CA2106683C - Inactivating enveloped viruses and sperm - Google Patents
Inactivating enveloped viruses and sperm Download PDFInfo
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- CA2106683C CA2106683C CA002106683A CA2106683A CA2106683C CA 2106683 C CA2106683 C CA 2106683C CA 002106683 A CA002106683 A CA 002106683A CA 2106683 A CA2106683 A CA 2106683A CA 2106683 C CA2106683 C CA 2106683C
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- betaine
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
- A01N33/16—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-oxygen bonds
- A01N33/24—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-oxygen bonds only one oxygen atom attached to the nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/25—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
- A01N37/20—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof containing the group, wherein Cn means a carbon skeleton not containing a ring; Thio analogues thereof
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
- A01N37/46—N-acyl derivatives
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- A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
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- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P15/16—Masculine contraceptives
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P15/18—Feminine contraceptives
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- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
- A61L2300/208—Quaternary ammonium compounds
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/408—Virucides, spermicides
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/452—Lubricants
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
Disclosed is a composition for inhibiting the activity of an enveloped virus or sperm, the composition comprising a mixture of (a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof, (b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof, and (c) acid in an amount to provide the composition with a pH of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition. Also disclosed is a contraceptive device containing the composition as a spermicide.
Description
1 ..
fNACTIVATINCi ENVELOPED VIRUSES AND SPERM
BACRGRODNQ OF TFiE INVENTION
1. Fiel.~i of the Invention The present invention relates to a novel method and novel articles for inhibiting the activity of enveloped viruses. The invention also relates to treatment: of viral infections. More particularly, the invention relates to a method for inhibiting the development of diseases and infections caused by enveloped viruses. In one aspect the invention particularly relates to a method of inhibiting the activity of viruses whose major mode of transmission is sexual. In other aspects the invention also relates to methods of inhibiting the activity of enveloped viruses whose mode of transmission is nonsexual. The compositions of use in the invention are also effective in the inhibition of bacteria and fungi Which coexist with viruses or viral infections. Additionally, the invention relates to a treatment for virus related diseases,-particularly sexually transmitted diseases related t.o AIDS, and to diseases related to this and other opportunistic infections of the immune-compromised host.
The method of the invention relates to using mixtures of betaines and amine oxides in the inhibition of viruses and treatment of viral infections. The betaine is selected from the group consisting of (a) an alkyl-N-betaine, an alkyl-N-sulfobetaine, an acyl-N-betaine, an alkyl N-substituted aminopropionic acid and an alkylimidazolinium betaine and the amine oxide is '1'4~P19211fe~01 ~, ~,,~~ ~ ~~ ~ ~ P~.'T/~JS9110S06!! , selected from the group consisting of (b) an alkyl-N, N-dimethylamine oxide, an alkyh-N, N-dihydroxyethylamfne oxide and an acylamide t-amide ~~cide. The term ~'betaine~' when used herein means an N-dimethyl glycine and their lo~rer alkyl homologs. The term includes N-dimethyl amino propionic acids and sulfo betaines which are the sulfonic acid analogs of such compounds. Unless otherwise specified a r1-dimethyl compound is intended.
Psore particularly, the .invention relates to a method for aGmploying mi~cture~s of alkyl. N-di (lower alkyl) betainss srrd alkyl N-di(lo~rer alkyl) amine oxides in the inhibition of enveloped virtases grad ease of these m3~etures in the treatment of infections caused by these viraases. The mixtures. may also be used as spermicides, either alone or in combination with conventional spermi.cides. These mixtures may be used in combination with contraoeptive devices or maybe incorporated into the contraceptive device.
2. ~scr~nt$on of the Prim A~
It is known that certain mixtures ~of amines are effective,antimicrobial. agents against gram negative and gram positive bacteria. For 3.nstance, it is known that certain mi9ctures of a) alkyl-3d-betaine, alkyl-id-su3.fob~taine, acyl-N-betaine, alkyl N-substituted aminopropionic acid or ma alkylimidazolinium betaine and (b) alkyl-N,t~-dimethylamine oxides alkyl-N, E~1-dihydroaeyethylamine oacide ~or acylamide t-amide oacide can bye wised for skin degaraaing, cleansing and deodorizing (see for e9tampla U.S. Patent 4,x82,952, issued to E.N.
~a~lsl ~.~e Patent N~. 4,~~~,~5~ issued t~ Ea~a ~i~h', and V.So ~at~.nt ~~. 4,i0~,3280 issued t~ E.~. .
~iichaelsj. These compositions are also useful for long term inhibition of body odor. fixtures of the same active ingredients are also known t~ enhance oral hygieaae by reducing oral ~aicroflora and inhibiting f~rmation of dental placy~ae. (U. S. Patent 4,839,158 issued to E.B. Michaelsj. Compositions iaf this type are ~'A19?J142~1 :~~ ,~ ~ ~i ~ ~ ~~'lllS91/
g also lm2own to be effective gurigicides. Corner, A.~I. , :et ' al. ~~ 9 ',~~ob'si ~,aerits arid Che~tother~nv. 32(3)x350 °
353 (lKarch 1988) s Corxaer, AwM. The.?oL?x'rial oø Clini _a7 Deritistrv. ~rol. 2(2,034 ° ~$w 'a99~)). (see also v.s.
Patents 4,75,35~, 4,1~~s328, 4,183,952 and 4,839,1,5$
issued to E.13. Michaels.) It is alho lcno~a that nonionic surface°active agents possessing ether or amide linkages between the hydrophilic and hydrophobic portions of the molecule 1~ rapidly inactivate the infectivity of herpes simplex erirus I and II. (Asculai, F. S . , et al w ~timicrobi~l ~gen~ts Cnemg pww vog. 13e6$6 ° 690 (19~$D~w .
hsculai et alw also states that cytocidal activity has been used as an index o~ antiviral activity. The compositions utilized 3.n t3ais invention have an ad~rantage over the compositions described in Ascaalai et al. in that these compositioaas inactivate viruses and bacteria tahila~ ~schibiting loss cytocidal activity.
The sperbnicfde Nonoxynol°9 (N°9), ~nas been found to have bactericidal and viricidal effects. For example, N°9 has been ~ouaad to inactivate viruses related t~ ~D~ (awgs - ~, h~an i~~nod~~iw°ien~ direst .
and herpes ~~p~~iruses (I and ~~) o In~y~tZ'o. $d°
~ has been shown to be egfective agaiazst the .organisms ~5 that cerise gonorrhea, chlamydia, syphilis, tricho~aoniasis, and other sexually transmitted diseases.
(U.s°. Fhas~acopeial convention UsPDI Update 199o pps. _ _ X55 ° 756j.
effective in inhibiting the activity of enveloped viruses.
The invention provides <~ method of inhibiting the activity of enveloped viruses fo:r which a major mode of transmission is sexual. The invention relates to a method for treating diseases and infections caused by enveloped viruses. These compositions are also effective in the inhibition of bacteria and fungi that co-exist with viruses or viral infections, a.nd for tre<~tment of bacterial and fungal infections wr.ich co-exi:~t with viruses or viral infections.
The invention. also provides a method for disinfecting air and surfaces contaminated with enveloped viruses.
More specifically, the present invention provides use of a composition for inhibiting the activity of an enveloped virus or as a spermicide, the composition comprising a mixture of (a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfcbetaine, aryl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more t=hereof, (b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof, and (c) acid in an amount to provide the composition with a pH of 4 - 8 as measured when the betaine and amine onside together comprise 0.5 weight percent of the composition.
4a The pre:~ent invention also provides a contraceptive device containing a spermicide composition, wherein the spermicide comprises a mixture of (a) a betaine selected from an alkyl--N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-sub:~tituted aminopropionic acid and an alkylimidazol.inium beta_ine, or a mixture of two or more thereof, (b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide,. or a mixture of two or more thereof, and (c) acid in an amount to provide the composition with a pH oj= 4 - 8 as measured when the betaine and amine oxide together- comprise 0.5 weight percent of the composition.
The present invention also provides a composition for inhibiting the activity of an enveloped virus or sperm, the composition comprising a mixture of (a) a betaine selected from an alkyl-N-betainE~, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof, (b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, o:r a mixture of two or more thereof, and (c) acid .:Ln an amount to provide the composition with a pH c.~f 4 - 8 as measured when the betaine 4b and amine oxide together comprise 0.5 weight percent of the composition.
The invention also provides a method for preventing the transmission of enveloped viruses.
The compositions used in the method of the present invention can also be u:~ed as spermicides. These compositions can be used alone, with other known spermicides and with, or incorporated into, contraceptive devices such as condoms, ~;ponges, vaginal inserts, contraceptive films, diaphragms, ~.uppositories, contraceptive patches or sustained release devi.cea. These compositions can also be incorporated into douches or wipes. For use as viricides, these compositions can x~E= applied alone, with other spermicides, and with, or incorporated into, the contraceptive devices described above. The compositions can also be applied in the i=orm of a foam, gel, cream, salve, jelly or lotion. The compositions can also be applied in the form of a liquid, aerosol, mist or spray.
DESCRIFTION OF THE DRAWINGS
Figure 1: is a graph showing the effect of C31G (a composition according tc> the present invention) and the effect of Nonoxynol-9 (N-9) on sperm motility.
Figure 2: is a gr<:~ph showing the effect of C31G and the effect of Nonoxynol-9 (I~1--9) on total sperm count.
°
cf' ~~I~~6~~~ . ~ ~ ~~ ~ ~ ~ ~ ~~~U.~~IO~J~Q
-Figure 3 o is ' a graph s3xowirag the effect of C31G and the effect of Nonoatoynol(Fi-9) on the mean progressive velocity of sperm.
Figure 4: ins a graph showing in vitro 5. toxicity of C31G vs. N-~ on sup-TI cells.
Figure 5: is a graph shoring a five day toxicity study of 0316 vs. N-9 on cells.
Figure 6: is a graph showing co~aparing the effects on 0316 vs. R1-9 on ~v.
Figure ~: is a graph showing the effect of 0316 on .
Figure ~: is a c,~raph comparing inactivation of HIV by e3lG and ~-~.
Figure 9: is a chart comparing. inactivation 3.5 of HIV by C31G and N-9.
19~L'A~T.~D r9Ea~~F~'~OPT OF IIdyENTION
The method of the inve:ation relates to using mixtures of betaines and amine oxides in the inhibition of ~nvelope~d viruses and treatment of viral infections ~0 caused by enveloped viruses. The method of the invention also relates to using lures of betaines and aanine oacides in the inactivation of enveloped viruses.
The betaines that can be used in this invention are alDcyl-N-betaines, alkyl-N-sulfobetaines, acyl-8d-25 betaines, alkyl N-substituted auinopropionic acids or alkyli~idazolinium betaines or. es thereof. The a~.ine oxides that can be used in this inveaation are a~.kyl,~-I1, Ie1-di9Ltethylamine o'tides, alkylmNs ~T~
dihydroscyethylamine oxidise or acyla~ide t-auide oxides 30 or mixtures thereof. ~'hese compositions are also effective for the treata~errt o~ viral, fungal, and ~aicrvbial infections anr~ cont~inations. These compo~~.tions are effective in inhibiting enveloped ~iz~tses that are transmitted se~ta~ally or nonse~cually.
35 These ~c~mp~sitions are also effective in the inhibition o~ bacteria and fungi which coexist with viruses or viral infections. These compositions can also be used 9p'°192/162~1 s ,~-a :a 4~ u3 pf.'T/US91/05060 topically.
Typically, these compositions are applied to areas wher~ viruses are or can be transmitted. This includes application in the vagina, to mucous membranes, and to the s~Cin.
These compositions can also be used as sper~nicides, either alone or in combination with other spermicides. These compositions can else be used with or incorp~rated into contraceptive devices such as, for.
1~ example, condo~as, diaphragms, sponges, contraceptive films, suppositories, sustained release devices, and contraceptive patches. Far ple, the compositioh may be incorporated into a lubricant applied to a condom or as part of a reservoir at the tip of a condom, or incorporated into a contraceptive sponge, contraceptive film, suppository, sustained release device or contraceptive patch. A contraceptive film can comprise ttae composition described above, together with, 7~ype A
gelatin, cellulose gum and a polyhydric alcohol. The compositions can also be used in contraceptive foams, gels, jellys, or~aams. 3'he compositions can also be used in douches or use in pre~veaating the transmission of viruses, these compositions can be used alone, Baith other sper~micid~s and ~aitia or incorporated into a contraceptive device as described above. fihis invention also comprises a method for inhibiting the transmission of viruses that cause sensually transmitted diseases which comprises applying the compositions to2those parts og the anatomy that ire erposed to body fluids emanating 3a from anotk~er during sexual activity.
These compositions have also unexpectedly been found t~ be less toxic to mammalian cells than Nonoxoynol-9 (P1-9) (See Figures ~ axed 5) . Table 1 shows that these camposition~ have equivalent ~perm3cidal activity to N-9,. which is one of the few surfactants approved by the FDA for use as a spermicide.
For use in topical applications, the ~~ 9~/1~r2~1 ,~,. ~' ~9 ~ ~ ~~ ~C~'/iJ~9g/05060 _ compositions can also be incorporated into liquids, creams, salves, lotions, foams and gels.
The invention also provides a method for disinfecting air and inanimate surfaces, for example, in an operating room or laboratory. Morn particularly, this invention provides a method for disinfecting areas which era contaminated with enveloped viruses. These compasitions can also be incorporated into sprays, mists, wipes, aerosols or devices which produce sprays, mists or aerosols. These compositions can also be applied as liqeaids. .
according to the method of this invention;
these compositions may be used as viricides, fungicides and bactericides.
The compositions eaaployed in the method of the invention comprise an admixture of betaine~a and amine oxides. The betaines used in this invention are sal~scted from the group- consisting of (a) al7cyl-N°
betaines, ~lltyl-N°sulfobetaines, aryl-~T°betainas, alkyl N°substituted aminopropionic acid, alkylimidazolinium betaines and mixtures of two or more thereof. Typically the betaines have two lower~alkyl groups bonded to the nitrogen atom. Most effectively they have two methyl substituetats on the nitrogen atom. The amine, oxides used in this invention are selected from the group ror~si~sting of b) a an alkyl°N,~1-dimethylamine oxides, . . alDcyl°N, g~°d~aydroxyathylamina oxide or . ~cylamida t°amine oxides and mixtures of two or more th0~~3of. Typically, the betaine and amine oxide components are present in a molar ratio of from a.a5 to 5:1, preferably in a molar ratio of iwi. T~~ alkyl°~°betaiJde, belie alkyl°~°
sulfobetaine~ the aryl-~1°betaine, the alkyl P1°
substituted 2paminopropionic acid and alhy~imidaaolinium betaine (also referred to-as cocoamphoacetates) employed ~5 ae the components (a) of the composition of the 3.nvention have structures; respectively, as followss ~~°~ 9~ois2o~ ~'~ ~ ~criusm,~o6o e~~c~~~~
~~,~~ omm.~~~~ ~ua~as~s where R is a higher al~eyl group having ~ro~ ZO to 18 carbon atoms, preferably ~ro~ 12 - 16 carbon atoa~e.
2p tWhen used herein the teran lower alkyl mm~eans an alkyl group of from 1 to 3 carboxs atoms.
Illustrative o~ these a~~re~ea°ationed substances are: (1) corn-N-betaine, cetyl-N-bstaine, etsa~ryl-N-~etaine, i~ostearyl,-N-betains, ol~yl-N-~5 betain~r (~) coco-N-aulphobetaine, ~etyl-N-~ulphobetaine, et~aryl-N-aul~obataine, ieost~aryl-N-~l~obetain~, oleyl-N-sul~ob~tainh~ (3j coc~amidc-N-b~taine, cetylaa~3.d~-H-betaine, etearylamido-N-b~taine, iaoetearyla~ido~N-b~taine, ~leyl.~a~irao~~'gbe~aine~ (~) N-~~ corn-2 ~nin~propioxai~ acid, N-~etyl~-~~a~inopropi~nic said, Nmst~a~rl~~-~a~einopropioa~ic amid, N-iaostearyl-2-aaainopropionic aciel, N-~oley7:-~-aaninopropionic acid, N~~tearyl~bas(2~-a~ainopropionic acid), N-~leyl~bis (~Winopropionic acid) ,. N~-Loco-bis (~~aaninoprogsionic ~~ acid) , N-cetyl-bis (~-~nian~propionic aca.d) , ~~ 921(201 , '~ y 'q~ ~~~.,~ ~ v~ PGT/U591/OS!?50 - ;,~, _ ~, ~ Ci ..
_ g _ (5a N-lauryl-bis(2-a:ninopropionic acid) 1-hydroxyethyl-1-carboxymethyl-2-decylimidazoliupn betaine;
1-hydroxyethyl-1-carboxymethyl-2-dodacylimidazoliun betaines 1-hydroxyethyl-1-carboxymethyl-Z-cocoi~nidazolium bat~ixaa; 1-hydroacyethyl-1-carboxyaaethyl-2-stearylimidazolium betaineo 1-hydroxyethyl-1-carboxymathyl-2-oleyli~aidazoliuan betainea or ~aixtures of the same.
When used here the term ~'coco~ is that used in ,the ~TF~ (designations of Cosmetic and Toiletry arid ~a~ran~~l sociation, lAasha, ~a~aD and is us~.d t~
indicate al~Cyl groups pr~sgnt in coconut oil~ is~o~a nniaetvare of alkyl groups of from 10 to 1~ carbon atoms.
The designations ~f the compounds listed herein are 9.5 those of the CTF'l~.
The ~l~ alkyl-N,N-diethylamine oxide, (2) alkyl-N,N-dihydroxylathylamine oxide, or (3, acylamide t-am3.ne oxide employed as component (b) of the aforementioned aura, respectively, have the structure:
~3 N~
30 where R is a higher alleyl group o~ from 10 to 1~ carbon atoms, for instance, radicals such as decyl, undecyl, lauryl, tridecyl, myristyl, cetyl, stea~yl, isostearyl or oleyla Eat~plary of the amine oxides are: decyl-N,N~di~ethyla~aine oxide, lauryl-N,N-dimethylamine oxide, 35 stearyl-N-N-dimethylamine oxide, oleyl-N,N-dianethylamine oxide, coco-N,N dihydroxyethylamine oxide, cetyl-N,N-.~~ 92/1!201 ~ ~ ~ ~ '~ ~ ~ ~'T/ZJS91/Ut5Q60 dihydroxyethyla~nina oxide, oleyl-N,N-dihydroxyethylamine oxide, N,N-dihydraatyethylamine oxide, oleyl-N,-N_ dihydroxyethyl-amine oxide and mixtures of the same.
The components (a) and (b) are usually admixed 5 and acid is then added in an amount necessary to adjust the pF1 of a 0.5~ solution to bete~een 4 - 0, :.preferably to pH ~.5 ~ 5.5. The pN of an aqueous solution comprising the above enumerated components of the invention is determiaaed by employing an ac;unous solution 10 of ~.5~, by weight, total of active components_typically at a glass electrode, to precisely define the acidity of the compositions In general, the acid used to adjust the overall composition to this reglaired pN is .any organic or inorganic acid'that is compatible with the intended use of the composition, for example, hydrochloric acid, phosphoric acid, sulfuric acid, citric acid, acetic acid or nicotinic acid. The balance of the composition, after allowing for the acid is usually an acceptable BO solvent, such as water or a lower (~~,-C,~) monohydric aliphatic alcohol, for a total of 1~0 parts or more.
i~Ihere water is employed, small amounts. of a lower alDcyl alcohol, such as ethanol or propanol, may.also be added to provide ease in formulati~n. acceptable diluents, carriers and excipients are, for example,. ethyl or isopropyl alcohols, polyethylene glycol, povidone, polyhydric.alcohols, glycerine, cellulose gums, gelatin, colorants and fragrances. ~f necessary, the p13 of the total composition is then adjusted to the reduisite pN
3t9 by adding a suitable inorganic or organic acid ~aereto.
The result is a substantially uniform, homogeneous, relatively nontoxic compositi~n having enhanced actier3ty against envelope viruses, bacteria amd fungi.
It has been unexpectedly found that tha~se compositions exhibit (1) row mammalian cell toxicity, a property which is known to correlate with low irritation ~?6'iu 92~1x2~~ , ~~ ..~ ~ ~ ~ ~,~ PCH'/IJS91/05050 - z~. -and low toxicity when used in contact with mucous membranes ~7,~u a C~.i.aaical Dmnt~.strv 2 (2) :34 - 38, (19~0D), and (2j highly efficacious inactivation of enveloped viruses although cytocidal activity is low.
a In the past, research has used cytocidal activity as an index of activity. (~Asculai, ~.5., l~ratianicrb. Agents ~lemother. 13:6°'x8 - 690 X1978) ) .
In practice, the total amount of the components (a) and (b] of the overall composition can A range from ~03~ ~ ~~~, preferably from .03~ - 30~
depending on the intended meant of use. Far example, concentrations used are, approximately 20~ ~ 30~ i»
contraceptive films and 0.2~ to 2~ in gels.
Compositions for use in this invention comprise alDcyl'N-di(lower alkyl) glycines and alkyl P1~
di(lower alkyl] amine oxides, wherein the lower alkyl is Cg-3. ~ne clays of betaines I have found to be partically useful in this invention are the alkyl N-d3.methyl betaines, such as cocobetaines and lauryl 20 betaines. Particularly useful amine oxides for use in this invention are the an alkyl N-dimethyl amine oxides, such as cocod3methyl amine pxides and lauryl dimethyl amine oxides.
Ane particular.camposition that can b~ used in 2~ this invention comprises cocobetaine, cocamine oxide and citric acid monohydrate.
mother composition that can be used in this :Lnvention comprises lauryl betaine, lauram3ne oxide and citric acid monohydrate.
30 In such compositions, the molar ratio of betaines to amine oxides is normally from 5:1 to 1:5, preferably in a molar ratio of 2:~. to 1:2, more preferably about l: ~..
~ther compositions that can be used in this 35 invention comprise mixtures of betaines, amine oxides, gelatin having a Bloom strength of 1.00 r 300 and a molecular weight from about 76,000 to about 300,000, c , i,,..> Y~ g'~.°TiUS91/~b5pG0. , , - la -polyhydric alcoYiols and cellulose gins.. Such compositions are described in a copending U.S.
application b~eingf filed simultaneously with the present application and having U.S. application Serial Edo.
D7/673, 63~..
Compositions used in this invention can .
inhibit flee activity of viruses that are related to AIDS. It is also expected that these compositions can.
inhibit the activity of I~SV--1 and ~S'V~2. It is also aD expected that the compasitions used in this inv~ea~ation can inhibit ~Iepatitis A, S and C. It is expected that the compositions can be used to inhibit virvases, bacteria and fungi which are associated ~aitb sexually transmitted diseases (STD°s).
The compositions of this invention may be useful in relation to the followings Transmission of ~I~l is often associated with the co~transmission of ~ther viral and~or anicrobial pathogens. Indeed, some investigators &ave suggested that HIV may not be the sole ageaat responsible for A7CDS
(asee D~aesba~rg, P.li. X1991) ~ Pratl. Aced. Sc~
88 s 1575 ~ 1579 J 7Gemaitxe, ~t.~, t~uetard, D. , Benin, ~C. , lbdontagnier, L. and serial, A. (199~j . ~t~s;V3~-~, 14105 16) . For tlaisv reason, ant~3.c~obial agents, such as ~5 those described in this application, a,~itb a broad spectrum of activities aga3rast viruses, bacteria, and ysasts such as Candida may be of particular value in the grnvention and treatment of Acquired Imxmune Deficiency Syndrome (AIDS).
~30 2) It is thought fleet certain bacteria knoxan to cause STD°s array aid in 1 transmission. In persons who hare been exposed to DIS1, certain bacteria which e:ause STD's often fail to respond to tberapies.that are otherwise highly effective. ~EIV infection may help the 35 spread of a bacterial STD that in turn helps to spread lil<i. STD's such as chlamydia, cbancroid, syphilis, genital herpes Grad gonorrhea which cause ulcerations of A~~H 9Z/16201 _ .. FCT/US91/05060 ~~~~~~~$.3 e~
-the genital skin seem to a.ncrease the risk of acquiring or transmitting I3IV infection seacually. oral, : . O. , et al.~cien~ific ~mer~.cana ~~~g~)ssa ~ ~9 ~gebruary m~~).
The compositions described above nay also be of use to inactivate other enveloped viruses, including vaccinia, varicella, herpes zoster, cytomegalovirus, Epstein Harr virus, influenza, mumps, measles, rhinovirus, rabies and rubella. In order to facilitate a further understanding of the invention, the following to examples are presented primarily for the purposes of illustrating more specific details thereof. Vitas invention is not to be deemed as limited thereby except as defined in the claims.
~~~~L a ~
~.5 Ttae composition described below is a concentrate of C~1G, an a~e,~ui~nolar preparation of cocobetaine and cocodimethylaaaine oxides (designations of CTF.~ Cosmetic and Toiletry and Fragrance association, Wash., D.C.) [t'FTA, which can be used in a number of different configurations.
Cocobetaine; 3A.5$ active ingredient (~1):
xs~.9 xg ~~05.~ 1b), cocamin~ oxid~,~~~.5~ ~~1)0 ~~a~.~ xg c3~s 1b), ~itri~r aid ~onohyt~, V w7JT i dl o 6D xg ~ ~ ~ 1b ) , ~5 ' ~rifi~d water, ~sCf.~°o 1'.e8 xg ca~ 1b) /
To ~aa'ce about ~5~.~ xg c~s2.5 1b) C31G at ~9m 6~ ~, at a citation ~~~ ~ ~ pH ~ ~ a ~ a r~a~~~.~
The spermicidal activity of C31G of eaca~aple 1 30 was compared to the spermicidal activity of nono9cynol~9 ~~s9) a (a1 The studies were con~hacted using the Hamilton--or~ ~pBr~ 8'lotility aly~~re ~a~pl~s of pooled washed seen were incubated with dilutions of the two compounds ~5 for fifteexi seconds and were analyzed din triplicate) for determination of the ~ini~aum concentration.for inmctivation by the following criteria:
!'V~D 9B/162~1 ~~ . ~~ ~; , 3~ PCT/1JS91/Q50~0 1. Inhibition of sperm motility (Figure 1j 2. Decrease,in total sperm count (Figure 2j 3. inhibition of the mean progressive sperm v~l~citye (1C figure .d j A.s shown in Table 3., c3lG and 1d--9 gave identical resultsm Table 1 C31G .N°9 Total Inhibition of motility 15o ppm 15o ppm g~~ Decrease in sperm Count 15o ppm 1l5~ ppm 50& Decrease in Progressive velocity 125 ppm 1.x5 ppm ~xamole ~
1.5 The cytotoa~ic effects of C31G and N°9 on mammalian cells were determined in several types of assaysa Cell thxicity is an indication of the relative safety and Comfort in use of surfactants in contraceptives or prophylactics.
2 o ~!s shown in Figure ~ ~ a taro week study monitoring drug effects on SiJIP-TI cells, (a human lymphocytic cell linej, C31G demonstrated minimal to~i~sity ~ at V . V od'~ t io ppm~ ~hil~ ~°~ at 4.iiB same concentration was ~tremely toxic.
~5 ~xalmpl.e ~
Figure 5 shows 3~iT reduction in Chi cells after five days of continuous ~xxposaare. T7nder these conditions C~lG showed no toxicity to ~aammalian cells at ' 3 PPm I~~0~3~, whale N°9 showing toxicity, reducing ~~ ~a~mm~lisn cell. viability by 50~ at the same coaacentration. It is unesepected that a compound having the same spermicidal activity as N-9 would be less toxic t~ mammalian cells than 1J-9.
lixamaale 5 ~5 hntiviral activity of C3lG~was tested using ~v°'~ and ~~~'~.
To test the effect of c3lG and ad~9 on herpes llv~D 9Z/1b201 , ~, .~ '~ ~ ~ ~ ~ PCT/v~91/05060 simplex virus type-1 (SOS strainj, the virus stock was prepared in Vero (~igrican green monkey kidney) cells.
The virdas was released from the cells by one freeze-thaw cycle followed by sonication. The virus titer was 4.5 ~c 5 108 plac~aae forming units (PF'Uj/ml, as determined on Vero cells. The drixg forgaulations used were identical to the drugs in the spermicidal study.
~'he stock concentration of each drug was 5%.
Two-fold serial dilutions were made, down to O.o4~, in 10 PBS pB ~.4 at room temperature. ~.~ u1 of each dilution was added to 220 u1 of virus (108 PFOj, giving final c~nas°entration~ ~~ ~ a 5 - ~ ~ ~~~t~ a ~ese sampl~.s were.
incubated at room temperature-gor 10 ;din, and then i0ou1 c~f each was immediately diluted to 1 ml with ice~cold 15 8% PBS. 10-fold serial dilutions were then made, down to ~.0-~ gor titration of remaining infectious virus on Vero cells in 2~-well plates. Plaques were counted 36 ~aours post-infection.
concentration t%1 ltasidual rus ~'~llml~
Vi _ ~ . C3~
0.004 ~ 3.5 108 3.5 x 108 x ~. ~~~ 2. 10~ ~ d o..T ~ ~0~~ . ' /
x ~sVlS - 1.1 ~~~ 2.5 x 105 .
x~
0.03 32~~ X1,67 ~.o$ <1~' ~wi~~
s 1~. ~16~ . ~~6~
0.25 ~16~ <167 ~.5 <157 <167 ~0 Note that these are titers PFU~mlj, rather than (ie.
a'~DSOlute nu3~ers o~ P~C1. The titer deter~'ned for untreated virus was X4.'7 108 x PF~~ml in the experiment wing N-9 and 4.5 ~c 108 in the experiment using PFU~mi ' ~~l~e . .
It is noted that complete inhibition o~ plaque ~ormati~n by C3lG occurs at more than one dilution below ttaat of N-9. See Figure 6.
vvo 9Z>m~~om ~~ ~3 ~a ~ ,~ PCT/~J59mB~5060. . .
_ 16 ~xam~?~.e 6 ' The inactivation of HIV-1 (d~IDS) virus was studied in two experiments. The first study compared the effects of C31G of H~1-1 at two different exposure times, 2 minutes and ~5 minutes. The x~ext study compared the relative activity of C31G and N-9 on HIV
using the same virus strain and measuring antiviral activity by reduction of virus titer as determined by reduction of P-24 HIV antigen.
1A The protocol and results of the first study follow:
CTS ~f C31G C2d HOH~ 0~7E~'TCIE~CY VIRUS .
Materials: .
~Tirus: HIV-1 strain 3B (5ac105 IDEA units/ml) Cells: SUP-Tl cell line (CD4~° lymphoid cells which produce characteristic cell fusion with giant cells and syncytia when infected with HIV) Protocol:
1. Serial fourfold dilutions of C31G in PBS (4.A~ -A.AA.~~ and PHS alone as control) were prepared. pH
2A was adjusted to 5w5.
2. Pooled aliquots of viral stock were prepared and ~C31G was added at each concentration~ at 1:9 d~t~rgents~~r~s ratio tl:lA detergent dilution) e' These were incubated for either 2 or 45 minutes.
3. Serial fourfold dilutions of each virus/detergent mixture down to 1:~A96 were prepared.
16.~ u1 of each virus/detergent dilution from each series were added to four replicate wails of SUP~T1 cells (10~ cells in 15A u1 volumem 1:1A detergent 3o dilution followed by further fourfold dilutions).
5. Then wells were examined twice weekly for two weeks and each well was scored positive or negative for the presence of characteristic viral syncytia ~r non-syncytial ghost formation due to detergent lysis.
dote a Virus was exposed to C31G at a 1:1A dilution of ;V5!~ 92116201 ~ ~ ~ ,~ ~ ~ ~cr/us9~/O~oso initial concentration for either 2 cr 4~ minutes, .
followed by another 1:10 dilution and then serial four-fold dilutions for the entire period.
Cells were exposed to C31G at a 1.:1.00 and then a serial fourfold dilutions of initial concentration for entire period.
fee Figure ~.
~,e Z
Tlae protocol and results of the second study follows:
~3aterials:
Cells: . cell line ~rTCC ~R19 T cell ~itirus: IIIIh .
Test compounds: Compounds C3RG and N-9, supplied as 5%
sohxtions, were filtered through a low binding oe~2 d gilter prior' t~ 'diluti89g.
~ot~col a 3.. aerial 2 fold dilut3ons of compounds N~9 and C31G
in ~~ ad just~.d t~ p.Ci ~ s ~ w~rø. pr~..par~.d o Aaighest concentration was ~~ and the lowest was ~~o0~~e ~~ initial reonc~ntrations were ~, ~,i, a ~, 0. rG:d, 0 a ~~~, 0 a 0~' and 0 a 0d'! ~ as will as a control wittaout drug. The control titration was done .twice.
3.4 1~ x 95mm sterile plastic tubes with 0.~ ml each 25 0~ concentrated w3rus (at least 1 x R~~ TCI0~0/ml) wars set~up. 0.b ml of each c~mpound.dilution were transgerr~d to a tubs (dilation of 1: ~.0 of ttae initial drug c~nc~antrations~.
~w Inati~n was ~~r, 3.0 ~inut~i~ at r~o~ t~p~rature, ~30 and was tersainated (or slowed) by diluting R:RO in complete growth medium fon_ice~.
~ a ~dd~.'gaonal s ,P..rial .~'~ fold dilutlon'Le' ('3 dilutions w~,~ a final dilution esiual t~ 1~T8R250) in complete mediu;~n on ice were garepared.
35 5. ~50 ~xl of the virus dilutions wexe added to ~plicat~ wells of 96 well trays (tT botto~a) containing 3 ~ 1:0~ ~C~I yells in 50 u1.
'~1'~ 92/lfi2Al ~ ~ ~ ~ ~ ~ ~ P~l'/ZT891/0~060 . . .
-~ 18 -.6o minutes were allowed for virus absorption. The y cells were washed twice by centrifuging the plates at l.SOA rpm for 5 minutes and aspirating the . supernatants. The final cell pellets were S resuspended in 10o u1 of mediuaa and transferred to flat bottom 96 well trays. The results are shown in figures 8 and 9.
~x~le 8 to Concentrate (CCon) Comprises:
zmauryl stains ~(~o~ ai) ~.ooo pts Lauramiaae oxide (3A~ ai) s7o pts Citric Acid ~aonohydrate 69 pts The above are stirred to a uniform solution. At a 15 dilution ~f one part to ~0, the composition should have a pIi of ~a8~ at the a~lass electrodes ~tative concentration es~aal to 28.5 active ingredients (a3) .
amp Supposito~ies (inserts) for use with or without Condoms 2o CCo~ (of E9Cample 8) ~~fr ,pts PEG-32 ~OO~ pts pEG-2o , aooo opts Povidone 7~ pts the above ara stirred to solution at 4S°C. and injected a~ into molds, cooled and ejected gor packaging.
~~x~ a ~o Contraceptive Sponge CCon (of Example 8) 3~S~
Added to each mold for Curine~ urethane: Charge in mold 3o provided taith polyester loop for pest ~oi~al removal of the sponge.
spez~icidal has, Cr or bellies for use with CerviCa7. Caps Condoms, diaphragms or alone~~prior to 3c C~itus.
Gc~:l--1 Con (of 'Example $) 7.~ pts Gelatin A2o0 ~ 1:5 pts ~!V~ 92/Ik2il1 fCT/US91/OSObO
Glycerine 10.0 pts Flydroxyethyl Cellulose (high viscosity Grade) 0.~ pts Water 81.1 pts ~ Gel~2 .~s above with the substitution of 1.0 pt of Nonoxynol-9 for 3.5 pts of CCon (of Example 8J.
Procedure - The gelating and cellulose gum are triturated in the glycerine and added to the water sit ~5°C. and stirred to solution. The surfactants are added to the vessel and the warm solution removed for packaging. ,~ uniform fluid high visca~sity gel forms on cooling.
~'elly 1 and 2 Clear fluid contraceptive bellies are prepaired by substitution of 1.~ pts of high viscosity grade hydrcxypropyl or hydroxypxopyhaethyl cellulose for the gelatin and hydroxyethyl cellulose of the abode examples.
Creme 1 and ~
The Gel formulations above are converted to Cream gormul~tions by incorporation ~f ~.~ pts of cetyl ~lcolaol in Gel 1 or ~ formulations by dissolving tie alc~hol in the glycerine at ~9°C. before trituration cg th~ gelating and cellulose guars.
Era r~~.e 12 Contraceptive Film ' ~.~ ~s of gelatin Type AIOC~ is tr3.tu~ated raith A.5 lbs of hydroxyethylcelluose. 31 fibs of 3~ glycerine are added. Solution is mixed thor~uglaly to form a slurry. add 33 lbs srf CCon of Example S and 15 lbs ~f water. Waran to ~0°C. Mix until gums and gelatin ire conn~letely hydrated. Solution is poured on ~olyel~taylsne sheet to cast a film of about ~ mm thick to ~5 bra cut for films to be.used as contraceptive films after coaging.
fNACTIVATINCi ENVELOPED VIRUSES AND SPERM
BACRGRODNQ OF TFiE INVENTION
1. Fiel.~i of the Invention The present invention relates to a novel method and novel articles for inhibiting the activity of enveloped viruses. The invention also relates to treatment: of viral infections. More particularly, the invention relates to a method for inhibiting the development of diseases and infections caused by enveloped viruses. In one aspect the invention particularly relates to a method of inhibiting the activity of viruses whose major mode of transmission is sexual. In other aspects the invention also relates to methods of inhibiting the activity of enveloped viruses whose mode of transmission is nonsexual. The compositions of use in the invention are also effective in the inhibition of bacteria and fungi Which coexist with viruses or viral infections. Additionally, the invention relates to a treatment for virus related diseases,-particularly sexually transmitted diseases related t.o AIDS, and to diseases related to this and other opportunistic infections of the immune-compromised host.
The method of the invention relates to using mixtures of betaines and amine oxides in the inhibition of viruses and treatment of viral infections. The betaine is selected from the group consisting of (a) an alkyl-N-betaine, an alkyl-N-sulfobetaine, an acyl-N-betaine, an alkyl N-substituted aminopropionic acid and an alkylimidazolinium betaine and the amine oxide is '1'4~P19211fe~01 ~, ~,,~~ ~ ~~ ~ ~ P~.'T/~JS9110S06!! , selected from the group consisting of (b) an alkyl-N, N-dimethylamine oxide, an alkyh-N, N-dihydroxyethylamfne oxide and an acylamide t-amide ~~cide. The term ~'betaine~' when used herein means an N-dimethyl glycine and their lo~rer alkyl homologs. The term includes N-dimethyl amino propionic acids and sulfo betaines which are the sulfonic acid analogs of such compounds. Unless otherwise specified a r1-dimethyl compound is intended.
Psore particularly, the .invention relates to a method for aGmploying mi~cture~s of alkyl. N-di (lower alkyl) betainss srrd alkyl N-di(lo~rer alkyl) amine oxides in the inhibition of enveloped virtases grad ease of these m3~etures in the treatment of infections caused by these viraases. The mixtures. may also be used as spermicides, either alone or in combination with conventional spermi.cides. These mixtures may be used in combination with contraoeptive devices or maybe incorporated into the contraceptive device.
2. ~scr~nt$on of the Prim A~
It is known that certain mixtures ~of amines are effective,antimicrobial. agents against gram negative and gram positive bacteria. For 3.nstance, it is known that certain mi9ctures of a) alkyl-3d-betaine, alkyl-id-su3.fob~taine, acyl-N-betaine, alkyl N-substituted aminopropionic acid or ma alkylimidazolinium betaine and (b) alkyl-N,t~-dimethylamine oxides alkyl-N, E~1-dihydroaeyethylamine oacide ~or acylamide t-amide oacide can bye wised for skin degaraaing, cleansing and deodorizing (see for e9tampla U.S. Patent 4,x82,952, issued to E.N.
~a~lsl ~.~e Patent N~. 4,~~~,~5~ issued t~ Ea~a ~i~h', and V.So ~at~.nt ~~. 4,i0~,3280 issued t~ E.~. .
~iichaelsj. These compositions are also useful for long term inhibition of body odor. fixtures of the same active ingredients are also known t~ enhance oral hygieaae by reducing oral ~aicroflora and inhibiting f~rmation of dental placy~ae. (U. S. Patent 4,839,158 issued to E.B. Michaelsj. Compositions iaf this type are ~'A19?J142~1 :~~ ,~ ~ ~i ~ ~ ~~'lllS91/
g also lm2own to be effective gurigicides. Corner, A.~I. , :et ' al. ~~ 9 ',~~ob'si ~,aerits arid Che~tother~nv. 32(3)x350 °
353 (lKarch 1988) s Corxaer, AwM. The.?oL?x'rial oø Clini _a7 Deritistrv. ~rol. 2(2,034 ° ~$w 'a99~)). (see also v.s.
Patents 4,75,35~, 4,1~~s328, 4,183,952 and 4,839,1,5$
issued to E.13. Michaels.) It is alho lcno~a that nonionic surface°active agents possessing ether or amide linkages between the hydrophilic and hydrophobic portions of the molecule 1~ rapidly inactivate the infectivity of herpes simplex erirus I and II. (Asculai, F. S . , et al w ~timicrobi~l ~gen~ts Cnemg pww vog. 13e6$6 ° 690 (19~$D~w .
hsculai et alw also states that cytocidal activity has been used as an index o~ antiviral activity. The compositions utilized 3.n t3ais invention have an ad~rantage over the compositions described in Ascaalai et al. in that these compositioaas inactivate viruses and bacteria tahila~ ~schibiting loss cytocidal activity.
The sperbnicfde Nonoxynol°9 (N°9), ~nas been found to have bactericidal and viricidal effects. For example, N°9 has been ~ouaad to inactivate viruses related t~ ~D~ (awgs - ~, h~an i~~nod~~iw°ien~ direst .
and herpes ~~p~~iruses (I and ~~) o In~y~tZ'o. $d°
~ has been shown to be egfective agaiazst the .organisms ~5 that cerise gonorrhea, chlamydia, syphilis, tricho~aoniasis, and other sexually transmitted diseases.
(U.s°. Fhas~acopeial convention UsPDI Update 199o pps. _ _ X55 ° 756j.
effective in inhibiting the activity of enveloped viruses.
The invention provides <~ method of inhibiting the activity of enveloped viruses fo:r which a major mode of transmission is sexual. The invention relates to a method for treating diseases and infections caused by enveloped viruses. These compositions are also effective in the inhibition of bacteria and fungi that co-exist with viruses or viral infections, a.nd for tre<~tment of bacterial and fungal infections wr.ich co-exi:~t with viruses or viral infections.
The invention. also provides a method for disinfecting air and surfaces contaminated with enveloped viruses.
More specifically, the present invention provides use of a composition for inhibiting the activity of an enveloped virus or as a spermicide, the composition comprising a mixture of (a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfcbetaine, aryl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more t=hereof, (b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof, and (c) acid in an amount to provide the composition with a pH of 4 - 8 as measured when the betaine and amine onside together comprise 0.5 weight percent of the composition.
4a The pre:~ent invention also provides a contraceptive device containing a spermicide composition, wherein the spermicide comprises a mixture of (a) a betaine selected from an alkyl--N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-sub:~tituted aminopropionic acid and an alkylimidazol.inium beta_ine, or a mixture of two or more thereof, (b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide,. or a mixture of two or more thereof, and (c) acid in an amount to provide the composition with a pH oj= 4 - 8 as measured when the betaine and amine oxide together- comprise 0.5 weight percent of the composition.
The present invention also provides a composition for inhibiting the activity of an enveloped virus or sperm, the composition comprising a mixture of (a) a betaine selected from an alkyl-N-betainE~, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof, (b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, o:r a mixture of two or more thereof, and (c) acid .:Ln an amount to provide the composition with a pH c.~f 4 - 8 as measured when the betaine 4b and amine oxide together comprise 0.5 weight percent of the composition.
The invention also provides a method for preventing the transmission of enveloped viruses.
The compositions used in the method of the present invention can also be u:~ed as spermicides. These compositions can be used alone, with other known spermicides and with, or incorporated into, contraceptive devices such as condoms, ~;ponges, vaginal inserts, contraceptive films, diaphragms, ~.uppositories, contraceptive patches or sustained release devi.cea. These compositions can also be incorporated into douches or wipes. For use as viricides, these compositions can x~E= applied alone, with other spermicides, and with, or incorporated into, the contraceptive devices described above. The compositions can also be applied in the i=orm of a foam, gel, cream, salve, jelly or lotion. The compositions can also be applied in the form of a liquid, aerosol, mist or spray.
DESCRIFTION OF THE DRAWINGS
Figure 1: is a graph showing the effect of C31G (a composition according tc> the present invention) and the effect of Nonoxynol-9 (N-9) on sperm motility.
Figure 2: is a gr<:~ph showing the effect of C31G and the effect of Nonoxynol-9 (I~1--9) on total sperm count.
°
cf' ~~I~~6~~~ . ~ ~ ~~ ~ ~ ~ ~ ~~~U.~~IO~J~Q
-Figure 3 o is ' a graph s3xowirag the effect of C31G and the effect of Nonoatoynol(Fi-9) on the mean progressive velocity of sperm.
Figure 4: ins a graph showing in vitro 5. toxicity of C31G vs. N-~ on sup-TI cells.
Figure 5: is a graph shoring a five day toxicity study of 0316 vs. N-9 on cells.
Figure 6: is a graph showing co~aparing the effects on 0316 vs. R1-9 on ~v.
Figure ~: is a graph showing the effect of 0316 on .
Figure ~: is a c,~raph comparing inactivation of HIV by e3lG and ~-~.
Figure 9: is a chart comparing. inactivation 3.5 of HIV by C31G and N-9.
19~L'A~T.~D r9Ea~~F~'~OPT OF IIdyENTION
The method of the inve:ation relates to using mixtures of betaines and amine oxides in the inhibition of ~nvelope~d viruses and treatment of viral infections ~0 caused by enveloped viruses. The method of the invention also relates to using lures of betaines and aanine oacides in the inactivation of enveloped viruses.
The betaines that can be used in this invention are alDcyl-N-betaines, alkyl-N-sulfobetaines, acyl-8d-25 betaines, alkyl N-substituted auinopropionic acids or alkyli~idazolinium betaines or. es thereof. The a~.ine oxides that can be used in this inveaation are a~.kyl,~-I1, Ie1-di9Ltethylamine o'tides, alkylmNs ~T~
dihydroscyethylamine oxidise or acyla~ide t-auide oxides 30 or mixtures thereof. ~'hese compositions are also effective for the treata~errt o~ viral, fungal, and ~aicrvbial infections anr~ cont~inations. These compo~~.tions are effective in inhibiting enveloped ~iz~tses that are transmitted se~ta~ally or nonse~cually.
35 These ~c~mp~sitions are also effective in the inhibition o~ bacteria and fungi which coexist with viruses or viral infections. These compositions can also be used 9p'°192/162~1 s ,~-a :a 4~ u3 pf.'T/US91/05060 topically.
Typically, these compositions are applied to areas wher~ viruses are or can be transmitted. This includes application in the vagina, to mucous membranes, and to the s~Cin.
These compositions can also be used as sper~nicides, either alone or in combination with other spermicides. These compositions can else be used with or incorp~rated into contraceptive devices such as, for.
1~ example, condo~as, diaphragms, sponges, contraceptive films, suppositories, sustained release devices, and contraceptive patches. Far ple, the compositioh may be incorporated into a lubricant applied to a condom or as part of a reservoir at the tip of a condom, or incorporated into a contraceptive sponge, contraceptive film, suppository, sustained release device or contraceptive patch. A contraceptive film can comprise ttae composition described above, together with, 7~ype A
gelatin, cellulose gum and a polyhydric alcohol. The compositions can also be used in contraceptive foams, gels, jellys, or~aams. 3'he compositions can also be used in douches or use in pre~veaating the transmission of viruses, these compositions can be used alone, Baith other sper~micid~s and ~aitia or incorporated into a contraceptive device as described above. fihis invention also comprises a method for inhibiting the transmission of viruses that cause sensually transmitted diseases which comprises applying the compositions to2those parts og the anatomy that ire erposed to body fluids emanating 3a from anotk~er during sexual activity.
These compositions have also unexpectedly been found t~ be less toxic to mammalian cells than Nonoxoynol-9 (P1-9) (See Figures ~ axed 5) . Table 1 shows that these camposition~ have equivalent ~perm3cidal activity to N-9,. which is one of the few surfactants approved by the FDA for use as a spermicide.
For use in topical applications, the ~~ 9~/1~r2~1 ,~,. ~' ~9 ~ ~ ~~ ~C~'/iJ~9g/05060 _ compositions can also be incorporated into liquids, creams, salves, lotions, foams and gels.
The invention also provides a method for disinfecting air and inanimate surfaces, for example, in an operating room or laboratory. Morn particularly, this invention provides a method for disinfecting areas which era contaminated with enveloped viruses. These compasitions can also be incorporated into sprays, mists, wipes, aerosols or devices which produce sprays, mists or aerosols. These compositions can also be applied as liqeaids. .
according to the method of this invention;
these compositions may be used as viricides, fungicides and bactericides.
The compositions eaaployed in the method of the invention comprise an admixture of betaine~a and amine oxides. The betaines used in this invention are sal~scted from the group- consisting of (a) al7cyl-N°
betaines, ~lltyl-N°sulfobetaines, aryl-~T°betainas, alkyl N°substituted aminopropionic acid, alkylimidazolinium betaines and mixtures of two or more thereof. Typically the betaines have two lower~alkyl groups bonded to the nitrogen atom. Most effectively they have two methyl substituetats on the nitrogen atom. The amine, oxides used in this invention are selected from the group ror~si~sting of b) a an alkyl°N,~1-dimethylamine oxides, . . alDcyl°N, g~°d~aydroxyathylamina oxide or . ~cylamida t°amine oxides and mixtures of two or more th0~~3of. Typically, the betaine and amine oxide components are present in a molar ratio of from a.a5 to 5:1, preferably in a molar ratio of iwi. T~~ alkyl°~°betaiJde, belie alkyl°~°
sulfobetaine~ the aryl-~1°betaine, the alkyl P1°
substituted 2paminopropionic acid and alhy~imidaaolinium betaine (also referred to-as cocoamphoacetates) employed ~5 ae the components (a) of the composition of the 3.nvention have structures; respectively, as followss ~~°~ 9~ois2o~ ~'~ ~ ~criusm,~o6o e~~c~~~~
~~,~~ omm.~~~~ ~ua~as~s where R is a higher al~eyl group having ~ro~ ZO to 18 carbon atoms, preferably ~ro~ 12 - 16 carbon atoa~e.
2p tWhen used herein the teran lower alkyl mm~eans an alkyl group of from 1 to 3 carboxs atoms.
Illustrative o~ these a~~re~ea°ationed substances are: (1) corn-N-betaine, cetyl-N-bstaine, etsa~ryl-N-~etaine, i~ostearyl,-N-betains, ol~yl-N-~5 betain~r (~) coco-N-aulphobetaine, ~etyl-N-~ulphobetaine, et~aryl-N-aul~obataine, ieost~aryl-N-~l~obetain~, oleyl-N-sul~ob~tainh~ (3j coc~amidc-N-b~taine, cetylaa~3.d~-H-betaine, etearylamido-N-b~taine, iaoetearyla~ido~N-b~taine, ~leyl.~a~irao~~'gbe~aine~ (~) N-~~ corn-2 ~nin~propioxai~ acid, N-~etyl~-~~a~inopropi~nic said, Nmst~a~rl~~-~a~einopropioa~ic amid, N-iaostearyl-2-aaainopropionic aciel, N-~oley7:-~-aaninopropionic acid, N~~tearyl~bas(2~-a~ainopropionic acid), N-~leyl~bis (~Winopropionic acid) ,. N~-Loco-bis (~~aaninoprogsionic ~~ acid) , N-cetyl-bis (~-~nian~propionic aca.d) , ~~ 921(201 , '~ y 'q~ ~~~.,~ ~ v~ PGT/U591/OS!?50 - ;,~, _ ~, ~ Ci ..
_ g _ (5a N-lauryl-bis(2-a:ninopropionic acid) 1-hydroxyethyl-1-carboxymethyl-2-decylimidazoliupn betaine;
1-hydroxyethyl-1-carboxymethyl-2-dodacylimidazoliun betaines 1-hydroxyethyl-1-carboxymethyl-Z-cocoi~nidazolium bat~ixaa; 1-hydroacyethyl-1-carboxyaaethyl-2-stearylimidazolium betaineo 1-hydroxyethyl-1-carboxymathyl-2-oleyli~aidazoliuan betainea or ~aixtures of the same.
When used here the term ~'coco~ is that used in ,the ~TF~ (designations of Cosmetic and Toiletry arid ~a~ran~~l sociation, lAasha, ~a~aD and is us~.d t~
indicate al~Cyl groups pr~sgnt in coconut oil~ is~o~a nniaetvare of alkyl groups of from 10 to 1~ carbon atoms.
The designations ~f the compounds listed herein are 9.5 those of the CTF'l~.
The ~l~ alkyl-N,N-diethylamine oxide, (2) alkyl-N,N-dihydroxylathylamine oxide, or (3, acylamide t-am3.ne oxide employed as component (b) of the aforementioned aura, respectively, have the structure:
~3 N~
30 where R is a higher alleyl group o~ from 10 to 1~ carbon atoms, for instance, radicals such as decyl, undecyl, lauryl, tridecyl, myristyl, cetyl, stea~yl, isostearyl or oleyla Eat~plary of the amine oxides are: decyl-N,N~di~ethyla~aine oxide, lauryl-N,N-dimethylamine oxide, 35 stearyl-N-N-dimethylamine oxide, oleyl-N,N-dianethylamine oxide, coco-N,N dihydroxyethylamine oxide, cetyl-N,N-.~~ 92/1!201 ~ ~ ~ ~ '~ ~ ~ ~'T/ZJS91/Ut5Q60 dihydroxyethyla~nina oxide, oleyl-N,N-dihydroxyethylamine oxide, N,N-dihydraatyethylamine oxide, oleyl-N,-N_ dihydroxyethyl-amine oxide and mixtures of the same.
The components (a) and (b) are usually admixed 5 and acid is then added in an amount necessary to adjust the pF1 of a 0.5~ solution to bete~een 4 - 0, :.preferably to pH ~.5 ~ 5.5. The pN of an aqueous solution comprising the above enumerated components of the invention is determiaaed by employing an ac;unous solution 10 of ~.5~, by weight, total of active components_typically at a glass electrode, to precisely define the acidity of the compositions In general, the acid used to adjust the overall composition to this reglaired pN is .any organic or inorganic acid'that is compatible with the intended use of the composition, for example, hydrochloric acid, phosphoric acid, sulfuric acid, citric acid, acetic acid or nicotinic acid. The balance of the composition, after allowing for the acid is usually an acceptable BO solvent, such as water or a lower (~~,-C,~) monohydric aliphatic alcohol, for a total of 1~0 parts or more.
i~Ihere water is employed, small amounts. of a lower alDcyl alcohol, such as ethanol or propanol, may.also be added to provide ease in formulati~n. acceptable diluents, carriers and excipients are, for example,. ethyl or isopropyl alcohols, polyethylene glycol, povidone, polyhydric.alcohols, glycerine, cellulose gums, gelatin, colorants and fragrances. ~f necessary, the p13 of the total composition is then adjusted to the reduisite pN
3t9 by adding a suitable inorganic or organic acid ~aereto.
The result is a substantially uniform, homogeneous, relatively nontoxic compositi~n having enhanced actier3ty against envelope viruses, bacteria amd fungi.
It has been unexpectedly found that tha~se compositions exhibit (1) row mammalian cell toxicity, a property which is known to correlate with low irritation ~?6'iu 92~1x2~~ , ~~ ..~ ~ ~ ~ ~,~ PCH'/IJS91/05050 - z~. -and low toxicity when used in contact with mucous membranes ~7,~u a C~.i.aaical Dmnt~.strv 2 (2) :34 - 38, (19~0D), and (2j highly efficacious inactivation of enveloped viruses although cytocidal activity is low.
a In the past, research has used cytocidal activity as an index of activity. (~Asculai, ~.5., l~ratianicrb. Agents ~lemother. 13:6°'x8 - 690 X1978) ) .
In practice, the total amount of the components (a) and (b] of the overall composition can A range from ~03~ ~ ~~~, preferably from .03~ - 30~
depending on the intended meant of use. Far example, concentrations used are, approximately 20~ ~ 30~ i»
contraceptive films and 0.2~ to 2~ in gels.
Compositions for use in this invention comprise alDcyl'N-di(lower alkyl) glycines and alkyl P1~
di(lower alkyl] amine oxides, wherein the lower alkyl is Cg-3. ~ne clays of betaines I have found to be partically useful in this invention are the alkyl N-d3.methyl betaines, such as cocobetaines and lauryl 20 betaines. Particularly useful amine oxides for use in this invention are the an alkyl N-dimethyl amine oxides, such as cocod3methyl amine pxides and lauryl dimethyl amine oxides.
Ane particular.camposition that can b~ used in 2~ this invention comprises cocobetaine, cocamine oxide and citric acid monohydrate.
mother composition that can be used in this :Lnvention comprises lauryl betaine, lauram3ne oxide and citric acid monohydrate.
30 In such compositions, the molar ratio of betaines to amine oxides is normally from 5:1 to 1:5, preferably in a molar ratio of 2:~. to 1:2, more preferably about l: ~..
~ther compositions that can be used in this 35 invention comprise mixtures of betaines, amine oxides, gelatin having a Bloom strength of 1.00 r 300 and a molecular weight from about 76,000 to about 300,000, c , i,,..> Y~ g'~.°TiUS91/~b5pG0. , , - la -polyhydric alcoYiols and cellulose gins.. Such compositions are described in a copending U.S.
application b~eingf filed simultaneously with the present application and having U.S. application Serial Edo.
D7/673, 63~..
Compositions used in this invention can .
inhibit flee activity of viruses that are related to AIDS. It is also expected that these compositions can.
inhibit the activity of I~SV--1 and ~S'V~2. It is also aD expected that the compasitions used in this inv~ea~ation can inhibit ~Iepatitis A, S and C. It is expected that the compositions can be used to inhibit virvases, bacteria and fungi which are associated ~aitb sexually transmitted diseases (STD°s).
The compositions of this invention may be useful in relation to the followings Transmission of ~I~l is often associated with the co~transmission of ~ther viral and~or anicrobial pathogens. Indeed, some investigators &ave suggested that HIV may not be the sole ageaat responsible for A7CDS
(asee D~aesba~rg, P.li. X1991) ~ Pratl. Aced. Sc~
88 s 1575 ~ 1579 J 7Gemaitxe, ~t.~, t~uetard, D. , Benin, ~C. , lbdontagnier, L. and serial, A. (199~j . ~t~s;V3~-~, 14105 16) . For tlaisv reason, ant~3.c~obial agents, such as ~5 those described in this application, a,~itb a broad spectrum of activities aga3rast viruses, bacteria, and ysasts such as Candida may be of particular value in the grnvention and treatment of Acquired Imxmune Deficiency Syndrome (AIDS).
~30 2) It is thought fleet certain bacteria knoxan to cause STD°s array aid in 1 transmission. In persons who hare been exposed to DIS1, certain bacteria which e:ause STD's often fail to respond to tberapies.that are otherwise highly effective. ~EIV infection may help the 35 spread of a bacterial STD that in turn helps to spread lil<i. STD's such as chlamydia, cbancroid, syphilis, genital herpes Grad gonorrhea which cause ulcerations of A~~H 9Z/16201 _ .. FCT/US91/05060 ~~~~~~~$.3 e~
-the genital skin seem to a.ncrease the risk of acquiring or transmitting I3IV infection seacually. oral, : . O. , et al.~cien~ific ~mer~.cana ~~~g~)ssa ~ ~9 ~gebruary m~~).
The compositions described above nay also be of use to inactivate other enveloped viruses, including vaccinia, varicella, herpes zoster, cytomegalovirus, Epstein Harr virus, influenza, mumps, measles, rhinovirus, rabies and rubella. In order to facilitate a further understanding of the invention, the following to examples are presented primarily for the purposes of illustrating more specific details thereof. Vitas invention is not to be deemed as limited thereby except as defined in the claims.
~~~~L a ~
~.5 Ttae composition described below is a concentrate of C~1G, an a~e,~ui~nolar preparation of cocobetaine and cocodimethylaaaine oxides (designations of CTF.~ Cosmetic and Toiletry and Fragrance association, Wash., D.C.) [t'FTA, which can be used in a number of different configurations.
Cocobetaine; 3A.5$ active ingredient (~1):
xs~.9 xg ~~05.~ 1b), cocamin~ oxid~,~~~.5~ ~~1)0 ~~a~.~ xg c3~s 1b), ~itri~r aid ~onohyt~, V w7JT i dl o 6D xg ~ ~ ~ 1b ) , ~5 ' ~rifi~d water, ~sCf.~°o 1'.e8 xg ca~ 1b) /
To ~aa'ce about ~5~.~ xg c~s2.5 1b) C31G at ~9m 6~ ~, at a citation ~~~ ~ ~ pH ~ ~ a ~ a r~a~~~.~
The spermicidal activity of C31G of eaca~aple 1 30 was compared to the spermicidal activity of nono9cynol~9 ~~s9) a (a1 The studies were con~hacted using the Hamilton--or~ ~pBr~ 8'lotility aly~~re ~a~pl~s of pooled washed seen were incubated with dilutions of the two compounds ~5 for fifteexi seconds and were analyzed din triplicate) for determination of the ~ini~aum concentration.for inmctivation by the following criteria:
!'V~D 9B/162~1 ~~ . ~~ ~; , 3~ PCT/1JS91/Q50~0 1. Inhibition of sperm motility (Figure 1j 2. Decrease,in total sperm count (Figure 2j 3. inhibition of the mean progressive sperm v~l~citye (1C figure .d j A.s shown in Table 3., c3lG and 1d--9 gave identical resultsm Table 1 C31G .N°9 Total Inhibition of motility 15o ppm 15o ppm g~~ Decrease in sperm Count 15o ppm 1l5~ ppm 50& Decrease in Progressive velocity 125 ppm 1.x5 ppm ~xamole ~
1.5 The cytotoa~ic effects of C31G and N°9 on mammalian cells were determined in several types of assaysa Cell thxicity is an indication of the relative safety and Comfort in use of surfactants in contraceptives or prophylactics.
2 o ~!s shown in Figure ~ ~ a taro week study monitoring drug effects on SiJIP-TI cells, (a human lymphocytic cell linej, C31G demonstrated minimal to~i~sity ~ at V . V od'~ t io ppm~ ~hil~ ~°~ at 4.iiB same concentration was ~tremely toxic.
~5 ~xalmpl.e ~
Figure 5 shows 3~iT reduction in Chi cells after five days of continuous ~xxposaare. T7nder these conditions C~lG showed no toxicity to ~aammalian cells at ' 3 PPm I~~0~3~, whale N°9 showing toxicity, reducing ~~ ~a~mm~lisn cell. viability by 50~ at the same coaacentration. It is unesepected that a compound having the same spermicidal activity as N-9 would be less toxic t~ mammalian cells than 1J-9.
lixamaale 5 ~5 hntiviral activity of C3lG~was tested using ~v°'~ and ~~~'~.
To test the effect of c3lG and ad~9 on herpes llv~D 9Z/1b201 , ~, .~ '~ ~ ~ ~ ~ PCT/v~91/05060 simplex virus type-1 (SOS strainj, the virus stock was prepared in Vero (~igrican green monkey kidney) cells.
The virdas was released from the cells by one freeze-thaw cycle followed by sonication. The virus titer was 4.5 ~c 5 108 plac~aae forming units (PF'Uj/ml, as determined on Vero cells. The drixg forgaulations used were identical to the drugs in the spermicidal study.
~'he stock concentration of each drug was 5%.
Two-fold serial dilutions were made, down to O.o4~, in 10 PBS pB ~.4 at room temperature. ~.~ u1 of each dilution was added to 220 u1 of virus (108 PFOj, giving final c~nas°entration~ ~~ ~ a 5 - ~ ~ ~~~t~ a ~ese sampl~.s were.
incubated at room temperature-gor 10 ;din, and then i0ou1 c~f each was immediately diluted to 1 ml with ice~cold 15 8% PBS. 10-fold serial dilutions were then made, down to ~.0-~ gor titration of remaining infectious virus on Vero cells in 2~-well plates. Plaques were counted 36 ~aours post-infection.
concentration t%1 ltasidual rus ~'~llml~
Vi _ ~ . C3~
0.004 ~ 3.5 108 3.5 x 108 x ~. ~~~ 2. 10~ ~ d o..T ~ ~0~~ . ' /
x ~sVlS - 1.1 ~~~ 2.5 x 105 .
x~
0.03 32~~ X1,67 ~.o$ <1~' ~wi~~
s 1~. ~16~ . ~~6~
0.25 ~16~ <167 ~.5 <157 <167 ~0 Note that these are titers PFU~mlj, rather than (ie.
a'~DSOlute nu3~ers o~ P~C1. The titer deter~'ned for untreated virus was X4.'7 108 x PF~~ml in the experiment wing N-9 and 4.5 ~c 108 in the experiment using PFU~mi ' ~~l~e . .
It is noted that complete inhibition o~ plaque ~ormati~n by C3lG occurs at more than one dilution below ttaat of N-9. See Figure 6.
vvo 9Z>m~~om ~~ ~3 ~a ~ ,~ PCT/~J59mB~5060. . .
_ 16 ~xam~?~.e 6 ' The inactivation of HIV-1 (d~IDS) virus was studied in two experiments. The first study compared the effects of C31G of H~1-1 at two different exposure times, 2 minutes and ~5 minutes. The x~ext study compared the relative activity of C31G and N-9 on HIV
using the same virus strain and measuring antiviral activity by reduction of virus titer as determined by reduction of P-24 HIV antigen.
1A The protocol and results of the first study follow:
CTS ~f C31G C2d HOH~ 0~7E~'TCIE~CY VIRUS .
Materials: .
~Tirus: HIV-1 strain 3B (5ac105 IDEA units/ml) Cells: SUP-Tl cell line (CD4~° lymphoid cells which produce characteristic cell fusion with giant cells and syncytia when infected with HIV) Protocol:
1. Serial fourfold dilutions of C31G in PBS (4.A~ -A.AA.~~ and PHS alone as control) were prepared. pH
2A was adjusted to 5w5.
2. Pooled aliquots of viral stock were prepared and ~C31G was added at each concentration~ at 1:9 d~t~rgents~~r~s ratio tl:lA detergent dilution) e' These were incubated for either 2 or 45 minutes.
3. Serial fourfold dilutions of each virus/detergent mixture down to 1:~A96 were prepared.
16.~ u1 of each virus/detergent dilution from each series were added to four replicate wails of SUP~T1 cells (10~ cells in 15A u1 volumem 1:1A detergent 3o dilution followed by further fourfold dilutions).
5. Then wells were examined twice weekly for two weeks and each well was scored positive or negative for the presence of characteristic viral syncytia ~r non-syncytial ghost formation due to detergent lysis.
dote a Virus was exposed to C31G at a 1:1A dilution of ;V5!~ 92116201 ~ ~ ~ ,~ ~ ~ ~cr/us9~/O~oso initial concentration for either 2 cr 4~ minutes, .
followed by another 1:10 dilution and then serial four-fold dilutions for the entire period.
Cells were exposed to C31G at a 1.:1.00 and then a serial fourfold dilutions of initial concentration for entire period.
fee Figure ~.
~,e Z
Tlae protocol and results of the second study follows:
~3aterials:
Cells: . cell line ~rTCC ~R19 T cell ~itirus: IIIIh .
Test compounds: Compounds C3RG and N-9, supplied as 5%
sohxtions, were filtered through a low binding oe~2 d gilter prior' t~ 'diluti89g.
~ot~col a 3.. aerial 2 fold dilut3ons of compounds N~9 and C31G
in ~~ ad just~.d t~ p.Ci ~ s ~ w~rø. pr~..par~.d o Aaighest concentration was ~~ and the lowest was ~~o0~~e ~~ initial reonc~ntrations were ~, ~,i, a ~, 0. rG:d, 0 a ~~~, 0 a 0~' and 0 a 0d'! ~ as will as a control wittaout drug. The control titration was done .twice.
3.4 1~ x 95mm sterile plastic tubes with 0.~ ml each 25 0~ concentrated w3rus (at least 1 x R~~ TCI0~0/ml) wars set~up. 0.b ml of each c~mpound.dilution were transgerr~d to a tubs (dilation of 1: ~.0 of ttae initial drug c~nc~antrations~.
~w Inati~n was ~~r, 3.0 ~inut~i~ at r~o~ t~p~rature, ~30 and was tersainated (or slowed) by diluting R:RO in complete growth medium fon_ice~.
~ a ~dd~.'gaonal s ,P..rial .~'~ fold dilutlon'Le' ('3 dilutions w~,~ a final dilution esiual t~ 1~T8R250) in complete mediu;~n on ice were garepared.
35 5. ~50 ~xl of the virus dilutions wexe added to ~plicat~ wells of 96 well trays (tT botto~a) containing 3 ~ 1:0~ ~C~I yells in 50 u1.
'~1'~ 92/lfi2Al ~ ~ ~ ~ ~ ~ ~ P~l'/ZT891/0~060 . . .
-~ 18 -.6o minutes were allowed for virus absorption. The y cells were washed twice by centrifuging the plates at l.SOA rpm for 5 minutes and aspirating the . supernatants. The final cell pellets were S resuspended in 10o u1 of mediuaa and transferred to flat bottom 96 well trays. The results are shown in figures 8 and 9.
~x~le 8 to Concentrate (CCon) Comprises:
zmauryl stains ~(~o~ ai) ~.ooo pts Lauramiaae oxide (3A~ ai) s7o pts Citric Acid ~aonohydrate 69 pts The above are stirred to a uniform solution. At a 15 dilution ~f one part to ~0, the composition should have a pIi of ~a8~ at the a~lass electrodes ~tative concentration es~aal to 28.5 active ingredients (a3) .
amp Supposito~ies (inserts) for use with or without Condoms 2o CCo~ (of E9Cample 8) ~~fr ,pts PEG-32 ~OO~ pts pEG-2o , aooo opts Povidone 7~ pts the above ara stirred to solution at 4S°C. and injected a~ into molds, cooled and ejected gor packaging.
~~x~ a ~o Contraceptive Sponge CCon (of Example 8) 3~S~
Added to each mold for Curine~ urethane: Charge in mold 3o provided taith polyester loop for pest ~oi~al removal of the sponge.
spez~icidal has, Cr or bellies for use with CerviCa7. Caps Condoms, diaphragms or alone~~prior to 3c C~itus.
Gc~:l--1 Con (of 'Example $) 7.~ pts Gelatin A2o0 ~ 1:5 pts ~!V~ 92/Ik2il1 fCT/US91/OSObO
Glycerine 10.0 pts Flydroxyethyl Cellulose (high viscosity Grade) 0.~ pts Water 81.1 pts ~ Gel~2 .~s above with the substitution of 1.0 pt of Nonoxynol-9 for 3.5 pts of CCon (of Example 8J.
Procedure - The gelating and cellulose gum are triturated in the glycerine and added to the water sit ~5°C. and stirred to solution. The surfactants are added to the vessel and the warm solution removed for packaging. ,~ uniform fluid high visca~sity gel forms on cooling.
~'elly 1 and 2 Clear fluid contraceptive bellies are prepaired by substitution of 1.~ pts of high viscosity grade hydrcxypropyl or hydroxypxopyhaethyl cellulose for the gelatin and hydroxyethyl cellulose of the abode examples.
Creme 1 and ~
The Gel formulations above are converted to Cream gormul~tions by incorporation ~f ~.~ pts of cetyl ~lcolaol in Gel 1 or ~ formulations by dissolving tie alc~hol in the glycerine at ~9°C. before trituration cg th~ gelating and cellulose guars.
Era r~~.e 12 Contraceptive Film ' ~.~ ~s of gelatin Type AIOC~ is tr3.tu~ated raith A.5 lbs of hydroxyethylcelluose. 31 fibs of 3~ glycerine are added. Solution is mixed thor~uglaly to form a slurry. add 33 lbs srf CCon of Example S and 15 lbs ~f water. Waran to ~0°C. Mix until gums and gelatin ire conn~letely hydrated. Solution is poured on ~olyel~taylsne sheet to cast a film of about ~ mm thick to ~5 bra cut for films to be.used as contraceptive films after coaging.
Claims (44)
1. Use of a composition for inhibiting the activity of an enveloped virus or as a spermicide, the composition comprising a mixture of:
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
2. Use of a composition for inhibiting the activity of an enveloped virus, the composition comprising a mixture of:
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
3. A use according to claim 1 or 2, wherein the virus is selected from human immunodeficiency virus, a virus associated with AIDS, herpes simplex virus-type I, herpes simplex virus-type II, hepatitis A, hepatitis B, hepatitis C, vaccinia, varicella, herpes zoster, cytomegalovirus, Epstein Barr virus, influenza, mumps, measles, rhinovirus, rabies and rubella.
4. A use according to claim 3, wherein the virus is a virus associated with a sexually transmitted disease and is selected from human immunodeficiency virus, herpes simplex virus-type I, herpes simplex virus-type II, cytomegalovirus, and Epstein Barr virus.
5. Use of a composition as a spermicide, the composition comprising a mixture of:
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
6. A use according to any one of claims 1 to 5, wherein the composition comprises an alkyl-N-di-(lower alkyl) betaine and an alkyl N-di-(lower alkyl) oxide, where the lower alkyl is C1-C3.
7. A use according to any one of claims 1 to 6, wherein the composition comprises:
(a) an alkyl dimethyl betaine;
(b) an alkyl dimethyl amine oxide; and (c) acid in an amount sufficient to adjust the pH of the medicine or composition from 4 - 8 when measured in an aqueous solution of components (a) and (b) in an acceptable carrier.
(a) an alkyl dimethyl betaine;
(b) an alkyl dimethyl amine oxide; and (c) acid in an amount sufficient to adjust the pH of the medicine or composition from 4 - 8 when measured in an aqueous solution of components (a) and (b) in an acceptable carrier.
8. A use according to any one of claims 1 to 7, wherein the composition comprises at least one alkyl dimethyl betaine and at least one alkyl dimethyl amine oxide.
9. A use according to any one of claims 1 to 7, wherein the betaine is cocobetaine or lauryl-betaine, and the amine oxide is cocoamine oxide or lauramine oxide.
10. A use according to claim 9, wherein the betaine is a cocobetaine and the amine oxide is a cocamine oxide.
11. A use according to any one of claims 1 to 10, wherein the betaine and the amine oxide are present in a molar ratio of from 1:5 to 5:1.
12. A use according to any one of claims 1 to 11, wherein the composition has a molar ratio of betaine to amine oxide of 1:5 to 5:1, and the betaine and amine oxide together are present in the composition at a concentration of 0.01 weight percent to 40 weight percent.
13. A use according to claim 12, wherein the composition has a molar ratio of betaine to amine oxide of 1:2 to 2:1, and the betaine and amine oxide together are present in the composition at a concentration of 0.03 weight percent to 30 weight percent.
14. A use according to claim 13, wherein the medicine or composition has a molar ratio of betaine to amine oxide of 1:1, and the betaine and amine oxide together are present in the medicine or composition at a concentration of 0.2 weight percent to 2 weight percent.
15. A contraceptive device containing a spermicide composition, wherein the spermicide comprises a mixture of:
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
16. A contraceptive device according claim 15, wherein the composition comprises an alkyl-N-di-(lower alkyl) betaine and an alkyl N-di-(lower alkyl) oxide, where the lower alkyl is C1-C3.
17. A contraceptive device according claim 15 or 16, wherein the composition comprises:
(a) an alkyl dimethyl betaine;
(b) an alkyl dimethyl amine oxide; and (c) acid in an amount sufficient to adjust the pH of the composition from 4 - 8 when measured in an aqueous solution of components (a) and (b) in an acceptable carrier.
(a) an alkyl dimethyl betaine;
(b) an alkyl dimethyl amine oxide; and (c) acid in an amount sufficient to adjust the pH of the composition from 4 - 8 when measured in an aqueous solution of components (a) and (b) in an acceptable carrier.
18. A contraceptive device according to claim 15, 16 or 17, wherein the composition comprises at least one alkyl dimethyl betaine and at least one alkyl dimethyl amine oxide.
19. A contraceptive device according to any one of claims 15 to 18, wherein the betaine is cocobetaine or lauryl-betaine, and the amine oxide is cocoamine oxide or lauramine oxide.
20. A contraceptive device according to claim 19, wherein the betaine is a cocobetaine and the amine oxide is a cocamine oxide.
21. A contraceptive device according to any one of claims 15 to 20, wherein the betaine and the amine oxide are present in a molar ratify of from 1:5 to 5:1.
22. A contraceptive device according to any one of claims 15 to 21, wherein the composition has a molar ratio of betaine to amine oxide of 1:5 to 5:1, and the betaine and amine oxide together are present in the medicine or composition at a concentration of 0.01 weight percent to 40 weight percent.
23. A contraceptive device according to claim 22, wherein the composition has a molar ratio of betaine to amine oxide of 1:2 to 2:1, and the betaine and amine oxide together are present in the medicine or composition at a concentration of 0.03 weight percent to 30 weight percent.
24. A contraceptive device according to claim 23, wherein the composition has a molar ratio of betaine to amine oxide of 1:1, and the betaine and amine oxide together are present in the medicine or composition at a concentration of 0.2 weight percent to 2 weight percent.
25. A contraceptive device according to any one of claims 15 to 24, wherein the composition is in a form selected from a foam, gel, cream, salve, jelly, lotion, liquid, spray, mist, aerosol and wipe.
26. A contraceptive device according to any one of claims 15 to 25, wherein the device is a condom in which the composition is incorporated in the device in a manner selected from incorporation into a lubricant applied to the condom and incorporation in a reservoir at a tip of the condom.
27. A contraceptive device according to any one of claims 15 to 25, wherein the composition is incorporated into a device selected from a wipe, a douche, a contraceptive sponge, a contraceptive film, a sustained-release device and a suppository.
28. A composition for inhibiting the activity of an enveloped virus or sperm, the composition comprising a mixture of:
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
29. A composition for inhibiting the activity of an enveloped virus, the composition comprising a mixture of:
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
30. A composition according to claim 28 or 29, wherein the virus is selected from human immunodeficiency virus, a virus associated with AIDS, herpes simplex virus-type I, herpes simplex virus-type II, hepatitis A, hepatitis B, hepatitis C, vaccinia, varicella, herpes zoster, cytomegalovirus, Epstein Barr virus, influenza, mumps, measles, rhinovirus, rabies and rubella.
31. A composition according to claim 30, wherein the virus is a virus associated with a sexually transmitted disease and is selected from human immunodeficiency virus, herpes simplex virus-type I, herpes simplex virus-type II, cytomegalovirus, and Epstein Barr virus.
32. A spermicidal composition comprising a mixture of:
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
(a) a betaine selected from an alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, an alkyl-N-substituted aminopropionic acid and an alkylimidazolinium betaine, or a mixture of two or more thereof;
(b) an amine oxide selected from an alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, or a mixture of two or more thereof; and (c) acid in an amount to provide the composition with a pH
of 4 - 8 as measured when the betaine and amine oxide together comprise 0.5 weight percent of the composition.
33. A composition according to any one of claims 28 to 32, wherein the composition comprises an alkyl-N-di-(lower alkyl) betaine and an alkyl N-di-(lower alkyl) oxide, where the lower alkyl is C1-C3.
34. A composition according to any one of claims 28 to 33, wherein the composition comprises:
(a) an alkyl dimethyl betaine;
(b) an alkyl dimethyl amine oxide; and (c) acid in an amount sufficient to adjust the pH of the medicine or composition from 4 - 8 when measured in an aqueous solution of components (a) and (b) in an acceptable carrier.
(a) an alkyl dimethyl betaine;
(b) an alkyl dimethyl amine oxide; and (c) acid in an amount sufficient to adjust the pH of the medicine or composition from 4 - 8 when measured in an aqueous solution of components (a) and (b) in an acceptable carrier.
35. A composition according to any one of claims 28 to 34, wherein the composition comprises at least one alkyl dimethyl betaine and at least one alkyl dimethyl amine oxide.
36. A composition according to any one of claims 28 to 34, wherein the betaine is cocobetaine or lauryl-betaine, and the amine oxide is cocoamine oxide or lauramine oxide.
37. A composition according to any one of claim 36, wherein the betaine is a cocobetaine and the amine oxide is a cocamine oxide.
38. A composition according to any one of claims 28 to 37, wherein the betaine and the amine oxide are present in a molar ratio of from 1:5 too 5:1.
39. A composition according to any one of claims 28 to 38, wherein the composition has a molar ratio of betaine to amine oxide of 1:5 to 5:1, and the betaine and amine oxide together are present in the composition at a concentration of 0.01 weight percent to 40 weight percent.
40. A composition according to claim 39, wherein the composition has a molar ratio of betaine to amine oxide of 1:2 to 2:1, and the betaine and amine oxide together are present in the medicine or composition at a concentration of 0.03 weight percent to 30 weight percent.
41. A composition according to claim 40, wherein the medicine or composition has a molar ratio of betaine to amine oxide of 1:1, and the betaine and amine oxide together are present in the medicine or composition at a concentration of 0.2 weight percent to 2 weight percent.
42. A composition according to any one of claims 15, wherein the composition is in a form selected from a foam, gel, cream, salve, jelly, lotion, liquid, spray, mist, aerosol and wipe.
43. A composition according to claim 42, wherein the composition is in a form selected from a foam, gel, cream and jelly.
44. A composition according to any one of claims 28 to 42, further comprising an acceptable diluent or carrier.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US673,784 | 1991-03-22 | ||
| US07/673,784 US5314917A (en) | 1991-03-22 | 1991-03-22 | Method for inactivating enveloped viruses and sperm |
| PCT/US1991/005060 WO1992016201A1 (en) | 1991-03-22 | 1991-07-17 | Method for inactivating enveloped viruses and sperm |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2106683A1 CA2106683A1 (en) | 1992-09-23 |
| CA2106683C true CA2106683C (en) | 2002-09-24 |
Family
ID=24704111
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002106683A Expired - Fee Related CA2106683C (en) | 1991-03-22 | 1991-07-17 | Inactivating enveloped viruses and sperm |
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| Country | Link |
|---|---|
| US (2) | US5314917A (en) |
| EP (2) | EP0733361B1 (en) |
| JP (2) | JP3228928B2 (en) |
| KR (1) | KR100221486B1 (en) |
| AP (1) | AP327A (en) |
| AT (2) | ATE176399T1 (en) |
| AU (1) | AU661968B2 (en) |
| CA (1) | CA2106683C (en) |
| DE (2) | DE69130871T2 (en) |
| OA (1) | OA09911A (en) |
| RU (1) | RU2110256C1 (en) |
| WO (1) | WO1992016201A1 (en) |
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| AU4214497A (en) * | 1996-09-12 | 1998-04-02 | Simon Everard Barton | Composition comprising an antiviral or antibacterial agent for preventing transmission of diseases |
| IT1305313B1 (en) | 1998-07-17 | 2001-05-04 | Colla Paolo | 3,4 - DIHYDRO- 6- BENZYL-4-OXOPYRIMIDINE REPLACED AND RELATED PROCESS OF PRODUCTION AND USE IN THE THERAPY OF HIV-1 INFECTIONS. |
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| US7086403B2 (en) * | 2000-12-05 | 2006-08-08 | Church & Dwight Co., Inc. | Condom with male genital desensitizer lubricant |
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| US6635679B2 (en) * | 2001-05-14 | 2003-10-21 | Akzo Nobel N.V. | Methods and compositions for inactivating viruses |
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| US7544696B2 (en) * | 2003-01-24 | 2009-06-09 | Research Triangle Institute | Spermicidal and/or antifungal composition and methods of using the same |
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| WO2005019417A2 (en) * | 2003-08-14 | 2005-03-03 | The Bio Balance Corporation | Bacterial strains, compositions including same and probiotic use thereof |
| AR057623A1 (en) | 2005-11-28 | 2007-12-05 | Omega Bio Pharma H K Ltd | MATERIALS AND METHODS FOR THE TREATMENT OF VIRAL INFECTIONS |
| WO2007100917A2 (en) * | 2006-02-28 | 2007-09-07 | Beierle John W | Antimicrobials and related methods |
| US20090118352A1 (en) * | 2007-11-07 | 2009-05-07 | Esawtech, Ltd. | Broad spectrum microbicidal and spermicidal compositions and methods |
| EP3610868A1 (en) | 2011-05-26 | 2020-02-19 | GRI Bio, Inc. | Amino- or ammonium-containing sulfonic acid, phosphonic acid and carboxylic acid derivatives and their medical use |
| ES2581482T3 (en) | 2011-05-26 | 2016-09-06 | Jado Technologies Gmbh | Hydroxy-substituted amino and ammonium derivatives and their medical use |
| EP2809648B1 (en) | 2011-05-26 | 2019-04-03 | GRI Bio, Inc. | Oxygenated amino- or ammonium-containing sulfonic acid derivatives and their medical use |
| EP2879691B1 (en) | 2012-08-06 | 2019-03-27 | Biogen MA Inc. | Methods for inactivating enveloped viruses |
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| CH600878A5 (en) | 1975-04-28 | 1978-06-30 | Gaba Ag | |
| US4117107A (en) | 1975-10-17 | 1978-09-26 | Noxell Corporation | Method and composition for improving oral hygiene |
| CA1052273A (en) * | 1975-12-18 | 1979-04-10 | Edwin B. Michaels | Antimicrobial compositions |
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| US4439355A (en) | 1976-12-02 | 1984-03-27 | Colgate-Palmolive Company | Elastic detergent product of improved foaming power after use |
| US4130637A (en) | 1977-01-31 | 1978-12-19 | Colgate-Palmolive Company | Anti-plaque agents |
| US4145436A (en) * | 1977-11-07 | 1979-03-20 | Michaels Edwin B | Antimicrobial compositions and method for using same |
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| US4213961A (en) | 1978-03-23 | 1980-07-22 | Beecham, Inc. | Oral compositions |
| US4209533A (en) | 1979-01-25 | 1980-06-24 | University Of Pittsburgh | Antibacterial agent and method |
| DE3138770A1 (en) | 1981-09-30 | 1983-04-14 | Hoechst Ag, 6230 Frankfurt | "HAIR AND BODY CLEANING AGENT CONTAINING ALKYLSULFATOBETAINES" |
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| US4490353A (en) | 1983-07-13 | 1984-12-25 | Colgate-Palmolive Company | Antiplaque dentifrice with improved fluoride stability |
| DE3528209C2 (en) * | 1984-08-07 | 1993-10-28 | Fresenius Ag | disinfectant |
| US4839158A (en) * | 1986-02-25 | 1989-06-13 | E. B. Michaels Research Associates Inc. | Process and composition for oral hygiene |
| DE3613944C1 (en) | 1986-04-24 | 1987-08-13 | Goldschmidt Ag Th | Process for the production of a highly concentrated, flowable and pumpable betaine solution |
| DE3706484A1 (en) * | 1987-02-27 | 1988-09-08 | Bernhard Dr Janiak | Virucides and spermicides containing quaternary ammonium salts |
| US5244652A (en) | 1991-03-22 | 1993-09-14 | E. B. Michaels Research Associates, Inc. | Viscous surface active composition |
-
1991
- 1991-03-22 US US07/673,784 patent/US5314917A/en not_active Expired - Lifetime
- 1991-07-17 RU RU93056144A patent/RU2110256C1/en not_active IP Right Cessation
- 1991-07-17 EP EP96108577A patent/EP0733361B1/en not_active Expired - Lifetime
- 1991-07-17 CA CA002106683A patent/CA2106683C/en not_active Expired - Fee Related
- 1991-07-17 AT AT91913586T patent/ATE176399T1/en not_active IP Right Cessation
- 1991-07-17 DE DE69130871T patent/DE69130871T2/en not_active Expired - Fee Related
- 1991-07-17 WO PCT/US1991/005060 patent/WO1992016201A1/en active IP Right Grant
- 1991-07-17 EP EP91913586A patent/EP0576425B1/en not_active Expired - Lifetime
- 1991-07-17 DE DE69132621T patent/DE69132621T2/en not_active Expired - Fee Related
- 1991-07-17 JP JP51247491A patent/JP3228928B2/en not_active Expired - Fee Related
- 1991-07-17 AU AU82227/91A patent/AU661968B2/en not_active Ceased
- 1991-07-17 AT AT96108577T patent/ATE201593T1/en active
- 1991-10-22 KR KR1019910018612A patent/KR100221486B1/en not_active IP Right Cessation
-
1992
- 1992-03-23 AP APAP/P/1992/000370A patent/AP327A/en active
-
1993
- 1993-09-16 OA OA60412A patent/OA09911A/en unknown
-
1994
- 1994-04-04 US US08/223,096 patent/US6297278B1/en not_active Expired - Lifetime
-
2001
- 2001-06-05 JP JP2001170022A patent/JP3940568B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| AU8222791A (en) | 1992-10-21 |
| AP9200370A0 (en) | 1992-04-30 |
| JP3940568B2 (en) | 2007-07-04 |
| ATE201593T1 (en) | 2001-06-15 |
| AU661968B2 (en) | 1995-08-17 |
| DE69132621T2 (en) | 2002-04-18 |
| KR920017649A (en) | 1992-10-21 |
| EP0576425A1 (en) | 1994-01-05 |
| JPH06505700A (en) | 1994-06-30 |
| KR100221486B1 (en) | 1999-09-15 |
| EP0733361B1 (en) | 2001-05-30 |
| US5314917A (en) | 1994-05-24 |
| US6297278B1 (en) | 2001-10-02 |
| EP0576425B1 (en) | 1999-02-03 |
| OA09911A (en) | 1994-09-15 |
| EP0733361A3 (en) | 1996-10-23 |
| AP327A (en) | 1994-03-21 |
| DE69132621D1 (en) | 2001-07-05 |
| JP3228928B2 (en) | 2001-11-12 |
| ATE176399T1 (en) | 1999-02-15 |
| CA2106683A1 (en) | 1992-09-23 |
| EP0733361A2 (en) | 1996-09-25 |
| DE69130871T2 (en) | 1999-09-23 |
| WO1992016201A1 (en) | 1992-10-01 |
| RU2110256C1 (en) | 1998-05-10 |
| DE69130871D1 (en) | 1999-03-18 |
| JP2002037733A (en) | 2002-02-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |