WO1990006125A1

WO1990006125A1 - Use of pyrithione-containing polymers as antimicrobial agents in personal care products

Info

Publication number: WO1990006125A1
Application number: PCT/US1989/005408
Authority: WO
Inventors: Samuel I. Trotz; Theodore H. Fedynyshyn
Original assignee: Olin Corporation
Priority date: 1988-12-05
Filing date: 1989-11-30
Publication date: 1990-06-14
Also published as: AU4819690A; CA2004647A1

Abstract

Antimicrobial agents for personal care items such as bath soaps, and more specifically, to a class of pyrithione-containing bioactive polymers characterized by exceptionally low toxicity when utilized in such items. The polymers useful in the present invention have many desirable attributes. They possess good antimicrobial activity and are compatible with components of conventional soaps, shampoos, skin-care medicaments, and the like. These polymers are also non-volatile, hydrolytically-stable, thermally-stable, and may be soluble in water and organic solvents. Furthermore, they form no undesirable colors in typical personal care items. Still further, they are cost competitive with known antimicrobial additives used in conventional skin care formulations.

Description

USE OF PYRITHIONE-CONTAINING POLYMERS AS

AI-πiMICRQglA AGENTS IN PERSONAL CARE PRODUCTS

This invention relates generally to antimicrobial agents for personal care items such as bath soaps, and more specifically, to a class of pyrithione-containing polymers characterized by exceptionally low toxicity, and excellent antimicrobial efficacy, when utilized in shampoos, skin-care medicaments, and the like.

Metal salts of pyrithione, such as zinc pyrithione, are well known to be effective antimicrobial agents for use in certain personal care items such as anti-dandruff shampoos. However, these metal salts of pyrithione have a relatively low molecular weight and are relatively quickly absorbed pyrithiones have resulted in limitations in both the total dosage level and the allowable uses for these metal salts in human health care products.

Pyrithione-containing bioactive polymers are also known in the art, as disclosed, for example, in U.S. Patent Nos. ,565,856; 4,596,864; and 4,632,881. However, the disclosed use of the polymers in these patents is as preservatives, mildewcides, and marine antifoulants in paints as well as wood preservatives.

Heretofore, the use of pyrithione-containing* polymers in personal care formulations, such as soaps, shampoos, and skin care medicaments, has not been known based on the knowledge of the present inventors. In one aspect, the present invention relates to a method of using a pyrithione-containing polyβer which comprises incorporating said polymer in an antimicrobial effective amount into a personal care product, said polymer being characterized by the empirical structural formula (I):

wherein R. , R. and R, are individually selected from hydrogen and alkyl groups having from 1 to 4 carbon atoms; and PT represents the pyrithione moiety which is defined by the following formula (II) wherein the pyrithione moiety is connected through the sulfur atom, or the oxygen atom, or a combination thereof;

wherein R. , R₅, R, and R₇ are individually selected from hydrogen, lower alkyl group having 1 to about 8 carbon atoms, lower alkoxy group having 1 to about 8 carbon atoms, a nitro group, and a halo group (e.g. F, Cl, Br and I). In another respect, the present invention relates to a soap, shampoo, or skin-care medicament comprising an antimicrobial effective amount of the above-described polymer.

**? These and other aspects will become apparent upon reading the following detailed description of the invention. The monomeric precursors to polymers of formula (I) may be made by reacting sodium- pyrithione with a corresponding vinyl-containing acid chloride compound. This 0 reaction may be carried out in the presence of water or suitable organic solvent. This reaction is illustrated by the following reaction (A) where sodium pyrithione is reacted with methacryloyl chloride:

Suitable vinyl-containing acid chloride reactants 5 include methacryloyl chloride, 3,3- dimethylacryloyl chloride and crotyl chloride. The most preferred is methacryloyl chloride, which will provide a polymer of formula (I) having R-=CH-, R-= ₃=H, because of cost considerations. 0 The preferred pyrithione moiety is the unsubstituted pyrithione (R,=R₅=R,=R_=H). It is widely available as sodium pyrithione.

The reaction between these vinyl acid chlorides and sodium pyrithione may be carried out with any conventional 5 reaction conditions for this type of condensation reaction. It is preferred to employ a molar excess of the vinyl acid chloride.- It is also preferred to employ water as a solvent -and to carry out the reaction at a temperature of between about -10" C. and about +30* C. and at atmospheric pressure. Suitable reaction times range from about 1 to about 5 hours. The formed product will precipitate from the reaction mixture and may be recovered by any conventional solids/liquid separation technique. It is preferred to purify the precipitated product by extraction with a dilute NaOH solution. The recovered product is preferably stored at temperature below room temperatures (e.g. -10^β C. to +10° C.) to prevent decomposition. It should be noted that the reaction parameters for making the moieties of formula (I) are not critical limitations to the present invention and the present invention contemplates any and all suitable reaction conditions.

The pyrithione-containing compounds aa described above may be homopoly erized or alternately these compounds may be co-polymerized with vinyl bond-containing monomers. xhe polymerization is conducted by any conventional method such as solvent, bulk, suspension or emulsion-type polymerization is conducted by any conventional method such as solvent, bulk, suspension or emulsion-type polymerization. Various polymerization initiators such as benzoyl peroxide, acetyl peroxide, azobis (isobutyronitrile) (also known as AIBN) or lauryl peroxide may be used. Specifically, the homopolymers and co-polymers of this invention may be prepared by any of the procedures conventionally employed for making acrylate or methacrylate homopolymers or co-polymers containing said monomers. It is preferred and desirable to conduct the polymerization under an inert gaseous atmosphere (e.g. nitrogen) and in an aqueous solution whereby the monomer or co-monomers are suspended. However, it may be desirable in some instances to carry out the polymerization in an organic solvent such as benzene, toluene, hexane, cyclohexane, tetrahydrofuran or ⁵ the like. Preferably, the monomers and solvent are agitated and the initiator is then added.

The conditions of the reaction, such as the concentrations of the monomer and the initiator, the type of initiator, and of the solvent, vary according to the desired 1° polymer to be formed.

The duration and the temperature of the reaction depends on the desired polymer as well as the solvent and the initiator. Preferably, reaction temperatures from about 40" C.to 100° C. are employed. Preferably, the reaction -*--¹ time is between about 1 and about 16 hours.

At the end of the reactions, the homopolymers or co-polymers are separated from the reaction mixture and dried according to conventional techniques.

Suitable ethylenically unsaturated co-monomers ² ~ include the following: ethylene, propylene, butadiene, isoprene, tetrafluoroethylene, vinyl chloride, vinylidene chloride, vinylidene flouride, styrene, indene, coumarone, vinyl acetate, vinyl alcohol, vinyl formal, acrolein, methyl vinyl ketone, vinyl pyrrolidone, maleic anhydride, " acrylonitrile, vinyl ethers having the formula

CH_=CH0R-, acrylic acid, acrylamide, methacrylic esters of the formula CH„=C(CH,)C0₂R₈, acrylic esters of the formula CH₂=CHC0-R₈ and cyanoacrylic esters having the formula CH =C(CN)C0_R_, wherein R_g is a lower

30 alkyl group having 1 to 4 carbon atoms.

Preferred co-polymers useful in the present invention contain polymeric units or moieties of formula (I), above, as well as polymeric units or moieties derived from other methacrylates or acr lates as disclosed in the preceding paragraph. In the case of co-polymers, terpolymers, .and the like, the weight fraction of the the monomers of formula (I) present is suitably any amount which results in an antimicrobiallyt-effective bioactive polymer. Preferably, this weight fraction may be from about 0.01X to about 50X by weight of the total polymer.

In an alternative embodiment, it is also possible to attach the pyrithione moiety to a preformed polymer. For example, pol Gnethylacryloyl chloride) could be reacted with sodium pyrithione to add the pyrithione moiety at certain sites on the polymer chain. Alternatively, a vinyl-containing pyrithione derivative can be grafted directly onto a cellulosic polymer, such as a polysaccharide, in the presence of a suitable polymerization catalyst.

It is also possible to attach other biocides (e.g., alkyl tin and quaternary ammonium moieties to the polymer chain besides the pyrithione moieties for a more comprehensive attack on invading organisms.

The polymers useful in the present invention have many desirable attributes. They possess good antimicrobial activity and are compatible with components of conventional soaps, shampoos, skin-care medicaments, and the like. These polymers are also non-volatile, hydrolytically-stable, thermally-stable, and may be soluble in water and organic solvents. Furthermore, they form no undesirable colors in typical personal care items. Still further, they are cost competitive with known antimicrobial additives used in conventional skin care formulations. The polymers useful in the present invention are suitably employed in an antimicrobially-effective amount in a desired personal care product. This "antimicrobially-effective amount" is preferably between about 0.1 weight percent and about 30 weight percent of such polymers based on the total weight of the personal care product.

While the invention has been described above with reference to specific embodiments thereof, it is apparent that many changes, modifications and variations can be made without departing from the inventive concept disclosed herein. Accordingly, it is intended to embrace all such changes, modifications and variations that fall within the spirit and broad scope of the appended claims. All patent applications, patents and other publications cited herein are incorporated by reference in their entirety.

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EXAMPLE 1

Part A— roduction of Pvrithione Methacrvlate Monomer

A 2-liter beaker was charged with 158.8 g of 40 percent aqueous sodium pyrithione (0.5 mole) and 200 ml of water. A dropping funnel was charged with 90.4 ml of methacryloyl chloride (0.75 mole). The 2-liter beaker was cooled to +5*C with an ice/water bath. The acid chloride was added dropwise over 90 minutes. During addition, the temperature of the solution was maintained between +5°C and +9^βC. After addition was completed, the solution was stirred at +6^βC to +7^βC for one hour. A solution of 20 g sodium hydroxide (0.5 mole) in 300 ml of water was added over 10 minutes. After stirring an additional 15 minutes at +8°C to +10^βC, the solution was 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 was dried over 60 g of magnesium sulfate for 15 minutes, filtered, and concentrated via roto-evaporation to give 69.18 g off a yellow solid, for a 66.7 percent yield, with an assay of 94.1 percent.

The structure was confirmed by H-NMR, C-NMR, and IR. Purification via preparative liquid chromatography gave an analytical sample having an m.p. of 146°-147°C.

Elemental Analysis: for C_H_NS0-: 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. Part B—Synthesis of 1:24 Pyrithione Methacrvlate/- Methvl Methacrylate Co-Polymer

A 100 ml flask was charged with 1.56 g pyrithione methacrylate (0.008 mole), 19.22 g of methyl methacrylate (0.192 mole), 1.384 g of 70 percent benzoyl peroxide (0.004 mole), and 20 ml of toluene. The flask was sealed and placed in an oven at 100°C for 18 hours. After cooling to room temperature, the solution was concentrated by roto-evaporation to yield 23.14 g of the crude, desired product. Twenty-one g of the crude polymer was dissolved in 40 ml methylene chloride and precipitated by adding the solution slowly to 700 ml of rapidly stirred hexane. The precipitated product was filtered, dried, and recrystallized from 40 ml ethanol. The dry recrystallized product was dissolved in 40 ml methylene chloride and precipitated 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 Kjedahl analysis, corresponding to a pyrithione content of 1.26 percent.

Part C — Synthesis of a 1:3 Pyrithione Methacr late/- Methvl Methacrylate Co-Polvmer

A 50 ml flask was charged with 4.88 g pyrithione 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 sealed and placed in an oven at 95^βC for 16 hours. After cooling to room temperature, the solution was concentrated by roto-evaporation to yield 9.60 g of the crude, desired product. The crude product was dissolved in 25 ml methylene chloride and precipitated by adding the solution to 800 ml of rapidly βtirred hexane. The product was filtered and dried and again dissolved in 25 ml methylene chloride and precipitated by adding the solution to 800 ml hexane. This precipitate was filtered and dried to produce 7.14 g of the desired product as a pale yellow powder. The structure was confirmed by NMR. The purified product was analyzed to contain 1.05 percent nitrogen by Kjedahl analysis, corresponding to a pyrithione content of 9.46 percent.

Part D — Preparation of the Shampoo Base

A shampoo base was prepared having the following composition:

(1) An aqueous solution of sodium laureth sulfate, a product of Henkel Corporation.

(2) An aqueous solution of cocamidopropyl betaine, a product of Inolex Corporation.

The pH of the shampoo base was adjusted to 7.11. Part E—Preparation of the Full Shampoo Formulation

Shampoo samples containing the polymers from Parts B and C were prepared for testing. Another shampoo sample containing zinc pyrithione was prepared for comparison purposes. Each shampoo was prepared to yield a pyrithione moiety concentration of 3 mg/ml of shampoo. The shampoo base from Part D was used in the preparation of all of the samples. Each shampoo sample was adjusted to a final pH of 7.2 with citric acid or triethanolamine, as required.

(3) A calculation error was discovered after the shampoo preparation and testing had been completed. This shampoo contained 1.3 mg/ml pyrithione moiety rather than 3 mg/ml. (4) 48.3 percent aqueous dispersion of zinc pyrithione,

(R) available a Zinc OMADINE , a product of Olin Corporation.

Part F-—Rat Testing

The backs of several groups of rats were shaved using an electric clipper. On Day 1, the rats were weighed; average 172 g (range, 117 to 208 g). The rats were weighed again on Day 4 (average 192 g; range 134 to 225g) to adjust the dosage. The dose of shampoo formulation used was 2 ml/kg. Three groups of four rate per group were used for the experiment. On Days 1 through 10, the following procedure was repeated daily. While the shampoo was being stirred on a magnetic stirrer, aliquotβ of the shampoo were removed and applied on the shaved area of the rat. The shampoo was spread evenly on an approximate area of 2 cm by 2 cm. The rat was then placed in a cylindrical meshed-wire restrainer for two hours after which the shampoo was washed off under running lukewarm tap water for one minute. The rat was removed from the restrainer and placed in a home cage.

On Day 11, 24 hours after the last shampoo application, the rats were anesthetized with ether, the abdomen opened, and blood was collected from the abdominal aorta into a heparinized syringe. The blood samples were centrifuged, and plasma was removed and stored in a freezer until analysis. The plasma samples were then analyzed for the presence of 2-methylsulfonyl-pyridine ("2MSP") by gas chromatography. The results are presented 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 nanogra ). The amount of blood collected from rats in Group III was insufficient to give reliable data. Only one rat yielded sufficient blood for analysis. Consequently, Comparison Formulation III was re-tested in a separate rat test and found to provide a 2MSP level in the rat's plasma of 42 ng/ml.

___6LE_I

Rat Blood Analysis for 2-Methvlsulfonvl-pvridine ("2MPS")

Shampoo Formulation

II

(5) Due to the small volume of plasma obtained from three of the rats in this group, results for this group were judged inconclusive. In a subsequent re-test wherein the rats yielded the proper 4 ml of plasma, average 2-MSP level was 42 mg/ml.

The above data- shows the pyrithione-containing polymers to be less readily absorbed into rat blood streams, and therefore less toxic, than pyrithione salts.

Claims

WHAT IS CLAIMED IS:

1. A method of using a pyrithione-containing polymer characterized by incorporating said polymer in an antimicrobial effective amount into a personal care product, said polymer being characterized by the empirical structural formula:

wherein R. , R. and R, are individually selected from hydrogen and alkyl groups having from 1 to 4 carbon atoms; and PT represents the pyrithione moiety which is defined by the following formula wherein the pyrithione moiety is connected through the sulfur atom, or the oxygen atom, or a combination thereof;

wherein R, , R_, R, and R_? are individually selected from hydrogen, lower alkyl group having 1 to about 8 carbon atoms, lower alkoxy group having 1 to about 8 carbon atoms, a nitro group, and a halo group.

2. The method of claim 1 characterized in that said personal care product is a soap, shampoo, or βkin-care medicament.

3. The method of claim 1 characterized in that R.-CH, and R„, R~, R. , R-, R_g, and R- are all hydrogens.

4. The method of claim 1 characterized in that said polymer is a homopolymer.

5. The method of claim 1 characterized in that said polymer has an average molecular weight of about 1000 to about 1,000,000.

6. The method of claim 1 characterized in that said polymer is a copolymer comprising said moieties derived from pyrithione and moieties derived from at least one other ethylenically unsaturated comonomer.

7. The method of claim 1 characterized in that said polymer has an average molecular weight of about 20,000 and about 150,000.

8.. The method of claim 1 characterized in that said polymer is a graft copolymer with a polysaccharide.

9. The method of claim 8 characterised in that said polysaccharide is a cellulosic polysaccharide.. *

10. A personal care product characterized by the inclusion -herein of an antimicrobial effective amount of a polymer of the empirical structural formula.

wherein R. , R_ and R. are individually selected from hydrogen and alkyl^"groups having from 1 to 4 carbon atoms; and PT represents the pyrithione moiety which is defined by the following formula wherein the pyrithione moiety is connected through the sulfur atom, or the oxygen atom, or a combination thereof;

wherein R. , R_, R, and R- are individually selected from hydrogen, lower alkyl group having 1 to about 8 carbon atoms, lower alkoxy^"group having 1 to about 8 carbon atoms, a nitro group, and a halo group.

11. The personal care product of claim 10 which is a soap, shampoo or skin-care medicament.

12. The product of claim 10 characterized in that

R-«CH_ andd R-, R,, ., R, and R- are all hydrogens.

13. The product of claim 10 characterized in that said polymer is a homopolymer.

14. The product of claim 10 characterized in that said polymer has an average molecular weight of about 1000 to about 1,000,000.

15. The product of claim 10 characterized in that said polymer is a copolymer comprising said moieties derived from pyrithione and moieties derived from at least one other ethylenically unsaturated comonomer.

16. The product of claim 10 characterized in that said polymer has an average molecular weight of about 20,000 and about 150,000.

17. The product of claim 10 characterized in that said polymer is a graft copolymer with a polysaccharide.

18. The product of claim 17 characterized in that said polysaccharide is a cellulosic polysaccharide.

19. The product of claim 10 characterized in that said polymer is a pyrithione methacrylate homopolymer. *■

20. The product of claim 10 characterized in that said polymer is a co-polymer of pyrithione methacrylate and methyl methacrylate.