Amphiphilic copolymeric material

Abstract

An amphiphilic polymeric material which has a straight or branched chain polymer backbone and a multiplicity of side chains attached to the backbone, wherein the backbone is a copolymer of at least one ethylenically-unsaturated aliphatic hydrocarbon monomer and maleic anhydride, or is a terpolymer of maleic anhydride, ethylene, and a further ethylenically unsaturated monomer. A method of synthesizing said polymeric material is also provided, together with chewing gum bases, compositions and emulsions comprising amphiphilic polymeric materials.

Claims

1. An amphiphilic polymeric material of general formula (I):
B—(OR).sub.x  (I) wherein: B consists of a copolymer where a straight or branched chain polymer backbone thereof is at least one ethyleneically-unsaturated aliphatic hydrocarbon monomer of 3-5 carbon atoms and maleic anhydride, wherein the copolymer is 5 to 75 wt % maleic anhydride; each OR is a hydrophilic side chain attached to the backbone; X denotes the number of side chains and is in the range of 1 to 5000; and R is general formula (II)
—(YO).sub.a—(ZO).sub.b—R.sup.3  (II) where: each of Y and Z is, independently, an alkylene group having from 2 to 4 carbon atoms; R.sup.3 is H or a C.sub.1-12 alkyl group; and each of a and b is, independently, an integer from 1 to 120 provided that the sum of a+b has a value in the range of 20 to 120.

2. An amphiphilic polymeric material according to claim 1, wherein the ethylenically unsaturated hydrocarbon monomer is selected from the group consisting of isobutylene, 1,3 butadiene and isoprene.

3. An amphiphilic polymeric material according to claim 1, wherein the side chains OR are attached to maleic anhydride in the backbone.

4. An amphiphilic polymeric material according to claim 1, wherein x is in the range of 1 to 300.

5. An amphiphilic polymeric material according to claim 1, wherein each side chain has a molecular weight in the range of 800-10,000.

6. An amphiphilic polymeric material according to claim 1, wherein the backbone has a molecular weight in the range of 1,000-10,000.

7. An amphiphilic polymeric material according to claim 1, wherein Y and Z are both —CH.sub.2CH.sub.2—.

8. An amphiphilic polymeric material according to claim 1, wherein R.sup.3 is H or CH.sub.3.

9. An amphiphilic polymeric material according to claim 1, wherein the copolymer of the backbone comprises 5-50 wt % maleic anhydride.

10. An amphiphilic polymeric material according to claim 1, wherein R.sup.3 is H.

11. An amphiphilic polymeric material according to claim 1, wherein R.sup.3 is a C.sub.1-4 alkyl group.

12. An amphiphilic polymeric material according to claim 1, wherein R.sup.3 is CH.sub.3.

13. A composition comprising: (i) an amphiphilic polymeric material according to claim 1; (ii) a backbone precursor which is a copolymer consisting of at least one ethylenically-unsaturated aliphatic hydrocarbon monomer of 3-5 carbon atoms and maleic anhydride, wherein the copolymer comprises 5 to 75 wt % of maleic anhydride; and (iii) side chain precursors of general formula (III), HO—R, wherein R is general formula (II):
—(YO).sub.a—(ZO).sub.b—R.sup.3  (II) where each of Y and Z is, independently, an alkylene group having from 2 to 4 carbon atoms; R.sup.3 is H or a C.sub.1-12 alkyl group; and each of a and b is, independently, an integer from 1 to 120, provided that the sum of a+b has a value in the range of 20 to 120.

14. A chewing gum base comprising the amphiphilic polymeric material as defined in claim 1.

15. A chewing gum composition comprising the chewing gum base as defined in claim 14.

16. An emulsion comprising the amphiphilic polymeric material according to claim 1, wherein said amphiphilic polymeric material is a surfactant.

17. An emulsion according to claim 16, which is a water-in-oil or oil-in-water emulsion.

18. A method of cleaning a surface, the method comprising: applying the amphiphilic polymeric material as defined in claim 1 to a surface, wherein said amphiphilic polymeric material is a surfactant and cleans said surface.

Description

(1) The invention will now be illustrated by the following Examples which refer to FIGS. 1 to 3, in which:

(2) FIG. 1 shows the contact angle measurements for the various graft copolymers;

(3) FIG. 2 shows cinnamaldehyde release from chewing gums; and

(4) FIG. 3 shows the release of Ibuprofen from samples.

REFERENCE EXAMPLE 1.0—POLYMER BACKBONES

(5) 1.1 Maleic Anhydride Copolymers

(6) Poly(Isobutylene-Alt-Maleic Anhydride):

(7) Two molecular weights (M.sub.n: 6000, 60 000 g mol.sup.−1, as declared by the supplier), both were obtained from the Sigma-Aldrich company.

(8) Poly(Maleic Anhydride-Alt-1-Octadecene):

(9) Molecular weight 30-50 000 g mol.sup.−1 (as declared by the supplier) obtained from the Sigma-Aldrich company.

(10) 1.2 Ethylene-Maleic Anhydride Terpolymers

(11) These are random copolymers of ethylene, maleic anhydride, and another monomer.

(12) Poly(Ethylene-Co-Butyl Acrylate-Co-Maleic Anhydride)

(13) This is a copolymer of ethylene (91 weight percent), N-butyl acrylate (6%), and maleic anhydride (3%). This material was obtained from Sigma-Aldrich (molecular weight undisclosed and propriety information).

(14) Poly(Ethylene-Co-Vinyl Acetate-Co-Maleic Anhydride)

(15) This is a copolymer of ethylene, vinyl acetate and maleic anhydride. The polymer was obtained from Arkema and sold under the Orevac trade name (grade 9304 was used).

REFERENCE EXAMPLE 2.0—SIDE CHAINS PRECURSORS

(16) In all cases the graft was methoxy poly(ethylene glycol) (MPEG), also known as poly(ethylene glycol) methyl ether (PEGME). Material was obtained from two suppliers, the Sigma-Aldrich company, and Clariant (sold as Polyglykol M 2000S). In both cases the polymers were sold as having a molecular weight of 2000, and are believed to be have a very similar chemical structure and properties. Polymers 1, 3-5, and 7 (Table 1) were synthesised using the Aldrich material, the others using the Clariant material.

REFERENCE EXAMPLE 3.0—GRAFT COPOLYMERS

(17) By “graft copolymer”, we mean “polymeric material”, and these two terms are used interchangeably.

(18) A number of graft copolymers where synthesised by grafting MPEG to the backbones described in Reference Examples 1 and 2.

(19) TABLE-US-00001 TABLE 1 Polymers Examined. Backbone Polymer MA MA Sample Backbone Graft Loading Targeted Number Backbone M.sub.n Graft M.sub.n (weight %) (mol %).sup.c 1 P(IB-alt-MA) 6000 MPEG 2000 64.sup.a 10 2 P(IB-alt-MA) 6000 MPEG 2000 64.sup.a 28 3 P(IB-alt-MA) 60 000 MPEG 2000 64.sup.a 10 4 P(MA-alt-O) 30-50 000 MPEG 2000 28.sup.a 11 5 P(MA-alt-O) 30-50 000 MPEG 2000 28.sup.a 11 6 P(MA-alt-O) 30-50 000 MPEG 2000 28.sup.a 100 7 P(E-co-BA-co-MA) Not known MPEG 2000  3 100 8 P(E-co-VA-co-MA) Not known MPEG 2000  3.sup.b 50 9 P(E-co-VA-co-MA) Not known MPEG 2000  3.sup.b 100 10 P(IB-alt-MA) 6000 JM- 1000 64.sup.a 100 1000.sup.d .sup.a= Polymers are approximately 50 mol % MA, value for weight % depends on Fw of monomer; .sup.b= Backbone loading variable between 1.6-3.2%, values calculated using 3.2% .sup.c= percentage of available MA targeted for reaction; .sup.d= Jeffamine M-1000 manufactured by Huntsman.

(20) “Backbone MA loading” means the percentage of the molar mass of the backbone that is comprised of MA. “MA targeted” means the percentage of the total number of moles of MA in the backbone that would be expected to react with the MPEG added to the reaction mixture. In the case of polymers where this value is 100, sufficient MPEG was added to graft a PEG chain to every MA unit on the backbone.

(21) As will be apparent from Table 1, often not all of the MA was targeted for reaction. For instance, in the case of Polymer samples 1-5 only a proportion of the maleic anhydride in the alternating copolymer backbone reacted. This leaves a number of maleic anhydride rings present on the backbones which can themselves be exploited by ring opening (see section on emulsification). It may be noted that in some cases not all of the maleic anhydride targeted for reaction with MPEG may have been reacted.

(22) 3.1 Synthesis of the Graft Copolymer

(23) Polymer 1:

(24) Poly(isobutylene-alt-maleic anhydride) (M.sub.n: 6000 g mol.sup.−1, 40 g) and poly(ethylene glycol) methyl ether (M.sub.n: 2000 g mol.sup.−1, 50 g) were dissolved in a mixture of DMF (100 mL) and toluene (100 mL) in a reaction flask. The flask was heated at reflux temperature under nitrogen gas for 24 h, any water present being removed from the reaction by means of azeotropic distillation and collection into a Dean-Stark apparatus. The resulting polymer solution was cooled and precipitated into diethyl ether, the polymer recovered using filtration, and dried to remove traces of solvent. The grafting of MPEG onto the backbone was confirmed using infra-red spectroscopy using a Bruker spectrometer by observing changes in the region 1700-1850 cm.sup.−1 associated with the maleic anhydride units.

(25) The concentration of maleic anhydride (MA) in the backbone is first determined by dissolving a sample in chloroform and measuring the transmittance at 1830 and 1790 cm.sup.−1. In the case of pure solvent a transmittance of approximately 83% is typically observed at these points. The presence of MA causes a reduction in the transmittance of infra-red radiation at these points, this reduction being directly proportional to the concentration of MA in the polymer. As the concentration of MA goes down as a result of the grafting process the transmittance is expected to increase again. Thus by comparing the transmittance at these two points before and after the reaction it is possible to estimate whether the grafting process has been successful.

(26) Polymer 2:

(27) Polymer 2 was synthesized in the same manner as Polymer 1 using poly(ethylene glycol) methyl ether (M.sub.n: 2000 g mol.sup.−1, 110 g) as the graft. Reaction was allowed to continue for a total of 36 h. The polymer was characterised in a similar manner to polymer 1.

(28) Polymer 3:

(29) Polymer 3 was synthesized in the same manner as Polymer 1 using Poly(isobutylene-alt-maleic anhydride) (M.sub.n: 60 000 g mol.sup.−1, 40 g) as the backbone. The polymer was characterised in a similar manner to polymer 1.

(30) Polymer 4:

(31) Polymer 4 was synthesized in the same manner as Polymer 1 using poly(maleic anhydride-alt-1-octadecene) (M.sub.n: 30-50 000 g mol.sup.−1, 50 g) as the backbone and poly(ethylene glycol) methyl ether (M.sub.n: 2000 g mol.sup.−1, 30 g) as the graft. Toluene (200 mL) was used as the reaction solvent; in this case the polymer solution was precipitated in water. The amphiphilic nature of the resulting graft copolymer led to a poor yield (25% of the theoretical). The polymer was characterised in a similar manner to polymer 1.

(32) Polymer 5:

(33) Polymer 5 was synthesised in the same manner as Polymer 4 except that the polymer solution was not precipitated in water, instead the reaction solvent was removed under vacuum. This material was consequently isolated in a higher yield than P4, and may be suitable for applications where excess PEG in the final product is not a critical issue. The polymer was characterised in a similar manner to polymer 1.

(34) Polymer 6:

(35) Polymer 6 was synthesised in the same manner as Polymer 4 using poly(maleic anhydride-alt-1-octadecene) (M.sub.n: 30-50 000 g mol.sup.−1, 20 g) poly(ethylene glycol) methyl ether (M.sub.n: 2000 g mol.sup.−1, 136 g) as the graft. Toluene (500 mL) was used as the reaction solvent; the polymer solution was precipitated in hexane. Reaction was allowed to continue for a total of 36 h. The polymer was characterised in a similar manner to polymer 1. Excess PEG may be removed from the polymer via dialysis or a similar methodology.

(36) Polymer 7:

(37) Polymer 7 was synthesized in the same manner as Polymer 1 using poly(ethylene-co-butyl acrylate-co-maleic anhydride) (40 g) as the backbone and poly(ethylene glycol) methyl ether (M.sub.n: 2000 g mol.sup.−1, 30 g) as the graft. A mixture of xylene (100 mL) and toluene (100 mL) was used as the reaction solvent; in this case the polymer solution was precipitated in ethanol. The polymer was characterised in a similar manner to polymer 1.

(38) Polymer 8:

(39) Polymer 8 was synthesized in the same manner as Polymer 1 using poly(ethylene-co-vinyl acetate-co-maleic anhydride) (40 g) as the backbone and poly(ethylene glycol) methyl ether (M.sub.n: 2000 g mol.sup.−1, 13 g) as the graft. A mixture of xylene (125 mL) and toluene (125 mL) was used as the reaction solvent; in this case the polymer solution was precipitated in ethanol. The polymer was characterised in a similar manner to polymer 1.

(40) Polymer 9:

(41) Polymer 9 was synthesized in the same manner as Polymer 8 using poly(ethylene glycol) methyl ether (M.sub.n: 2000 g mol.sup.−1, 39 g) as the graft. The polymer was washed thoroughly with more ethanol after filtration to remove PEG from the polymer. The polymer was characterised in a similar manner to polymer 1.

(42) Polymer 10:

(43) Polymer 10 was synthesized in a similar manner to polymer 1 using (isobutylene-alt-maleic anhydride) (Mn: 6000 g mol-1, 20 g) and Jeffamine M-1000 (amine functionalised polyether, Mn: 1000 g mol-1, 129 g) as the graft. Reaction was allowed to continue for a total of 24 h and used toluene (200 mL) as a solvent. The resulting polymer solution was cooled and precipitated into hexane at 0° C. The polymer was characterised in a similar manner to polymer 1.

EXAMPLE 4: APPLICATION TESTS

(44) In all cases with the exception of Test 2 (adhesion tests, 4.2) all of the tests are based around a property which is a result of the amphiphilicity of the graft copolymers.

(45) 4.1 Use of the Polymers as Emulsifiers/Surfactants—Test 1

(46) 4.1.1 Aim

(47) To measure the ability of the polymers to act as emulsifiers (demonstrate surfactancy) for emulsions of two immiscible liquids. Since the amphiphilic polymeric material acts as a surfactant (surface active agent) it will be present at the interfaces between the two phases. The hydrophilic portions (PEG) and possibly hydrolysed MA units will be in or adjacent to the aqueous phase, whereas the hydrocarbon backbone portions of polymer will associate with the oil (which is not usually completely water miscible).

(48) 4.1.2 Methodology

(49) Materials

(50) 2M NaOH solution: NaOH (8 g, Aldrich, ACS grade) was dissolved in water (100 mL).

(51) Silicone oil: Dow Corning Corporation 200® fluid, viscosity 5 cSt (25° C.).

(52) Water in Oil emulsion

(53) Applicable where the graft copolymer is soluble in an oil (in this case demonstrated with toluene) but has a lower, or no significant, solubility in water (this dissolution pattern is common to all of the graft copolymers described in the examples to some degree except 6), demonstrated here with polymer 9. Without being bound to theory the colloidal mixture of oil and water formed is believed to have oil as the dispersion medium, and water as the dispersed phase; and may hence be described as a water in oil emulsion. It is generally recognised that the phase in which the emulsifier (surfactant) is the more soluble tends to be the dispersion medium (this generalisation is known as Bancroft's rule). Therefore a water in oil emulsion is typically formed when an emulsion is successfully generated from the addition of water to a solution of a relatively hydrophobic or water insoluble surfactant in an oil, as is the case here. Information on whether oil or water is the dispersion medium in an emulsion can be obtained by various means by those skilled in the art. They are described for instance in Introduction to Colloid & Surface Chemistry (Duncan J. Shaw, 4.sup.th edition, ISBN: 0750611820). One suitable method described involves adding water and the oil (or oil mixture) to two different aliquots of the emulsion. If the emulsion can be mixed readily with oil (i.e. without the formation of a separate layer of oil) then the dispersion medium is oil, and the emulsion is of a water in oil structure; if the emulsion can be mixed with water then the dispersion medium is water, and the emulsion oil in water.

(54) Polymer 9 (0.44 g) and toluene (44 g, 50 mL) were weighed into a 100 mL beaker, and the polymer dissolved by heating the mixture at 80 t in a water bath. Deionised water (50 mL) was heated in a separate beaker in the same water bath. Both were then removed from the water bath and a paddle stirrer powered by an overhead stirrer placed in the solution. Whilst both were still hot the deionised water was then added gradually to the vigorously stirred toluene solution. Once addition was complete (˜2 min) the emulsion was shear stirred using a Silverson laboratory emulsifier for 1 min. Stirring with the paddle stirrer was then restarted, and maintained until the emulsion reached room temperature. A sample of the emulsion was then placed into a sealed screw top jar, and monitored visually at timed intervals (1 h, 24 h, 1 week).

(55) An aliquot of the emulsion was mixed with toluene and one with water. The emulsion mixed readily with the toluene, but not with the water which formed a separate layer. The resultant colloidal mixture was therefore believed to be a water in oil emulsion in which the surfactant is 0.5 weight % of the total emulsion.

(56) Oil in Water Emulsion

(57) Applicable where without further modification the graft copolymer is intrinsically soluble in water (in this case demonstrated with toluene) but has a lower, (as in this case) or no significant, solubility in oil. Without being bound by theory the colloidal mixture of oil and water formed is believed to have water as the dispersion medium, and oil as the dispersed phase; and may hence be described as a oil in water emulsion. This structure is commonly encountered when an emulsion is formed via the addition of an oil to a solution of a relatively hydrophilic surfactant in water.

(58) Polymer 6 (2 g) and deionised water (50 mL) were added into a 100 mL beaker, and the polymer dissolved by stirring the mixture with a magnetic follower. The polymer solution was then shear stirred using a Silverson laboratory emulsifier whilst silicone oil (50 mL) was added gradually to it. Once addition was complete (˜2 min), a sample of the emulsion was then placed into a sealed screw top jar, and monitored visually at timed intervals (1 h, 24 h, 1 week).

(59) An aliquot of the emulsion was mixed with silicone oil and one with water. The emulsion mixed readily with the water, but not with the silicone oil which formed a separate layer. The resultant colloidal mixture was therefore believed to be an oil in water emulsion in which the surfactant is approximately 2 weight % of the total emulsion.

(60) Oil in Water Emulsion Using Ring-Opened Graft Copolymers

(61) In these cases the graft copolymers whilst amphiphilic, are not sufficiently water soluble to be dissolved in useful concentrations to serve as emulsifiers. Thus unreacted maleic anhydride present on the backbones is ring-opened by hydrolysis, most preferentially using the assistance of a base. The ring opened acid or salt groups assist in the dissolution of the graft copolymer. Without being bound to theory the colloidal mixture of oil and water formed is believed to have water as the dispersion medium, and oil as the dispersed phase; and may hence be described as an oil in water emulsion.

(62) Polymer 3 (2 g) and 2 M NaOH solution (50 mL) were added into a 100 mL beaker, and the polymer dissolved by stirring the mixture with a magnetic follower. The polymer solution was then shear stirred using a Silverson laboratory emulsifier whilst silicone oil (50 mL) was added gradually to it. Once addition was complete (˜2 min), a sample of the emulsion was then placed into a sealed screw top jar, and monitored visually at timed intervals (1 h, 24 h, 1 week).

(63) An aliquot of the emulsion was mixed with silicone oil and one with water. The emulsion mixed readily with the water, but not with the silicone oil which formed a separate layer. The resultant colloidal mixture was therefore believed to be a oil in water emulsion in which the surfactant is approximately 2 weight % of the total emulsion.

(64) 4.1.3 Results

(65) Emulsions have been made via the three different methods. A water in oil emulsion was stabilised by polymer 9, and an oil in water emulsion was stabilised by polymer 6. In the case of polymer 3 the graft polymer was dissolved by ring-opening residual maleic anhydride in the polymer backbone using a base. The emulsions appeared to be stable for a period of a week, in the case of the emulsion of polymer 6 a small amount of separation was observed after this period, which was immediately easily redispersed by gently shaking the mixture by hand. The stability of the emulsions is dependent on a number of factors including the concentration of the surfactant (emulsifier), and may thus be altered to a certain degree by altering its concentration. The use of more emulsifier may be expected to increase the length of stability of the emulsions. In some cases the use of another surfactant (for instance an ionic surfactant like sodium dodecyl sulfate, or a non-ionic surfactant like an alcohol ethoxylate) may be used to increase the stability of emulsions containing these surfactants. It will be appreciated that in industrial or consumer use the emulsions may be enhanced by a number of other ingredients, which may include functional or active ingredients specific to the application, stabilizers, preservatives, pigments and colouring agents, fragrances, thickeners, anti-foaming agents, film forming agents, amongst other ingredients. The amphiphilic nature of the graft copolymers leads to their surface activity, and activity as emulsifiers. Since the hydrophilicity of the polymeric material can be varied, they have the potential to be used to stabilise emulsions of various oils and water, which have both an oil in water and water in oil structure.

(66) 4.1.4 Conclusions

(67) It is possible to use the graft copolymers as surfactants for emulsions of oil and water. The polymers may be used without modification, or in a ring-opened form. Graft copolymers with a high degree of grafting with PEG typically have a better solubility in water than oil and are thus more likely to be useful as oil in water emulsifiers. Conversely, those with lower degrees of grafting with hydrophile are more likely to find use as surfactants for water in oil emulsions. The solubilities of the polymers in water can be increased by ring opening residual maleic anhydride in these cases, allowing the use of the resultant material as an oil in water emulsifier.

EXAMPLE 4.2.0: ADHESION TESTS—TEST 2

(68) 4.2.1 Aim

(69) To measure the ability of films of the graft copolymers to reduce the ability of an adhesive substance (commercial chewing gum) to stick to a substrate, thus creating a non-stick surface.

(70) 4.2.2 Methodology

(71) Preparation of Discs

(72) A series of smooth discs of 5 cm diameter and 3 mm thickness were created by cutting rods of nylon, PTFE, brass, and stainless steel to the appropriate size. Solutions of the polymers under test were then prepared. Polymer 1 was dissolved in THF (5 weight % solution); 3 was dissolved in THF (3.3 weight % solution); 6 in THF (2.5 weight % solution); polymers 2, 7, 8 and 9 were dissolved in toluene (5 weight % solutions), and 4 dissolved in ethyl acetate (2.5 weight % solution). The still warm solutions were then carefully applied to the discs with the aid of a small brush, one of each substrate being coated with each solution. The discs were left for at least 30 minutes to dry, prior to being recoated. The total number of coats was adjusted according to the concentration of the solutions, so that for instance a total of four coats were applied in the case of 5 weight percent solutions, eight in the case of 2.5 weight percent solutions. The discs were left overnight in the fume cupboard to fully dry.

(73) Test Conditions

(74) Pieces of chewing gum (Wrigley's Extra brand, peppermint flavour) were chewed for 5 min, and a freshly chewed piece applied to each dry disc. A square piece of PTFE film was then placed on top of the gum, and a weight comprised of a 1 L glass bottle filled with 1 L of water was placed on top of the PTFE square.

(75) The samples were left for three nights after which the weights were removed and the PTFE squares (with gum cuds attached) were then carefully peeled back using the human hand to gauge the force with which the cuds were stuck to the surface of the discs. PTFE was used since it creates a thin, inert layer, which is easy to remove.

(76) 4.2.3 Results

(77) Nine polymers were tested on the four substrates, the stickiness of the gum to the discs was assessed on a scale between 1-5, one representing a test with very low adhesion between gum cud and substrate surface, five representing a surface with very high adhesion between the two (Table 2). Control experiments in which no polymer coating was present were also carried out, in order to determine the effect of the coating in reducing adhesion compared with the unprotected substrate.

(78) TABLE-US-00002 TABLE 2 Results of the Adhesion Tests of Chewing Gum to films of the Polymers. Stainless Polymer Nylon PTFE Brass Steel 1 1 3 2 1 2 1 3 1 1 3 1 5 1 1 4 1 1 2 1 6 1 1 3 1 7 3 5 2 1 8 1 2 1 1 9 1 1 1 3 Control 3 5 4 5

(79) It is clear from the control that generally high adhesion is observed between the four substrates and the gum cuds. The graft copolymers are all suitable for reducing the adhesiveness of the surfaces. In all cases, with the sole exception of polymer 7, the graft copolymers created a non-stick surface on nylon; with the exception of polymers 3 and 7 they created a non-stick surface or surface with reduced stickiness on the PTFE discs. All of the graft copolymers created a non-stick or surface with reduced stickiness on both of the metal surfaces.

(80) 4.2.4 Conclusion

(81) The graft copolymers are suitable for reducing the adhesion of surfaces. Universally they reduced the adhesiveness of metal surfaces, and in almost all cases reduced adhesiveness of gum to polymer substrates.

EXAMPLE 4.3.0: CONTACT ANGLE MEASUREMENTS—TEST 3

(82) 4.3.1 Aim

(83) To measure the ability of the graft copolymers to mediate the properties of the surface by using the varying hydrophilicity of the materials to make surfaces either water repellent or to encourage wetting of the surface.

(84) 4.3.2 Methodology

(85) Smooth glass discs of 5 cm diameter and 3 mm thickness were prepared by cutting glass rods to the appropriate size. These were coated using solutions prepared in a similar manner to Test 2 (4.2.2). The concentrations of all the solutions were 2.5 weight percent, polymers 1-3, and 6 were dissolved in THF; 4 was dissolved in ethyl acetate, and 7-9 dissolved in toluene.

(86) In all cases the still warm solutions were carefully applied to the glass discs with the aid of a small brush. The discs were left for at least 30 minutes to dry, prior to being recoated. The total number of coats was adjusted according to the concentration of the solutions, so that for instance a total of four coats were applied in the case of 5 weight percent solutions, eight in the case of 2.5 weight percent solutions. The discs were left overnight in the fume cupboard to fully dry.

(87) Following this a drop of water was placed on each disc and the contact angle between the water and substrate measured using a Kruss prop Shape Analysis contact angle goniometer (Model no. DSA 10-Mk2).

(88) 4.3.3 Results

(89) The contact angle of a droplet of water was measured on films of the polymers and an uncoated glass control every 30 s for 10 min. In some cases, the water droplet's contact angle decreased so rapidly that it was not possible to measure its value over the full period of ten minutes. In these cases, an attempt was made to measure the initial contact angles.

(90) TABLE-US-00003 TABLE 3 Initial and Final Contact Angles for the Various Graft Copolymers Contact Angle Polymer t = 0 min t = 4 min P3 57.4 55.5 P4 82.8 80.2 P7 77.6 75 P8 83.3 80.7 P9 86.1 82.6 Control 41.6 34.6

(91) The contact angle data is probably most easily compared and visualised in FIG. 1.

(92) Water was observed to make a contact angle with the glass of approximately 42° after 0 min, and 35° after 4 min. FIG. 1 depicts the contact angle of water with discs coated with a number of different polymers. Whilst some wetting of the surfaces occurs on the discs, it will be seen that the graft copolymers increase the contact angle of water with the discs indicating that they provide some degree of water repellency to the surface. Polymers 7, 8 and 9 offer the highest degrees of water repellency, probably due to their high hydrophobicity as the materials have a fairly low loading of PEG. In general, materials with a lower hydrophobicity had a lower contact angle. Whilst samples P3 and P4 had a similar loading of PEG, those in P4 had long chain alkyl octadecene groups which will affect the overall hydrophilic/lipohiphilic balance (HLB) of the graft copolymers, and thus explaining the lower contact angle observed on films of P3. Thus whether the amphiphilic copolymers are more hydrophilic or hydrophobic and the subsequent behaviour of the graft copolymers can be altered by changing the backbone and the loading of PEG to that required. A contact angle of 0° was recorded after 2 min on a disc coated with P6 (not show in FIG. 1). This is (without being bound to theory) presumably because the water soluble polymer had been dissolved at this stage, or had absorbed the water. It is of note that the backbone of P4 and P6 is identical, differing only in the loading of PEG (that in P6 being five times higher). This suggests that the hydrophilicity of the graft copolymers can be adjusted to render them as either wetting or water repellent agents.

(93) 4.3.4 Conclusions

(94) The tunable amphiphilic nature of the graft copolymers means the interaction of water with surfaces coated with them, can be altered by changing the backbone and degree of amphiphile grafted to the backbone.

EXAMPLE 4.4.0: USE OF THE AMPHIPHILIC GRAFT COPOLYMERS TO MEDIATE THE RELEASE OF A CHEMICAL ENTITY FROM CHEWING GUM

(95) 4.4.1 Aims

(96) To demonstrate that the use of the graft copolymers in chewing gum in mediating the release of a chemical entity (in this case the commercial flavour cinnamaldehyde).

(97) 4.4.2 Methodology

(98) Chemicals

(99) Calcium carbonate (CaCO.sub.3), ester gum, hydrogenated vegetable oil (HVO, hydrogenated soy oil), polyisobutylene (PIB, of molecular weight 51,000), poly(vinyl acetate) (PVAc, of molecular weight 26,000), glyceromonostearate (GMS), microcrystalline wax (microwax of m.p. 82-90° C.), sorbitol liquid, and sorbitol solid, were all food grade materials obtained from the Gum Base Company. Cinnamaldehyde (98+%) was obtained from Fisher-Scientific UK.

(100) Manufacture of Chewing Gum

(101) The chewing gum base had the composition as shown in the table below:

(102) TABLE-US-00004 TABLE 4 Recipe for the Manufacture of the Gum Bases: X is one of the new graft copolymers, or microcrystalline wax in the case of the S3 control, HVO = hydrogenated vegetable oil, PVAc = poly(vinyl acetate). Stage Component % Composition Mass/g 1 PIB 13 1.04 PVAc 6 0.48 CaCO.sub.3 6 0.48 Ester Gum 3.6 0.288 2 Ester Gum 5.4 0.432 CaCO.sub.3 9 0.72 3 PVAc 9 0.72 Ester Gum 9 0.72 CaCO.sub.3 15 1.2 4 HVO 12 0.96 GMS 6 0.48 X 6 0.48 Total 100 8

(103) The gum base materials were mixed on a Haake Minilab micro compounder manufactured by the Thermo Electron Corporation, which is a small scale laboratory mixer/extruder. The ingredients were mixed together in four steps, the gum only being extruded after the final step. The gum base was mixed at 100° C.

(104) The chewing gum was mixed according to the following table.

(105) TABLE-US-00005 TABLE 5 Ingredients for the Chewing Gum: X is one of the new graft copolymers, or microcrystalline wax in the case of the S3 control. Stage Time Component Amount 1 15 min 37.5% Gum Base Containing X 3 g 10% Sorbitol Liquid 0.8 g 17% Sorbitol Powder 1.36 g 2 15 min 25.5% Sorbitol Powder 2.04 g 6% X 0.48 g 3% Sorbitol Liquid 0.24 g 1% Cinnamaldehyde Flavour 0.08 mL 30 min TOTAL 8 g

(106) The gum was mixed using the same equipment as the base and extruded after the final step. The gum was mixed at 60° C. In stage 1 the sorbitol liquid and powder were premixed prior to adding them to the gum.

EXPERIMENTAL METHOD

(107) Each pre-shaped piece of gum was weighed before chewing, and the weight recorded to allow estimation of the total quantity of drug in each piece.

(108) A ‘ERWEKA DRT-1’ chewing apparatus from AB FIA was used, which operates by alternately compressing and twisting the gum in between two mesh grids. A water jacket, with the water temperature set to 37° C. was used to regulate the temperature in the mastication cell to that expected when chewed in vivo, and the chew rate was set to 40 ‘chews’ per minute. The jaw gap was set to 1.6 mm.

(109) 40 mL artificial saliva (composed of an aqueous solution of various salts, at approx pH 6—see below, Table 6) was added to the mastication cell, then a plastic mesh placed at its bottom. A piece of gum of known weight was placed on the centre of the mesh, and a second niece of mesh out on too.

(110) TABLE-US-00006 TABLE 6 Artificial Saliva Formulation Components Quantity (mmol/L) KH.sub.2PO.sub.4 2.5 Na.sub.2HPO.sub.4 2.4 KHCO.sub.3 15 NaCl 10 MgCl.sub.2 1.5 CaCl.sub.2 1.5 Citric acid 0.15 PH adjusted to 6.7 with HCl
Procedure for Analysing the Release Profiles of Active Ingredients from Gum

(111) The parameters in Table 7 were always used in chewing unless otherwise noted.

(112) TABLE-US-00007 TABLE 7 Chewing Parameters Parameter Value Temperature 37° C. Gaps between jaws 1.6 mm Twisting angle 20° Chew Frequency 40 strokes/min

(113) At the start of each run, the cell containing the artificial saliva and gum was left for 5 minutes so that the system could equilibrate to 37° C. The gum was then masticated. A sample volume of 0.5 mL was then withdrawn from the test cell periodically during a release run (5, 10, 15, 20, 25, 30, 40, 50 and 60 minutes).

(114) All the samples were then analysed by HPLC using a typical Perkin Elmer HPLC Series 200 system, equipped with an autosampler, pump, and diode array detector. Data handling and instrument control was provided via Totalchrom v 6.2 software.

(115) The gums (approximately 1 g pieces of known weight) were placed between two plastic meshes and chewed mechanically in artificial saliva. They were all analysed using HPLC apparatus. Details of this equipment are as follows:

(116) A typical Perkin Elmer HPLC system—data handling and instrument control via Totalchrom v 6.2. System based on a Series 200 system, equipped with an autosampler, pump, and diode array detector.

(117) In this case the HPLC analysed free cinnamaldehyde in solution that had been released by chewing. The set of conditions for cinnamaldehyde are as follows:

(118) Column: Varian Polaris 5u C18-A 250×4.6 m

(119) Mobile Phase: Acetonitrile/0.05% orthophosphoric acid (60/40)

(120) Flow: 1 mL/min

(121) Detection: UV 25 0 nm

(122) Inj vol: 5 uL

(123) Samples in saliva were injected neat after filtration through a 10 mm PTFE acrodisc syringe filter.

(124) The samples were compared against standards (prepared in artificial saliva) covering the range 0.02-1.00 mg/mL. The retention time of cinnamaldehyde was determined to be 4.9 min on this equipment, thus the peak at this retention time was used to detect the released cinnamaldehyde. The samples were chewed two or three times, and in all cases two consistent release curves were generated. All of the samples were run in duplicate on the HPLC apparatus, indicating the results were highly reproducible.

(125) 4.4.3 Results

(126) Gums have been made with polymers 1-4 and 6-9, and chewed in artificial saliva. The released cinnamaldehyde is analyzed by HPLC. A control (S3) in which the graft copolymers were replaced with microwax was also made, and analyzed in the same manner (FIG. 2).

(127) The control (S3) is observed to give a fairly steady release of cinnamaldehyde culminating in approximately 60% release after 60 min. Whilst two (P8 and P9) graft copolymer containing gums have release profiles similar to the microwax material, most have either faster and higher maximum, or slower and lower maximum release profiles of the cinnamaldehyde. For instance, polymer 8 only releases 40% of the cinnamaldehyde in the gum after 60 min; compared with 50% in the case of the control. By contrast, cinnamaldehyde release from the gum made using P4 appears to have reached a plateau of approximately 70% cinnamaldehyde release before 30 min. The release rate from the gum containing P3 was slower, but the maximum release was comparable or slightly higher.

(128) 4.4 Conclusions

(129) By altering the backbone and the degree of grafting (therefore hydrophilicity) of the amphiphile it is possible to alter the release profile of chemical species from chewing gum, in this case demonstrated with cinnamaldehyde. The release rate seems to be determined by a number of factors including chemical identity of the backbone, and degree of grafting, resulting in changes in the interactions with saliva and other components of the gum. Therefore graft copolymer systems with a range of different release rates potentially available for formulation into chewing gum are disclosed.

(130) 4.5.0 Use of the Amphiphilic Graft Copolymers to Mediate the Release of an Active Ingredient

(131) 4.5.1 Aims

(132) To demonstrate the use of the amphipihilic graft copolymers to deliver and release active ingredients, demonstrated by looking at the release of ibuprofen from solid mixtures of the polymers and ibuprofen, i.e. where the ibuprofen has been encapsulated. By encapsulated, we mean that the active ingredient is physically coated by, or encased, within the graft copolymer.

(133) 4.5.2 Methodology

(134) Materials

(135) Ibuprofen (40 grade) was obtained from Albemarle.

(136) Creation of Solid Mixes of Polymer and Ibuprofen

(137) The powdered graft copolymer and ibuprofen were weighed out into a beaker to ensure that the ibuprofen comprised 1 weight percent. The two were premixed with a spatula to create a roughly homogenous mixture, and then mixed and extruded using the Haake Minilab micro compounder at 60° C. In the case of Polymer 2 3.96 g of polymer and ibuprofen (0.04 g) were used; in the case of Polymer 3 2.97 g of polymer and ibuprofen (0.03 g) were used.

(138) Testing Method

(139) The encapsulated ibuprofen samples (approximately 1 g material of known weight) were placed between two plastic meshes and chewed mechanically in artificial saliva. Details of the mastication of the encapsulated ibuprofen is identical to that used with the cinnamaldehyde chewing gum (4.4.2), samples being taken after 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 40 min, 50 min, and 60 min. Following this they were prepared for HPLC analysis by filtering them through a 10 mm PTFE acrodisc syringe filter. The samples were analyzed using the HPLC apparatus described previously (4.4.2), using the following experimental details:

(140) Ibuprofen HPLC details: (Column: Hypersil C18 BDS, 150×4.6 mm; Mobile phase: Acetonitrile/0.05% aqueous orthophosphoric acid in a 60/40 ratio, 1 mL/min; UV detector, wavelength—220 nm).

(141) The encapsulated ibuprofen samples were chewed two or three times, and in all cases two consistent release curves were generated. All of the samples were run in duplicate on the HPLC apparatus, indicating the results were highly reproducible.

(142) 4.5.3 Results

(143) Two different polymers were used to encapsulate the ibuprofen, both were chewed and the release profile monitored by HPLC (FIG. 3).

(144) Both of the polymer/ibuprofen mixtures released ibuprofen into solution during chewing, and released similar total amounts of ibuprofen into the saliva—around 60% of the maximum total, a point at which the release seems to plateau in the two examples tested. Interestingly the release of ibuprofen is much more rapid in the case of polymer 2 than polymer 3. Whereas both polymers have chemically similar backbones, the amount of MPEG grafted to the backbone is much higher in the case of 2. A possible explanation therefore is that increasing the hydrophilicity of the polymers aids disintegration of the encapsulated samples, resulting in faster release during chewing/grinding (the polymers are hard solids).

(145) 4.5.4 Conclusions

(146) Ibuprofen was encapsulated in two samples of the graft copolymers, and released by masticating the samples in artificial saliva. Graft copolymer 2 releases ibuprofen more rapidly than graft copolymer 3; the former also contains more PEG and is more hydrophilic. It seems that by adjusting the hydrophilicity of the amphiphilic graft copolymers it is possible to alter the release rate of the ibuprofen.