WO2007071325A2

WO2007071325A2 - Composition containing and active agent and polymeric carrier particles comprising a copolymer of a hydrophobic monomer and a hydrophilic polysaccharide

Info

Publication number: WO2007071325A2
Application number: PCT/EP2006/011731
Authority: WO
Inventors: Qingsheng Tao; Caigen Yuan
Original assignee: Unilever Plc; Unilever Nv; Hindustan Unilever Limited
Priority date: 2005-12-21
Filing date: 2006-12-04
Publication date: 2007-06-28
Also published as: WO2007071325A3

Abstract

A composition s provided comprising: a) polymeric particles comprising a copolymer of a hydrophobic monomer and a hydrophilic Polysaccharide; b) a pharmaceutical and/or skin and/or hair and/or laundry active residing within and/or on the surface of the polymeric particles; and c) a pharmaceutically and/or cosmetically acceptable vehicle within which the polymeric particles are dispersed. The composition shows improved target specificity for skin, hair and silk fibres, synthetic fibres (including nylon and polyester) for delivery of pharmaceutical and/or skin and/or hair and/or laundry actives.

Description

AN IMPROVED COSMETIC COMPOSITION

The invention in suite relates to polymeric carrier particles comprising a pharmaceutical and/or skin and/or hair active with improved delivery and controlled release of the active at the target site, and a process for their manufacture.

Polymeric carrier particles comprising a pharmaceutical compound or perfume active have been previously described. One problem with the prior art carrier particles is their lack of specificity to the target site. The inventors have surprisingly observed that polymeric carrier particles stabilised with hydrophilic polysaccharides provide improved target specificity to skin, keratin fibres, cotton fibres, silk fibres and synthetic fibres such as nylon and polyester.

Thus in a first aspect of the invention, a pharmaceutical and/or cosmetic and/or hair and/or laundry composition is provided comprising:

a) polymeric particles comprising a copolymer of a hydrophobic monomer and a hydrophilic polysaccharide; b) a pharmaceutical and/or skin and/or hair and/or laundry active residing within and/or on the surface of the polymeric particles; and c) a pharmaceutically and/or cosmetically acceptable vehicle within which the polymeric particles are dispersed.

The hydrophobic monomer may be selected from the group consisting of n-butyl methacrylate, vinyl acetate, styrene, 2-(diethylamino) ethyl methacrylate, N-isopropyl acrylamide and butyl acrylate. One advantage of using a hydrophobic monomer is that the polymer particles will only slowly release hydrophobic pharmaceutical and/or skin and/or hair and/or laundry actives. By careful matching of the hydrophobic properties of the hydrophobic monomer and pharmaceutical and/or skin and/or hair and/or laundry active, release of the active may be controlled.

When the hydrophobic monomer is 2-(diethylamino) ethyl methacrylate, release of the active may be controlled by varying the pH of the pharmaceutically and/or cosmetically acceptable vehicle.

The copolymer may consist of N-isopropyl acrylamide and n-butyl acrylate or optionally additionally comprise a hydrophilic monomer to provide, for example, a copolymer of N-isopropyl acrylamide and sodium acrylate, An advantage of either combination of monomers is that the phase transition point of the polymeric particles may be easily controlled by varying the ratio of each of the two monomers thereby to produce polymer particles where release of the active is controlled by varying the temperature of the polymeric particles. The term "phase transition point" refers to the temperature at which a solution changes from a single phase to two phases.

The copylmer may additionally comprise a crosslinking monomer, such as ethylene glycol dimethacrylate. Such polymeric particles release active more slowly than their uncrosslinked analogues.

The hydrophilic polysaccharide may be selected from the group consisting of chitosan, sodium carboxy methyl cellulose, starch, guar gum and hydroxyethyl cellulose. Optionally the polymeric particles are additionally prepared from a crosslinking agent for the hydrophilic polysaccharide. A preferred combination is chitosan as the hydrophilic polysaccharide and glutaraldehyde as the crosslinking agent for the hydrophilic polysaccharide. An advantage of such a morphology is that the active is released more slowly than from corresponding uncrosslinked analogues.

In another aspect of the invention, a method for manufacturing the pharmaceutical and/or cosmetic and/or hair and/or laundry composition of the invention is provided comprising the steps of: a) chemically reacting the hydrophilic polysaccharide with a free radical initiator thereby to produce polysaccharide fragments; b) polymerising the hydrophobic monomer, optionally the hydrophilic monomer and optionally the crosslinking monomer with the polysaccharide fragments thereby to produce a dispersion of the polymeric particles in the pharmaceutically and/or cosmetically acceptable vehicle; and then c) mixing the pharmaceutical and/or skin and/or hair and/or laundry active into the dispersion of polymeric particles.

An alternative method for manufacturing the pharmaceutical and/or cosmetic and/or hair and/or laundry composition of the invention comprises the steps of: a) chemically reacting the hydrophilic polysaccharide with a free radical initiator thereby to produce polysaccharide fragments; and then b) polymerising the hydrophobic monomer, optionally the hydrophilic monomer and optionally the crosslinking monomer with the polysaccharide fragments in the presence of the pharmaceutical and/or skin and/or hair and/or laundry active thereby to produce a pharmaceutical and/or cosmetic and/or hair and/or laundry composition of the invention.

Yet another method for manufacturing a pharmaceutical and/or cosmetic and/or hair and/or laundry composition of the invention comprises the steps of: a) polymerising the hydrophobic monomer, optionally the hydrophilic monomer and optionally the crosslinking monomer with a free radical initiator in the presence of the hydrophilic polysaccharide thereby to produce a dispersion of the polymeric particles in the pharmaceutically and/or cosmetically acceptable vehicle; and then b) mixing the pharmaceutical and/or skin and/or hair and/or laundry active into the dispersion of polymeric particles.

A further method for manufacturing a pharmaceutical and/or cosmetic and/or hair and/or laundry composition of the invention comprises the step of polymerising the hydrophobic monomer, optionally the hydrophilic monomer and optionally the crosslinking monomer with a free radical initiator in the presence of the hydrophilic polysaccharide and pharmaceutical and/or skin and/or hair and/or laundry active.

The methods for manufacturing a pharmaceutical and/or cosmetic and/or hair and/or laundry composition may comprise the additional step of crosslinking the hydrophilic polysaccharide with the crosslinking agent for the hydrophilic polysaccharide.

Brief Description of the Figures

The invention will now be described in more detail with reference to the figures wherein:

Figure 1 shows the size of n-butyl methacrylate/chitosan polymeric particles (examplei ) without (figure 1a) and with (figure 1b) the fragrance p- cymene as the pharmaceutical and/or skin and/or hair and/or laundry active; Figure 2 shows the residual levels over time at room temperature of p-cymene in the polymeric particles of example 1 and in water;

Figure 3 shows a graph of particle size (nm) versus temperature (degrees Centigrade) for a range of N-isopropyl acrylamide/sodium acrylate/hydroxyethyl cellulose polymeric particles prepared according to example 8;

Figure 4 shows a graph of particle size (nm) versus temperature (degrees Centigrade) for a range of N-isopropyl acrylamide/n-butyl acrylate/hydroxyethyl cellulose polymeric particles prepared according to example 9;

Figure 5 shows the UV spectra of the biocide climbazole as the pharmaceutical and/or skin and/or hair and/or laundry active in ethyl acetate (dotted line), as ethyl acetate extracts of climbazole in respectively styrene/ chitosan polymeric particles (example 11 ) (full line) and in water (dot/dash line);

Figure 6 shows the residual levels over time of p-cymene in vinyl acetate/chitosan polymeric particles at various levels of glutaraldehyde crosslinking (example 12); and

Figure 7 shows the residual levels over time of p-cymene in vinyl acetate/chitosan polymeric particles with/without ethylene glycol dimethacrylate crosslinking (example 13).

Figure 8 shows the as the Y-axis the absorbance value (or optical density) of Malassizia furfur cells for the samples of example 15.

Figure 9 shows as the Y-axis the absorbance value (or optical density) of Malassizia furfur cells for the samples of example 16.

Detailed Description of the Invention The hydrophobic monomer includes a hydrophobic group which may be, but are not limited to, an alkyl, a cycloalkyl, an aryl, an alkaryl, an aralkyl, an ester, and an amine group and mixtures thereof.

Examples of hydrophobic monomers include, but is not limited to, methyl acrylate, ethyl acrylate, n-propyl acrylate, iso-propyl acrylate, n-butyl acrylate, iso-butyl acrylate, 2-ethylhexyl acrylate, n-propyl methacrylate, iso-propyl methacrylate, n- butyl methacrylate, iso-butyl methacrylate, styrene, cyclohexyl methacrylate, a- methyl styrene, phenyl methacrylate, t-butyl methacrylamide, p-hydroxyphenyl methacrylamide, vinyl ketones, vinyl acetates, vinyl phenols, 2-diethyl amino ethyl methacrylate, 2-dimethyl amino ethyl methacrylate, Λ/-isopropylacrylamide, N₁N- dimethylacrylamide, Λ/,Λ/-diethylacrylamide and 10-undecenoic acid.

The polymeric particles may be copolymers of more than one hydrophobic monomer, for example two or three hydrophobic monomers.

Furthermore the polymeric particles may also be copolymers of hydrophilic monomers in combination with one or more hydrophobic monomers. Examples of suitable hydrophilic monomers include, but are not limited to, acrylamide, acrylic acid, sodium acrylate, methacrylic acid, acrylonitrile, hydroxyethyl methacrylate, hydroxyethyl acrylate, N-acryloyl morpholine, N-hydroxymethyl acrylamide, poly(ethylene glycol) methyl ether methacrylate and 1-vinyl-2-pyrrolidone.

The polymeric particles may additionally be copolymers of a cross-linking monomer examples of which include, but are not limited to, ethylene glycol diacrylate, diethylene glycol diacrylate, ethylene glycol dimethacrylate, triethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, divinylbenzene, trivinyl benzene, divinyl toluene, trivinyl toluene, 1 ,3-propanediol diacrylate, 1 ,4-butanediol diacrylate,

1 ,6-hexanediol diacrylate, diallylmaleate, triallylmaleate, divinyl ether, pentaerythritol triacrylate, polyallyl sucrose and allylmethacrylate.

The hydrophilic polysaccharide can be either a natural polysaccharide and/or a synthetic polysaccharide. Examples of suitable natural polysaccharides include, but are not limited to, chitosan, guar gum, soluble starch, locust bean gum, arabic gum, dextran, xanthum and sodium alginate. Examples of suitable synthetic polysaccharides include, but are not limited to, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl hydroxypropyl cellulose, sodium carboxymethyl starch, hydroxyethyl starch, cationic cellulose containing N- hydroxypropyl-N.N.N-trimethylammonium substituents, cationic guar gum containing N-hydroxypropyl-N,N,N-trimethylammonium substituents and sodium cellulose sulfonate.

The pharmaceutical and/or skin and/or hair and/or laundry active may be a perfume, a dye, a drug, a functional additive and mixtures thereof. Examples of hydrophobic actives include, but are not limited to, p-cymene, citronellol, 2-hexyl decanol, geraniol, benzyl alcohol, phenylethyl alcohol, cinnamyl alcohol, linalool, menthol, terpineol, decyl aldehyde, citronellal, hydroxycitronellal, piperonal, cinnamic aldehyde, ionone, p-methyl acetophenone, methyl cinnamate, ethyl phenylacetate, benzyl acetate, eugenol, vanillin, pyrene, rhodamine, oil red O, sudan black, sudan brown, sudan red, β-carotene, climbazole, vitamin E and vitamin A.

The average particle size of the polymeric particles is in the range 50-500 nm, for example in the range 100-300 nm.

The polymeric particles can be prepared by surfactant free emulsion polymerisation or emulsion polymerisation. In two-step surfactant free emulsion polymerisation, the hydrophilic polysaccharide is dissolved in water and then the initiator is added to the dissolved hydrophilic polysaccharide which reacts with the hydrophilic polysaccharide to form a hydrophilic polysaccharide free radical (a polysaccharide fragment). Subsequently the hydrophobic monomer and any other monomers (eg the hydrophilic monomer and crosslinking monomer) are added to the solution of polysaccharide fragments and polymerization initiated. In one-step surfactant free emulsion polymerisation, all the reactants are mixed together and polymerisation initiated.

Examples of suitable initiators include, but are not limited to, ammonium cerium nitrate, ammonium cerium sulfate, potassium periodate, potassium persulfate, ammonium persulfate, vanadium V salt, manganese III/IV salt, the combination of potassium persulfate and sodium hydrogen sulfite, the combination of ammonium persulfate and sodium thiosulfate, the combination of ammonium persulfate and thiourea, the combination of potassium persulfate and an iron Il salt (for example ferrous sulfate or ferrous chloride), the combination of hydrogen peroxide and an iron

Il salt (for example ferrous sulfate or ferrous chloride) and the combination of potassium permanganate and sulphuric acid. The reaction temperature is dependent on the nature of the initiator and can be in the range 5-95 degrees Centigrade, for example 50-70 degrees Centigrade.

The pharmaceutical and/or skin and/or hair and/or laundry active can be added to the pre-prepared polymeric particles, typically at room temperature, or together with the hydrophobic monomer.

The invention will now be illustrated with reference to the examples hereinbelow.

Example 1

500mg of chitosan (Aldrich Chemical Co.; 85% deacylated) was added to 50ml of distilled water, then 2.7ml 36% aqueous acetic acid was added. The solution was then heated to 70 degrees Centigrade under stirring. After all of the chitosan had dissolved, 100mg of potassium persulfate was added and then ten minutes later 5ml of n-butyl methacrylate was added and heating continued for three hours. The resulting latex had a pH of 5.5, the particle size of the polymeric particles was 210nm (Zetasizer Nano ZS from Malvern; polystyrene in water at 25 degrees Centigrade reference) and the zeta potential was 38.7mV at pH 5.5 (Zetasizer Nano ZS from Malvern; 25 degrees Centigrade).

Example 2 500mg of sodium carboxy methyl cellulose (Acros Chemical Co.; average molecular weight 9000; degree of substitution 0.7) was dissolved in 50ml of distilled water. The solution was then heated to 70 degrees Centigrade under stirring after which 50mg of potassium persulfate was added and then ten minutes later 2.5ml of vinyl acetate was added and heating continued for five hours. The resulting latex comprised polymeric particles of particle size 195nm (Zetasizer Nano ZS from Malvern; polystyrene in water at 25 degrees Centigrade reference) and a zeta potential of - 6OmV at pH 5 (Zetasizer Nano ZS from Malvern; 25 degrees Centigrade).

Example 3

500mg of soluble starch (grade AR available from Yixing No.2 Chemical Reagent Plant) was dissolved in 50ml of distilled water. The solution was then heated to 70 degrees Centigrade under stirring after which 50mg of potassium persulfate was added and then ten minutes later 2.5ml of vinyl acetate was added and heating continued for five hours. The resulting latex comprised polymeric particles of particle size 1031nm (Zetasizer Nano ZS from Malvern; polystyrene in water at 25 degrees Centigrade reference).

Example 4

500mg of guar gum (Jaguar C-162, supplied from Rhodia Co.) was dissolved in 50ml of distilled water. The solution was then heated to 70 degrees Centigrade under stirring after which 100mg of potassium persulfate was added and then ten minutes later 2.5ml of vinyl acetate was added and heating continued for five hours. The resulting latex comprised polymeric particles of particle size 157nm (Zetasizer Nano ZS from Malvern; polystyrene in water at 25 degrees Centigrade reference).

Example 5

500mg of chitosan (Aldrich Chemical Co.; 85% deacylated) was added to 50ml of distilled water, then 2.7ml 36% aqueous acetic acid was added. The solution was then heated to 70 degrees Centigrade under stirring. After all of the chitosan had dissolved, 50mg of potassium persulfate was added and then ten minutes later 2.5ml of styrene was added and heating continued for five hours. The resulting latex comprised polymeric particles of particle size 238nm (Zetasizer Nano ZS from Malvern; polystyrene in water at 25 degrees Centigrade reference).

Example 6

500mg of hydroxyethyl cellulose (Fluka Biochemika Co.; viscosity of 75-125mPa S at 20 degrees Centigrade (2wt%, in water)) was dissolved in 50ml of distilled water. The solution was then heated to 70 degrees Centigrade under stirring after which 50mg of potassium persulfate was added and then ten minutes later 2.5ml of 2-diethyl amino ethyl methacrylate was added and heating continued for five hours. Table 1 summarises the particle size of the polymeric particles (Zetasizer Nano ZS from Malvern; polystyrene in water at 25 degrees Centigrade reference) in the resulting latex at various pH's from which it is apparent that the latex is stable when the pH is greater than 6.5 and the polymeric particles are soluble in water when the pH is less than 6.5. Thus the polymeric particles are pH sensitive.

Table 1 : The particle size of 2-diethyl amino ethyl methacrylate grafted hydroxyethyl cellulose copolymer at different pH values.

pH value Particle size (nm)

5.46 6.3

6.02 12.7

6.38 7.4

6.55 213.9

6.76 214.8

6.87 265.1

7.21 291.9

Example 7

500mg of hydroxyethyl cellulose (Fluka Biochemika Co.; viscosity of 75-125mPa S at 20 degrees Centigrade (2wt%, in water)) was dissolved in 50ml of distilled water. The solution was then heated to 70 degrees Centigrade under stirring after which 50mg of potassium persulfate was added and then ten minutes later 0.2g of N-isopropyl acrylamide was added and heating continued for five hours. The phase transition temperature of the resulting polymeric particles was 305 degrees Kelvin and thus they are thermo-sensitive at ambient temperatures.

The phase transition temperature was determined by measuring the particle size of the polymeric particles (Zetasizer Nano ZS from Malvern; polystyrene in water at 25 degrees Centigrade reference) against temperature. The phase transition temperature was indicated when there was a large drop in particle size as the polymeric particles dissolved in the aqueous latex phase.

Example 8

500mg of hydroxyethyl cellulose (Fluka Biochemika Co.; viscosity of 75-125mPa S at 20 degrees Centigrade (2wt%, in water)) was dissolved in 50ml of distilled water. The solution was then heated to 70 degrees Centigrade under stirring after which 50mg of potassium persulfate was added and then ten minutes later a 0.2g mixture of N- isopropyl acrylamide and sodium acrylate according to table 2 was added and heating continued for five hours. The phase transition temperatures of the resulting polymeric particles are summarised in table 2 and indicate that the phase transition temperature of N-isopropyl acrylamide graft hydroxyethyl cellulose polymeric particles (see example 7) is increased by copolymerising sodium acrylate.

The phase transition temperatures were determined by measuring the particle size of the polymeric particles (Zetasizer Nano ZS from Malvern; polystyrene in water at 25 degrees Centigrade reference) against temperature. The phase transition temperature was indicated when there was a large drop in particle size as the polymeric particles dissolved (see Figure 3) in the aqueous latex phase.

Table 2: The effect on the phase transition temperature (degrees Kelvin) of N- isopropyl acrylamide (NIPAM) graft hydroxyethyl cellulose (HEC) polymeric particles of copolymerising sodium acrylate (SA).

Composition Phase transition temperature (degrees Kelvin) NIPAM/HEC (40/100) 305

NIPAM/SA/HEC (38/2/100) 306

NIPAM/SA/HEC (36/4/100) 308

NIPAM/SA/HEC (32/8/100) 310

NIPAM/SA/HEC (28/12/100) 318

Example 9

500mg of hydroxyethyl cellulose (Fluka Biochemika Co.; viscosity of 75-125mPa S at 20 degrees Centigrade (2wt%, in water)) was dissolved in 50ml of distilled water. The solution was then heated to 70 degrees Centigrade under stirring after which 50mg of potassium persulfate was added and then ten minutes later a 0.2g mixture of N- isopropyl acrylamide and n-butyl acrylate according to table 3 was added and heating continued for five hours. The phase transition temperatures of the resulting polymeric particles are summarised in table 3 and indicate that the phase transition temperature of the N-isopropyl acrylamide graft hydroxyethyl cellulose polymeric particles (see example 7) is decreased by copolymerising n-butyl acrylate.

The phase transition temperatures were determined by measuring the particle size of the polymeric particles (Zetasizer Nano ZS from Malvern; polystyrene in water at 25 degrees Centigrade reference) against temperature. The phase transition temperature was indicated when there was a large drop in particle size as the polymeric particles dissolved (see Figure 4) in the aqueous latex phase.

Table 3: The effect on the phase transition temperature (degrees Kelvin) of N- isopropyl acrylamide (NIPAM) graft hydroxyethyl cellulose (HEC) polymeric particles of copolymerising n-butyl acrylate (BA).

Composition Phase transition temperature (degrees Kelvin)

NIPAM/HEC (40/100) 305

NIPAM/BA/HEC (38/2/100) 303

NIPAM/BA/HEC (36/4/100) 295

NIPAM/BA/HEC (34/6/100) 289

Example 10

25ml of the latex of example 1 was diluted to 250ml with distilled water and then 45mg of p-cymene (fragrance) added and stirred for 24 hours at room temperature. The particle size of the polymeric particles was observed to increase from 210nm to 255nm (Zetasizer Nano ZS from Malvern; polystyrene in water at 25 degrees Centigrade reference). The increase in polymeric particle size is illustrated by the scanning electron micrographs (Jeol JSM-5600LV) shown in Figure 1a (without p- cymene) and Figure 1 b (with p-cymene).

0.1 ml of p-cymene was added to 10ml of the latex of example 1 (test sample) and 10ml of distilled water (control sample) respectively at room temperature and the p- cymene stirred into the latex for five hours. Then 1 ml aliquots of each of the test and control samples were taken over time and each extracted with 5ml of n-hexane. The levels of p-cymene in the n-hexane extracts were measured using a UV spectrophotometer (Shimadzu UV-2501 PC, 272nm) and are summarised in Figure 2. The results appear to show delayed release of p-cymene from the polymeric particles of example 1 with respect to the control.

Example 11

500mg of chitosan (Aldrich Chemical Co.; 85% deacylated) was dissolved in 100ml of distilled water. The solution was then heated to 70 degrees Centigrade under stirring after which 50mg of potassium persulfate was added and then ten minutes later 2.5ml of styrene was added with 500mg climbazole (a biocide) and heating continued for three hours.

A 1ml aliquot of the resulting latex was extracted with 5ml of ethyl acetate. As a control sample, 500mg climbazole was dispersed in distilled 100ml water and a 1 ml aliquot extracted with 5ml of ethyl acetate. As a further control sample, 5mg climbazole was dissolved in 5ml of ethyl acetate. The ultra-violet absorbance of the ethyl acetate samples were measured on a Shimadzu UV-2501 PC and are shown in Figure 5. Figure 5 shows that both the ethyl acetate extract of the latex of example 11 and climbazole in ethyl acetate have an absorption peak at 288nm. However there is no absorption at 288nm for the aqueous control sample. It was observed that climbazole precipitated in water and formed a sediment under gravity. In the latex sample of example 11 , the climbazole also precipitated but, it is surmised, onto the polymeric particles themselves.

Example 12

500mg of chitosan (Aldrich Chemical Co.; 85% deacylated) was added to 50ml of distilled water, then 2.7ml 36% aqueous acetic acid was added. The solution was then heated to 70 degrees Centigrade under stirring. After all of the chitosan had dissolved, 50mg of potassium persulfate was added and then ten minutes later 2.5ml of vinyl acetate was added and heating continued for five hours. After the resulting latex was cooled to room temperature, 0.2ml of p-cymene was added to the latex and agitation carried out for six hours. The chitosan was then crosslinked at room temperature by addition of 0.1ml, 0.2ml and 0.3ml of 25% aqueous solution of glutaraldehyde to 10ml aliquots of the resulting latex of example 12. 1ml aliquots of (crosslinked) the latices were taken over time and each extracted with 5ml of n-hexane. The levels of p-cymene in the n-hexane extracts were measured using a UV spectrophotometer (Shimadzu UV-2501 PC, 272nm) and are summarised in figure 6. The control was uncrosslinked polymeric particles from example 12. The results appear to show increased delayed release of p-cymene from the polymeric particles of example 12 with increased levels of glutaraldehyde (and crosslinking of the chitosan shell of the polymeric particles).

Example 13

500mg of chitosan (Aldrich Chemical Co.; 85% deacylated) was added to 50ml of distilled water, then 2.7ml 36% aqueous acetic acid was added. The solution was then heated to 70 degrees Centigrade under stirring. After all of the chitosan had dissolved, 50mg of potassium persulfate was added and then ten minutes later 2.5ml of vinyl acetate and 0.25ml of ethylene glycol dimethacrylate was added together with 0.2ml of p-cymene and heating continued for five hours.

1 ml aliquots of the resulting latex were taken over time and each extracted with 5ml of n-hexane. The levels of p-cymene in the n-hexane extracts were measured using a UV spectrophotometer (Shimadzu UV-2501 PC, 272nm) and are summarised in figure 7. The control was uncrosslinked polymeric particles from example 13 (ie

2.5ml of vinyl acetate and without the ethylene glycol dimethacrylate). The results appear to show increased delayed release of p-cymene from the polymeric particles of example 13 with crosslinking of the vinyl acetate core of the polymeric particles.

Example 14

Five samples were prepared, namely: a chitosan/polystyrene latex containing climbazole; a guar gum/polystyrene latex containing climbazole; a chitosan/polystyrene latex; a guar gum/polystyrene latex and climbazole in water. The latices were prepared using the 2-step surfactant-free emulsion polymerisation process and required 500mg of the hydrophilic polysaccharide, 2.5ml of the monomer, 100ml of water and 50mg of potassium persulphate initiator. Climbazole was added, where necessary, at a level of 500mg. The climbazole in water sample comprised 500mg of climbazole in 100ml of water. The minimum inhibitory concentrations (MICs) of the yeast Malassizia furfur tor each of the samples were measured using the following protocol:

1. lnnoculate 10ml Leeming broth with one loopful from a freshly cultured Malassizia furfur plate and incubate in an orbital shaker at 32 degrees Centigrade for three days.

2. Transfer 5ml of the broth culture to 5ml of fresh Leeming brothand dilute the culture to a cell density of 10⁵.

3. Prepare 100μg/ml stock solutions of the aforementioned samples in sterile water and then dilute each stock solution to produce samples in the concentration range 0.4-100 μg/ml.

4. Dispense 50μl of each sample dilution into the wells of an untreated 96-well microtitre plate and dispense 50μl of Leeming broth into positive, negative and blank wells.

5. lnnoculate the sample and positive wells with 50//I of the diluted Malassezia furfur culture (see step 2) and add 50μl of Leeming broth to the negative and blank wells mixing the contents thoroughly with a multichannel pipettor.

6. Incubate the wells at 32 degrees Centigrade for three days, add 50μl of Alarm Blue to each well and continue incubating the wells at 32 degrees Centigrade for one further day.

7. Each well is visually assessed for a colour change with the highest dilution remaining blue indicating the MIC.

The results are set out in table 4 and show that both the chitosan/polystyrene latex containing climbazole and the guar gum/polystyrene latex containing climbazole show excellent antimicrobial activity. The chitosan/polystyrene latex also shows some antimicrobial activity because chitosan has a bacteriostatic effect itself. In contrast the guar gum/polystyrene latex shows little antimicrobial activity. As climbazole is insoluble in water, the solution (without precipitate) shows little antimicrobial activity. Thus it is clear that the latices have absorbed or adsorbed climazole.

Table 4: The minimum inhibitory concentrations (MICs) of the yeast Malassizia furfur for the four samples of example 14 (PS ≡polystyrene).

^~Sample MIC(ugTml)

Chitosan/PS containing climbazole 0.4

Guar gum/PS containing climbazole 1.56 Chitosan/PS latex 6.25

Guar gum/PS latex >50

Climbazole in water >50

Example 15

Three samples were prepared, namely: a chitosan/polystyrene latex containing climbazole; a guar gum/polystyrene latex containing climbazole; and a chitosan/polystyrene latex. The lattices were prepared according to example 14.

A deposition experiment was conducted on the samples in accordance with the following protocol:

1. Inoculate 10ml Leeming broth with one loopful from a freshly cultured Malassizia furfur plate and incubate in an orbital shaker at 32 degrees Centigrade for three days.

2. Centrifuge inoculated Leeming broth at 3000rpm for 15 minutes, discard the supernatant, resuspend the cells in 10ml phosphated buffer solution (PBS) by vortexing briefly, recentrifuge at 3000rpm for 15 minutes, discard the supernatant and resuspend the cells in 3-4ml PBS by vortexing briefly.

3. Using a microtitre plate, measure the optical density (OD) at 610nm (Bio-rad model 550) of two 100μl samples of the inoculate from step 2 diluting with

PBS until the OD is 0.2.

4. Pipette 100//I samples of the diluted inoculate from step 3 into the wells of a microtitre plate leaving the last row empty for the controls and leave at rest at room temperature for two hours to allow the cells to settle onto the bottom of the wells.

5. Discard the supernatant from each well, rinse each well with 200μl of PBS discarding supernatant together with any loose cells.

6. Each latex sample was subjected to a 1-in-10 dilution with sterile water, mixed briefly and 100 μ\ pipetted into wells in duplicate. Controls were included in duplicate consisting of untreated wells and wells treated with Leeming broth.

7. After two minutes, the supernatant was discarded from each well and each well twice rinsed with 200μl of PBS.

8. 200μl of Leeming broth is added to all the wells and an initial OD measured.

9. The wells are then incubated at 32 degrees Centigrade for 24, 48 and 72 hours successively with OD measurements being taken at each interval.

The results are illustrated in figure 8 wherein the Y-axis is the absorbance value (or optical density) Malassizia furfur cells. A higher absorbance value indicates the presence of a higher density of Malassizia furfur cells. The results indicate that both the chitosan/polystyrene latex containing climbazole and the guar gum/polystyrene latex containing climbazole exhibit good deposition within three days compared with the control sample.

Example 16

Four shampoo compositions were prepared according to the formulations given in table 5.

Table 5: Shampoo formulations (SDS ≡ sodium dodecyl sulphate; HEC s is hydroxyethyl cellulose Natrosol HHR 250 (Hercules Co.); betaine is 30% in water (Rhodia Co.); PS ≡ polystyrene; each latex contained climbazole). Ingredient (g) samplei sample2 sample3 sample4

Betaine (30%) 10 10 10 10

SDS 12 12 12 12

Chitosan/PS latex - - 40 Guar gum/PS latex 40

Climbazole - 1 - -

Propylene glycol 3 3 3 3

HEC 0.7 0.7 0.3 0.3

Distilled water (balance to) 100 100 100 100

Each latex set out in table 5 was prepared using the 2-step surfactant-free emulsion polymerisation process and consisted of 500mg of hydrophilic polysaccharide, 50ml water, 500mg climbazole, 2.5ml styrene and 50mg potassium persulphate. Thus samples 3 and 4 each comprised approximately 0.4% by weight climbazole.

A deposition experiment was conducted on the samples in accordance with the protocol described in example 15 and the results are illustrated in figure 9 wherein the Y-axis is the absorbance value (or optical density) Malassizia furfur cells. A higher absorbance value indicates the presence of a higher density of Malassizia furfur cells. The results indicate that although the climbazole concentration in sample 3 and sample 4 is lower than that in sample 2, sample 3 and sample 4 still exhibit better deposition compared with sample 2 (or sample 1 ). Thus it is clear that the chitosan/PS latex or guar bean gum/PS latex can act as an excellent climbazole carrier in shampoo.

Claims

1. A pharmaceutical and/or cosmetic and/or hair and/or laundry composition comprising: a) polymeric particles comprising a copolymer of a hydrophobic monomer and a hydrophilic polysaccharide; b) a pharmaceutical and/or skin and/or hair and/or laundry active residing within and/or on the surface of the polymeric particles; and c) a pharmaceutically and/or cosmetically acceptable vehicle within which the polymeric particles are dispersed.

2. A pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to claim 1 wherein the hydrophobic monomer is selected from the group consisting of n-butyl methacrylate, vinyl acetate, styrene, 2-diethyl amino ethyl methacrylate, N-isopropyl acrylamide and butyl acrylate.

3. A pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to claim 1 wherein the hydrophobic monomer is 2-diethyl amino ethyl methacrylate.

4. A pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to any one of the preceding claims wherein the copolymer additionally comprises a hydrophilic monomer.

5. A pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to claim 4 wherein the hydrophilic monomer is sodium acrylate.

6. A pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to anyone of the preceding claims wherein the copolymer additionally comprises a crosslinking monomer.

7. A pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to claim 6 wherein the crosslinking monomer is ethylene glycol dimethacrylate.

8. A pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to any one of the preceding claims wherein the hydrophilic polysaccharide is selected from the group consisting of chitosan, sodium carboxy methyl cellulose, starch, guar gum and hydroxyethyl cellulose.

9. A pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to any one of the preceding claims wherein the polymeric particles are additionally prepared from a crosslinking agent for the hydrophilic polysaccharide.

10. A pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to claim 9 wherein the hydrophilic polysaccharide comprises chitosan and the crosslinking agent for the hydrophilic polysaccharide comprises glutaraldehyde.

11. A method for manufacturing a pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to any one of the preceding claims comprising the steps of: a) chemically reacting the hydrophilic polysaccharide with a free radical initiator thereby to produce polysaccharide fragments; b) polymerising the hydrophobic monomer, optionally the hydrophilic monomer and optionally the crosslinking monomer with the polysaccharide fragments thereby to produce a dispersion of the polymeric particles in the pharmaceutically and/or cosmetically acceptable vehicle; and then c) mixing the pharmaceutical and/or skin and/or hair and/or laundry active into the dispersion of polymeric particles.

12. A method for manufacturing a pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to any one of claims 1 to 10 comprising the steps of: a) chemically reacting the hydrophilic polysaccharide with a free radical initiator thereby to produce polysaccharide fragments; and then b) polymerising the hydrophobic monomer, optionally the hydrophilic monomer and optionally the crosslinking monomer with the polysaccharide fragments in the presence of the pharmaceutical and/or skin and/or hair and/or laundry active.

13. A method for manufacturing a pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to any one of claims 1 to 10 comprising the steps of: a) polymerising the hydrophobic monomer, optionally the hydrophilic monomer and optionally the crosslinking monomer with a free radical initiator in the presence of the hydrophilic polysaccharide thereby to produce a dispersion of the polymeric particles in the pharmaceutically and/or cosmetically acceptable vehicle; and then b) mixing the pharmaceutical and/or skin and/or hair and/or laundry active into the dispersion of polymeric particles.

14. A method for manufacturing a pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to any one of claims 1 to 10 comprising the step of polymerising the hydrophobic monomer, optionally the hydrophilic monomer and optionally the crosslinking monomer with a free radical initiator in the presence of the hydrophilic polysaccharide and pharmaceutical and/or skin and/or hair and/or laundry active.

15. A method for manufacturing a pharmaceutical and/or cosmetic and/or hair and/or laundry composition according to claim 9 or claim 10 comprising the additional step of crosslinking the hydrophilic polysaccharide with the crosslinking agent for the hydrophilic polysaccharide.