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1. (WO1991006280) PRODUCTION OF POLYMERS WITH IMPROVED PROPERTIES
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Production of Polymers With Improved Properties

The present invention relates to compositions of improved quality for use in the prevention of undesired adsorption on surfaces .

There are many surfaces exposed to aqueous environments which are susceptible to undesired adsorbed build-up of e.g protein and/or mucopolysaccharide, which can for example result in colonisation by micro-organisms. The surfaces which suffer from this kind of build-up are diverse in character. They include the surfaces of teeth where the bacteria which colonise the teeth cause tooth decay. The hulls of ships and marine structures submerged in water become fouled by micro-organisms which colonise them. The micro-organisms for example tend to slow the progress of ships. Cooling towers and heat exchangers become covered with slime which forms as a result of micro-organism build-up and their efficiency is reduced. In food processing, plant equipment can become fouled for example by adsorption of protein from process liquid. These are some examples of some surfaces which suffer from fouling. However there are many other industrial and medical applications which also suffer from undesired build-up and also domestic applications, for example bacterial colonisation in lavatories.

In British Patent No 2 139 635,it was disclosed that a significant reduction in the build-up of the protein/mucopolysaccharide layer could be achieved by treating a required surface with a solution comprising: a first polymer containing reactive groups capable of bonding to the surface to be treated and hydrophobic groups; a second polymer containing at least one hydrophilic polymeric chain and at least one hydrophobic group and a compound capable of reducing or preventing hydrogen bond formation in the presence of water.

However, it has now been discovered that the working of the invention disclosed in British Patent No. 2139635 is not commercially viable. This is largely a result of the process by which the polymers are manufactured and the nature of the polymers produced by this process.

In the above mentioned patent, the polymer containing the reactive groups and hydrophobic groups is prepared by firstly degassing an aqueous solution of ammonium persulphate catalyst and then slowly, over a period of considerable time spanning hours and in some instances days depending on the nature of the co-polymer to be produced, adding to this solution one or more monomers which have been distilled to remove inhibitors . The reaction is continued at raised temperature for some time and, when it is complete, excess water is removed under reduced pressure to leave a concentrated solution from which the product is precipitated with acetone. The product is dried under vacuum.

Despite the significant advantages to be gained from the composition described in British Patent No. 2139635 the above described production process has several inherent disadvantages which make it impossible to exploit commercially. Firstly, as is well known, commercially available monomers are provided with inhibitors in order to prolong the shelf-life of the monomers and thus safeguard against spontaneous polymerisation. Typical inhibitors include 2, 4 dimethyl-6-tertiary butyl phenol better known as Tapanol A, or methyl ether hydroquinone better known as MEHQ, or hydroquinone better known as HQ. In the production process described in British Patent No. 2139635 the acrylic acid is distilled to remove the inhibitors, and the C^n alkyl ester of metacrylic acid is washed with 0.1N NaOH solution to remove the inhibitors.

The distillation not only entails an additional step in the reaction process which requires costly plant equipment, but it also renders the monomers extremely reactive, making them liable to spontaneous self polymerisation before the correct conditions can be achieved. This is particularly inconvenient when a copolymer product is required.

Another disadvantage of the process disclosed in British Patent No 2139635 is that water is used as the reaction solvent. The relatively high boiling point of water renders its removal under reduced pressure, once the polymerisation reaction has been completed, a lengthy process.

Moreover, the polymeric product of the process described in the abovementioned patent is obtained by precipitation from the concentrated aqueous solution using acetone and problems arise with this method because it is expensive and low yielding.

Finally, the nature of the product itself produced in accordance with the aforedescribed method is difficult to handle because it comprises a rubbery mass which is difficult to redissolve. This represents a considerable disadvantage because in most cases the final product must be in solution so that the composition of the invention can be formulated.

The present invention seeks to overcome the above disadvantages by providing a commercially viable method for producing a composition for the prevention of protein accretion on pre-selected surfaces and moreover the method provides for the production of the composition in solution thereby facilitating further formulation of the composition in, for example, various treatment solutions.

In the present invention there is provided a method for producing a composition for treating a surface to render the surface resistant to undesired adsorption, the method comprising:
(i) heating a solution of at least an organic solvent to reflux temperature;
(ii) feeding a mixture of pre-selected inhibited monomers and an organically soluble catalyst into the refluxed organic solvent in order to produce a reaction mixture;
(iii) further heating the reaction mixture until polymerisation is complete.

Preferably the organic solvent is either industrial methylated spirit (IMS) or absolute ethyl alcohol.

Preferably the feeding time is between 1 to 5 hours but more preferably it is 3 hours.

Preferably the further heating is undertaken for at least 30 minutes, and more preferably for 1 hour.

Preferably the inhibited monomers comprise a mixture of:
(i) a first monomer, the monomer being acrylic acid and (ii) a second monomer, the monomer being an n alkyl ester of methacrylic acid having a carbon chain length between Cg-C2 «

Preferably the second monomer is C^-^ n alkyl ester of methacrylic acid.

Preferably the catalyst is a free radical producing catalyst.

Preferably the catylist comprises azobisisobutylnitriie (AZDN) .

Preferably further still the solution of organic solvent comprises a mix of the aforementioned inhibited monomers.

Preferably the organic solvent is heated to reflux temperature under nitrogen.

Preferably the feeding of the mixture is followed by a first further addition of catylist before commencing the said further heating.

Preferably the first further addition of of is made one hour after the feeding is commenced.

Preferably the first further addition of is made one hour after after the feeding is completed. Preferably the said first addition is followed by a further second addition of one hour after the said first addition.

Preferably the product produced in accordance with the above method was further formulated to provide a mouth wash solution containing 2.5% by weight of the polymer composition.

Preferably the above method is carried out in solution and can be manipulated so as to control the molecular weight distribution of the product polymer.

Preferably the copolymer produced in accordance with the above method is a random co-polymer of acrylic acid and C6-C24 alkyl esters of methacrylic acid with a number of average molecular weight of between 1,300 and 32,000 and a weight average molecular weight of between 2,000 and 70,000.

Preferably the copolymer produced in accordancewith the invention is random co-polymer of molecular weight distribution which is essentially a normal distribution.

Preferably a copolymer derived in accordance with the above method may be further formulated by combining the product solution of the above method directly with other preselected components of a pre-determined treatment solution without any further need for purification or other treatment steps.

The copolymer produced in accordance with the method comprises :

(i) a polymer containing (a) reactive groups capable of bonding with a surface, and (b) hydrophobic groups.

The copolymer may be used for the surface treatment of teeth to increase their resistance to protein accretion and plaque build-up and in this case the monomers for the synthesis of the copolymer may comprise acrylic acid and C6-24 n alkyl ester of methacrylic acid and the solvent may be absolute ethyl alcohol.

The copolymer produced in accordance with the method of the invention may be further formulated to provide a treatment composition wherein the composition comprises:

(i) a first polymer containing (a) reactive groups capable of bonding with a surface, and (b) hydrophobic groups and (ii) a second polymer comprising (c) at least one hydrophylic polymeric chain and (d) at least one hydrophobic group; preferably the molar ratio of hydrophobic groups (b) of the first polymer to hydrophobic groups (d) of the second polymer is between 0.9:1 and 1:1.5.

The treatment composition may comprise the copolymer product diluted with water and combined with the said second polymer which is polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydride such as are sold under the trade mark TWEEN.

In the case where the polymer (i) is for use in a composition for the treatment of teeth it may be a random copolymer of acrylic acid and Cg - C24 n alkyl ester of methacrylic acid with
a number average molecular weight (Mn) of between 1300 and

32000 and a weight average molecular weight (Mw) of between

2000 and 70000.

The following examples relate to the preparation of a polymer and its use in a composition for the treatment of teeth.

Example 1

Preparation of batch 2/1 copolymer of acrylic acid and C13 n alkyl ester of methacrylic acid.

900 g of industrial methylated spirit (IMS) was heated to reflux temperature under nitrogen. A feed mixture containing 300 g IMS; 200 g acrylic acid; 100 g C13 n alkyl methacrylate and 5 g azobisisobutylnitrile (AZDN) catalyst was added to the IMS over a period of three hours. Heating was continued for one hour after which the reaction was complete. The product, batch 2/1 polymer, was obtained in solution, the solids content of the solution being about 20%.

Example 2

Preparation of batch 2/2 higher molecular weight copolymer of acrylic acid and C13 n alkyl ester of methacrylic acid.

A monomer mix was prepared containing 320 g acrylic acid; 160 g C13 n alkyl methacrylate; 200 g IMS and 3.6 g AZDN." A solution of 225 g monomer mix in 400 g IMS was heated to reflux temperature under nitrogen. This solution was maintained at reflux temperature during the addition over a period of two hours of a solution of 440 g monomer mix in 320 g IMS. After the first hour of feeding, 0.5 g AZDN in 5.0 g IMS was added to the reaction mixture. When the reaction was completed, the solution of the product polymer 2/2 had a non-volatile content of about 35%.

Example 3

Preparation of batch 2/3 copolymer of acrylic acid and C-^3 n alkyl ester of methacrylic acid.

A monomer mix was prepared containing 320 g acrylic acid; 160 g C13 n alkyl methacrylate; 200 g IMS and 7.2 g AZDN. A solution of 240 g monomer mix in 400 g IMS was heated to reflux temperature under nitrogen. This solution was maintained at reflux temperature during the addition over a period of two hours of a solution of 440 g monomer mix in 320 g IMS. After the feed had been completed, the solution was maintained at reflux temperature and after one hour, 0.5 g AZDN in 5.0 g IMS was added to the reaction mixture. A finishing catalyst of 0.5 g AZDN in 5.0 g IMS was added to the reaction mixture after a second hour and following this the reaction mixture was held at reflux temperature for a further two hours. The solids content of the batch 2/3 product solution was 33.45%.

Example 4

Preparation of batch 2/4 copolymer of acrylic acid and C13 n alkyl ester of methacrylic acid.

The method used for the preparation of the batch 2/4 copolymer was identical to that used for the batch 2/3 copolymer except that the IMS was replaced by absolute ethyl alcohol so that the final product would be suitable for human consumption.

Analysis of the copolymers of batches 2/1 - 2/4 showed that batch 2/1 had Mw = 26400 and Mn = 19000 and polydispersity index D (Mw/Mn) = 1.39. The copolymer of batch 2/2 had Mw = 73200, Mn ***■ 32800 and D = 2.23. The polymers of batches 2/3 and 2/4 had similar properties and were of slightly lower average molecular weight than the polymer of batch 2/1.

A fifth batch oT copolymer of acrylic acid and C^3 n alkyl ester of methacrylic acid, batch X, was prepared using the method of British Patent No. 2139635. This polymer was found to have Mw = 1818, Mn = 1200 and D = 1.51. The molecular weight distributions of the polymers of batches X, 2/1 and 2/2 are shown in diagrammatic form in Figs. 1 - 3 although, in Fig. 1, the lower end of the molecular weight range is not shown.

Example 5

Preparation of a composition for the treatment of teeth.

The non-volatile content of the batch 2/1 solution was adjusted with IMS to a level at which the final mouthwash solution contained 2.5% by weight of active polymer. To prepare the mouthwash, 12.5 ml of this solution was mixed with 50 ml of a 15% aqueous solution of TWEEN 60 (trade mark) . A small amount of coagulant was formed and this was dispersed using absolute alcohol and the whole mixture was made up to 100 ml with water.

Example 6

A similar procedure was carried out with the solution of batch 2/2 but using 7.15 ml of the adjusted starting solution. It was observed that much more coagulant was formed with the batch 2/2 solution than with the batch 2/1 solution and not all of the coagulant could be dispersed even with the addition of 4 ml absolute alcohol. The composition containing the batch 2/2 polymer had to be filtered before use.

The compositions of Examples 5 and 6 and a composition prepared with the batch X polymer made according to the method of British Patent No 2139635 were tested for their effect on the adsorption of protein at a surface. A column of hydroxy apatite was treated by allowing a known volume of the test composition to pass through it. A fixed amount of bovine serum albumin (BSA) was placed upon the column and eluted with phosphate buffer. The eluent was tested for the presence of protein using Folins reagent and the concentration of BSA in each fraction was determined colorimetrically. A control experiment was carried out in which the column was not treated. The results of the tests are shown in Figures 4, 5 and 6.

Figure 4 shows the results for an untreated column compared with a column treated with doses of 1 ml, 2 ml and 10 ml of the composition containing 5% batch X copolymer of British Patent No 2139635. It can be seen that for the untreated column after 35 ml of phosphate buffer have been eluted from the column, over 40% of the BSA still remains on the column. When the column is treated with 1 ml of the test composition, less than 20% of the BSA remains on the column after 15 ml phosphate buffer have been eluted but that this amount cannot be decreased with further elution. When the column is treated with 2 ml of the test composition, less than 5% of the BSA remains after 10 ml have been eluted but this again does not decrease further. When the column is treated with 10 ml of the test composition, substantially all of the BSA can be removed from the column using less than 10 ml eluent. The results show therefore that the composition of British Patent No 2139635 has at least some effect on the amount of protein adsorption.

Figure 5 shows the results for a column treated with the composition of Example 5 containing 2.5% copolymer of batch 2/1. The results show that this polymer is considerably more effective at preventing protein adsorption on the column than is the composition of British Patent No 2139635. When 10 ml of the composition of Example 5 was used, substantially all of the BSA was removed from the column in the first 2 ml fraction of eluent. When 1 ml of the compositon was used, substantially all of the BSA was removed in 6 ml of eluent.

It is probable that the increased effectiveness of the composition of Example 5 over the composition of British Patent No 2139636 arises from the method of preparation of the invention as compared with the method outlined in the previous patent. The fact that the polymer as well as its constituent monomers, is soluble in the reaction solvent leads to increased control over the molecular weight distribution of the product. If water is used as the polymerisation medium, the limited solubility of the resultant polymer and the reduced mobility of the polymer chains impedes access of the monomer molecules hence limiting chain growth. This is not a problem when ethanol is used as the polymerisation medium because the solubility of the polymer in ethanol is greater than its solubility in water. For the same reason the random nature of the polymer is also increased and this means that in the final composition a more effective coating layer can be built up on the surface to be protected.

Figure 6 shows the results for a column which has been treated with the composition of Example 6 which contains 2.5% batch 2/2 copolymer of Example 2 which has a higher molecular weight than the copolymer of batch 2/1. The results show that once again when the column was treated with 10 ml of the composition of Example 6, substantially all of the BSA was removed in the first 2 ml fraction of eluent. However, when the column was treated with 1 ml of the composition of Example 6, approximately 4% of the BSA still remained on the column after 10 ml of phosphate buffer had been eluted and this level did not decrease further. This was a surprising result because the composition of Example 6 contains a polymer of higher molecular weight than the composition of Example 5 and it would have been expected that this solution would have been the more effective of the two at removing adsorbed protein. It appears therefore that there is an optimum molecular weight for polymers for use in these compositions and that effectiveness increases with average molecular weight until a certain point is reached after which the composition becomes less effective once more.

Similar mouthwash compositions were formulated using the polymers of batches 2/3 and 2/4. These compositions gave similar results to the mouthwash of Example 5 which contains the batch 2/1 polymer.

Further tests were carried out in which the compositions were tested for their effectiveness as antibacterial mouthwash preparations. The teeth were cleaned in the normal way in the evening and the morning but at 12 O'clock midday disclosing tablets were used to disclose the level of plaque in the mouth. The teeth were then cleaned and following this the mouth was rinsed for 30 seconds with 10 ml of the mouthwash solution of Example 5. The regime was continued for one week during which time it was noted on disclosure that not only did the mouthwash solution of Example 5 made with the batch 2/1 polymer prevent the further build up of plaque on the teeth but that it also decreased the level of plaque which existed before the start of the treatment.

The present invention makes it possible to implement the invention of British Patent No 2139635 on a commercial basis and also increases by a factor of ten the effectiveness of the compositions described in that patent.