NO870839L - MATERIAL FOR DISINFINING THE VAGINA MASK AND OTHER LOW PH. - Google Patents
MATERIAL FOR DISINFINING THE VAGINA MASK AND OTHER LOW PH. Download PDFInfo
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- NO870839L NO870839L NO870839A NO870839A NO870839L NO 870839 L NO870839 L NO 870839L NO 870839 A NO870839 A NO 870839A NO 870839 A NO870839 A NO 870839A NO 870839 L NO870839 L NO 870839L
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- chlorhexidine
- tris
- salt
- vagina
- buffered
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- 239000000463 material Substances 0.000 title claims description 20
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 claims description 62
- 229960003260 chlorhexidine Drugs 0.000 claims description 46
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 29
- 239000007983 Tris buffer Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 16
- WDRFFJWBUDTUCA-UHFFFAOYSA-N chlorhexidine acetate Chemical compound CC(O)=O.CC(O)=O.C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 WDRFFJWBUDTUCA-UHFFFAOYSA-N 0.000 claims description 9
- 229960001884 chlorhexidine diacetate Drugs 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 210000004400 mucous membrane Anatomy 0.000 claims description 7
- 230000000249 desinfective effect Effects 0.000 claims description 6
- 210000004877 mucosa Anatomy 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000006071 cream Substances 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- QDCORQHOROFMIA-UHFFFAOYSA-N 2-[n'-[6-[[amino-(diaminomethylideneamino)methylidene]amino]hexyl]carbamimidoyl]-1,3-bis(2-chlorophenyl)guanidine Chemical compound C=1C=CC=C(Cl)C=1NC(=NC(N)=NCCCCCCN=C(N)N=C(N)N)NC1=CC=CC=C1Cl QDCORQHOROFMIA-UHFFFAOYSA-N 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 210000004379 membrane Anatomy 0.000 claims description 2
- 239000012528 membrane Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000000003 vaginal tablet Substances 0.000 claims description 2
- 229940044977 vaginal tablet Drugs 0.000 claims description 2
- KCVBGCILISJEDN-UHFFFAOYSA-N 2-[amino-[6-[[amino-(diaminomethylideneamino)methyl]amino]hexylamino]methyl]-1,3-bis(4-chlorophenyl)guanidine Chemical compound C=1C=C(Cl)C=CC=1NC(=NC(N)NCCCCCCNC(N)N=C(N)N)NC1=CC=C(Cl)C=C1 KCVBGCILISJEDN-UHFFFAOYSA-N 0.000 claims 1
- WJLVQTJZDCGNJN-UHFFFAOYSA-N Chlorhexidine hydrochloride Chemical compound Cl.Cl.C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 WJLVQTJZDCGNJN-UHFFFAOYSA-N 0.000 claims 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims 1
- 229960004504 chlorhexidine hydrochloride Drugs 0.000 claims 1
- FBWNMEQMRUMQSO-UHFFFAOYSA-N tergitol NP-9 Chemical compound CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 FBWNMEQMRUMQSO-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 229920004918 nonoxynol-9 Polymers 0.000 description 12
- 229940087419 nonoxynol-9 Drugs 0.000 description 12
- 210000001215 vagina Anatomy 0.000 description 11
- 238000005406 washing Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- -1 Gibitan Chemical compound 0.000 description 6
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000000845 anti-microbial effect Effects 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 229960000281 trometamol Drugs 0.000 description 4
- 239000000872 buffer Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- RARSHUDCJQSEFJ-UHFFFAOYSA-N p-Hydroxypropiophenone Chemical compound CCC(=O)C1=CC=C(O)C=C1 RARSHUDCJQSEFJ-UHFFFAOYSA-N 0.000 description 3
- 239000013049 sediment Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- IEORSVTYLWZQJQ-UHFFFAOYSA-N 2-(2-nonylphenoxy)ethanol Chemical compound CCCCCCCCCC1=CC=CC=C1OCCO IEORSVTYLWZQJQ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000035606 childbirth Effects 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000644 isotonic solution Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 229920000847 nonoxynol Polymers 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- GJWZTZWDFBKFHI-UHFFFAOYSA-N 2-[n'-[6-[[amino-(diaminomethylideneamino)methylidene]amino]hexyl]carbamimidoyl]-1,3-bis(4-chlorophenyl)guanidine Chemical compound C=1C=C(Cl)C=CC=1N=C(NC(=N)NCCCCCCNC(=N)NC(=N)N)NC1=CC=C(Cl)C=C1 GJWZTZWDFBKFHI-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920000153 Povidone-iodine Polymers 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006161 blood agar Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960002152 chlorhexidine acetate Drugs 0.000 description 1
- 229960003333 chlorhexidine gluconate Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- GSGDTSDELPUTKU-UHFFFAOYSA-N nonoxybenzene Chemical compound CCCCCCCCCOC1=CC=CC=C1 GSGDTSDELPUTKU-UHFFFAOYSA-N 0.000 description 1
- 230000009984 peri-natal effect Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229960001621 povidone-iodine Drugs 0.000 description 1
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 239000007078 todd-hewitt medium Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Den foreliggende oppfinnelse vedrører et materiale til desinfisering av vaginaslimhinnen og andre slimhinner med lav pH, samt anvendelse av materialet. The present invention relates to a material for disinfecting the vaginal mucosa and other mucous membranes with a low pH, as well as the use of the material.
Klorheksidin-løsninger anvendes mye for desinfisering av vagina før operasjon og fødsel. Likevel er dokumentasjonen ved-rørende anvendelsen av klorheksidin i vagina meget sparsom (1-6), Chlorhexidine solutions are widely used for disinfecting the vagina before surgery and childbirth. Nevertheless, the documentation regarding the use of chlorhexidine in the vagina is very sparse (1-6),
i motsetning til andre anvendelser av klorheksidin.unlike other uses of chlorhexidine.
Klorheksidin ble utviklet på 1950-tallet og har siden vist seg effektivt som et et desinfiseringsmiddel for hud og slimhinner. Det er blitt utført et studium vedrørende muligheten for å hemme streptokokker av gruppe B (GBS) i vagina ved vasking av vagina med klorheksidin. GBS er bakterier som forårsaker infek-sjoner hos mor og barn i forbindelse med graviditet og fødsel. Chlorhexidine was developed in the 1950s and has since proven effective as a disinfectant for skin and mucous membranes. A study has been carried out regarding the possibility of inhibiting group B streptococci (GBS) in the vagina by washing the vagina with chlorhexidine. GBS are bacteria that cause infections in mother and child in connection with pregnancy and childbirth.
Ved forsøk in vitro har det vist seg at avlivningskinetikken for GBS er avhengig av klorheksidinkonsentrasjonen og av tiden hvor midlet er i kontakt med GBS. F.eks. var det nødvendig med 7 In experiments in vitro, it has been shown that the killing kinetics for GBS is dependent on the chlorhexidine concentration and the time during which the agent is in contact with GBS. E.g. 7 was necessary
timers påvirkning ved en konsentrasjon på 63 mg klorheksidin/1, mens det bare var nødvendig med én time ved 500 mg/l (1). hours of exposure at a concentration of 63 mg chlorhexidine/1, while only one hour was required at 500 mg/l (1).
Ved forsøk in vivo har det vist seg at det var nødvendigIn vivo experiments have shown that it was necessary
med minst 1 times kontakt mellom slimhinnen og klorheksidin for å hemme veksten av GBS i vagina (2). Når klorheksidin anvendes før operasjon eller f.eks. før innføring av et apparat i livmoren startes operasjonen eller anvendelsen umiddelbart etter klor-heksidinvaskingen. Det er derfor klart at klorheksidin er uten virkning i disse situasjoner. with at least 1 hour of contact between the mucosa and chlorhexidine to inhibit the growth of GBS in the vagina (2). When chlorhexidine is used before surgery or e.g. before introducing a device into the uterus, the operation or application is started immediately after the chlorhexidine wash. It is therefore clear that chlorhexidine is ineffective in these situations.
Det er blitt påvist at klorheksidin er ca. 100 ganger mindre effektivt ved pH 5 enn ved pH 7 (7). pH i vagina hos friske, ikke-gravide kvinner i kjønnsmoden alder ligger som regel mellom 3 og 4. Under graviditet er pH litt høyere (se nedenfor). Dessuten er bufferkapasiteten til klorheksidinløsninger som for tiden er på markedet meget lav (7). It has been demonstrated that chlorhexidine is approx. 100 times less effective at pH 5 than at pH 7 (7). The pH in the vagina of healthy, non-pregnant women of sexually mature age is usually between 3 and 4. During pregnancy, the pH is slightly higher (see below). In addition, the buffering capacity of chlorhexidine solutions currently on the market is very low (7).
For å undersøke virkningen av en ikke-bufret klorheksidin-løsning på pH i vagina ble pH i vaginaslimhinnen hos gravide kvinner bestemt før og etter vasking av vagina med klorheksidindiacetat, 2 g/l, i forbindelse med en klinisk undersøkelse hvor vaskingen ble utført slik som beskrevet ovenfor (2). Resultatene var: To investigate the effect of a non-buffered chlorhexidine solution on pH in the vagina, the pH in the vaginal mucosa of pregnant women was determined before and after washing the vagina with chlorhexidine diacetate, 2 g/l, in connection with a clinical examination where the washing was carried out as described above (2). The results were:
Ingen statistisk vesentlige forskjeller (student's t-test) ble påvist mellom pH-verdiene før, umiddelbart etter og 30 min. etter vasking. Konklusjonen var at pH-verdiene ikke forandret seg ved anvendelse av den tilgjengelige klorheksidinløsning. Det skal No statistically significant differences (student's t-test) were detected between the pH values before, immediately after and 30 min. after washing. The conclusion was that the pH values did not change when using the available chlorhexidine solution. It shall
også bemerkes at pH-verdien hos friske, ikke-gravide kvinner i kjønnsmoden alder er enda lavere. Virkningen av klorheksidindiacetat på pH i vagina hos 10 slike kvinner ble også undersøkt. Alle pH-verdiene var under 5 umiddelbart etter vasking. it is also noted that the pH value in healthy, non-pregnant women of sexually mature age is even lower. The effect of chlorhexidine diacetate on vaginal pH in 10 such women was also investigated. All pH values were below 5 immediately after washing.
Det har overraskende vist seg at en blanding av klorheksidin og en buffer vil gi en bedre kapasitet når det gjelder å hemme og utrydde mikroorganismer i vagina sammenlignet med klor-heksidinløsninger som for tiden er tilgjengelige. It has surprisingly been shown that a mixture of chlorhexidine and a buffer will provide a better capacity when it comes to inhibiting and eradicating microorganisms in the vagina compared to chlorhexidine solutions currently available.
Oppfinnelsen vedrører således et materiale til desinfisering av vaginaslimhinnen og andre slimhinner med lav pH, og materialet er kjennetegnet ved at det omfatter et salt av klorheksidin (N,N"-bis-(klorfenyl)-3,12-diimino-2,4,11,13-tetraazatetradekandiimidamid) og en etoksylert alkylfenol, idet materialet er bufret til en pH på minst 7. The invention thus relates to a material for disinfecting the vaginal mucosa and other mucous membranes with a low pH, and the material is characterized by the fact that it comprises a salt of chlorhexidine (N,N"-bis-(chlorophenyl)-3,12-diimino-2,4, 11,13-tetraazatetradecandiimidamide) and an ethoxylated alkylphenol, the material being buffered to a pH of at least 7.
Klorheksidin anvendes som et salt, f.eks. acetat, hydro-klorid eller glukonat av klorheksidin. Synonymer til klorheksidin er: (N,N"-bis-(4-klorfenyl)-3,12-diimino-2,4,11,13-tetraazatetradekandiimidamid, 1,1'-heksametylenbis|5-(p-klorfenyl)biguanid|, 1,6-bis-(N<5->p-klorfenyl-N'-diguanido)-heksan, 1,6-di(4 *-klor-fenyldiguanido)-heksan, (Hibitane, Nolvasan, Rotersept, Sterilon, Hibiscrub, Hibisol, Clorhexamed, Corsodyl, Gibitan, Soretol, Clorohex, Fimeil, Hexadol, Tubulicid, Disteryl, Abacil, Septeal). Chlorhexidine is used as a salt, e.g. acetate, hydrochloride or gluconate of chlorhexidine. Synonyms of chlorhexidine are: (N,N"-bis-(4-chlorophenyl)-3,12-diimino-2,4,11,13-tetraazatetradecanediimidamide, 1,1'-hexamethylenebis|5-(p-chlorophenyl)biguanide |, 1,6-bis-(N<5->p-chlorophenyl-N'-diguanido)-hexane, 1,6-di(4 *-chloro-phenyldiguanido)-hexane, (Hibitane, Nolvasan, Rotersept, Sterilon , Hibiscrub, Hibisol, Chlorhexamed, Corsodyl, Gibitan, Soretol, Clorohex, Fimeil, Hexadol, Tubulicid, Disteryl, Abacil, Septeal).
Materialet ifølge oppfinnelsen er fortrinnsvis bufret med en TRIS-buffer. Synonymer til TRIS-buffer er: Trometamine (2-amino-2-hydroksymetyl-l,3-propandiol), trimetylol-aminometan, TRIS (hydroksymetyl)aminometan, trisamin, aminotris (hydroksometyl)metan, metanamin, aminotrimetylolmetan, tris(hy-droksymetyl )metanamin , tris-buffer, trometamol, Tromethane, THAM, TRIS, Talatrol, Tham-E, Tris Amino, Tris-steril, Trizma, Peha-norm, Tutofusin tris, Addex-Tham, Trisaminol, Triladye). For å stabilisere materialet tilsettes det en etoksylert alkylfenol. Et eksempel på etoksylerte alkylfenoler er nonoksynol-9 som har formelen The material according to the invention is preferably buffered with a TRIS buffer. Synonyms for TRIS buffer are: Tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol), trimethylol-aminomethane, TRIS (hydroxymethyl)aminomethane, trisamine, aminotris (hydroxomethyl)methane, methanamine, aminotrimethylolmethane, tris(hy- droxymethyl )methanamine , tris-buffer, trometamol, Tromethane, THAM, TRIS, Talatrol, Tham-E, Tris Amino, Tris-steril, Trizma, Peha-norm, Tutofusin tris, Addex-Tham, Trisaminol, Triladye). To stabilize the material, an ethoxylated alkylphenol is added. An example of ethoxylated alkylphenols is nonoxynol-9 which has the formula
hvor n er antallet etylenoksid (EO) grupper, som varierer fra 5 til 18 med et gjennomsnitt på 9. where n is the number of ethylene oxide (EO) groups, which varies from 5 to 18 with an average of 9.
Synonymer til nonoksynol-9 er:Synonyms for nonoxynol-9 are:
Etylenglykolnonylfenyleter, nonylfenoksypolyetoksyetanol, nonylfenoksypolyetoksyetanol, PEG nonylfenyleter, polyetylenglykolno-nylfenyleter, poly(etylenglykol)-p-nonylfenyleter, polyoksyety-lennonylfenyleter, nonylfenylpolyetylenglykoleter, p-nonylfenyl-poly(oksyetylen)eter, nonylfenoksypoly(etylenoksy)etanol, nonyl-fenoletoksylat. Ethylene glycol nonylphenyl ether, nonylphenoxypolyethoxyethanol, nonylphenoxypolyethoxyethanol, PEG nonylphenylether, polyethyleneglycolnonylphenylether, poly(ethyleneglycol)-p-nonylphenylether, polyoxyethylenenonylphenylether, nonylphenylpolyethyleneglycolether, p-nonylphenyl-poly(oxyethylene)ether, nonylphenoxypoly(ethyleneoxy)ethanol, nonylphenolethoxylate.
Alle den ovennevnte forbindeler er kjente.All of the above compounds are known.
Toksikologien for klorheksidin, TRIS og dietoksylerte alkylfenoler (særlig nonoksynol-9) er blitt grundig undersøkt, og det er velkjent at forbindelsene er meget lite toksiske. The toxicology of chlorhexidine, TRIS and diethoxylated alkylphenols (especially nonoxynol-9) has been thoroughly investigated, and it is well known that the compounds are very little toxic.
Materialet kan foreligge som en vandig løsning eller i form av en vaginaltablett, -pulver, -krem eller -salve. Fortrinnsvis er materialet en vandig løsning som inneholder 0,1-20 g/l av saltet av klorheksidin, 1-40 g/l av den etoksylerte alkylfenol og som er bufret med 0,01-1 M TRIS-buffer til en pH på minst 7. The material can be available as an aqueous solution or in the form of a vaginal tablet, powder, cream or ointment. Preferably, the material is an aqueous solution containing 0.1-20 g/l of the salt of chlorhexidine, 1-40 g/l of the ethoxylated alkylphenol and which is buffered with 0.01-1 M TRIS buffer to a pH of at least 7.
I en annen foretrukket utførelse er ionekonsentrasjonen ekvivalent med en løsning av natriumklorid på høyst 0,1%. In another preferred embodiment, the ion concentration is equivalent to a solution of sodium chloride of at most 0.1%.
Når materialet er i form av en tablett, et pulver, en krem eller en salve er konsentrasjonen av bestanddelen: 0,1-20 g/kg av klorheksidinsaltet, 1-40 g/kg av den etoksylerte alkylfenol og 0,01 M TRIS-buffer. When the material is in the form of a tablet, powder, cream or ointment, the concentration of the ingredient is: 0.1-20 g/kg of the chlorhexidine salt, 1-40 g/kg of the ethoxylated alkylphenol and 0.01 M TRIS- buffer.
Oppfinnelsen vedrører også en fremgangmsåte til desinfisering av vagina eller andre slimhinner, hvorved disse slimhinner bringes i kontakt med et materiale som omfatter et salt av klorheksidin og en etoksylert alkylfenol, og som er bufret til en pH på minst 7 . The invention also relates to a method for disinfecting the vagina or other mucous membranes, whereby these mucous membranes are brought into contact with a material comprising a salt of chlorhexidine and an ethoxylated alkylphenol, and which is buffered to a pH of at least 7.
Den medfølgende tegning viser et diagram av virkningen av tilsetning av TRIS-buffer til klorheksidin ved avliving av streptokokker av gruppe B suspendert i en løsning med pH 5. The accompanying drawing shows a diagram of the effect of adding TRIS buffer to chlorhexidine in killing group B streptococci suspended in a pH 5 solution.
ForenlighetsforsøkCompatibility test
Forenligheten mellom et klorheksidinsalt og forskjellige buffere er blitt undersøkt. I en serie gjentatte forsøk ble klor-heksidinglukonat, 10 g/l og 1 g/l, samt klorheksidinacetat, 2 g/l og 0,1 g/l blandet med buffersubstanser i konsentrasjoner på 1, 0,1 eller 0,01 M. Løsningenes pH var 7,5. Etter en time ved 22°C ble blandingene inspisert med det blotte øye angående sedimen-tering. The compatibility between a chlorhexidine salt and various buffers has been investigated. In a series of repeated experiments, chlorhexidine gluconate, 10 g/l and 1 g/l, as well as chlorhexidine acetate, 2 g/l and 0.1 g/l were mixed with buffer substances in concentrations of 1, 0.1 or 0.01 M The pH of the solutions was 7.5. After one hour at 22°C, the mixtures were visually inspected for sedimentation.
Som det fremgår forårsaket TRIS ingen dannelse av sediment sammen med et salt av klorheksidin i dette forsøk. As can be seen, TRIS caused no formation of sediment together with a salt of chlorhexidine in this experiment.
Ved andre forenlighetsforsøk ble blandinger av et klorheksidinsalt og TRIS i de ovennevnte konsentrasjoner plassert alternerende ved -15°C og +45°C i et tidsrom på 12 timer ved hver temperatur. Allerede etter en fryseperiode ble et hvitt sediment synlig for det blotte øye. In other compatibility tests, mixtures of a chlorhexidine salt and TRIS in the above concentrations were placed alternately at -15°C and +45°C for a period of 12 hours at each temperature. Already after a period of freezing, a white sediment became visible to the naked eye.
StabilitetstesterStability tests
I andre forsøk ble et salt av klorheksidin, TRIS-buffer og etoksylert alkylfenol, representert ved nonoksynol-9, blandet under anvendelse av følgende konsentrasjon av forbindelsene: A. Klorheksidindiglukonat 20 g/l og 10 g/l eller klorheksidindiacetat 5 g/l, 2 g/l, 1 g/l og 0,1 g/l. In other experiments, a salt of chlorhexidine, TRIS buffer and ethoxylated alkylphenol, represented by nonoxynol-9, was mixed using the following concentration of the compounds: A. Chlorhexidine digluconate 20 g/l and 10 g/l or chlorhexidine diacetate 5 g/l, 2 g/l, 1 g/l and 0.1 g/l.
B. TRIS-buffer 1 M, 0,1 M, 0,05 M og 0,01 M.B. TRIS buffer 1 M, 0.1 M, 0.05 M and 0.01 M.
C. Nonoksynol-9 40 g/l, 20 g/l, 10 g/l, 5 g/l, 2 g/l og 1 C. Nonoxynol-9 40 g/l, 20 g/l, 10 g/l, 5 g/l, 2 g/l and 1
g/l. g/l.
Løsningenes pH ble regulert til 8,0 med 1 M eddiksyre. The pH of the solutions was adjusted to 8.0 with 1 M acetic acid.
Klorheksidins kjemiske stabilitet ble undersøkt ved gasskromato-grafisk analyse ved ekstraksjon og avledning som beskrevet i re-feranse nr. 9. Ingen kjemisk forandring av klorheksidinmolekylet ble iakttatt. I forsøk med varierende temperaturer slik som beskrevet ble det iakttatt hvite sedimenter i alle løsninger med The chemical stability of chlorhexidine was investigated by gas chromatographic analysis by extraction and derivation as described in reference no. 9. No chemical change of the chlorhexidine molecule was observed. In experiments with varying temperatures as described, white sediments were observed in all solutions with
nonoksynol-9-konsentrasjon på under 5 g/l, noe som beviser at nærværet av en etoksylert alkylfenol gjør materialet mer stabilt. nonoxynol-9 concentration below 5 g/l, proving that the presence of an ethoxylated alkylphenol makes the material more stable.
Antimikrobiell testAntimicrobial test
Den antimikrobielle virkning av blandinger av et salt av klorheksidin og TRIS ble studert in vitro. Kulturer av 10 forskjellige bakteriestammer av Staphylococcus aureus, 10 forskjellige Escherishia coli og 10 GBS, alle stammer isolert fra vagina hos kvinner, ble fremstilt ved inpoding av stammene i 18 timer ved 37°C på Todd Hewitt medium. pH ble deretter regulert til 5,0 i alle medier under anvendelse av 1 M eddiksyre. The antimicrobial action of mixtures of a salt of chlorhexidine and TRIS was studied in vitro. Cultures of 10 different bacterial strains of Staphylococcus aureus, 10 different Escherichia coli and 10 GBS, all strains isolated from female vaginas, were prepared by inoculating the strains for 18 hours at 37°C on Todd Hewitt medium. The pH was then adjusted to 5.0 in all media using 1 M acetic acid.
Klorheksidindiglukonat 10 g/l eller klorheksidindiacetat 5 g/l, 2 g/l, 1 g/l eller 0,0 g/l ble blandet med TRIS-buffer IM, 0,1 M, 0,05 M eller 0,01 M. Serier av dobbelte fortynninger av hver blanding ble fremstil i sterilt, destillert vann. 1 ml av hvert klorheksidinpreparat ble deretter blandet med 1 ml av hver av de ovenfor beskrevne baktriekulturer. Med forskjellige inter-valler etter blanding ble 2 ul av hver suspensjon strøket på en konvensjonell blodagar plate, som deretter ble inkubert ved 3 7°C i 4 8 timer. Platene ble inspisert for opptreden av bakteriekolo-nier. I alle tilfeller kunne løsningene som inneholdt TRIS-buffer tynnes mer en løsningen som innehold de samme konsentrasjoner av bare klorheksidinsaltet, og likevel avlive bakteriene hurtigere. Chlorhexidine digluconate 10 g/l or chlorhexidine diacetate 5 g/l, 2 g/l, 1 g/l or 0.0 g/l was mixed with TRIS buffer IM, 0.1 M, 0.05 M or 0.01 M Serial two-fold dilutions of each mixture were prepared in sterile distilled water. 1 ml of each chlorhexidine preparation was then mixed with 1 ml of each of the bacterial cultures described above. At different intervals after mixing, 2 µl of each suspension was streaked onto a conventional blood agar plate, which was then incubated at 37°C for 48 hours. The plates were inspected for the appearance of bacterial colonies. In all cases, the solutions containing TRIS buffer could be diluted more than the solution containing the same concentrations of only the chlorhexidine salt, and still kill the bacteria more quickly.
Figuren viser et slik eksempel med en GBS-stamme. Den opp-rinnelige konsentrasjon av klorheksidindiglukonat var 10 g/l i dette forsøk med en tilsetning av 0,01 M TRIS. Med fortynningene som tilsvarte klorheksidinkonsentrasjoner på 0,5 g/1-15 mg/l ble det oppnådd en mye hurtigere avliving ved nærvær av TRIS. Det kan også utledes av figuren at den såkalte minimale baktericidkonsen-trasjon for klorheksidin falt fra 0,125 g/l til 0,031 g/l i dette eksempel. The figure shows such an example with a GBS strain. The initial concentration of chlorhexidine digluconate was 10 g/l in this experiment with the addition of 0.01 M TRIS. With the dilutions corresponding to chlorhexidine concentrations of 0.5 g/1-15 mg/l, a much faster killing was achieved in the presence of TRIS. It can also be deduced from the figure that the so-called minimum bactericide concentration for chlorhexidine fell from 0.125 g/l to 0.031 g/l in this example.
Eksempel 1Example 1
5 g klorheksidindiacetat og 9,1 g TRIS ble blandet i 850 ml destillert vann under omrøring. 31,25 g 64% nonoksynol-9 ble deretter tilsatt, etterfulgt av ytterligere omrøring, noe som resul-terte i ehklar løsning. pH ble regulert til 8,0 med 1 m eddiksyre (53 ml). Det totale volum ble økt til 1000 ml med destillert vann. 5 g of chlorhexidine diacetate and 9.1 g of TRIS were mixed in 850 ml of distilled water with stirring. 31.25 g of 64% nonoxynol-9 was then added, followed by further stirring, resulting in a clear solution. The pH was adjusted to 8.0 with 1 M acetic acid (53 ml). The total volume was increased to 1000 ml with distilled water.
Eksempel 2Example 2
En løsning av tilsvarende konsentrasjoner som i eksempel 1 av klorheksidindiacetat og TRIS med pH 8,0 ble fremstilt i destillert vann, men uten nonoksynol-9. Levende suspensjoner av de ovenfor beskrevne bakteriestammer ble fremstilt. Dessuten ble det fremstilt et par tilsvarende løsninger som inneholdt 2 g/l klbr-heksidindiacetat/1 istedenfor 5 g/l. A solution of similar concentrations as in example 1 of chlorhexidine diacetate and TRIS with pH 8.0 was prepared in distilled water, but without nonoxynol-9. Live suspensions of the above-described bacterial strains were prepared. In addition, a pair of corresponding solutions containing 2 g/l chlorhexidine diacetate/l instead of 5 g/l were prepared.
Blandinger av testløsninger og bakterier ble fremstilt etter forskjellige kontakttider. Mixtures of test solutions and bacteria were prepared after different contact times.
Et eksempel på virkningen av nonoksynol-9 med en gruppe stammer av streptokokker fra gruppe B er vist i den etterfølgende tabell, men lignende resultater ble oppnådd med de andre bakterier. Nonoksynol-9 nedsatte således ikke virkningen av klorheksidindiacetat. Tvert imot ble det iakttatt en liten, men betydelig økning i antibakteriell virkning når nonoksynol-9 var tilstede. An example of the action of nonoxynol-9 with a group of strains of group B streptococci is shown in the following table, but similar results were obtained with the other bacteria. Nonoxynol-9 thus did not reduce the effect of chlorhexidine diacetate. On the contrary, a small but significant increase in antibacterial activity was observed when nonoxynol-9 was present.
Under anvendelse av de tre forbindelser er det mulig å fremstille isotoniske løsninger. Den ovennevnte blanding av 5 mg/ml av 0,05 M TRIS, 20 g/l nonoksynol-9 og 20-30 ml eddiksyre til 1 liter destillert vann er et eksempel på en slik isotonisk løsning. Using the three compounds, it is possible to prepare isotonic solutions. The above mixture of 5 mg/ml of 0.05 M TRIS, 20 g/l of nonoxynol-9 and 20-30 ml of acetic acid to 1 liter of distilled water is an example of such an isotonic solution.
Referanser:References:
1. Christensen KK, Christensen P, Dykes A-K, Kahlmeter G, Kurl DN & Linden V: Clorhexidine for prevention of neonatal colonization with group B streptococci. I. In vitro effect of chlorhexi-dine on group B streptococci. Europ J Obstet Gynes Biol. 16, 1983, p 157-176. 2. Dykes A-K, Christensen KK, Christensen P&Kahlmeter G: Clorhexidine for prevention of neonatal colonization with group B streptococci. II. Clorhexidine concentrations and recovery of group B streptococci following vaginal washing in pregnant women. Europ J Obstet Gynec reprod Biol. 16, 1983, p. 167-172. 3. Christensen KK, Christensen P, Dykes A-K & Kahlmeter G: Clorhexidine for prevention of neonatal colonization with group B streptococci. III. Effect of vaginal wahing with clorhexidine before rupture of the membranes. Europ J Obstet Gynes reprod Biol. 19, 1985, p. 231-236. 4. Christensen KK, Dykes A-K & Christensen P: Reduced colonization of newborns with group B streptococci following vaginal washing of the birth canal with clorhexidine. J Perinat Med. 13, 1985, p. 239-243. 5. Vorherr H, Vorherr UF, Mehta P, Ulrich JA & Messer RH: Antimicrobial effect of clorhexidine and povidoneiodine of vaginal bacteria. Journal of Infection 8, 1984, p. 195-199. 6. Christensen KK, Christensen P: Clorhexidine for prevention of neonatal colonization with GBS. In: Christensen KK, Christensen P&Ferrieri P: Neonatal group B streptococcal infections. Antibiot Chemother. 35, p. 296-302, Karger, Basel 1985. 7. Hellstrom H, Cardell B, Loven G, Nihléhn B & Persson A-L: Antimikrobiell effekt av klorhexidin i olika preparationsformer. Lakersallskapets riksstamma, 28-30 nov. 1984 (8P). 1. Christensen KK, Christensen P, Dykes A-K, Kahlmeter G, Kurl DN & Linden V: Chlorhexidine for prevention of neonatal colonization with group B streptococci. I. In vitro effect of chlorhexidine on group B streptococci. Europ J Obstet Gynes Biol. 16, 1983, p 157-176. 2. Dykes A-K, Christensen KK, Christensen P&Kahlmeter G: Chlorhexidine for prevention of neonatal colonization with group B streptococci. II. Chlorhexidine concentrations and recovery of group B streptococci following vaginal washing in pregnant women. Europ J Obstet Gynec Reprod Biol. 16, 1983, pp. 167-172. 3. Christensen KK, Christensen P, Dykes A-K & Kahlmeter G: Chlorhexidine for prevention of neonatal colonization with group B streptococci. III. Effect of vaginal washing with chlorhexidine before rupture of the membranes. Europ J Obstet Gynes Reprod Biol. 19, 1985, pp. 231-236. 4. Christensen KK, Dykes A-K & Christensen P: Reduced colonization of newborns with group B streptococci following vaginal washing of the birth canal with chlorhexidine. J Perinatal Med. 13, 1985, pp. 239-243. 5. Vorherr H, Vorherr UF, Mehta P, Ulrich JA & Messer RH: Antimicrobial effect of chlorhexidine and povidoneiodine of vaginal bacteria. Journal of Infection 8, 1984, pp. 195-199. 6. Christensen KK, Christensen P: Chlorhexidine for prevention of neonatal colonization with GBS. In: Christensen KK, Christensen P&Ferrieri P: Neonatal group B streptococcal infections. Antibiotic Chemother. 35, p. 296-302, Karger, Basel 1985. 7. Hellstrom H, Cardell B, Loven G, Nihléhn B & Persson A-L: Antimicrobial effect of chlorhexidine in different preparation forms. Lakersallskapet's national team, 28-30 Nov. 1984 (8P).
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SE8503256A SE8503256L (en) | 1985-07-01 | 1985-07-01 | MIXTURE OF CHLOREXIDE AND TRIS BUFFER FOR USE IN THE VAGINA, SKIN AND OTHER MUSCLES WITH ADDED PH |
PCT/SE1986/000310 WO1987000005A1 (en) | 1985-07-01 | 1986-06-26 | A COMPOSITION FOR DISINFECTION OF THE VAGINAL AND OTHER MUCOUS MEMBRANES WITH LOW pH |
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