MXPA01005020A - Antiviral formulations comprising propylene glycol and an isopropyl alkanoic acid ester - Google Patents
Antiviral formulations comprising propylene glycol and an isopropyl alkanoic acid esterInfo
- Publication number
- MXPA01005020A MXPA01005020A MXPA/A/2001/005020A MXPA01005020A MXPA01005020A MX PA01005020 A MXPA01005020 A MX PA01005020A MX PA01005020 A MXPA01005020 A MX PA01005020A MX PA01005020 A MXPA01005020 A MX PA01005020A
- Authority
- MX
- Mexico
- Prior art keywords
- composition
- weight
- approx
- glucocorticoid
- hydrocortisone
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 148
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 150000002148 esters Chemical class 0.000 title claims abstract description 24
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 title claims abstract description 5
- 239000002253 acid Substances 0.000 title claims description 15
- 230000000840 anti-viral Effects 0.000 title abstract description 23
- 239000003862 glucocorticoid Substances 0.000 claims abstract description 29
- 239000003443 antiviral agent Substances 0.000 claims abstract description 19
- 239000002777 nucleoside Substances 0.000 claims abstract description 18
- 230000000699 topical Effects 0.000 claims abstract description 15
- 150000003833 nucleoside derivatives Chemical class 0.000 claims abstract description 14
- 230000000069 prophylaxis Effects 0.000 claims abstract description 9
- 230000003110 anti-inflammatory Effects 0.000 claims abstract description 8
- 208000006213 Herpesviridae Infection Diseases 0.000 claims abstract description 6
- 239000003937 drug carrier Substances 0.000 claims abstract description 4
- 238000009472 formulation Methods 0.000 claims description 36
- 239000012071 phase Substances 0.000 claims description 25
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 22
- 229960000890 hydrocortisone Drugs 0.000 claims description 22
- 229960004150 aciclovir Drugs 0.000 claims description 16
- MKUXAQIIEYXACX-UHFFFAOYSA-N acyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims description 16
- JNTOCHDNEULJHD-UHFFFAOYSA-N 9-(4-hydroxy-3-(hydroxymethyl)butyl)guanine Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 claims description 15
- 229960001179 penciclovir Drugs 0.000 claims description 15
- 229940023040 Acyclovir Drugs 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000008346 aqueous phase Substances 0.000 claims description 12
- -1 clobatasone Chemical compound 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 6
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl myristate Chemical group CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 claims description 5
- 229940074928 isopropyl myristate Drugs 0.000 claims description 5
- IRSCQMHQWWYFCW-UHFFFAOYSA-N Ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 claims description 4
- 229960002963 Ganciclovir Drugs 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 claims description 4
- SCBFBAWJWLXVHS-UHFFFAOYSA-N 2-amino-9-[4-hydroxy-2-(hydroxymethyl)butyl]-3H-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CC(CO)CCO)C=N2 SCBFBAWJWLXVHS-UHFFFAOYSA-N 0.000 claims description 3
- 239000000651 prodrug Substances 0.000 claims description 3
- 229940002612 prodrugs Drugs 0.000 claims description 3
- YVHXHNGGPURVOS-SBTDHBFYSA-N (8S,9R,10S,11S,13S,14S,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-16-methylidene-7,8,11,12,14,15-hexahydro-6H-cyclopenta[a]phenanthren-3-one Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](C(=C)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 YVHXHNGGPURVOS-SBTDHBFYSA-N 0.000 claims description 2
- SUPKOOSCJHTBAH-UHFFFAOYSA-N 2-(6-aminopurin-9-yl)ethoxymethylphosphonic acid Chemical compound NC1=NC=NC2=C1N=CN2CCOCP(O)(O)=O SUPKOOSCJHTBAH-UHFFFAOYSA-N 0.000 claims description 2
- BPWUPPWUQNNFOU-UHFFFAOYSA-N 2-[cyclopropylmethyl(hydroxymethyl)amino]-8-(hydroxymethyl)-3,7-dihydropurin-6-one Chemical compound N=1C=2N=C(CO)NC=2C(=O)NC=1N(CO)CC1CC1 BPWUPPWUQNNFOU-UHFFFAOYSA-N 0.000 claims description 2
- FJXOGVLKCZQRDN-PHCHRAKRSA-N Alclometasone Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O FJXOGVLKCZQRDN-PHCHRAKRSA-N 0.000 claims description 2
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 claims description 2
- WBGKWQHBNHJJPZ-LECWWXJVSA-N Desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 claims description 2
- 229940013399 Flumethasone Drugs 0.000 claims description 2
- UUOUOERPONYGOS-CLCRDYEYSA-N Fluocinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3C[C@H](F)C2=C1 UUOUOERPONYGOS-CLCRDYEYSA-N 0.000 claims description 2
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N Fluocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 claims description 2
- BMCQMVFGOVHVNG-TUFAYURCSA-N Hydrocortisone 17-butyrate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O BMCQMVFGOVHVNG-TUFAYURCSA-N 0.000 claims description 2
- DALKLAYLIPSCQL-YPYQNWSCSA-N Methylprednisolone aceponate Chemical compound C1([C@@H](C)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@](C(=O)COC(C)=O)(OC(=O)CC)[C@@]2(C)C[C@@H]1O DALKLAYLIPSCQL-YPYQNWSCSA-N 0.000 claims description 2
- 229960001664 Mometasone Drugs 0.000 claims description 2
- 229940105132 Myristate Drugs 0.000 claims description 2
- IXTCZMJQGGONPY-XJAYAHQCSA-N Rofleponide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3O[C@@H](CCC)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O IXTCZMJQGGONPY-XJAYAHQCSA-N 0.000 claims description 2
- 229950004432 Rofleponide Drugs 0.000 claims description 2
- 229960002117 Triamcinolone Acetonide Drugs 0.000 claims description 2
- YNDXUCZADRHECN-JNQJZLCISA-N Triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 claims description 2
- 229960001997 adefovir Drugs 0.000 claims description 2
- 229960000552 alclometasone Drugs 0.000 claims description 2
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 claims description 2
- 229960003662 desonide Drugs 0.000 claims description 2
- 229960003469 flumetasone Drugs 0.000 claims description 2
- WXURHACBFYSXBI-GQKYHHCASA-N flumethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-GQKYHHCASA-N 0.000 claims description 2
- 229940043075 fluocinolone Drugs 0.000 claims description 2
- 229960003238 fluprednidene Drugs 0.000 claims description 2
- 229960001067 hydrocortisone acetate Drugs 0.000 claims description 2
- 229960001524 hydrocortisone butyrate Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229960002037 methylprednisolone aceponate Drugs 0.000 claims description 2
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 claims description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-M myristate Chemical compound CCCCCCCCCCCCCC([O-])=O TUNFSRHWOTWDNC-UHFFFAOYSA-M 0.000 claims description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 2
- UREBDLICKHMUKA-DVTGEIKXSA-N Betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 1
- 229960002537 betamethasone Drugs 0.000 claims 1
- 239000000839 emulsion Substances 0.000 claims 1
- 239000000969 carrier Substances 0.000 abstract description 7
- 230000001225 therapeutic Effects 0.000 abstract description 3
- 230000003902 lesions Effects 0.000 description 27
- 229960004063 Propylene glycol Drugs 0.000 description 22
- 239000003921 oil Substances 0.000 description 21
- 239000000306 component Substances 0.000 description 18
- 229940068196 placebo Drugs 0.000 description 12
- 239000000902 placebo Substances 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 239000003995 emulsifying agent Substances 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 241000700198 Cavia Species 0.000 description 7
- 208000009889 Herpes Simplex Diseases 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 239000006071 cream Substances 0.000 description 6
- 201000009910 diseases by infectious agent Diseases 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 229940044519 Poloxamer 188 Drugs 0.000 description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 5
- 229940057995 liquid paraffin Drugs 0.000 description 5
- 229920001993 poloxamer 188 Polymers 0.000 description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 5
- 229940099259 Vaseline Drugs 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229940065521 Glucocorticoid inhalants for obstructive airway disease Drugs 0.000 description 3
- 210000003491 Skin Anatomy 0.000 description 3
- 229940037128 Systemic Glucocorticoids Drugs 0.000 description 3
- 125000000129 anionic group Chemical group 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 210000001519 tissues Anatomy 0.000 description 3
- IQXJCCZJOIKIAD-UHFFFAOYSA-N 1-(2-methoxyethoxy)hexadecane Chemical compound CCCCCCCCCCCCCCCCOCCOC IQXJCCZJOIKIAD-UHFFFAOYSA-N 0.000 description 2
- 229940007825 Acyclovir / Hydrocortisone Drugs 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 229950009789 Cetomacrogol 1000 Drugs 0.000 description 2
- 210000004392 Genitalia Anatomy 0.000 description 2
- 208000007514 Herpes Zoster Diseases 0.000 description 2
- 206010019973 Herpes virus infection Diseases 0.000 description 2
- 229920002675 Polyoxyl Polymers 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 230000002051 biphasic Effects 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 229940082500 cetostearyl alcohol Drugs 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000003612 virological Effects 0.000 description 2
- MLHOXUWWKVQEJB-UHFFFAOYSA-N 1-acetyloxypropan-2-yl acetate Chemical class CC(=O)OC(C)COC(C)=O MLHOXUWWKVQEJB-UHFFFAOYSA-N 0.000 description 1
- NZJXADCEESMBPW-UHFFFAOYSA-N 1-methylsulfinyldecane Chemical compound CCCCCCCCCCS(C)=O NZJXADCEESMBPW-UHFFFAOYSA-N 0.000 description 1
- LGEZTMRIZWCDLW-UHFFFAOYSA-N 14-methylpentadecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC(C)C LGEZTMRIZWCDLW-UHFFFAOYSA-N 0.000 description 1
- PWVUXRBUUYZMKM-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOCCO PWVUXRBUUYZMKM-UHFFFAOYSA-N 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- SFAAOBGYWOUHLU-UHFFFAOYSA-N 2-ethylhexyl hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(CC)CCCC SFAAOBGYWOUHLU-UHFFFAOYSA-N 0.000 description 1
- 229940035674 ANESTHETICS Drugs 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L Calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 229960000724 Cidofovir Drugs 0.000 description 1
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovirum Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 240000007170 Cocos nucifera Species 0.000 description 1
- 206010011409 Cross infection Diseases 0.000 description 1
- 229940075882 Denavir Drugs 0.000 description 1
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 1
- 108010093894 EC 1.17.3.2 Proteins 0.000 description 1
- MGNNYOODZCAHBA-GQKYHHCASA-N Fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
- 206010018175 Genital rash Diseases 0.000 description 1
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 1
- 241000701027 Human herpesvirus 6 Species 0.000 description 1
- 229940078545 ISOCETYL STEARATE Drugs 0.000 description 1
- 206010022114 Injury Diseases 0.000 description 1
- SKRDXYBATCVEMS-UHFFFAOYSA-N Isopropyl nitrite Chemical compound CC(C)ON=O SKRDXYBATCVEMS-UHFFFAOYSA-N 0.000 description 1
- 208000007766 Kaposi Sarcoma Diseases 0.000 description 1
- 229920002884 Laureth 4 Polymers 0.000 description 1
- 210000000088 Lip Anatomy 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229940049964 Oleate Drugs 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 229940066842 Petrolatum Drugs 0.000 description 1
- 229940044476 Poloxamer 407 Drugs 0.000 description 1
- 229940068965 Polysorbates Drugs 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010037888 Rash pustular Diseases 0.000 description 1
- 229940080350 SODIUM STEARATE Drugs 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M Sodium stearate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical class OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000001756 Virus Disease Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 102100002634 XDH Human genes 0.000 description 1
- 229940057977 Zinc stearate Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000003444 anaesthetic Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 238000010420 art technique Methods 0.000 description 1
- UKMSUNONTOPOIO-UHFFFAOYSA-M behenate Chemical compound CCCCCCCCCCCCCCCCCCCCCC([O-])=O UKMSUNONTOPOIO-UHFFFAOYSA-M 0.000 description 1
- 229940116224 behenate Drugs 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- ULBTUVJTXULMLP-UHFFFAOYSA-N butyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCC ULBTUVJTXULMLP-UHFFFAOYSA-N 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- SASYSVUEVMOWPL-NXVVXOECSA-N decyl oleate Chemical compound CCCCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC SASYSVUEVMOWPL-NXVVXOECSA-N 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 230000002996 emotional Effects 0.000 description 1
- 230000001667 episodic Effects 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- HQSFGCUUTBCFPF-UHFFFAOYSA-N ethane-1,2-diol;octadecanoic acid Chemical compound OCCO.CCCCCCCCCCCCCCCCCC(O)=O HQSFGCUUTBCFPF-UHFFFAOYSA-N 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229960002714 fluticasone Drugs 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000004914 menses Anatomy 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000001537 neural Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- KREXGRSOTUKPLX-UHFFFAOYSA-N octadecanoic acid;zinc Chemical compound [Zn].CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O KREXGRSOTUKPLX-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 230000001717 pathogenic Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000005426 pharmaceutical component Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 229960000776 sodium tetradecyl sulfate Drugs 0.000 description 1
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(E)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 1
- UPUIQOIQVMNQAP-UHFFFAOYSA-M sodium;tetradecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCOS([O-])(=O)=O UPUIQOIQVMNQAP-UHFFFAOYSA-M 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000475 sunscreen Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
Abstract
A topical composition comprising an antiinflammatory glucocorticoid and a nucleoside analogue antiviral agent in a pharmaceutical carrier characterized in that the carrier comprises about 15 to about 25 weight%propylene glycol and about 10 to about 25 weight percent isopropyl C12-C22 alkanoic ester. The compositions have utility in the treatment or prophylaxis of herpesvirus infections and exhibit superior antiviral and therapeutic efficacy and an improved shelf life.
Description
ANTIVIRAL FORMULATIONS COMPRISING PROPYLENGLYCOL 1 AN ISTERPYL ALCOHOLIC ISOPROPYL ESTER
Field of the Invention This invention relates to topical antiviral formulations suitable for orofacial or genital application and comprising an anti-inflammatory substance and an antiviral substance. The invention also relates to a treatment or prophylaxis of viral herpes diseases using said formulations and their preparation. Background of the Invention International Patent Application No. WO 96/24355 discloses pharmaceutical compositions comprising an antiviral substance suitable for topical use and an anti-inflammatory glucocorticoid in a pharmaceutically acceptable carrier. The carrier disclosed in this application comprises conventional formulations for each of the respective active substances, ie, a conventional antiviral formulation is combined with a conventional glucocorticoid formulation. Said combined formulations have a large number of ingredients that can potentially interact with each other, which gives them stability and unknown physicochemical characteristics.
European Patent Application No. EP 44543 relates to oil-in-water formulations of the acyclic nucleoside antiviral substance, acyclovir, and discloses that for topical penetration the carrier is required to comprise at least 30% by weight, preferably at least 40% by weight of propylene glycol. This formulation, called the MAC formulation, forms the basis for the most widespread topical preparation of acyclovir on the market. International Patent Application No. 91/1 1 187 relates to aqueous or oil-in-water topical formulations of the acyclic nucleoside antiviral substance, penciclovir. These formulations must contain at least 30% by weight, preferably at least 35% by weight, of propylene glycol. European Patent Application No. EP 416739 relates to topical penciclovir formulations comprising at least 30% by weight of propylene glycol and a decyl methyl sulfoxide emulsifier. International Patent Application No. 93/00905 relates to topical penciclovir formulations containing at least 30% by weight, preferably at least 35% by weight of propylene glycol and an emulsifier of cetomacrogol 1000. The formulation of a product combination containing a strongly lipophilic component, such as hydrocortisone and a moderately lipophobic component such as an acyclic nucleoside analogue, is difficult in the case of conventional pharmaceuticals, but is even more difficult, in the case of a topical preparation in which the rate of release of active ingredients in target tissues should be taken into account. As described in the publications mentioned in the two preceding paragraphs, it has been considered essential to use a high proportion of propylene glycol when acyclic nucleosides are formulated, in order to achieve an adequate penetration of the antiviral substance into the skin or dermal mucosa. However, we have found that although within the scope of the above-mentioned WO 96/24355 conventional carriers of high concentration of propylene glycol can be used to prepare effective antiviral compositions (i.e., compositions comprising a glucocorticoid and an antiviral substance), these carriers conventional have the disadvantage of making the product have a short useful life and less than optimal antiviral therapeutic functioning. SUMMARY OF THE INVENTION According to the invention, a topical composition comprising an anti-inflammatory glucocorticoid and an antiviral substance of a nucleoside analog in a pharmaceutical carrier is characterized in that the transporter comprises ca. 15 to approx. 25% by weight of propylene glycol and of approx. 10 to approx. 25% by weight of ε-propyl-C 12 -C 22 -alkanoic acid ester. In the context of the invention, this combination of lower concentration of propylene glycol with an ester of isopropyl-alkanoic acid allows a good penetration and release of the antiviral component and at the same time, avoids the instability presented by the conventional antiviral compositions. The compositions of the invention are useful for the treatment or prophylaxis of diseases caused by members of the herpesvirus family, such as herpes simplex type 1 (predominantly an orofacial infection), herpes simplex type 2 (predominantly a genitoanal infection), primary virus infection of varicella zoster (pustule of the hens) and secondary infection (herpes), human herpesvirus type 6 and 8 (has to do with the state of the skin in Kaposi's sarcoma) and the like. In the context of the invention, prophylaxis includes the prevention of infections (including the prevention of transmission to healthy adjacent tissues) and the prevention of a reactivation of previous herpes virus infections, such as the reactivation of sleeping herpes in neuronal tissues. Another aspect of the invention offers the use of the composition defined above in medicaments, particularly in the manufacture of a topical medicament for the treatment or prophylaxis of herpes virus infections in humans, especially herpes simplex type 1 and herpes simplex type 2. An aspect The invention provides a method for the treatment or prophylaxis of herpes virus infections in humans comprising the topical administration of the composition described above to a subject in need of such treatment. The percentages by weight here refer to the weight of the component with respect to the weight of the composition. Preferred antiviral substances include ganciclovir, N-7 ganciclovir, bis-hydroxymethylcyclopropylmethylguanine, lobucovir, adefovir, cidofovir and the like. Particularly preferred antiviral substances include penciclovir, 9- [4-hydroxy-2- (hydroxymethyl) butyl] guanine (H2G) and especially acyclovir. The antiviral substance may be in the form of a prodrug which is metabolised in situ, for example with epidermal esterases or xanthine oxidases, to form an antiviral substance such as one of those mentioned above.
The antiviral substance is included in the formulation in substantially conventional concentrations for the respective nucleoside, e.g. ex. 0.5 to 15% by weight, preferably 1 -7% by weight, as p. ex. 4-5% by weight. Advantageously the formulation is quite or completely saturated with respect to the antiviral substance. Examples of glucocorticoids include alclometasone, desonide, fluprednidene, flumethasone, hydrocortisone and their esters, such as hydrocortisone butyrate or hydrocortisone acetate, clobatasone, triamcinolone acetonide, betametasoria, budenoside, deoxymetasone, diflorosana, fluocinolone, fluoccinonide acetonide, fluorocortolone, fluticasone, methylprednisolone aceponate, mometasone, rofleponide and the like. Gentle glucocorticoids, such as those of the Nordic Class I, are preferred. Hydrocortisone and its esters are particularly preferred.
The glucocorticoid is included in the formulation in a substantially conventional concentration of the respective glucocorticoid, whose concentrations are well known in the art of glucocorticoids and fall in the general range of 0.005 to 12% by weight, for example from 0.1 to 10% in weigh. For example, when a mild glucocorticoid (Nordic Class I), such as hydrocortisone, is used, the formulation may contain 0.1 to 10% by weight, preferably 0.5 to 2% by weight, for example 1% by weight of hydrocortisone . The antiviral and glucocorticoid components may be in substantially dissolved form, depending on the carrier, although they are conveniently prepared from a micronized raw material, such as those having > 75%, preferably more than 90% of particles without defined particle size. For example, the glucocorticoid hydrocortisone is conveniently prepared from raw material having a particle size of less than 5 μm. Acyclovir or antiviral penciclovir is conveniently presented with a particle size of less than 15 μm, preferably less than 7 μm. In general, the compositions of the invention are biphasic and comprise separate oil and aqueous phases, either as an oil-in-water or water-in-oil emulsion. Preferably, the composition comprises a dispersed oil phase and a continuous aqueous phase. The isopropyl alkanoic acid ester and the characteristically lipophilic giucocorticoid component will preferably be found in the oil phase, while the antiviral nucleoside will, in general, be found in the aqueous phase, typically together with the propylene glycol. The components of the oil phase may include conventional fats and oils and their esters, as described in the European Pharmacopoeia and others. The components of the oil phase are preferably non-fatty, do not stain and are washable. Conventional pharmaceutical components of the oil phase include mineral oils such as petrolatum, liquid paraffin and the like, alkanoic acids such as stearic acid and fatty alcohols, such as ketoestearylalcohol, straight or branched chain mono- or dibasic alkylesters, such as diisopropyl adipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, decyl oleate, butyl stearate, 2-ethylhexyl palmitate and other esters of 2-ethylhexanoic acid and the like. Preferred isopropylalcanic acid esters include dodecanate, myristate, palmitate, stearate, eicosanate or behenoate esters, especially isopropyl myristate. The composition of the invention comprises of approx. 10 to approx. 25% by weight of isopropylalkanoic acid ester, preferably of approx. 12 to approx. 18% by weight, as p. ex. 15% by weight. The composition of the invention comprises from about 15 to about. 25% by weight of propylene glycol, as of approx. 18 to approx. 22% in weight. Conveniently, the propylene glycol content is approx.
% by weight, since this concentration ensures, in general, a good preservation without the composition needing exogenous preservatives. The composition of the invention conveniently includes an emulsifier (surfactant), typically in amounts of 0.05 to
, preferably from 0.1 to 1% by weight. The European pharmacopoeia describes a number of pharmaceutically acceptable emulsifiers, including anionic, cationic and nonionic emulsifiers. Examples of nonionic emulsifiers include cetomacrogoles, such as cetomacrogol 1000, ethylene or diethylene glycol monostearate, glyceryl esters, such as behenate, oleate, stearate, etc. , lauro compounds such as lauromacrogoles, macrogol monomethyl esters, mono and diglycerides, nonoxinols, octoxins, poloxamers such as poloxamer 407, polyoxyls of castor oils, polyoxyl stearates, polysorbates, polyvinylalcohols, propylene glycol diacetates, sorbitan esters and the like. Poloxamer 188 is a preferred nonionic surfactant. Examples of anionic emulsifiers include aluminum monostearate, calcium stearate, sulfated castor oil, magnesium stearate, pendecamain, sodium oleate, sodium stearate, sodium stearyl fumarate, sodium tetradecylsulfate, zinc stearate and the like. A preferred anionic emulsifier is sodium lauryl sulfate. The compositions of the invention may also include conventional auxiliaries, such as surface anesthetics, sunscreens, flavors, essences, emollients or tonalizers and skin masks. The compositions of the invention can be prepared with conventional mixing techniques. Preferably, the compositions are prepared with conventional biphasic mixing techniques, in which the oil and aqueous / propylene glycol phases are mixed and homogenized separately and brought to a common temperature before mixing. The active ingredients (ie, the glucocorticoid and the nucleoside analogue) can be mixed to their respective oil and water phase before or after mixing. To minimize the tendency to recrystallization, the active ingredients are preferably added after mixing the two phases. This means that there is a higher volume when the active ingredients are added and in addition, the biphasic mixture is generally found at a lower temperature. Another aspect of the invention offers a method for preparing an antiviral composition comprising carrying an oil phase containing from 10 to 25% by weight (based on the total weight of the proposed formulation) of isopropylalkanoic acid ester at a defined temperature, carrying a aqueous phase containing 15-25% by weight (based on the total weight of the proposed formulation) of propylene glycol at the defined temperature, mixing and optionally homogenizing the two phases, optionally allowing the mixture to cool to a lower temperature, add effective amounts of an anti-inflammatory glucocorticoid and an analogous nucleoside antiviral substance and homogenize the resulting mixture. Virus states, such as herpes simplex lesions on the lips and / or genitals or herpes zoster (herpes), are episodic. As in all antiviral treatments, it is advisable to start the application of the medication as soon as possible after the reactivation of a sleeping herpes infection that manifests or is suspected to be an incipient lesion. For example, many people feel a warmth or itching at the focal point one or several days before the first signs of a herpes lesion become visible. The application of the composition of the invention is preferably started at that time. In some patients, exposure to certain stimuli, such as UV light when skiing or the tropical sun, severe emotional stress or menstruation can induce a reactivation of herpes lesions in particular places. The composition of the invention can be applied prophylactically after exposure to these stimuli. In any case it is convenient that people prone to herpes lesions have easy access to the composition for a quick application when necessary. Accordingly, it is desirable that the composition of the invention have a long shelf life without the need for refrigeration, so that the medicament can be stored at home, at work and / or packed for travel.
The composition will be applied, generally on incipient or obvious lesions, two to twelve times a day during an episode, such as every three hours. The applications will preferably continue at least until the hard crust stage, which usually takes 3 to 10 days after the first feeling that an episode is expected. The composition of the invention is preferably presented in a tube of 0.25 to 50 ml of content. It is convenient that the tube contains a sufficient amount for a single episode of sudden or genital rash, such as 1 to 5 ml. This will allow several daily applications for a period no longer than a week or ten days, the rest must be discarded, to minimize potential contamination of the open tube and / or cross infections between individuals sharing the same tube. The preclinical efficacy of the compositions of the invention can be tested as demonstrated in the examples or in the adoptive transfer of the immunity model which is described in WO 96/24355 and WO 96/24963. BRIEF DESCRIPTION OF THE DRAWINGS Different embodiments will be illustrated by way of example only with reference to the following non-limiting examples and drawings, in which: Figure 1 is a curve of the evolution of a lesion of guinea pigs infected with herpes , treated topically with a composition of the invention or a placebo;
Fig. 2 is a curve of the evolution of a lesion of guinea pigs infected with topically treated herpes with a composition comprising a conventional transporter or a placebo; Figure 3 is a cuvette of the evolution of a lesion of guinea pigs infected with herpes treated topically with a composition falling outside the scope of the invention or a placebo; Figure 4 is a microphotograph showing the growth of crystals in a conventional formulation; Fig. 5 is a microphotograph showing the lack of growth of crystals in a formulation of the invention; Figure 6 is a curve of the evolution of a lesion of guinea pigs infected with herpes treated topically with a composition of the invention or a composition prepared according to Example 3 of WO 96/24355. Figure 7 is a curve of the evolution of a lesion of guinea pigs infected with herpes treated topically with an alternative composition of the invention or a composition prepared analogously to that of WO 96/24355. Detailed Description of the Invention Example 1 A composition of the invention is prepared from the following ingredients: Oil phase Cetostearyl alcohol 6.75 g 6.75% Vaseline 1 0.00 g 1 0.0% Liquid paraffin 5.65 g 5.65% Isopropyl myristate 15.00 g 15.0% Aqueous phase Propylene glycol 20.00 g 20.0% Sodium lauryl sulfate 0.80 g 0.8% Poloxamer 188 1.00 g 1.0% Purified water 34 , 8 g 34.8% Active ingredients Aciclovir 5.00 g 5.0% Hydrocortisone 1.00 g 1.0% The particle size of acyclovir (micronized Recordati, Pat. USA 23 / BP93 / Eur Ph lll) was 10% = 2 μm, 50% = 4 μm, 90% = 7 μm, and 100% = 15 μm. The particle size of the hydrocortisone (micronized Pharmacia &Upjohn Pat. USA / EP / BP) was 100% < 5μm, geometric diameter 2 μm. The purified water was obtained by inverted osmosis. The components of the oil and water phase are added to respective mixing vessels which are heated to 70 ° C while stirring. When the phases are at the same temperature, the oil phase is poured on the aqueous phase from above while continuing to stir for 3-5 minutes at the highest possible speed, which prevents the incorporation of air into the mixture. Then, the mixture thus emulsified is homogenized, cooled to 32-25 ° C while stirring. The active ingredients are added and stirring is continued until the active ingredients have been soaked and incorporated. The mixture is re-homogenized and cooled until the cream thickens at approximately 30 ° C, before packing it. Example 2 The composition of penciclovir / hydrocortisone of the invention was prepared from the following components: Oil phase Keto-stearyl alcohol 6.75 g 6.75% Vaseline 10.00 g 10.0% Liquid paraffin 5.65 g 5.65 % Isopropyl myristate 15.00 g 15.0% Propylene glycol aqueous phase 20.00 g 20.0% Sodium lauryl sulfate 0.80 g 0.8% Poloxamer 188 1.00 g 1.0% Purified water 34.8 g 34 , 8% Component active Penciclovir 5.00 g 5.0% Hydrocortisone 1.00 g 1.0% The particle size of hydrocortisone (micronized Pharmacia & amp;; Upjohn Pat. USA / EP / BP) was 100% < 5μm, geometric diameter 2 μm. The purified water was treated by inverted osmosis. Penciclovir was micronized to a mean diameter of 5 μm. The components of the oil and water phase are added to respective mixing vessels which are heated to 70 ° C while stirring. When the phases are at the same temperature, the oil phase is poured on the aqueous phase from above while continuing to stir for 3-5 minutes at the highest possible speed, which prevents the incorporation of air into the mixture. Then, the mixture thus emulsified is homogenized and cooled to 32-25 ° C while continuing to stir. The active ingredients are added and stirring is continued until the active ingredients have been soaked and incorporated. The mixture is again homogenized and cooled until the cream thickens, at approximately 30 ° C, before packing it. COMPARATIVE EXAMPLE 1 An acyclovir / hydrocortisone composition employing a MAC carrier of the prior art, described and claimed in EP 44543, was prepared from the following components: Oil phase Keto stearyl alcohol 33.75 g 6.75% Vaseline 50, 00 g 10.0% Liquid paraffin 28.25 g 5.65% Aqueous phase Propylene glycol 200.0 g 40.0% Sodium lauryl sulphate 4.0 g 0.8% Poloxamer 188 5.0 g 1.0% Purified water 148.82 g 29.8% Active component Aciclovir 28.19 g 5.0% Hydrocortisone 5.02 g 1.0% The ingredients were mixed substantially as described in Example 1. COMPARATIVE EXAMPLE 2 An acyclovir / hydrocortisone composition was prepared using a low concentration of propylene glycol (PG) (with respect to the MAC formulation of the prior art) but without the isopropylalkanoic ester (IPM) of the composition of the invention, from the following components: Oil phase Ceto-stearyl alcohol 6.75 g 6.75% Vaseline 10.0 g 10.0% Liquid paraffin 5.65 g 5.65% Aqueous phase Propylene glycol 25.0 g 25.0% Sodium lauryl sulfate 0, 80 g 0.8% Poloxamer 188 1, 0 g 1.0% Purified water 44.8 g 44.8% Active component Aciclovir 5.00 g 5.0% Hydrocortisone 1.00 g 1.0% The ingredients were mixed substantially as described in Example 1. Biological Example 1 The antiviral efficacy of the compositions of this invention and the comparative examples was tested in a model of guinea pigs (Alenius et al., J.Inf.Dis.145 569-573 (1982)). In summary, the model is aimed at establishing a primary infection of herpes simplex in areas depilated from the dorsal surface of guinea pigs. 24 hours after the inoculation, the test compositions and the placebo were applied to the incipient lesions of herpes. Topical administration was repeated twice a day for 3 or 4 days. A double-blind daily score was awarded to the appearance of the lesions and the score of multiple animals was averaged. The score was as follows: 0 represented no lesion 1 represented a few isolated lesions 2 represented severe lesions, some confluent 3 represented maximum development of confluent lesions. Figure 1 shows the results of a composition of this invention (Example 1) compared to those of a placebo formulation (the MAC formulation, analogous to Comparative Example 1, but without the active ingredients) representing an uninhibited viral growth. Figure 2 shows a composition substantially of the prior art (Comparative Example 1 - acyclovir and hydrocortisone in a MAC formulation) compared to the corresponding placebo. Figure 3 depicts a composition that falls outside the scope of the invention (Comparative Example 2, low PG-free content and no I PM) compared to placebo. With reference first to the placebo formulations, it is evident that in the absence of the combination of antiviral and glucocorticoid substance, severe lesions are formed within 3 days and remain uncured for 8 days. A fresh composition containing the antiviral / glucocorticoid combination according to the above WO 96/24355 (Comparative Example 1) was prepared with an antiviral nucleoside analog and an anti-inflammatory glucocorticoid in a conventional MAC formulation. This formulation delays the development of serious lesions (day 1 to 5) and somewhat reduces the intensity of the lesion (maximum score 2 on day 6). As suggested in WO 96/24355, such formulations are useful for the treatment and prophylaxis of herpes infections. However, as described in the test of Example 1, this MAC formulation is not practical for combined regimens from a commercial point of view. With reference now to Comparative Example 2 of Figure 3, as described by the disclosure of the above-mentioned EP 44543, WO 91/1 1 187, EP 416 739 and WO 93/00905, addressed to different aspects and applications of the MAC formulation by reducing the proportion of propylene glycol below the "at least 30% by weight" that is advised in these patents and applications, antiviral efficacy is significantly reduced and a formulation is obtained that is only marginally more useful than placebo. In particular, the score of the lesions is less than half a unit less than for the placebo with hardly measurable decreases in time / injury and time / cure. In contrast, as described in Figure 1, the compositions of the invention exhibit significantly improved efficacy with respect to both placebo and the substantially formulation of the prior art of Fig. 2. In particular, the score of the lesions remains at all times less than 1 and is below 0.5 on day 8. The combination with a reduced concentration of propylene glycol together with the addition of isopropylalkanoic acid ester and isopropyl myristate clearly significantly improves the antiviral and therapeutic efficacy of combination products that they comprise an antiviral substance and an anti-inflammatory glucocorticoid. Figure 6 shows, in general, the score of lesions as a function of days in the guinea pig model, as described above, but using a slightly more pathogenic herpes simplex type 1 strain from an experiment comparing the composition of the invention (Example 1) with a composition also comprising hydrocortisone and acyclovir, but prepared according to Example 3 of our also pending application WO 96/24355. It will be apparent that both compositions promote healing well, but the composition of the present invention has an improved performance in terms of the severity of the lesion at the beginning of the infection. In the disappearance curve of the lesion, the area that lies below the curve of the composition of the invention is approx. 10% lower than the formulation of the previous art. Figure 7 shows the lesion score as a function of days in the guinea pig model described in relation to Figure 6, from an experiment applying the cream of Example 2, which contains an alternative antiviral penciclovir and the glucocorticoid hydrocortisone. For comparative purposes, a cream was prepared analogously to the method described in WO 96/24355 also in progress, using commercially available cream Denavir® (penciclovir) (SmithKine Beecham) and hydrocortisone 1% ACO. The composition of the invention makes the score of the lesions significantly less severe. The antibodies treated with placebo, the same cream with the active ingredient free of transporter, are also described in fig. 7. Test Example 1 Figures 4 and 5 are photomicrographs with x40 magnification of the composition that substantially reflects the prior art (Figure 4, Comparative Example 1) and a composition of the invention (Figure 5). Example 1 ) . Referring first to Figure 5 which shows a composition of the invention after being stored for 6 months at 25 ° C, it will be evident that the crystalline acyclovir and the oil phase globules are well dispersed in the aqueous phase . The appearance of the formulation after 6 months of storage is effectively equal to that of the freshly prepared formulation. In contrast, Figure 4 shows an x40 magnification of a formulation comprising a glucocorticoid and an analogous nucleoside antiviral substance in a carrier which is formulated according to prior art techniques., specifically with approx. 40% by weight of propylene glycol. When it was freshly prepared, this formulation could not be distinguished under the microscope of the formulation shown in Fig. 5. However, after only 3 months and 3 weeks of storage at 25 ° C, long crystals had grown in the form of agues in this formulation of the previous art. The analysis showed that these needles contain the hydrocortisone component of the formulation that has been precipitated in the oil phase from the solution, which means that only significantly sub-optimal amounts of this component are topically available. in the formulation. Furthermore, it will also be evident that the oil phase is less dispersed than what is observed in FIG. 5. Although this invention has been illustrated with reference to certain proposed and concrete embodiments, exemplified by the antiviral substance acyclovir , the isopropylalcananoic acid ester I PM, etc. , it will be understood that the invention is not limited by this description and extends to the spirit and scope of the appended claims.
Claims (19)
- CLAIMS 1 .- A topical composition comprising an anti-inflammatory glucocorticoid and an antiviral substance of nucleoside analogue in a pharmaceutical carrier, CHARACTERIZED BECAUSE the transporter comprises of approx. 15 to approx. 25% by weight (with respect to the total weight of the proposed formulation) of propylene glycol and of approx. 10 to approx. 25% by weight (with respect to the total weight of the proposed formulation) of isopropyl C 2 -C 22 -alkanoic acid ester.
- 2. A composition of claim 1, CHARACTERIZED BECAUSE the conveyor comprises of approx. 18 to approx. 33% by weight of propylene glycol, preferably approx. 20% by weight.
- 3. A composition of claim 1, CHARACTERIZEDBECAUSE the conveyor comprises approx. 12 to approx. 18% by weight of isopropylalkanoic acid ester, preferably approx. 15% by weight.
- 4. A composition of claim 3, CHARACTERIZEDBECAUSE the isopropylalkanoic acid ester is selected from the group consisting of dodecanate, myristate, palmitate, stearate, eicosanate or behenoate esters or mixtures thereof.
- 5. A composition of claim 4, CHARACTERIZEDBECAUSE the isopropyl alkanoic acid ester is isopropyl myristate.
- 6. A composition of claim 1, CHARACTERIZEDBECAUSE the nucleoside analogue is selected from the group consisting of ganciclovir, N-7 ganciclovir, bis-hydroxymethylcyclopropylmethylguanine, lobucovir, cidifovir, adefovir, penciclovir, 9- [4-hydroxy-2- (hydroxymethyl) butyl] guanine and acyclovir or prodrug hydrolyzed dermally thereof or mixtures thereof.
- 7 '.- A composition of claim 6, CHARACTERIZEDBECAUSE the nucleoside analogue is penciclovir, 9- [4-hydroxy-2- (hydroxymethyl) butyl] guanine or acyclovir.
- 8. A composition of claim 7, CHARACTERIZEDBECAUSE the nucleoside analogue is acyclovir.
- 9. A composition of claim 1, CHARACTERIZEDBECAUSE the nucleoside analog comprises from 1-15% by weight of the composition, preferably 4-7% by weight.
- 10. A composition of claim 1, CHARACTERIZED
- BECAUSE the glucocorticoid is selected from the group consisting of alclometasone, desonide, fluprednidene, flumethasone, hydrocortisone and its esters, such as hydrocortisone butyrate or hydrocortisone acetate, clobatasone, triamcinolone acetonide, betamethasone, budenoside, deoximetasone, diflorosana, fluocinolone, fluoccinonide acetonide, fluorocortolone, flucticasone, methylprednisolone aceponate, mometasone and rofleponide. 1 - A composition of claim 1, CHARACTERIZED BECAUSE the glucocorticoid is a mild glucocorticoid.
- 12. A composition of claim 10, CHARACTERIZEDBECAUSE the glucocorticoid comprises hydrocortisone or an ester thereof.
- 13. - A composition of claim 1, CHARACTERIZEDBECAUSE the glucocorticoid comprises from 0.005-12% by weight of the composition, preferably from 0.1-10% by weight.
- 14. A composition of claim 1, characterized in that the glucocorticoid is hydrocortisone or an ester thereof and the antiviral substance is acyclovir or penciclovir or a prodrug hydrolyzed dermally thereof.
- 15. A composition of claim 14, CHARACTERIZEDBECAUSE acyclovir comprises 4-7% by weight of the composition and the hydrocortisone comprises 0.5-2% by weight of the composition.
- 16. A composition of claim 14, CHARACTERIZEDBECAUSE penciclovir comprises 1-7% by weight of the composition and hydrocortisone comprises 0.5-2% by weight of the composition.
- 17. A composition of claim 1, CHARACTERIZED BECAUSE it is in the form of an emulsion of water in oil or preferably of oil in water.
- 18. The use of a composition of claim 1,CHARACTERIZED BECAUSE it is used in the manufacture of a medicine for the treatment or prophylaxis of herpes virus infections.
- 19. A method for the treatment or prophylaxis of herpes virus infections, CHARACTERIZED BECAUSE it comprises the topical administration of a composition of clause 1 to a subject who needs it. 20.- A method for the preparation of a topical compositionCHARACTERIZED BECAUSE it comprises carrying an oil phase containing from 10 to 25% by weight (with respect to the total weight of the proposed formulation) of α-propionic acid ester-12-C2-alkanoic acid at a defined temperature, carrying an aqueous phase containing 15-25% by weight (based on the total weight of the proposed formulation) of propylene glycol at the defined temperature, mix and optionally homogenize the two phases, optionally let the mixture cool to a lower temperature, add effective amounts of an anti-inflammatory glucocorticoid and an analogous nucleoside antiviral substance and homogenize the resulting mixture.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9803929-0 | 1998-11-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA01005020A true MXPA01005020A (en) | 2001-12-04 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20170020882A1 (en) | Antiviral formulation | |
US7223387B2 (en) | Antiviral formulations comprising propylene glycol and an isopropyl alkanoic acid ester | |
IE51120B1 (en) | Topical formulations of 9-(2-hydroxyethoxymethyl)guanine | |
JP5420583B2 (en) | Antiviral formulation containing propylene glycol and alkanoic acid isopropyl ester | |
JP2013515020A (en) | Pharmaceutical composition or analogue comprising a solvent mixture and a vitamin D derivative | |
WO1998010768A1 (en) | Antiviral compositions | |
EP3836934B1 (en) | Phase stable topical composition comprising acyclovir and hydrocortisone | |
MXPA01005020A (en) | Antiviral formulations comprising propylene glycol and an isopropyl alkanoic acid ester | |
EP1140117B1 (en) | Aciclovir compositions containing dimethicone | |
SA99200836B1 (en) | Antiviral formulations include propylene glycol and isopropyl alkanoic acid ester. | |
WO2022043952A1 (en) | Low dose topical composition comprising triamcinolone acetonide or salt thereof | |
MXPA01006490A (en) | Aciclovir compositions containing dimethicone | |
SK279096B6 (en) | Non-irritant skin ointment |