zno-~6~
PC~-101~
~S~ OF~ D~ U~l~L:~PoLYM~RS AS
ANTIMICRO~I~L AGENTS IN P~RSONAL CAnR PRO~UCT~
Thls lnvention relates generally to ant~icrobial agents for per~onal care items such as bath soapR~ and more specifically, to a cla6s of pyrlthione-containing polymers character~2ed by exceptionally low toxicity, and excellent anti~croblal efficacy, when ut~lized in ~hampoos, skin-care medicament~, and the like.
Metal salts of pyrlthione, such as zinc pyr~thione, are well known to be effective antimicroblal agents for use ~n cereain per60nal care items such as anti-dandruff shampoo~. However5 these metal salts of pyrithione have a relat~vely low molecular weight and are relatively quickly absorbed pyr~thiones have re6ulted in limitations in both the total dosage level snd the allowable uses for these metal ~alt3 in human health care productc.
Pyrlthlone-conta~nlng bioactive polymers are also known in the art, as dlsclosed, for example, in U.S. Patent Nos. 4,565,856; 4,596,864; and 4,632,881. However, the disclosed use of the polymers in these patent~ is as pre6ervatlves, mildewcides, and marine antifoulants in paints a8 well as wood preservatives.
Heretofore, the use of pyrithione-containin~
polymers ln personal care formulations, such as soaps, shampoos, and 6kin care medicament6, has not been known based on the knowledge of the precent inventors.
- 2 -In one a~pect, the present lnvention relatec to a method of u~ing a pyrithione-containlng polymer which comprises incorporating said pol~mer in a7a anti~icrobial effective amount into a personal care product, said polymer being characterized by the empirical structural formula (I):
~2 ~~ (I) ~ 1_1~ .
Pr wherein Rl, R2 and R3 are indivldually selected from hydrogen and alkyl groups havlng from l to 4 carbon atoms;
and PT repre~ents the pyrlth~one moiety which i8 defined by the follow~ng formula (II) wherein the pyrithione molety i8 connected through the sulfur atom, or the oxygen atom, or a combinatlon thereof;
(II) ~7 ~ 0 ~ s-wherein R4, R5, R6 and R7 are individually selected from hydrogen, lower aikyl group havlng 1 to about 8 carbon atoms, lower alkoxy group having l to about 8 carbon atoms, a n~tro group, and a halo group (e.g. F, Cl~ Br and I~.
In another respect, the preseDt invention relatec to a soap, ~hampoo, or skin-care medicament compri8ing an antimlcrob~al effective amou~t of the above-descrlbed polymer.
These and other aspect~ will become appar~nt upon readin~ the following detailed description of the invention.
The monomerlc precursors to poly~ers of formula ~I~
may b0 made by reacting sodium pyrithione ~ith a correspondlng vinyl-containing acid chloride compound. Th$s 13 reaction may be carried out in the presence of water or suitable or~anic solvent. This reaction ~B illustrated by the following reaction (A) where sodium pyrithione i6 reacted with methacryloyl chlor~de:
~ H C O C C + N~CI (A) cl ~ c-o W' r~
(ON~O
\ -Suitable vinyl-containing acid chloride reactant~
1~ include methacryloyl chloride, 393- di~ethylacryloyl chloride ~nd crotyl chloride. The mo~t preferred is methacryloyl chlorid~, whlch will provide a polymer of formula (I) having Rl=CH3, R2= R3-H, because of cost considerations.
The preferred pyrithione moiety is the unsubstituted pyrithione (R4=R5=R6=R7=Hj. It is widely avallable as ~odium pyrithioneO
T~e reaction between these vinyl acid chlor~des and sodium pyrithione may be carried out with any conventional reaction conditiona for this type of condensatlon reaction.
It 18 preferred to employ ~ molar exce~a of the vinyl acid chlorlde. It 1~ also preferred to employ water a~ ~ solvent and to carry out the reaction at a temperature of bet~een about -10 C. and about ~30 C. and at atmoEpherlc pre~sure.
Su~table reaction time~ ran8e from about 1 to about 5 hours. The formed product will precipitate from the reactSon mlxture and may be recovered by any conventional solids/liquid aeparatlon technique. It is preferred to purlfy the precipitated product by extractlon with a dllute NaOH solution. The recovered product is preferably stored at temperature below room temperatures (e.g. -10 C. to ~10 C.) to prevent decomposltion. It should be noted that the reactlon parameters for making the moietles of formula ~I) are not crltlcal limitatlons to the present inventlon and the present invention contemplates any and all ~uitable reaction condlt~ons.
The pyrlthione-containing compounds as described above may be homopolymerized or alternately the~e compounds may be co-polymerized with v~nyl bond-containing monomers.
The polymerization is conducted by any conventlonal method such as ~olvent, bulk, suspenslon or emulslon-type polymerizatlon i~ conducted by any conventional method such as solvent, bulk, suspenslon or emul~ion-type polymerizatlon. Varlous polymerlzatlon initlator6 such as benzoyl peroxide, acetyl peroxide, azob~s (isobutyronitrile) (also known as AIBN~ or lauryl peroxide may be used.
Speclfically, the homopolymers and co-polymer6 of thi~
~nventlon may be prepared by any of the procedures conventionally employed for making acrylate or methacrylate homopolymerR or co-polymer6 contalning 6aid monomer6. It 18 preferred and deslrRble to conduct the polymerlzation under an inert gaseous atmosphere (e.g. nltrogen) and i~ ~n Z(~ 647 aqueous solutlon whereby the mono~er or co-m omer~ are ~u~pended. However, ~t may be del~irable in ~ome in~tance~
to carry out the polymerl~ation in an orgAn~C solvent ~uch aR benzene, toluene, hexane, cyclohexane, tetrahydrofuran or the llke. Preferably, the monomer~ and solvent are ag~tated and the inltlator in then added.
The conditlons of the reaction, such as the concentrations of the monomer and the lnitlator, the type of inltlator~ and of the solvent, vary according to the desired polymer to be formed.
The duratlon and the temperature of the reactlon depeDds on the desired polymer aa well as the ~olvent and the ln~tiator. Preferably, reaction temperatures from about 40 C. to 100 C. are employed. Preferably, the reaction time is between about 1 and about 16 hour~.
At the end of the reactlons, the homopolymers or co-polymers are separated from the react~on mixture and dried according to convent~onal technlques.
Sultable ethylenically unsaturated co-monomers include the follow~ng: ethylene, propylene, butadiene, leoprene, tetrafluoroethylene, vinyl chloride, vinylidene chloride, vinylldene flourlde, 8 tyrene, indene, coumarone, vinyl acetate, vinyl alcohol, vlnyl formal, acrolein, methyl vinyl ketone, vinyl pyrrolidone, maleic anhydride, acrylonitrlle, v~nyl ether~ having the formula CH2=CHOR8, acrylic acid, acrylamlde, methacrylic esters of the formula C~2=C(CH3)C02R8. acrylic e8ter8 of the formula C~2=CHC02R8 and cyanoacrylic esters havlng the formula CH2=C(CN)C02R8, wherein R8 i~ a lower alkyl group havlng 1 to 4 carbon atoms.
Preferred co-polymerfi u~eful in the present lnvention contain polymerlc units or moieties of formula (I), above, a8 well a~ poly~eric unit~ or moleties derived from other methacrylate~ or acrylates 118 discloced n the preceding peragraph. In the case of co-polymes~, terpolymer~, and the like, the weight fraction of the the monomer~ of for~ula (I) pre~ent i8 sultably any amount which results in an antimicrobially-effective bioactive polymer.
Preferably, thi~ welght fraction may be from about 0.01% to about 50% by w~ight of the total polymer.
In an alternative embodiment, it i~ also possible to attach the pyrithione moiety to 8 preformed poly~er. For example, poly~methylacryloyl chloride) could be reacted with sodium pyrithione to add the pyrithione moiety at certaln site~ on the polymer chain. Alternatively, a vinyl-contalning pyrlthione derivative can be grafted directly onto a cellulo~ic polymer, auch a6 a polysaccharlde, in the presence of a 6uitable polymerlzation catalyst.
It i8 also possible to attach other biocides (e.g., alkyl tin and quaternary ammonium moieties to the polymer chaln beslde6 the pyrlthione moietles for a more comprehens~ve attack on invading org~nlsms.
Tbe polymerc useful in the present lnvention have many deslrable attributes. They possess good antimicrobial activity and are compatible w~th components of conventional soaps, shsmpoos, skin-care med~caments, and the like. The~e polymers are also non-volatile, hydrolytlcally-stable, thermally-stable, and may be soluble in water and organic solvent~. Furthermore, they form no undesirable color~ in typical per~onal care items. Still further, they are co~t competit~ve with known antimicrobial additives used ln conventional ~kln care formulatlon~.
2(~ 7 Ihe polymers useful in the present lnvention are suitably employed in an antimlcroblally-effective a~ount in a dealred personal care product. Thi8 "ant~mlcrobiall~-effective amount" 1~ preferably between about 0.1 welght percent and about 30 weight percent of cuch polymer~ ba~ed on the total weight of the personal care product.
Whlle the invention has been described above with reference to speclfic embodiments thereof, it is apparent that many changes, modlficatlons and variations can be made without departing from the inventive concept d~sclosed herein. Accordlngly, lt is intended to embrace all such changes, modlflcations and variatlons that fall within the spir~t and broad scope of the appended claims. A11 patent appllcations, patents and other publicat~ons cited here~n are lncorporated by reference ln thçir entirety.
@~W~l ~art ~--PrQductio~ of Pyri~hi~n~ Methacrylat~ Mono~er A 2-liter bea~er was charged with 15g.8 g of 40 percent aqueoua ~odiu~ pyrlthione (0.5 ~ole) and 200 ~1 of water. A dropping funnel was charged with 90.4 ml of methacryloyl chloride (0.75 mole)~ The 2-llter beaker was cooled to +5C with aD ice/water bath. The ac~d chloride was added dropwi~e over 90 minutes. During addition, the temperature of the solution was maintained between +5C and +9C. After addltion was completed, the ~olution was stirred at +6C to ~7C for one hour. A ~olution of 20 g fiodium hydroxide (0.5 mole) in 300 ml of water was added over 10 minutes. After ~tirring an addltlonal 15 minutes at ~8C to ~10C, the 601ution wa~ brought to room temperature and stirred for one hour. The yellow solid that had formed was filtered and then washed with 200 ml of water. The solid was dissolved in 800 ml of methylene chloride and extracted three times with 500 ml of 4 percent sodium hydroxide. The methylene chloride solution wa~ dried over 60 g o magnesium sulfate for 15 minutes, filtered, and concentrated v~a roto-evaporation to ~ive 69.18 g off a yellow solid, for a 66.7 percent yield, with an a~ay of 94.1 percent.
The ~tructure was confirmed by lH-NMR, 13C-NMR
and IR.
Purification via preparatlve liquid chromatography gave an analytlcal sample having an m.p. of 146-147C.
Elemental Analysis: for CgHgNS02 Theory:
C, 55.37; H, 4.65; N, 7.17; S, 16.42: Found: C, 56.08; H, 4.80; N, 6.52; S, 14.87.
6~7 _ 9 _ ~art ~--Svnthe~ia_gf 1:24 Pvrithl~ne Methacrylate/-MethY1 Meth~rY1ate CO~PQ1VIne~
A 100 ~1 flas~ was charged w~th 1.56 g pyrlth~one methacrylat~ (0.008 mole), 19.~2 g of methyl methacrplate (0.192 mole), 1.384 g of 70 percent benzoyl peroxide (0.004 mole), and 20 ml of toluene. The fl~k ~a~ sealed and placed in an oven at 100C for 18 hours. After cooling to room temperature~ the ~olution wa~ concentrated by roto-evaporat~on to yield 23.14 ~ of the crude, desired product.
Twenty-one g of the crude polymer was dissolved ln 40 ml methylene chloride and precipitated by addin~ the 301ution 810wly to 700 ml of rapidly stirred hexane. The precipitated product was filtered, dr~ed, and recry~tallized from 40 ml ethanol. The dry recrystallized product was di~solved in 40 ml methylene chloride and precipltated by adding the solution to 700 ml of rapidly stirred hexane. After filtration and drying, 16.23 g of the desired product was obtained as an off-white powder. The structure was confirmed by NMR. The purified product was found to contain 0.14 percent nitrogen by K~edahl analy~is, corresponding to a pyrithione content of 1.2~ percent.
Part C -- Synthesis of a 1:3 Pyrithione Methacrylate/-Methyl MethacrylAte ~Q=polvmer A 50 ml flask wa6 charged with 4.88 g pyrlthione methacrylate (0.025 mole), 7.51 g of methyl methacrylate (0.075 mole), 0.692 g of 70 percent benzoyl peroxide (0.002 mole), and 10 ml of toluene. The flask was 6esled and placed in an o~en at 95~C for 16 hours. After cooling to room temperature, the 601ution was concentrated by roto-evaporat~on to yield 9.60 g of the crude, de~ired product.
Tbe crude product was di~solved in 25 ml ~ethylene chlor~de and precipitated by addin8 the solution to 800 ~1 of rapidly stirred hexane. The product wa~ flltered and drled ant again dissolYed in 25 ml methylene chloride and preclp~tated by adding the 801ution to 800 ml hexane. Thi~ preclpltate ~a~
filtered and drled to produce 7.14 g of the de~ired product as a pale yellow powder. The structure w~s conflrmed by N~R. The purified product wa6 analyzed to contain 1.05 percent nitrogen by ~jedahl analysi6, corresponding to a pyrithione content of 9.46 pereent.
Part D -- Preparation of the Shampoo Ba~e A shampoo ba~e wa~ prepared having the followlng compo~ition:
Weight Percent Grams STANDAPOL ES-2(1) 18.1 181.0 LEXAINE C( ) 11.4 114.0 Water 70.5 7Q5.0 Total 100.0 1000.0 (1) An aqueous solutlon of ~odium laureth sulfate, a product 2~ of Henkel Corporation.
(2) An aqueous 601ution of cocamidopropyl be~aine, a product of Inole~ Corporation.
The pH of the shampoo base was adju~ted to 7.11.
6~
Part ~--Preparation of the Full_~h~mRoo Fonmula~lon Shamp~o sample~ conta~ning the polymers frG~ Part~
and C were prepared for te~tlng. .Another 8hampoo ~mple cont&lning ~inc pyrlthione Wa8 prepare~ for comparson purpo~es. ~ach shampoo wa~ prep~red to yleld a pyrithione mo~ety concentration of 3 mg/ml of shampoo. The shampoo ba~e from Part D wa~ used ln the preparation of all of the Ramples.
~ach shampoo ~ample was ad~u~ted to a final p~ of 7.2 with citrlc acid or triethsnolamine, a~ requlred~
Componellt Sha~poo Formulati~n ln_~rams I II III
Shampoo Base 54 48.5 99.24 Polymer From Part ~(3) 6 Polymer From Part C - 1.5 Zinc ~y~ithione(4) - - O.Z~
Total ~si~ht in grams 60 50 100 Pyrlth~one Moiety Concentrat~on Smg/ml ) 1. 3 3 3
(3) A calculation error was di6eovered after the 8hampoo preparatiGQ and te~ting had been c~pleted. Thl~ 8hampoo contalned 1.3 ~g/ml pyrith~one ~o~ety rather than 3 ~g/~l.
14) 48.3 percent aqueou5 di~per~lon of zine pyrithione, ava~lable a Zinc OMADINE ( ), a product of Olln Corporation.
Par~ F- ~at Te8tin&
The backs of several group~ of rat~ were shaved using an electric cllpper. ~n Day 1, the rats were welghed~ a~erage 172 g (range9 117 to 208 g). The rats were weighed a~ain on Day 4 (average 192 g; range 134 to 225g3 to ad~ust the dosage.
The do~e of ~hampoo formulation used was 2 ml/kg. Three groups of four rats per group were used for the experiment.
On Days 1 through 10, the following procedure ~as repeated daily. While the shampoo was being stirred on a magnet~c atirrer9 aliquot~ of the shampoo were removed and applied on the cha~ed area of the rat. The shampoo wa8 spread evenly on an ~pproximate area of 2 c~ by 2 cm. The rat was i5 then placed in a cylindrical meshed-wlre restrainer for two hours after which tbe shampoo was washed off under running lukewarm tap water for one m~nute. The rat wa~ removed from the restra~ner and placed in a home cage.
On Day 11, 24 hours after the last sha~poo application, the rats were anesthetized with ether, the abdomen opened, and blood was collected from the abdominal aorta ~nto a heparln~zed syrlnge. The blood samples were centrifuged, and plasma was removed and stored in a freezer until analys~s.
The plasma samples were then analyzed for the presence of 2-methylsulfonyl-pyridine ("2MSP") by ga~ chromatography. The results are pre~ented in TABLE I below.
The average 2MSP level in Group I was 4 ng/ml and that in Group II was 8 ng/ml ("ng" denotes nanogram). The a~ount of blood collected from rats in Group III was insuff~cient to give relia~le data. Only one rat yielded sufficient blood for ~0~ 7 analy~s. Consequently9 Compari~on Formulatlo~ III wa0 re-te~ted ln a separate rat te~t ~nd found to prov~de ~ 2M~P
level in the rat'~ pla~ma of 42 n~/ml.
R~t B~ hJaL~al8 fQr 2-Methrl~ul~onyl-~yr~ine~2~rE~
Shampoo PlasmaZMSP
Formula1~n Rat No. (ml~ ~n~/ml)
4 4 3 6 4 ll III(5)9,10,11 1 each 0
(5) Due to the small volume of plasma obtained from three of the rats in this group, results for this group were judged inconclu6ive. In a subsequent re-te~t wherein the rats yielded the proper 4 ml of pla~ma, average 2-MSP level wa~ 42 mglml.
The above data shows the pyrithione-containing polymers to be less readily absorbed into rat blood strea~s, and therefore less toxic, than pyrithione salts.