AU599026B2 - Antiseptic compositions - Google Patents

Description

I

ATT-AI 5 6 6 7/86 PCT WORLD INTELLECTUAL PROPBY NI lPCT wInternational BU 9 2 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: WO 86/ 05359 ON 59/12, A61K 33/18 Al (43) International Publication Date: C11D 3/48 25 September 1986 (25.09.86) (21) International Application Number: PCT/AU86/00069 (22) International Filing Date: (31) Priority Application Number: (32) Priority Date: (33) Priority Country: 13 March 1986 (13.03.86) PG 9677 13 March 1985 (13.03.85) (71)(72) Applicant and Inventor: GLUCK, Bruno, Anthony [AU/AU]; 20 King Avenue, Balgowlah, NSW 2093

(AU).

(74) Agent: SPRUSON FERGUSON; G.P.O. Box 3898, Sydney, NSW 2001 (AU).

(81) Designated States: AT (European patent), AU, BE (European patent), BR, CH (European patent), DE (European patent), DK, FI, FR (European patent), GB (European patent), IT (European patent), JP, KR, LU (European patent), NL (European patent), NO, SE (European patent), US.

Published With international search report.

This document contains the amendments made under Section 49 and is correct for printing.

A.O.J.P. -6 NOV 1986

AUSTRALIAN

13 OCT 1986 PATENT OFFICE (54) Title: ANTISEPTIC COMPOSITIONS (57) Abstract Antiseptic compositions having both rapic and residual persistent biocidal activity, comprising an iodine complex with a bacteriostat exhibiting synergistic antimicrobial activity and good shelf stability. The compositions find a use as antiseptic skin cleansers, antiseptic solutions for use under plaster casts and dressings, antiseptic lotions for skin disinfection, preoperative skin washers and shower preparations, shampoos, medicated after-shave preparations, tinea preparations, hospital laundry rinsers, nappy (diaper) sanitisers, surface sprays, foot-rot preparations and animal shampoos.

86/05359 PCT/AU86/00069 1

DESCRIPTION

ANTISEPTIC COMPOSITIONS TECHNICAL FIELD The present invention relates to antiseptic compositions which have both a rapid and residual antimicrobial and antiviral action. More particularly, the invention relates to compositions .ntaining an iodophor which has a rapid action together wit one or more agents having a residual antibacterial and/or antiviral action.

The compositions of the invention find use in medical applications such as antiseptic skin cleansers, antiseptic solutions for use under plaster casts and dressings, antiseptic lotions for skin disinfection, e.g. prior to surgery or first aid procedures, preoperative skin wash and shower preparations, shampoos, medicated after-shave preparations, tinea preparatons, hospital laundry rinses, nappy (diaper) sanitisers and surface sprays.

Agricultural/veterinary applications in which'the compositions of the invention find use include preparations for treatment and prophylaxis of foot rot and animal shampoos.

It has been surprisingly discovered that some synergism occurs between the iodophor and the residual antibacterial antiviral agent.

BACKGROUND ART There is continuous demand by surgeons and members of the medical profession for a practical method of handcleansing other than using only soap and water, but which would provide additionally to the cleansing of the skin, rapid disinfection combined with residual protection against immediate re-infection.

A desirable hand and skin cleansing composition would be one which would combine, additionally to the effective cleansing of the skin, rapid disinfection and protection against subsequent re-infection.

Iodine, because of its exceptional biocidal properties has long been a favoured germicidal ingredient for skin cleansing compositions.

WO 86/05359 PCT/AU86/000

U

2 The advantages of iodine in combination with iodine carriers resulting in complex formation, having available iodine as active biocidal constituent, over previous iodine preparations having the iodine solubilised by forming the triiodide with an alkali or hydrogen iodide, such as tincture of iodine or Lugol's solution, are well known and as exemplified in US Patent No 3 777 022.

Iodine, in its complex formation, especially in combination with polyvinylpyrrolidone, known as povidone-iodine, has, because of its rapid action and wide microbicidal spectrum been used as the active germicidal ingredient in various brands of antiseptic skin cleansers for pre-operative scrub-up and general ward use.

Despite the great advantages of these antiseptic hand and skin cleansing products over others, not containing iodine, they suffer from the disadvantage, that once used, they leave the skin with no residual prophylactic protection against re-infection.

Other germicides such as the quaternary ammonium compounds or chlorhexidine salts, although not quite as fast acting as the iodophors, have found wide application in various antiseptic preparations.

Although such other germicides do not possess the wide microbicidal spectrum of the iodophors, and are not equally active against the various strains of Gram-positive and negative micro-organisms, they do provide a persistant antibacterial effect on the skin after application.

Bacteriostats form a third group of antimicrobial agents which have found wide use in skin and handwashing preparations. They have a high affinity to the skin and confer remanent antibacterial properties, which continue to build up on repeated application, eventually conferring a complete shield on the skin against re-infection. They also reduce the resident bacterial flora of the skin to a minimum, which is not removed by the conventional antibacterial agents mentioned previously.

-3- The importance of combining a fast acting broad spectrum biocide such as the iodine complex lacking persistent action after application with an agent providing residual and continuous anti microbial activity is self evident.

This is true in a wider sense of all applications where rapid disinfection of any surface is required and persistent protection against re-infection is desired, even if only for a limited time.

This is of special importance for medical personnel when an antiseptic hand and skin cleansing preparation combining an iodine complex with a bacteriostat with residual properties allows the immediate disinfection of the skin and additionally provides an antibacterial shield against possible re-infection.

The provision of an antiseptic composition combining even, rapid Ii biocidal action over practically the complete microbiological spectrum, j 15 combined with remanent antibacterial effectiveness present therefore an S important advance in the technique of hand and skin sanitation and I disinfection of surfaces in general.

S o Various attempts have been made to combine bacteriostats with iodine in disinfectant solutions. Most of these have been unsuccessful, as due to 4 possible reaction between iodine and the bacteriostat component of the i preparation shown by considerable loss of iodine occurring on standing.

Such attempts have been desired in U.S. Patent No. 3,777,022 and Canadian Patent No. 729,597.

DESCRIPTION OF THE INVENTION The present invention provides an antiseptic composition comprising at least one iodine complex (as hereinbelow defined) and at least one residual antibacterial agent in a proportion sufficient to obtain rapid biocidal action and persistent antibacterial effectiveness together with a pharmaceutically, veterinary or agriculturally acceptable carrier or diluent therefor.

S In the specification and claims, the term "iodine complex" (as I hereinbelow defined) is a complex of iodine with polyvinylpyrrolidone known also as povidone-iodine, or nonionic surfactants of the general formula

R(CH

2 CH20) H TMS/1084u WO 86/05359 PCT/AU86/00069 4 where R represehts and alkylphenol, a fatty alcohol or acid residue and x is 6 to 100, and preferably 7 to 15, or polycondensates of ethylene oxide and propylene oxide of a molecular weight of not less than 1000, preferably between 2500 and 4000. Such complexes have because of their rapid action and wide microbicidal spectrum become the active germicidal ingredient in various brands of antiseptic skin cleansers for pre-operative scrub-up, general medical and household antiseptic preparations, veterinary uses and disinfetant cleansers for the food and allied industries.

Iodine complexes with amphoteric surface active agents and quaternary ammonium compounds are also included in the definition.

The preferred complex of iodine and polyvinylpyrollidorl has 10% available iodine and a K-value of Other suitable iodine complexes include nonylphenoxy- (ethyleneoxy)-iodine, polyethyleneoxypolypropyleneoxy-iodine and undecoylinium-ch.loride-iodine, as well as the other commercially available products.

Suitable bacteriostats which may be employed in compositions of the invention include halogenated hydroxydiphenyl derivatives or halogenated salicyl and carbanilides.

Examples of these bacteriostats are those of the formula R R 9

R

1

R

R7 0 O R I R6 R5 H

R

wherein each of R 1 to R 9 may be hydrogen, halogen, lower alkyl, haloloweralkyl, lower alkoxy, allyl, cyano, amino or acetyl and the O-acyl derivatives thereof provided that at least one of R 1 to Rg is halogen; X9_ X1 0 X1 X 2

X

8 '-NH-CO--NH-X II X XX X 4 7 6 5 4 x WO 86/05359 PCT/AU86/00069 wherein each of X 1 to X10 may be hydrogen, halogen, haloalkyl, nitro or alkoxy provided that at least one of X 1 to X is halogen; Y 7--NH-C Y III 7 Y 6 Y5 H Y4 wherein each of Y to Y is hydrogen or halogen, provided that at least two of Y1 to Y are halogen; and

Z

7 Z8 Z1 Z 2 6 Q CH 2 z 3 Z H H Z 4 wherein each of Z, to Z may be hydrogen or halogen provided that there is at least two halogen substituents on each Phemyl ring.

Such compounds are disclosed in Australian Patents Nos.

200 868, 209 986, 236 460, 273 941, 278 661 and 283 658 and in US Patent Nos. 2 250 840, 2 967 885, 3 254 121, 3 057 920 and 3 064 048.

Examples of the preferred bacteriostats include 2,4,4'trichloro-2'-hydroxydiphenyl ether (triclosan); 2,2'-dihydroxy- 3,3',5,5',6,6'-hexachlorodiphenylmethane systematic name (hexachlorophene); 3,5,4'-tribromosalicylanilide (tribromsalan) and 3,4,4'-trichloro- or 3-trifluoromethyl- 4,4'-dichloro-carbanilides (triclocarban and cloflucarban)'.

Triclosan is preferred for carrying out the invention.

It is preferred that the compositions of the invention contain a greater amount by weight of available iodine than of bacteriostat.

It is preferred that the iodine complexes are present in the compositions of the invention so as to provide from 0.01 to 5.0% w/v especially 0.35 to 2.0% w/v available iodine. It is preferred that the compositions contain 0.01 to 3.0% w/v, especially 0.5 to 2.0% w/v of the bacteriostats.

WO 86/05359 PCT/AU86/00069 6 It is further preferred that if one or more surfactants should be part of the composition according to the invention, one at least should be a nonionic surface agent.

Antiseptic compositions of the invention remain stable at temperatures below 25 0 C over considerable time of up to two years in the absence of light.

The combined biocidal activity of the available iodine and the bacteriostat is greater against certain bacteria than could be expected from the values of the biocidal strength of the separate iodine or bacteriostat components added together.

The cumulative effect of the iodine complex and bacteriostat is shown by minimum inhibitory tests in vitro by serial dilutions using Difco AOAC medium and illustrated by the following table: Triclosan 1.0% w/v in a detergent solution Test Cultures Dilutions 1/25 1/50 1/100 1/200 1/400 E.coli 6.4 x 109 Staph.aureus 6.3 x 109 P valgaris 6.0 x 109 Ps.aeruginosa Povidone-Iodine 0.75% av.iodine in same detergent solution E.coli 6.4 x 10 Staph.aureua 6.3 x 10 9 P. Vulgaris 6.0 x 10 Pr.aeruginosa Povidone-Iodine 0.5% and Triclosan 1.0% w/v in same E.coli 6.4 x 10 Staph.aureus 6.3 x 10 9 Ps.vulgaris 6.0 x 10 9 PS.aeruginosa 6.0 x 10 bacterial growth no growth ;i 'WO 86/05359 PCT/AU86/00069 7 Where surface active agents are used to supply the necessary detergency in compositions where detergency is needed, they must not only be saturated compounds but also be stable in solution having a pH less than 6 to avoid separating from solution on prolonged standing. Hand cleansers of the invention retain satisfying foaming properties at the pH of the composition. Although the pH of the composition can range for practical reason between 2 to 6, it is preferable to select a pH between 4 to 5 for skin cleansers and antiseptics and around 2 for surface disinfectant cleansers.

Suitable surface active agents are nonionics such as the nonylphenolpolyethoxy condensates, the alkali, ammonium and triethanolamine salts of phenoxy-or alkyloxypolyoxyethylene sulfonates, or polycondensates with ethylene oxide and propylene oxide, used on their own, or mixtures thereof.

It is advantageous to use, in conjunction with the surfactants, foaming agents such as the fatty acid diethanolamides or an alkyldimethylamine oxide such as a lauryldimethylamine oxide, lauryldiethanolamide being preferred.

The bacteriostat is suitably added in a common solvent such as ethanol, isopropanol or propylene glycol or directly, provided the composition has sufficient solubilising power to keep the bacteriostat in solution.

According to the various compositions and their different applications, various ingredients will have to be added to give the composition additional desired properties.

Care has to be taken in the choice of such ingredients to assure that they will be compatible with the iodine complex and not affect its stability.

If desired, glycerine or other emollients commonly used in hand and skin cleansing preparations can be added, provided they are compatible with the iodine complex and bacteriostat used in the composition.

WO 86/05359 PcT/AU86/00049 8 MODES FOR CARRYING OUT THE INVENTION The following examples illustrate preferred embodiments of the present invention. They should not be construed as limiting the claims hereto. The ingredients are combined by standard cold mixing processes.

EXAMPLE 1 ANTISEPTIC SKIN AND HAND CLEANSER iodine complex nonionic surfactants sodiumlaurylethoxysulfato lauryldimethylamineoxide glycerol trichlocarban propanol phosphoric acid to adjust to water to make 20.0g 1 Og pH 100.0mL (Antarox VRO 20 available from GAF Corp. USA) (Antarox CO 730 available from GAF Corp. USA) (Empigen 5Q25 available from Albright Wilson Inc.) (Empigen OB available from Albright Wilson Inc.) .WO 86/05359 PCT/A U86/00069 9- EXAMPLE 2 SANITISING CLEANSER povidone-iodine, containing 10.0% w/v available iodine sodium salt of suiphonated alkylphbenoxypoly (ethyleneoxy)ethano. 20. og lauryld 'iethano lamide 2. Og glycerol 1. Og tE iclosan 0. isopropanol .OmL phosphoric acid to adjust to pH water to make 100. 0mL *(Fenopan Co., available from GAF Corp. USA) The bacteriostat is dissolved in the isoproparol prior to mixing with the other ingredients.

EXAMPLE 3 ANTISEPTIC SOLUTION povidone--iodine, containing 10.0% w/v available iodine ethanol isopropanol mixture 2:1 tribromsalan nonionic surfactant phosphate--citrate buffer to adjust to water to volume 10. Og 40. OmL 0. 0. pH 4. 100 OOmL The triclosan is dissolved in the alcohol mixture prior to mixing.

WO 8605359PCT/At;86100069 NVO 86/05359 10 ANTISERTIC TINCTURE povidone-iodile, containing 10.0% wJ/v available iodine lanogel 61 0 ethanol 70,00mL triclosan 0.25g phosphate-citrate buffer to adjuist to pH Water to volume 100.OmL Nonionic lanolin derived surfactant (Ametcho. Corp. New Jersey USA) EXAMPLE PREOPERATIVE SKIN WASH SHOWER-PREPARATION povidone--jodine, containing 10.0% w/v available iodine nonionic surfactant sodium laurylethoxysulfate* Coconutdiethanolamide propylene glycol triclosan phosphoric acid to adjust to Water to volume 10. Og 5. Og 30, Og 2 .Og 10. OmL 1. Og pH 4. 100 OmL *(Empigen 5Q25 available from Albright Wilson Inc.) The PVP-I and the sodium lauryl and coconutdiethanolamide were dissolved in water and triclosan dissolved in the propylene glycol was added slowly with efficient stirring, The pH was adjusted and the composition adjusted to final volume with water.

I 86105359 PCT/A U8/0I69

J~A~LLA

~~S~S~t".B1 povidone-iodine, containing 10.0% w/v available ione 0.Sg Glucan E 10* Olucan P 20W ethanol propylene glycol triclocan triclocarban glycerin phosphate-oittate buffer to perfume, colour water to volume 4 S. OML 10. OmL 0, Olq p.H 5, 100,OmL S[nodiionicpropoxylated glucose derivato (Amerohol Corp, New Jersey, EXAMPLE 7 TINEA TREATMET povidone-iodine, containing 10.0% w/v available iodine polyethylene glycol 400 polyethylene glycol 4000 triclosan water 10.09 60, Og 25.09 0. Bg 4. Og The mixture of the polyethylene glycols was heated to 450C and the triciosan dissolved with slight stirring followed by the PVP-I. The clear melt was left to cool slowly until a creamy consistency was obtained. The ointment like product is then ready for packing.

I

T,7 I r WO 8-6/05359 WO 8605359PCT/AU86/00069 12 EXAMPLE 8 TEAT DIP for mastitis prophylaxis iodine complex* glycerin propylenglycol triclosan phosphate--citric buffer t~o water to volume 2 4 Og 3 OmL 0. pH 4. 0 100 0mL *(Antarox VRO 20 available from GAF Corp. USA) EXAMPLE 9 DOG SHAMPOO iodine complex nonionic surfactant sodium lauryl ethoxy s1llfate coconutdiethano lamide propylene glycol hexachlorophene phosphoric acid to adjust to water to volume 5 Og 5 Og 20. Og 2 .Og 5 Og 0. pH 100 OOmL *(Antarox VRO 20 available from GAF Corp. USA) EXAMPLE BATH PREPARATION FOR PRE--OP AND DERMATOLOGICAL CONDITIONS iodine complex nonionic surfactant, triclosan sodium laurylethc,,.y sulphate coconut d et ha no lmide citric acid to adjust to Water to make 10. Og 10. Og 1.75g 40. Og S Og pH 4. 100 0OmL (Antarox VRO 20 available from GAF Corp. USA) WO 86/05359 PCT/AU86/00069 13 COMPARATIVE EXAMPLE 1 An aqueous cleansing solution containing povidone-iodine (0.94% w/v available iodine) was divided into two parts, whereby to one part thereof was added 2.0% of triclosan.

After standing for two years at ambient temperatures both products showed identical small losses of available iodine, demonstrating that no reaction between the bacteriostat and the iodine had occurred.

ik

Claims (12)

1. An antiseptic composition comprising at least one iodine complex (as hereinbefore defined) and at least one residual antibacterial agent in a proportion sufficient to obtain rapid biocidal action and persistent antibacterial effectiveness together with a pharmaceutically, veterinary or agriculturally acceptable carrier or diluent therefor.

2. A composition as defined in claim 1 wherein the iodine complex is a complex between iodine, and polyvinylpyrolidone or a polycondensate of ethyleneoxide with propyleneoxide, alkylphenols, fatty alcohols, fatty acids, quaternary ammonium compounds or amphoterics surface active agent.

3. The composition as defined in claim 2 wherein the iodine complex is povidone-lodine.

4. A composition as defined in claim 1, wherein the bacteriostat is a halogenated hydroxydiphenyl derivative, a halogenated salicylanilide or a halogenated carbanilide. A composition as defined in claim 4, wherein the bacteriostat is 2,4,4'-trichloro-2'-hydroxydiphenyl ether, 2,2'dihydroxy-3,3',5,5',6,6'- r hexachlorodiphenylmethane, 3,5,4'-tribromosalicylanilide, 3,4,4'-trichloro- carbanalide, or 3-trifluoromethyl-4,4'-dichlorocarbanilide.

S

6. A cumposition as defined in claim 4, wherein the bacteriostat is 2,4,4'-trichloro-2'-hydroxydiphenyl ether.

7. A composition as defined in claim 1, further comprising a saturated surface active agent stable in solution having a pH less than six.

8. A composition as defined in claim 7, wherein the surface active agent is a nonylphenolpolyethoxy condensate or an alkali ammonium or triethanolamine salt of a phenoxy- or alkyloxypolyoxyethylene sulfonate or a polycondensate of ethylene oxide and propylene oxide or a mixture of two or more thereof.

9. A composition as defined in claim 7, further comprising a foaming agent.

10. A composition as defined in claim 9, wherein the foaming agent is a fatty acid diethanolamide of alkyldimethylamine oxide. is a fatty acid diethanolamide of alkyldimethylamine oxide.

11. A composition as defined in claim 1, having a pH-value less than 7.

12. An antispetic composition substantially as hereinbefore described with reference to any one of the Examples. DATED this SECOND day of MAY 1989 BRUNO ANTHONY GLUCK Patent Attorneys for the Applicant SPRUSON FERGUSON ZI t- 4.-S u *P LI* r U I I INTERNATIONAL SEARCH REPORT International Aoolication No PCT/AU 86/00069 1. CLASSIFICATION OF SUBJECT MATTER( steea' classilc~lion symoo's 3201Y Mc'die 111' According to Intefrnationial Patent Classification (IPC) or to Ooth National Classification and IPC Int. C1.4 A01N 59/12, A61K 33/18, C11D 3/48 It. FIELDS SIARCMEO MinimUm ocumentation Searched Classification System Classificationt symbols IPC A01N 59/12, A61K 33/18, 27/00, 7/50 us Cl. 424/150 ocumentation Searched other than Minimum Docuimentation to thie Exteft the, such occuments are Included in the Fields Searched AU IPC as above; Australian Classification 87.16 1ll. DOCUMENTS CONSIOEMED TO 91 RELEVANTO Category Citation of Document. 11 with indication, where sooroorlate. of the relevant passages It Relevant to Claim No. X GB,A, 2084464 (BETA MEDICAL PRODUCTS LIMITED) April 1982 C15.04.82) X US,A, 3751565 (SANTORELLI) 7 August 1973 (07.08.73) (1-3,11) X US,A, 4206204 CLANGFORD) 3 June 1980 (.03.06.80) (1,2,7,11) X US,A, 4288428 (FOLL) 8 September 1981 (08.09.81) (1-3,7,8,11) X AU,B, 40487/68 (436196) (WEST LABORATORIES, INC.) (1-3,7,8,11) 28 May 1973 (.28.05.73) X AU,B, 2412/51 (156301) (.GENERAL ANILINE FILM (1-3) CORPORATION) 3 May 1954 (03.05.54) Special categories of cited documents: i0 later document oublished after the international riling a ate or priority date and not in conflict with the goolictition "out dlocument defining ti'4 general state of the am which Is hot cited to understanid the principle or theory undarlynmg tne Considered to be of particular relevanlce inlvention E" earlier document but published on or &hier the international document of paricular relevance: the claimed invention riling data cannot be considered novel of cannot be consioered to document which may throw doubts oft priority claim(s) or involve an inventive also wnMictM is cited to establish tne publication date of another document of particular relevance: the claimed invention citatiorl or other soocisl reason (as specified) Cannot be considered to involve an Inventive aso when, tho document referring to en Oral disclosure, use. shibitlon or document ia combined with one or more other such docu* other means monrts. sucht comaiination being obvious to a person &killed P document oublished Prior to the International filing date but in the arn. later than the priority date claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Completion of the Itnternational Search sat* of Mailing of this iternationael Search Reort June 1986 (.20.06.86) ,O(/Z-UAY International Searching Authority Signature oV' r Australian Patent Office BOYS Form PCTIISAI210 (second sheet) (January ill1S1) i: i. ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL APPLICATION NO. PCT/AU 86/00069 This Annex lists the known publication level patent family members relating to the patent documents cited in the above-mentioned international search report. The Australian Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent Document Cited in Search Patent Family Members Report GB 2084464 GB 8032051 US 3751565 US 3764669 BE 687578 BR 6681662 DE 1617798 NL 6614878 US 4206204 AT 9067/75 BE 836125 CA 1058071 CH 608965 DE 2553956 DK 5386/75 FR 2292429 GB 1514490 IT 1060080 SE 7513505 US 4207310 US 4288428 AU 57001/80 DK 1401/80 EP 17639 FI 801026 NO 800934 NZ 193312 SE 7902893 AU 40487/68 CH 516639 FR 1576016 GB 1226985 NL 6809889 US 3539520 JP 52093578 END OF ANNEX L-.