.5 |
| 20％柠檬酸 | 0.6 |
| 4-羟基苯甲酸甲酯 | 0.15 |
| 苯扎氯铵 | 0.2 |
| 聚二甲基硅氧烷 | 0.2 |
| 纯净水，加至 | 100 |
| 总计 | 100 |
将形成油相的赋型剂(半液体石蜡油、聚氧乙烯单硬脂酸酯、鲸蜡/硬脂醇、vasilinum album、聚二甲基硅氧烷、二甲基硅油)在75℃至80℃之间融化。另外将亲水性乳膏基质(20％柠檬酸、纯净水、丙二醇[部分量]、苯扎氯铵、4-羟基苯甲酸甲酯)加热到75℃至80℃之间。将两相在预先加热过的制药匀浆器的容器中混合。然后将混合物在75℃至80℃之间、在低压下搅拌并匀化。
然后将赋型剂二氧化钛、氧化铝、甘油和二氧化硅加入到乳膏基质中。将混合物在75℃至80℃之间、在低压下搅拌并匀化。然后将乳膏冷却至室温，保持搅拌和低压。
将溴夫定分散于丙二醇(剩余量)中。将该分散体加入到乳膏中。混合物在20℃至30℃之间、在低压下搅拌并匀化。
乳膏避光储存于密闭容器中，直至进一步的操作。
实施例2：唇膏制剂：
实施例3：脂凝胶
实施例4：W/O-乳液：
实施例5：水凝胶：
实施例6：W/O-乳液：
实施例7：水凝胶：
实施例8：脂凝胶：
实施例9：O/W乳膏：
实施例10：O/W乳膏：
| 成分 | 量[g]，每100g |
| 溴夫定 | 5 |
| 二氧化钛 | 20 |
| 单硬脂酸甘油酯 | 10 |
| C10-C18脂肪酸甘油酯 | 20 |
| 丙二醇 | 15 |
| 辛酸三甘油酯、癸酸三甘油酯 | 15 |
| 白蜂蜡 | 4 |
| 辛酸、癸酸、异硬酯酸、己二酸的二甘油酯 | 11 |
| 总计 | 100 |
| 成分 | 量[g]，每100g |
| 溴夫定 | 5 |
| 液体石蜡 | 34 |
| 肉豆蔻酸异丙酯 | 25 |
| 二氧化硅 | 6.25 |
| 脱水山梨糖醇单油酸酯 | 3 |
| 二氧化钛 | 16.25 |
| 氧化铝 | 5.125 |
| 氧化铁黄 | 2.1 |
| 氧化铁红 | 0.6 |
| 氧化铁黑 | 0.3 |
| 甘油 | 2.375 |
| 总计 | 100 |
| 成分 | 量[g]，每100g |
| 溴夫定 | 0.5 |
| 氧化锌 | 10 |
| 二氧化钛 | 10 |
| 半液体石蜡油 | 15 |
| 丙二醇 | 8 |
| Vasilinum album | 6 |
| 羊毛脂 | 5 |
| 脱水山梨糖醇单油酸酯 | 3 |
| 白蜂蜡 | 1.5 |
| 硬脂酸锌 | 1.0 |
| 硬脂酸镁 | 1.0 |
| 4-羟基苯甲酸甲酯 | 0.15 |
| 苯扎氯铵 | 0.2 |
| 没食子酸丙酯 | 0.02 |
| 20％柠檬酸 | 0.6 |
| 纯净水，加至 | 100 |
| 总计 | 100 |
| 成分 | 量[g]，每100g |
| 溴夫定 | 5 |
| 二氧化钛 | 21.25 |
| 氧化铝 | 1.25 |
| 二氧化硅 | 0.125 |
| 甘油 | 2.375 |
| 氧化铁黄 | 3.25 |
| 氧化铁红 | 1.25 |
| 氧化铁黑 | 0.5 |
| 丙二醇 | 20 |
| 半液体石蜡油 | 5 |
| 肉豆蔻酸异丙酯 | 5 |
| 鲸蜡醇 | 3 |
| 聚氧乙烯单硬脂酸酯 | 0.8 |
| 羟乙基纤维素 | 0.3 |
| 柠檬酸 | 适量 |
| 纯净水，加至 | 100 |
| 总计 | 100 |
| 成分 | 量[g]，每100g |
| 溴夫定 | 5 |
| 二氧化钛 | 22.5 |
| 半液体石蜡油 | 15 |
| 丙二醇 | 10.5 |
| Vasilinum album | 6 |
| 羊毛脂 | 5 |
| 脱水山梨糖醇单油酸酯 | 3 |
| 白蜂蜡 | 1.5 |
| 硬脂酸锌 | 1 |
| 硬脂酸镁 | 1 |
| 4-羟基苯甲酸甲酯 | 0.15 |
| 苯扎氯铵 | 0.2 |
| 没食子酸丙酯 | 0.02 |
| 纯净水，加至 | 100 |
| 总计 | 100 |
| 成分 | 量[g]，每100g |
| 溴夫定 | 1 |
| 二氧化钛 | 27 |
| 丙二醇 | 15 |
| 半液体石蜡油 | 5 |
| 肉豆蔻酸异丙酯 | 5 |
| 鲸蜡醇 | 3 |
| 聚氧乙烯单硬脂酸酯 | 0.8 |
| 羟乙基纤维素 | 0.3 |
| 4-羟基苯甲酸甲酯 | 0.15 |
| 苯扎氯铵 | 0.2 |
| 柠檬酸 | 适量 |
| 纯净水，加至 | 100 |
| 总计 | 100 |
| 成分 | 量[g]，每100g |
| 溴夫定 | 2 |
| 氧化铁黄 | 0.75 |
| 氧化铁红 | 0.15 |
| 氧化铁黑 | 0.1 |
| 肉豆蔻酸异丙酯 | 24 |
| 二氧化钛 | 15 |
| 半液体石蜡油 | 15 |
| 丙二醇 | 15 |
| Vasilinum album | 12 |
| 氧化锌 | 5 |
| 二氧化硅 | 5 |
| 脱水山梨糖醇三油酸酯 | 3 |
| 白蜂蜡 | 3 |
| 总计 | 100 |
| 成分 | 量[g]，每100g |
| 溴夫定 | 5 |
| 氧化锌 | 10 |
| 二氧化钛 | 10 |
| 氧化铝 | 0.6 |
| 二氧化硅 | 0.032 |
| 甘油 | 0.1 |
| 氧化铁黄 | 2.6 |
| 氧化铁红 | 1 |
| 氧化铁黑 | 0.4 |
| 丙二醇 | 20 |
| Vasilinum album | 10 |
| 半液体石蜡油 | 6 |
| 聚氧乙烯单硬脂酸酯 | 3 |
| 鲸蜡/硬脂醇 | 2 |
| 20％柠檬酸 | 0.6 |
| 聚二甲基硅氧烷 | 0.5 |
| 纯净水，加至 | 100 |
| 总计 | 100 |
| 成分 | 量[g]，每100g |
| 溴夫定 | 2 |
| 二氧化钛 | 21.27 |
| 氧化铝 | 1.38 |
| 二氧化硅 | 0.07 |
| 甘油 | 0.28 |
| 氧化铁黄 | 1.4 |
| 氧化铁红 | 0.4 |
| 氧化铁黑 | 0.2 |
| 丙二醇 | 20 |
| Vasilinum album | 9 |
| 半液体石蜡油 | 5 |
| 聚氧乙烯单硬脂酸酯 | 3 |
| 鲸蜡/硬脂醇 | 2 |
| 20％柠檬酸 | 0.8 |
| 聚二甲基硅氧烷 | 0.3 |
| 纯净水，加至 | 100 |
| 总计 | 100 |
将形成油相的赋型剂(半液体石蜡油、聚氧乙烯单硬脂酸酯、鲸蜡/硬脂醇、vasilinum album、聚二甲基硅氧烷)在75℃至80℃之间融化。另外将亲水性乳膏基质(20％柠檬酸、纯净水、丙二醇[部分量])加热至75℃至80℃之间。将两相在预热过的制药匀浆器的容器中混合。然后将混合物在75℃至80℃之间、在低压下搅拌并匀化。然后，将赋型剂二氧化钛、氧化铁黄、氧化铁黑、氧化铁红、氧化铝、甘油和二氧化硅加入到乳膏基质中。将混合物在75℃至80℃之间、在低压下搅拌并匀化。然后将乳膏冷却至室温，保持搅拌和低压。
将溴夫定分散于丙二醇(剩余量)中。将该分散体加入到乳膏中。混合物在20℃至30℃之间、在低压下搅拌并匀化。
乳膏避光储存于密闭容器中，直至进一步的操作。
Claims (13)
1.一种稳定化的局部药物组合物，含有活性物质溴夫定((E)-5-(2-溴乙烯基)-2′-脱氧尿苷)和浓度为10％至50％w/w的一种或多种金属氧化物颜料，以及可药用赋型剂。
2.权利要求1的药物组合物，其中金属氧化物浓度为15％至35％w/w。
3.权利要求2的药物组合物，其中所述的浓度为20％至30％w/w。
4.前述任一项权利要求的药物组合物，其中的颜料选自二氧化钛、氧化铁、氧化锌。
5.权利要求4的药物组合物，其中的氧化铁是氧化铁黄、氧化铁红或氧化铁黑。
6.权利要求4-5的药物组合物，其中的颜料是二氧化钛或氧化铁黄。
7.前述任一项权利要求的药物组合物，其中含有0.3-8％w/w的溴夫定。
8.权利要求7的药物组合物，其中含有0.5-5％w/w的溴夫定。
9.前述任一项权利要求的药物组合物，该组合物是(O/W或W/O型)乳膏、唇膏、脂凝胶、水凝胶形式的。
10.权利要求9的药物组合物，其选自：
i)O/W乳膏，其中含有溴夫定1％、二氧化钛25％、氧化铝1.6％、二氧化硅0.1％、甘油0.4％、二甲基硅油0.5％、硬脂酸1.9％、丙二醇15％、Vasilinum album 9％、聚氧乙烯单硬脂酸酯2％、鲸蜡/硬脂醇1.5％、柠檬酸(20％)0.6％、4-羟基苯甲酸甲酯0.15％、苯扎氯铵0.2％、聚二甲基硅氧烷0.2％、水加至100％；
ii)唇膏制剂，其中含有溴夫定5％、二氧化钛20％、单硬脂酸甘油酯10％、C10-C18脂肪酸甘油酯20％、丙二醇15％、辛酸三甘油酯、癸酸三甘油酯15％、白蜂蜡4％、以及辛酸二甘油酯、癸酸二甘油酯、异硬脂酸二甘油酯、己二酸二甘油酯共11％；
iii)脂凝胶，其中含有溴夫定5％、液体石蜡34％、肉豆蔻酸异丙酯25％、二氧化硅6.25％、脱水山梨糖醇单油酸酯3％、二氧化钛16.25％、氧化铝5.125％、氧化铁黄2.1％、氧化铁红0.6％、氧化铁黑0.3％、甘油2.375％；
iv)W/O-乳液，其中含有溴夫定0.5％、氧化锌10％、二氧化钛10％、半液体石蜡油15％、丙二醇8％、Vasilinum album 6％、羊毛脂5％、脱水山梨糖醇单油酸酯3％、白蜂蜡1.5％、硬脂酸锌1.0％、硬脂酸镁1.0％、4-羟基苯甲酸甲酯0.15％、苯扎氯铵0.2％、没食子酸丙酯0.02％、柠檬酸(20％)0.6％、水加至100％；
v)水凝胶，其中含有溴夫定5％、二氧化钛21.25％、氧化铝1.25％、二氧化硅0.125％、甘油2.375％、氧化铁黄3.25％、氧化铁红1.25％、氧化铁黑0.5％、丙二醇20％、半液体石蜡油5％、肉豆蔻酸异丙酯5％、鲸蜡醇3％、聚氧乙烯单硬脂酸酯0.8％、羟乙基纤维素0.3％、柠檬酸适量、水加至100％；
vi)W/O-乳液，其中含有溴夫定5％、二氧化钛22.5％、半液体石蜡油15％、丙二醇10.5％、Vasilinum album 6％、羊毛脂5％、脱水山梨糖醇单油酸酯3％、白蜂蜡1.5％、硬脂酸锌1％、硬脂酸镁1％、4-羟基苯甲酸甲酯0.15％、苯扎氯铵0.2％、没食子酸丙酯0.02％、水加至100％；
vii)水凝胶，其中含有溴夫定1％、二氧化钛27％、丙二醇15％、半液体石蜡油5％、肉豆蔻酸异丙酯5％、鲸蜡醇3％、聚氧乙烯单硬脂酸酯0.8％、羟乙基纤维素0.3％、4-甲基对羟基苯甲酸酯0.15％、苯扎氯铵0.2％、柠檬酸适量、水加至100％；
viii)脂凝胶，其中含有溴夫定2％、氧化铁黄0.75％、氧化铁红0.15％、氧化铁黑0.1％、肉豆蔻酸异丙酯24％、二氧化钛15％、半液体石蜡油15％、丙二醇15％、Vasilinum album 12％、氧化锌5％、二氧化硅5％、脱水山梨糖醇三油酸酯3％、白蜂蜡3％；
ix)O/W乳膏，其中含有溴夫定5％、氧化锌10％、二氧化钛10％、氧化铝0.6％、二氧化硅0.032％、甘油0.1％、氧化铁黄2.6％、氧化铁红1％、氧化铁黑0.4％、丙二醇20％、Vasilinum album 10％、半液体石蜡油6％、聚氧乙烯单硬脂酸酯3％、鲸蜡/硬脂醇2％、柠檬酸(20％)0.6％、聚二甲基硅氧烷0.5％、水加至100；
x)O/W乳膏，其中含有溴夫定2％、二氧化钛21.27％、氧化铝1.38％、二氧化硅0.07％、甘油0.28％、氧化铁黄1.4％、氧化铁红0.4％、氧化铁黑0.2％、丙二醇20％、Vasilinum album 9％、半液体石蜡油5％、聚氧乙烯单硬脂酸酯3％、鲸蜡/硬脂醇2％、柠檬酸(20％)0.8％、聚二甲基硅氧烷0.3％、水加至100％。
11.用于局部治疗水痘带状疱疹病毒和1型单纯疱疹病毒感染的前述任一项权利要求的药物组合物。
12.金属氧化物颜料作为光稳定剂用于溴夫定局部制剂的用途。
13.一种或多种选自二氧化钛、氧化铁、氧化锌的颜料的根据权利要求12所述的用途。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102300563A (zh) * | 2009-01-29 | 2011-12-28 | 大日本住友制药株式会社 | 具有内核的口腔崩解片剂 |
| CN104988791A (zh) * | 2015-06-25 | 2015-10-21 | 广东义晟实业有限公司 | 一种抗病毒添加剂及添加该添加剂的胶水和uv漆 |
| CN107427483A (zh) * | 2015-03-19 | 2017-12-01 | 第三共株式会社 | 含有着色剂的固体制剂 |
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| DE102005046769A1 (de) * | 2005-09-29 | 2007-04-05 | Berlin-Chemie Ag | Lichtstabile, brivudinhaltige pharmazeutische Formulierung zur Behandlung von Augenherpes (Herpes Ophthalmicus) |
| FR2936706B1 (fr) * | 2008-10-08 | 2010-12-17 | Oreal | Composition cosmetique contenant un derive de dibenzoylmethane et un compose dithiolane ; procede de photostabilisation du derive de dibenzoylmethane |
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| EP0072137A1 (en) * | 1981-08-01 | 1983-02-16 | Beecham Group Plc | Antiviral deoxyuridine compounds |
| HU196038B (en) * | 1987-08-07 | 1988-09-28 | Mta Koezponti Kemiai Kutato In | Process for producing antiherpetic pharmaceutics for external use, containing 5-isopropyl-2'-beta-deoxy-uridine |
| DE4122337A1 (de) * | 1991-07-05 | 1993-01-14 | Cedona Pharm Bv | Pharmazeutische zubereitung |
| FR2737118B1 (fr) * | 1995-07-28 | 1997-09-05 | Oreal | Composition dermatologique ou pharmaceutique, procede de preparation et utilisation |
| GB9521454D0 (en) * | 1995-10-19 | 1995-12-20 | Kappa Pharmaceuticals Ltd | Compositions for the treatment of conditions caused by herpes virus |
| US6558710B1 (en) * | 1999-06-14 | 2003-05-06 | Helen Rebecca Godfrey | Topical zinc compositions and methods of use |
| DE10162593A1 (de) * | 2001-12-19 | 2003-07-03 | Menarini Ricerche Spa | Stabilisierte topische Brivudin-Formulierungen |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102300563A (zh) * | 2009-01-29 | 2011-12-28 | 大日本住友制药株式会社 | 具有内核的口腔崩解片剂 |
| CN107427483A (zh) * | 2015-03-19 | 2017-12-01 | 第三共株式会社 | 含有着色剂的固体制剂 |
| CN104988791A (zh) * | 2015-06-25 | 2015-10-21 | 广东义晟实业有限公司 | 一种抗病毒添加剂及添加该添加剂的胶水和uv漆 |
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| BG107988A (bg) | 2004-09-30 |
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| HUP0302741A3 (en) | 2007-06-28 |
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