US2735798A - Acyl amevo-nitrothiazole compositions - Google Patents
Acyl amevo-nitrothiazole compositions Download PDFInfo
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- US2735798A US2735798A US2735798DA US2735798A US 2735798 A US2735798 A US 2735798A US 2735798D A US2735798D A US 2735798DA US 2735798 A US2735798 A US 2735798A
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- US
- United States
- Prior art keywords
- nitrothiazole
- acyl
- tablet
- trichomonas vaginalis
- trichomonadicidal
- 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.)
- Expired - Lifetime
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- 239000000203 mixture Substances 0.000 title claims description 46
- 125000002252 acyl group Chemical group 0.000 title description 20
- 206010046914 Vaginal infection Diseases 0.000 claims description 36
- 201000008100 vaginitis Diseases 0.000 claims description 36
- 241000224527 Trichomonas vaginalis Species 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 description 32
- 239000000463 material Substances 0.000 description 22
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 20
- 239000002775 capsule Substances 0.000 description 18
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 16
- 239000002702 enteric coating Substances 0.000 description 16
- 239000012055 enteric layer Substances 0.000 description 16
- 239000003085 diluting agent Substances 0.000 description 14
- 238000009505 enteric coating Methods 0.000 description 14
- 241000220479 Acacia Species 0.000 description 12
- ZPWVASYFFYYZEW-UHFFFAOYSA-L Dipotassium phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 12
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 12
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 235000019797 dipotassium phosphate Nutrition 0.000 description 12
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 12
- 239000008101 lactose Substances 0.000 description 12
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 12
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 12
- 230000028327 secretion Effects 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 210000002784 Stomach Anatomy 0.000 description 10
- 239000001913 cellulose Substances 0.000 description 10
- 229920002678 cellulose Polymers 0.000 description 10
- 239000008121 dextrose Substances 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 239000012530 fluid Substances 0.000 description 10
- 229920000159 gelatin Polymers 0.000 description 10
- 235000019322 gelatine Nutrition 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 230000000968 intestinal Effects 0.000 description 10
- 235000019359 magnesium stearate Nutrition 0.000 description 10
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 8
- 108010010803 Gelatin Proteins 0.000 description 8
- 229940014259 Gelatin Drugs 0.000 description 8
- 235000021355 Stearic acid Nutrition 0.000 description 8
- -1 acetic Chemical class 0.000 description 8
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000008273 gelatin Substances 0.000 description 8
- 235000011852 gelatine desserts Nutrition 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- 239000001963 growth media Substances 0.000 description 8
- 239000008117 stearic acid Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 230000001225 therapeutic Effects 0.000 description 8
- WNROFYMDJYEPJX-UHFFFAOYSA-K Aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 6
- 241000416162 Astragalus gummifer Species 0.000 description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 6
- ZQBAKBUEJOMQEX-UHFFFAOYSA-N Phenyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 ZQBAKBUEJOMQEX-UHFFFAOYSA-N 0.000 description 6
- 229920000175 Pistacia lentiscus Polymers 0.000 description 6
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 6
- 229920001615 Tragacanth Polymers 0.000 description 6
- 210000001215 Vagina Anatomy 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 6
- 125000004432 carbon atoms Chemical group C* 0.000 description 6
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 6
- 229910000397 disodium phosphate Inorganic materials 0.000 description 6
- 235000019800 disodium phosphate Nutrition 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000006011 modification reaction Methods 0.000 description 6
- KREXGRSOTUKPLX-UHFFFAOYSA-N octadecanoic acid;zinc Chemical compound [Zn].CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O KREXGRSOTUKPLX-UHFFFAOYSA-N 0.000 description 6
- 229960000969 phenyl salicylate Drugs 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000001488 sodium phosphate Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000005720 sucrose Substances 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- MIHADVKEHAFNPG-UHFFFAOYSA-N 2-Amino-5-nitrothiazole Chemical compound NC1=NC=C([N+]([O-])=O)S1 MIHADVKEHAFNPG-UHFFFAOYSA-N 0.000 description 4
- 229940018167 2-amino-5-nitrothiazole Drugs 0.000 description 4
- QUOZWMJFTQUXON-UXXRCYHCSA-N Androsin Natural products COC1=CC(C(C)=O)=CC=C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 QUOZWMJFTQUXON-UXXRCYHCSA-N 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N Citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- 210000004051 Gastric Juice Anatomy 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 229940060367 Inert Ingredients Drugs 0.000 description 4
- 206010061217 Infestation Diseases 0.000 description 4
- 210000002011 Intestinal Secretions Anatomy 0.000 description 4
- JKXJETCCPVNCSS-UHFFFAOYSA-N N-(5-nitro-1,3-thiazol-2-yl)propanamide Chemical compound CCC(=O)NC1=NC=C([N+]([O-])=O)S1 JKXJETCCPVNCSS-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- TYTYIUANSACAEM-UHFFFAOYSA-M silver;2,4,6-trinitrophenolate Chemical compound [Ag+].[O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O TYTYIUANSACAEM-UHFFFAOYSA-M 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000000699 topical Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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 4
- KANJSWOVFIVFDI-UHFFFAOYSA-N 2,6-diiodocyclohexa-2,5-diene-1,4-dione Chemical compound IC1=CC(=O)C=C(I)C1=O KANJSWOVFIVFDI-UHFFFAOYSA-N 0.000 description 2
- 206010001526 Air embolism Diseases 0.000 description 2
- PZZYQPZGQPZBDN-UHFFFAOYSA-N Aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- 208000002109 Argyria Diseases 0.000 description 2
- 241001554566 Argyria Species 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- NDYCDNOHJYRUBU-UHFFFAOYSA-N C(CCCCC)(=O)NC=1S(C=CN1)[N+](=O)[O-] Chemical compound C(CCCCC)(=O)NC=1S(C=CN1)[N+](=O)[O-] NDYCDNOHJYRUBU-UHFFFAOYSA-N 0.000 description 2
- 229920002301 Cellulose acetate Chemical class 0.000 description 2
- 229940107161 Cholesterol Drugs 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- UJRRDDHEMZLWFI-UHFFFAOYSA-N N-(5-nitro-1,3-thiazol-2-yl)acetamide Chemical compound CC(=O)NC1=NC=C([N+]([O-])=O)S1 UJRRDDHEMZLWFI-UHFFFAOYSA-N 0.000 description 2
- DZKKRHBAMGNRCD-UHFFFAOYSA-N N-(5-nitro-1,3-thiazol-2-yl)dodecanamide Chemical compound CCCCCCCCCCCC(=O)NC1=NC=C([N+]([O-])=O)S1 DZKKRHBAMGNRCD-UHFFFAOYSA-N 0.000 description 2
- YRLOBRGEGAIJJY-UHFFFAOYSA-N N-(5-nitro-1,3-thiazol-2-yl)hexanamide Chemical compound CCCCCC(=O)NC1=NC=C([N+]([O-])=O)S1 YRLOBRGEGAIJJY-UHFFFAOYSA-N 0.000 description 2
- 239000000020 Nitrocellulose Substances 0.000 description 2
- 229940096826 Phenylmercuric Acetate Drugs 0.000 description 2
- 229960002553 Phenylmercuric nitrate Drugs 0.000 description 2
- XEBWQGVWTUSTLN-UHFFFAOYSA-M Phenylmercury acetate Chemical compound CC(=O)O[Hg]C1=CC=CC=C1 XEBWQGVWTUSTLN-UHFFFAOYSA-M 0.000 description 2
- 208000010362 Protozoan Infections Diseases 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- 229920001800 Shellac Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N Stearyl alcohol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 229940116362 Tragacanth Drugs 0.000 description 2
- 241000224526 Trichomonas Species 0.000 description 2
- 229940093612 Zein Drugs 0.000 description 2
- 229920002494 Zein Polymers 0.000 description 2
- FJWGYAHXMCUOOM-QHOUIDNNSA-N [(2S,3R,4S,5R,6R)-2-[(2R,3R,4S,5R,6S)-4,5-dinitrooxy-2-(nitrooxymethyl)-6-[(2R,3R,4S,5R,6S)-4,5,6-trinitrooxy-2-(nitrooxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-3,5-dinitrooxy-6-(nitrooxymethyl)oxan-4-yl] nitrate Chemical class O([C@@H]1O[C@@H]([C@H]([C@H](O[N+]([O-])=O)[C@H]1O[N+]([O-])=O)O[C@H]1[C@@H]([C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@@H](CO[N+]([O-])=O)O1)O[N+]([O-])=O)CO[N+](=O)[O-])[C@@H]1[C@@H](CO[N+]([O-])=O)O[C@@H](O[N+]([O-])=O)[C@H](O[N+]([O-])=O)[C@H]1O[N+]([O-])=O FJWGYAHXMCUOOM-QHOUIDNNSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
- 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 description 2
- 230000002411 adverse Effects 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 235000013871 bee wax Nutrition 0.000 description 2
- 239000012166 beeswax Substances 0.000 description 2
- 229940092738 beeswax Drugs 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000004203 carnauba wax Substances 0.000 description 2
- 235000013869 carnauba wax Nutrition 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000007598 dipping method Methods 0.000 description 2
- 229940079593 drugs Drugs 0.000 description 2
- TUCNEACPLKLKNU-UHFFFAOYSA-N ethanone Chemical group C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000005908 glyceryl ester group Chemical group 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 230000002147 killing Effects 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000002609 media Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 239000000025 natural resin Substances 0.000 description 2
- 229920001220 nitrocellulos Polymers 0.000 description 2
- PDTFCHSETJBPTR-UHFFFAOYSA-N nitrooxy(phenyl)mercury Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 2
- 230000003000 nontoxic Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000005702 oxyalkylene group Chemical group 0.000 description 2
- 230000003071 parasitic Effects 0.000 description 2
- 230000036961 partial Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 125000005498 phthalate group Chemical class 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 2
- 229920001522 polyglycol ester Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002035 prolonged Effects 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- 230000001235 sensitizing Effects 0.000 description 2
- 239000004208 shellac Substances 0.000 description 2
- 235000013874 shellac Nutrition 0.000 description 2
- 229940113147 shellac Drugs 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000001187 sodium carbonate Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 230000003381 solubilizing Effects 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000012178 vegetable wax Substances 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 239000005019 zein Substances 0.000 description 2
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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
United States Patent ACYL AMINO-NITROTHIAZOLE COMPOSITIONS FOR ORAL ADMINISTRATION IN CONTROL OF TRICHOMONAS VAGINALIS VAGINITIS Alfred B. Kupferberg, Somerville, William C. Mende, Neshanic, Nathan Millman, Somerville, and Heron O. Singher, Plainfield, N. J., assignors to Ortho Pharmaceutical Corporation, a corporation of New Jersey No Drawing. Application October 21, 1952,
7 Serial No. 316,088
12 Claims. (Cl. 167-55) The present invention relates to a new and improved therapeutic tablet for the treatment of certain protozoan infections, and more particularly to a novel and highly effective pharmaceutical preparation designed for the treatment of Trichomonas vaginalis vaginitis.
Trichomonas vaginalis, a parasitic protozoon primarily infests the human vagina and is the ethological agent of a very troublesome and prevalent form of vaginal infestation known as Trichomonas vaginalis vaginitis.
Various medicaments and methods of treatment have heretofore been employed in the treatment of T richomonas vaginalis vaginitis, particularly by topical application to the vaginal mucosa, but all have been subjected to numerous limitations and disadvantages. Organic acids such as acetic, lactic, and citric acids are commonly used topically but are characterized by very low trichomonadicidal action, and in many instances they fail satisfactorily to clear up the infestation, even when the therapy is continued for long periods of time. Silver picrate, another agent in common topical use, has good trichomonadicidal properties but is objectionable for it frequently gives rise to severe sensitization's, argyria and the like, and also because it produces aesthetically inacceptable stains. Phenyl mercuric nitrate or acetate are active trichomonadicidal compounds, but are reported to be unstable except at a limited pH range (7.4 to 7.6) which diiiers considerably from the pH of a human vagina moderately or heavily infested with Trichomonas vaginalzr. Other preparations comprising various agents in powdered form such as boric acid, diiodoquinone, lactose, dextrose, and silver picrate, are commonly applied to an infested vagina by insufiiation. However, vaginal insufilation of pregnant women has been reported to result in air embolisms and death, and this method is now seriously criticized and infrequently used. For these and other reasons, a more satisfactory trichomonadicide has long been desired and in particular a trichomonadicide effective by oral administration has been desired.
The object of the present invention is to provide a new and improved therapeutic tablet for the treatment of Trichomonas vaginalis vaginitis, with a view to obviating the disadvantages of the medicaments and modes of treatment heretofore employed.
A more particular object is the provision of a therapeutic tablet characterized by high, trichomonadicidal power and capable of giving symptomatic relief to patients suffering from Trichomonas vaginalis vaginitis.
Still another object is the provision of a tablet which is free of adverse side reactions upon the patient and is characterized by a high degree of efiicacy in the treatment of Trichomonas vaginalis vaginitis.
Other objectsand advantages of the invention will become apparent as the description progresses.
The foregoing objectives may be attained in. accordance with the present invention which .is based on the discovery that therapeutic formulations in the form of tablets or capsules, or ent ris coated tablets or capsules 2,735,798 Patented Feb 21, 1956 "ice containing an acyl derivative of 2-amino-5-nitrothiazole as the active agent and an inert solid diluent have tri-.
chomonadicidal activity of a high order and upon oral administration result in prompt relief from the symptoms of Trichomonas vaginalis vaginitis and a high incidence of cures. Acyl derivatives of Z-amino-S-nitrothiazole are represented by the general formula in which R is an acyl radical. Acyl derivatives of Z-amino- 5-nitr0thiaz0le in which the acyl radical is acetyl, propinyl, butyrl, isobutyrl, caproyl, or lauroyl have been found particularly effective trichomonadicidal agents for use in the formulations of this invention.
The in vitro trichomonadicidal activity of acyl derivatives of Z-aminO-S-nitrothiazole has been established by a series of tests which established the minimal inhibitory concentration of these compounds. Minimal inhibitory concentration, as used above, is defined as the minimalconcentrationof a trichomonadicidal compound capable of preventing the growth of and killing Trichomonas vaginalis organisms introduced into a culture medium, capable alone of supporting a vigorous growth of the organisms, and containing the trichomonadicidal compound to be tested. The culture medium used in the tests is described in a publication of Kupferberg, Johnson and Sprince, Proceedings of the Society for Experimental Biology and Medicine, volume 67, pages 304-308, 1948.
in making the tests to determine minimal inhibitory concentrations, 0.05 ml. of a 48-hour culture of Trichomonus vaginalis was placed in a series of tubes containing 10 ml. of the culture medium and increasing amounts of' the compound to be tested. The inoculated culture medium was then incubated at 37 C. for nine days and ex- Minimal Inhibitory Concentration, gamma per cc.
Compound 2-amino-5-nitrothiazo1e 13.
2-aeetylamino-5-nitrothiazole.; 0 33-1. 20 2-propionylamino.-. 2. 30 2-butyr oylamino- 0 47-0. 94 2-eaproylamino 0. 93 2'iso-caproylamino 1; 2-lauroylamiuo 1. 10
In employing the trichomonadicides in the present invention for the treatment of T rich'omomzs vaginalis vaginitis, one or more of the active agents are uniformly dis tributed in a suitable vehicle that is chemically compatible with the particular trichomonadicide selected, formed into a tablet and in a specific embodiment of the invention, the tablet is coated or surrounded with an en'teric coating in the nature of a layer or film of material which is substantially soluble in or disintegrated and removed by intestinal secretions but substantially insoluble in gastric juices and secretions or disintegrated and removed thereby.
The minimal inhibitory concentration of the Inert diluents or fillersarechosen which arechemically compatible with the trichomonadicidal agent. Satisfactory diluents include lactose, dextrose, sucrose, sodium chloride, glycine, kaolin and starch. Itis desirable. that a binder such as acacia, zein, tragacanth, gelatin, sodium carboxymethylcellulose, or methyl cellulose and also, in order that a tablet maybe readily prepared, that a lubricant such as magnesium stearate, zinc stearate, mineral oil, stearic acid, stearyl alcohol or monoand polyglycol esters also be intimately admixed with the filler and active agent. The above ingredients including the trichomonadicidal material, may beformed into a tablet by thoroughly mixing the ingredients in a moist condition, granulating and compressing the mixture into tablets by conventional methods.
It is preferred that an alkaline material also be present in the'tablet formulation because the solubility of the acyl derivatives of 2-acetylamino-S-nitrothiazole is low at an acid 'pH but issubstantially increased'at an alkaline pH. 2-acetylan1ino-5-nitrothiazole has a solubility in water at pH 5.6 of about one part in 50,000 by weight, Whereas the solubility in water at pH 7.0 by weight is about ten times as great. The presence in the formulation of an alkaline agent assists in solubilizing the active agent. Satisfactory alkaline agents include aluminum hydroxide, disodium phosphate, dipotassium phosphate, sodium carbonate, sodium bicarbonate and alkaline or alkaline earth salts of glycine.
In the preferred modification of the invention, the tablet or capsule is coated or surrounded with a composition which is substantially soluble in or disintegrated by intestinal secretions but substantially insoluble in and not disintegrated'by the secretions of the stomach. The trichomonadicidal agents are more effective when administered in the form of an enteric or coated tablet or capsule and it is believed that this is due to the fact that the active ingredients are many times more soluble in an alkaline than in an acid medium. Because of the alkaline nature of intestinal fluids, the active ingredients are more readily solubilized and absorbed therein. There is also some possibility that the acyl group may be removed from the amino group of the active agents by prolonged contact with gastric juices by hydrolysis, and this would result in the conversion of the 2-acylamino-5-nitrothiazole into 2-amino-5-nitrothiazole which, has been demonstrated to have less in vitro trichomonadicidal activity than its acyl derivatives.
Any conventional enteric coating is suitable for use in coating-or surrounding the tablets or capsules of this invention. Examples of coatings which have been found satisfactory include acid-insoluble, alkali-soluble ion exchange resins, high-melting fats of both animal and vegetable origin, high-melting vegetable Waxes such as carnauba wax and bees wax, lipid materials such as glyceryl esters of fatty acids, esters of polyhydric compounds such as long chain fatty acidpartial esters of hexitol anhydrides and oxyalkylene derivatives of long'chain fatty acid partial esters of hexitol anhydrides; natural resins such as gum mastic, shellac, and rosin; fat-soluble compounds such as abietic a cid, bile acids and cholesterol; as well as cellulose derivatives such as cellulose nitrate, cellulose acetate, cellulose derivatives containing free carboxyl groups such as cellulose phthalate and cellulose acetate-phthalate, non-toxic water-soluble salts of polyvinyl phthalates and phenyl salicylate; or mixtures of any of the above compounds.
The enteric coatings may be formed into a capsule in which the active agents in association with an inert filler 1s contained. In general, a tablet may be coated by dipping directly into a solution of an enteric coating material capable of being put into solution in a suitable solvent. It is also contemplated that a powder or tablet containing the active agent in association with the inert ingredients may first be coated with or engaged in gelatin and then dipped into a solution in a suitable solvent of an enteric coating.materialsuszh.asfin OLUliQnfiL DsY, QQ LQ IQQ: ture of the cellulose derivatives listed above. The thick-- ness of the coating of the tablet or capsule may be controlled by varying the concentration of the solution of the ester in the solvent. A plurality of immersions to form a plurality of coatings may also be used. Certain enteric coating materials, such as cellulose'derivatives, are adapt-- ed to be formed into capsules composed of separate telescoping units into which the medicament may be placed and sealed therein by the application of a small amount of solution of the enteric coating material at the edge of' the telescoping segments. The enteric coating material may be, for example, about'five percent to ten per cent of the weight of thetablet or other form of the medica-- ment.
Acyl derivatives of Z-amino-S-nitrothiazole may be present in the formulations of the above examples in amounts ranging from 200 milligrams to 500 milligrams and be highly effective in the treatment of Trichomonas vaginalis vaginitis; however, it is preferred that about 300 milligrams of the trichomonadicidal agent be present.
In order to disclose more clearly the nature of the: present invention several specific examples will hereafter be described in considerable detail. It should be understood that they are presented solely for purposes of illustration and not with the object of either delineating the scope of the application or restricting the scope of the appended claims. The amounts in the examples are expressed in milligrams.
Example I Z-acetylamino-S-nitrothiazole 300 Dipotassium phosphate 50 Acacia 50 Magnesium stearate Lactose 70 Example I1 2-acetylamino-5-nitrothiazole 300 Dipotassium phosphate 50 Acacia 5O Magnesium stearate 3O Lactose 70 Cellulose acetate-phthalate 50 Example III 2-propionylamino-5-nitrothiazole 350 Disodium phosphate 50 Gum tragacanth 50 Stearic acid Dextrose 75 Example IV 2-propionylamino-5-nitrothiazole 350 Disodium phosphate 50 Gum tragacanth 50 Stearic acid 35 Dextrose 75 Phenylsalicylate Example V 2-caproylamino-S-nitrothiazole 400 Aluminum hydroxide Gelatin Zinc stearate 30 Sucrose Example VI 2-caproylamino-5-nitrothiazole 400 Aluminum hydroxide 45 Gelatin 55 Zinc stearate 30 Sucrose 70 Gum mastic 55 Example VII 2-lauroylamino-5-nitrothiazole 425 Dipotassium phosphate 50 Acacia 50 Stearic acid 35 Dextrose 65 Example VIII It will be apparent to those skilled in the art that numerous variations, modifications, and extensions of the principles involved may be made without departing from the spirit and scope of the invention. Thus, for example, the inert ingredients and enteric coating materials employed in the various examples are merely illustrative and it will be apparent that many others may be used in place of those illustrated in the examples. Likewise, acyl derivatives of Z-amino-S-nitrothiazole other than those specifically mentioned may be used either singly or in combination. All such variations, modifications, and extensions are to be understood as included within the ambit of the appended claims.
What is claimed is:
1. A composition of matter in dosage unit form for oral administration effective in the control of Trichomonas vaginalis vaginitis which comprises a compound of the formula in which R is an acyl radical in intimate admixture with an inert solid diluent and surrounded by an enteric layer of substance which is substantially insoluble in acid stomach secretions and soluble in alkaline intestinal fluids. 2. A composition of matter in dosage unit form for oral administration effective in the control of Trichomonas vaginalis vaginitis which comprises a compound of the formula H-0-N ll lg NOr-C NHR in which R is an acyl radical having not more than ten carbon atoms in intimate admixture with an inert solid diluent and surrounded by an enteric layer of a substance which is substantially insoluble in acid stomach secretions and soluble in alkaline intestinal fluids.
3. A composition according to claim 2 in which R is an acetyl radical.
4. A composition of matter in the form of a tablet for oral administration which is effective in the control of Trichomonas vaginalis vaginitis which comprises a compound of the formula in which R is an acyl radical having not more than ten carbon atoms in intimate admixture with an inert solid diluent, a binder, an alkaline material, and a lubricant.
5. A composition of matter in the form of a tablet for oral administration which is effective in the control of Trichomonas vaginalis vaginitis which comprises a compound of the formula HCN LE ll NOz- C-NHR in which R is an acyl radical having not more than ten carbon atoms in intimate admixture with an inert solid diluent, a binder, an alkaline material, and a lubricant; and surrounded by an enteric layer of a substance which is substantially insoluble in acid stomach secretions and soluble in alkaline intestinal fluids.
6. A composition according to claim 5 in which the enteric layer is composed of cellulose acetatephthalate.
7. A composition according to claim 5 in which the enteric layer is composed of phenyl salicylate.
8. A composition according to claim 5 in which the enteric layer is composed of gum mastic.
9. A composition of matter in the form of a tablet for oral administration which is eflective in the control of T richomonas vaginalis vaginitis comprising Z-acetylamino-S-nitrothiazole intimately admixed with lactose, acacia, magnesium stearate and dipotassium phosphate.
10. A composition of matter in the form of a tablet for oral administration which is effective in the control of Trichomonas vaginalis vaginitis comprising Z-acetylamino-S-nitrothiazole intimately admixed with lactose, acacia, magnesium stearate, and dipotassium phosphate; and surrounded by an enteric layer of a substance which is substantially insoluble in acid stomach secretions and soluble in alkaline intestinal fluids.
11. A composition according to claim 10 in which the enteric layer is composed of cellulose acetate-phthalate.
12. A composition of matter in dosage unit form for oral administration effective in the control of Trichomonas vaginalis vaginitis which comprises the compound of the formula:
HCN Nor-il (PF-NEH.
in which R is an acyl radical, in intimate admixture with an inert solid diluent and sealed in a gelatine capsule.
References Cited in the file of this patent UNITED STATES PATENTS 2,531,756 Waletsky NOV. 28, 1950
Claims (1)
1. A COMPOSITION OF MATTER IN DOSAGE UNIT FORM FOR ORAL ADMINISTRATION EFFECTIVE IN THE CONTROL OF TRICHOMONAS VAGINALIS VAGINITIS WHICH COMPRISES A COMPOUND OF THE FORMULA
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| Publication Number | Publication Date |
|---|---|
| US2735798A true US2735798A (en) | 1956-02-21 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US2735798D Expired - Lifetime US2735798A (en) | Acyl amevo-nitrothiazole compositions |
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| Country | Link |
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| US (1) | US2735798A (en) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2857313A (en) * | 1956-03-27 | 1958-10-21 | Ciba Pharm Prod Inc | Self-lubricating granulation |
| US2877159A (en) * | 1957-04-26 | 1959-03-10 | Ciba Pharm Prod Inc | Method for preparing tablet granulations |
| DE1136705B (en) * | 1959-02-20 | 1962-09-20 | Wallace & Tiernan Inc | Process for the preparation of 2- (4'-acetylpiperazino) -5-nitrothiazole |
| US3124588A (en) * | 1964-03-10 | Z-acylamtoo-s-nitrothiazole | ||
| US3124507A (en) * | 1964-03-10 | Antimicrobial compositions comprising | ||
| US3156699A (en) * | 1960-04-20 | 1964-11-10 | Ortho Pharma Corp | Nu-(5-nitro-thiazolyl-2) 2, 4-dinitropyrrole-1-acetamide |
| US3496187A (en) * | 1967-03-20 | 1970-02-17 | American Home Prod | N-(heterocyclyl)aconamides |
| US3515538A (en) * | 1965-08-11 | 1970-06-02 | Mitsui Koatsu Chem Inc | 2-acylamino-4-methyl-5-halothiazoles as selective herbicides |
| US3950351A (en) * | 1973-08-08 | 1976-04-13 | S.P.R.L. Phavic | New derivatives of 2-benzamido-5-nitro thiazoles |
| US5387598A (en) * | 1994-04-13 | 1995-02-07 | Rossignol; Jean-Francois | Composition and galenic formulation suitable for combatting affections of the lower abdomen |
| US20120010187A1 (en) * | 2009-03-20 | 2012-01-12 | University Of Virginia Patent Foundation | Broad spectrum benzothiophene-nitrothiazolide and other antimicrobials |
| US9333193B2 (en) | 2010-09-20 | 2016-05-10 | University Of Virginia Patent Foundation | Compositions and methods for treating tuberculosis |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2531756A (en) * | 1949-07-02 | 1950-11-28 | American Cyanamid Co | Turkey blackhead control composition |
-
0
- US US2735798D patent/US2735798A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2531756A (en) * | 1949-07-02 | 1950-11-28 | American Cyanamid Co | Turkey blackhead control composition |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3124588A (en) * | 1964-03-10 | Z-acylamtoo-s-nitrothiazole | ||
| US3124507A (en) * | 1964-03-10 | Antimicrobial compositions comprising | ||
| US2857313A (en) * | 1956-03-27 | 1958-10-21 | Ciba Pharm Prod Inc | Self-lubricating granulation |
| US2877159A (en) * | 1957-04-26 | 1959-03-10 | Ciba Pharm Prod Inc | Method for preparing tablet granulations |
| DE1136705B (en) * | 1959-02-20 | 1962-09-20 | Wallace & Tiernan Inc | Process for the preparation of 2- (4'-acetylpiperazino) -5-nitrothiazole |
| US3156699A (en) * | 1960-04-20 | 1964-11-10 | Ortho Pharma Corp | Nu-(5-nitro-thiazolyl-2) 2, 4-dinitropyrrole-1-acetamide |
| US3515538A (en) * | 1965-08-11 | 1970-06-02 | Mitsui Koatsu Chem Inc | 2-acylamino-4-methyl-5-halothiazoles as selective herbicides |
| US3496187A (en) * | 1967-03-20 | 1970-02-17 | American Home Prod | N-(heterocyclyl)aconamides |
| US3950351A (en) * | 1973-08-08 | 1976-04-13 | S.P.R.L. Phavic | New derivatives of 2-benzamido-5-nitro thiazoles |
| US5387598A (en) * | 1994-04-13 | 1995-02-07 | Rossignol; Jean-Francois | Composition and galenic formulation suitable for combatting affections of the lower abdomen |
| US20120010187A1 (en) * | 2009-03-20 | 2012-01-12 | University Of Virginia Patent Foundation | Broad spectrum benzothiophene-nitrothiazolide and other antimicrobials |
| US8835644B2 (en) * | 2009-03-20 | 2014-09-16 | University Of Virginia Patent Foundation | Broad spectrum benzothiophene-nitrothiazolide and other antimicrobials |
| US9376430B2 (en) | 2009-03-20 | 2016-06-28 | University Of Virginia Patent Foundation | Broad spectrum benzothiophene-nitrothiazolide and other antimicrobials |
| US9333193B2 (en) | 2010-09-20 | 2016-05-10 | University Of Virginia Patent Foundation | Compositions and methods for treating tuberculosis |
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