RESORBABLE INSERT

The present invention relates to a dental insert which provides slow release of therapeutic agents into the mouth of a wearer. More specifically the present invention relates to the provision of a dental insert that is soluble when worn in the mouth of a user.

For the treatment of dental and oral diseases, particularly dental caries (decay) the delivery of a therapeutic agent or medicament by means that provide a more or less continuous dose into the mouth of a patient has advantages. For example, in a fluoride treatment for prevention of caries, a continuous dosage with fluoride has the benefit of providing continuous protection from the decay process.

Devices designed to provide such a continuous dose of fluoride as anti-caries agent are known. They are "slow- release" inserts which are attached to a tooth or teeth of a subject by a dentist. These inserts then release fluoride over a period of time before being removed and replaced if necessary. One of the known devices uses glass beads as the carrier of the therapeutic agent (fluoride) , - as described by ME Curzon and J Toumba in "In vitro and in vivo assessment of a slow fluoride releasing device: a pilot study [British Dental Journal 196(9) 543-546, 2004] and also by J Toumba, "Slow-release devices for fluoride delivery to high risk individuals" [Caries Research 35 (Suppl 1) , 10-13, 2001] . Another known device uses hydroxyapatite in combination with an acrylate polymer in a matrix to provide slow release of fluoride (Y. B. Altinova et al Caries Research 39, 191-194, 2005)

Both devices require removal from the mouth, preferably by a dentist, when they no longer supply sufficient fluoride to be effective. Furthermore, their use appears to be restricted to the delivery of fluoride as an anti-caries agent .

An alternative fluoride releasing device, providing only relatively short term (a few hours) delivery of fluoride as anti-caries reagent has been proposed by Bottenberg et al in the Journal of Dental Research 77(1), 68-72, 1998. This consists of a corn starch tablet, which is attached to the oral mucosa (soft tissues in the mouth) of a subject for the short period of its action.

A more specialised device, developed only for a specific application is the PerioChip® (www.periochip.com) which contains the antibacterial chlorhexidine in a biodegradable crosslinked collagen matrix for the treatment of the condition of periodontitis, caused by bacterial infection. The PerioChip® is inserted by a dentist into periodontal pockets, the deep crevices formed between individual teeth and their sockets, of subjects suffering from the condition. A further development of this concept, for the same application, is described by Yue et al in Biomaterials, 25(17), 3743-3750, 2004. A device consisting of a ^λ chip' for insertion into periodontal pockets is described. The device is made from microparticles of poly (dl-lactic-co-glycolic acid) (PLGA) which encapsulate chlorhexidine or chlorhexidine digluconate in combination with cyclodextrin derivatives. These ^λ chip' type inserts require the presence of periodontal pockets, present only where there is substantial gum disease, for attachment of the insert into a subject's mouth.

It is an object of the invention to provide dental inserts for the provision of the slow release of therapeutic agents which avoid or at least minimise some of the aforementioned disadvantages .

It is a further object of the invention to provide dental inserts for the treatment and the prevention of disease.

It is a further object of the invention to provide methods of treatment using dental inserts for the treatment and prevention of disease states.

It is a further object of the invention to provide a process for the manufacture of dental inserts.

The present invention provides a resorbable insert, formed for attachment within the oral cavity of a subject and comprising: a polymer material slowly soluble in the mouth; and at least one therapeutic agent, for slow release in use.

The present invention provides a resorbable insert, formed for attachment, in use, to a tooth or teeth of a subject and comprising: a polymer material slowly soluble in the mouth; and at least one therapeutic agent, for slow release in use.

The present invention provides; a resorbable insert, formed for attachment within the oral cavity of a subject and comprising a polymer material slowly soluble in the mouth and at least one therapeutic agent, for slow release in use, for use as a medicament.

The present invention provides a method of treatment or prevention of a disease state comprising the steps of; providing a resorbable insert formed for attachment within the oral cavity of a subject comprising a polymer material slowly soluble in the mouth and at least one therapeutic agent, for slow release in use; and attaching said resorbable insert within the oral cavity of a said subject.

Desirably the said at least one therapeutic agent is dispersed in, and/or is coated on, the polymer material.

Alternatively the therapeutic agent or agents may be contained within a cavity of the polymer material, for example when the polymer material takes the form of a hollow fibre. In this case the therapeutic agent is released by permeating through the polymer material or by passing out of holes in the polymer material covering.

The concentration of therapeutic agent employed is adjusted to give the desired release rate, for a given size and form of insert. Desirably the therapeutic agent is present in concentrations from 0.05 to 30% by weight in an insert of the invention, preferably at concentrations from 5 to 15% by weight.

The insert of the invention is attached within the oval cavity of a subject when used to deliver the therapeutic agent or therapeutic agents. The insert may be attached to the mucosal membranes within the oral cavity, by a suitable adhesive such as are known to those skilled in the art . Any convenient mucoadhesive polymer may be used, depending upon desired release rates of the therapeutic agent, biocompatibility , the adhesive strength required for a long-term application and other factors . For example the

mucoadhesive may be selected from one or more of sodium carboxymethyl cellulose, polyacrylic acid, such as sold under the designation Carbopol or polycarbophil, polyvinylpyrrolidone, polyethylene oxide, polyvinylmethylether/maleic anhydride copolymer, methyl cellulose, methylethyl cellulose, polyacrylamide, polyethyleneglycol, polyvinylalcohol, polyhydroxypropyl cellulose, and polyhydroxyethylmethacrylate . The insert may by attached to any part of the mucosal membranes, for example between the cheek and gum or under the tongue.

In some embodiments the insert may be formed for attachment to the tooth or teeth of a subject. It will be understood by the reader that this means that the insert can be fixed in place, to remain attached to a tooth or teeth, above the gum, of a subject using the insert for a desired period of time. Providing an insert that is attachable to a tooth or teeth above the gum allows the insert to be conveniently and securely held in the mouth of a subject throughout the period that treatment is provided by the therapeutic agent. The insert may be formed to be attachable by bonding of a surface of the insert to a tooth or teeth using a suitable bonding agent such as resin-bonding agent, which can be attached to an acid etched surface of a tooth.

Alternatively the insert may be formed to comprise a loop or a length of polymer material that can be placed round, or tied to, a tooth or teeth. As a yet further alternative a subject using an insert of the invention may wear a dental brace, in which case the insert can be attached to the teeth by making use of the brace to hold or clamp the insert in the desired position on the teeth.

In some preferred embodiments the insert of the invention is formed so that it can be attached to the teeth simply by locating it in a position between a pair of teeth, adjacent the gum, as described in more detail hereafter with reference to a specific embodiment.

It will be understood that the term resorbable means that the insert of the invention will, over time, dissolve or disperse in the mouth of a subject, by virtue of the polymer material being slowly soluble when in the mouth i.e. the polymer material dissolves in the fluids found in the mouth. Typically the insert dissolves over a period of several days or weeks. For some applications it may be formed to dissolve over an even longer period, some months or more. The insert of the invention provides a slow release of the therapeutic agent. The term slow release herein described, typically means that an effective dose of the therapeutic agent is released from the insert of the invention over a period of at least one day. Typically the therapeutic agent is released over twelve months, generally over six months, e.g. over 6 weeks to 6 months. The benefit of providing a resorbable insert for slow release of a chosen therapeutic agent, in comparison to previous known insoluble inserts, is that the insert does not have to be removed, typically by a dentist, after the course of treatment is completed. Furthermore the resorbable insert of the invention can be used with a wide range of therapeutic agents as discussed below.

Preferably the polymer of the polymer material is a starch co-polyester material. Preferably the polymer is an aliphatic aromatic starch co-polyester material. The starch can be obtained from any suitable source such as milk, corn or potatoes. For example, Solanyl®, available

from Rodenburg Biopolymers, Oosterhout, Netherlands which is an aliphatic aromatic copolyester derived from potato starch. Suitable polymer materials for the devices of the invention may be made by the processes described in WO99/29733 (Rodenburg Veeroeders B.V.).

These materials have the benefit of being biocompatible (non-toxic) and the physical properties can be adjusted to provide the required rate of dissolution in oral fluids. The starch co-polyesters are thermoplastic and therefore readily moulded or extruded into a desired shape. Typically the rate of dissolution required is at least several days and it can be several months depending on the treatment being given.

The polymer material may be produced in the desired form by any suitable manufacturing method for a given polymer. The material may be thermally moulded into a desired solid form or extrusion of a polymer melt through a die may be employed. The therapeutic agent may be mixed in with the polymer melt to provide a polymer material with therapeutic agent dispersed within it. Alternatively the therapeutic agent may be absorbed into the polymer material or coated onto it after manufacture.

When the polymer material is produced from a melt by a die extrusion process the extruded product can be produced in the form of a tape, a monofilament wire or fibre or a multifilament ^λ yarn' of fibres depending on the die shape and the size and number of holes in the die, as is well known in the art . The extruded material may then be further processed into a desired shape for an insert.

The polymer material can be formed into an insert of the invention in a number of ways. For example, the insert may simply take the form of a tape or multifilament yarn or string of polymer material or the polymer material may be woven or knitted into a three-dimensional shape. A knitted or woven structure has the benefit that it provides a large surface area for release of the therapeutic agent. Additionally when the insert has a coating, as described hereafter with respect to preferred embodiments, the knitted or woven structure assists the binding of the coating to the base portion.

Advantageously the resorbable insert is elastic. This can be achieved by using a polymer material with elastic properties and/or by the way in which the insert is formed. For example, a knitted structure will have an inherent elasticity depending on the type of knit stitching employed. An insert with elastic properties has the advantage that it can be conformed easily, where required, to the tooth or teeth of a user. Furthermore, where the insert is, for example, looped around a tooth, the insert can be stretched on fixing so that elastic tension helps secure the insert to the tooth.

Preferably the insert is sterilizable by suitable means, such as ethylene oxide, α-beam gamma irradiation or heat, without loss of function.

The polymer material may be formed as a solid or may, for example, be manufactured as a ^λ hollow fibre' which can contain therapeutic agent, depending on the therapeutic agent (s) employed and the desired release properties.

Preferably the therapeutic agent is an anti-caries agent. For example, it may be a fluoride-containing agent such as sodium fluoride or stannous fluoride or a non fluoride- containing anti-caries agent. The desirable amount of these agents to be released is typically between 0.05 and 2mg per day. Preferably the amount of anti-caries agent released is between 0.15mg and 0.5mg per day. In general the release rate for anti-caries fluoride agents is adjusted to provide an increase in the level of fluoride found in the saliva of between 0.5 to 1.5ppm. To obtain the desired increase in saliva fluoride levels from the insert concentrations of from 0.05 to 30% by weight of fluoride-containing anti- caries agent may be present, preferably concentrations of from 5 to 15% of fluoride-containing anti-caries agent.

Alternatively the therapeutic agent may be an anti- hypersensitivity agent. For example, it may be selected from the group consisting of sodium fluoride, potassium chloride, strontium acetate, strontium chloride, potassium nitrate and strontium fluoride.

For fluoride-containing anti-caries agents and equally for other therapeutic agents that may be employed in an insert, the release rate can be adjusted in a number of ways known to those skilled in the art to achieve the desired combination of rate of release and time period of release. For example the concentration of the therapeutic agent in the insert may be adjusted. Other means of varying the release of the therapeutic agent include adjusting the size, shape and/or form of the insert employed. For example, adjusting the thickness of an insert has been shown to affect the release rate. Alternatively or additionally the insert may further comprise additional coatings.

Preferably the resorbable insert of the invention further comprises a hydrogel coating, slowly soluble in the mouth of a subject. The hydrogel coating serves to moderate the release of the therapeutic agent from the polymer material. This is especially the case where the therapeutic agent is a coating on the surface of the polymer material . Preferably the hydrogel coating has a second therapeutic agent dispersed in it, for slow release.

Preferably the hydrogel coating is selected from the group consisting of carrageenan, agar agar, mixed acacia and xanthan gum, caroube (locust bean gum) , non-ionic poly (ethylene oxide) polymer, xanthan gum, hydroxyethylcellulose, gum arabic, and chitosan

(glucosamine polymer) . Examples of commercially available carrageenans include Carrageenan CM500 and Carrageenan

GU399. Thixogum X® is an example of a commercially produced mixed acacia and xanthan gum. Polyox™ is an example of a commercially available poly (ethylene oxide) polymer and Natrosol® is an example of a commercially available hydroxyethylcellulose .

Preferably the second therapeutic agent is an antibacterial agent. For example, the second therapeutic agent may be chlorhexidine or a chlorhexidine salt or any antibiotic composition.

By providing a resorbable insert that comprises two or more therapeutic agents, the present invention allows for the treatment of two or more different diseases disorders, or deficiencies at the same time. For example, the insert may release a fluoride anti-caries agent and chlorhexidine as antibacterial. More than two therapeutic agents may be

used, as more than one agent can be in or on the polymer material or in the hydrogel coating, when the insert is coated.

The therapeutic agents employed in the resorbable insert of the invention are not restricted to those suitable for the treatment of intra-oral diseases or disorders. Other therapeutic agents, for the treatment of systemic disorders of any kind where oral slow release of the therapeutic agent (i.e. medicament) can be effective, may be employed in the insert of the invention.

Resorbable inserts of the invention comprising an anti- caries agent are particularly suited to use not only in the treatment of dental caries, in particular paediatric dental caries, but in the prevention of caries i.e. in prophylactic use. Inserts of the invention can find particular use in the prevention of caries, or other oral conditions such as gum disease, in children, especially children who are particularly vulnerable to such conditions . The inserts may be fitted to the mucus membrane or teeth of a subject child during a dental appointment. The insert then provides a continuous dosage of therapeutic agent or agents, to treat or provide prophylaxis against target disease states. On (a) return visit (s) to the dentist, typically spaced at four- to six- week intervals for vulnerable children, a fresh insert is put in place to continue treatment until the next dental appointment . The inserts of the invention are particularly suited to such usage as they can provide a therapeutic dosage of, for example, an anti-caries agent for four- to six-week periods. For normal adult use, where dental appointments are typically at 6-month intervals or more, inserts of the invention can be constructed that deliver a

therapeutic agent for much longer periods, desirably for up to twelve months, e.g. for up to six-months from insertion into the subject's oral cavity.

Thus inserts of the invention containing appropriate therapeutic agents can be used advantageously for the treatment or prophylaxis of diseases of the oral cavity. Preferably inserts of the invention are used for the treatment or prophylaxis of diseases of the oral cavity in children. In such paediatric use the prevention of dental caries using anti-caries agents in the inserts is a particularly preferred use.

Preferably the resorbable insert further comprises a polysaccharide outer coating. The polysaccharide coating will dissolve rapidly on insertion into a subject's mouth, generally within a matter of a few seconds or minutes. The polysaccharide coating therefore serves to protect the insert and its associated therapeutic agent (s) from degradation before use. It will be understood that the polysachoride outer coating may be provided on the hydrogel layer, if present.

Any one of the polymer material, the hydrogel coating or the polysaccharide coating may contain other components, for example colourants or flavourings .

As discussed above the resorbable insert of the invention may be formed and arranged for attachment to a tooth or teeth of a user/subject. This can be arranged in a number of different ways.

Preferably the insert is provided in the form of a rod, sized for insertion between a pair of upper or lower teeth,

adjacent the gum. Generally the insert, in the form of a rod will be inserted between molars to provide more secure fixing. Preferably the rod is shaped so as to be wider at either end than in the middle. A rod shaped insert of this form, with widened ends, is particularly secure, as the widened ends tend to stop the rod from slipping out from between the pair of teeth. Rod shaped inserts have the benefit that they are easily inserted into the mouth of a wearer even by the wearer themselves, without assistance from a dentist being necessary.

As an alternative, where the insert is formed from a tape or a ^string' of polymer material, the insert may be a loop. The loop can be sized to fit securely over a single tooth and pushed down adjacent the gum. The loop may also have a bead or beads of insert material attached to it, to provide a greater reservoir of therapeutic agent (s). If the insert is in the form of a tape or string but it is not in the form of a closed loop, it can be attached by winding round a number of teeth or by winding round a dental brace, worn by the user of the insert. Other alternatives are possible and will be described in more detail hereinafter with reference to specific embodiments. For example the insert may be in the form of a plate, shaped to correspond to the surface of the side of a tooth, to which it is attached in use by bonding means such as a suitable adhesive material such as resin bonding agent. Alternatively the insert may be formed as a component of an orthodontic brace, such as one of the brackets.

According to another aspect of the invention there is provided a process for the manufacture of a resorbable dental insert according to the invention comprising the steps of:

providing a polymer material soluble, in use, in the mouth of a subject; providing a therapeutic agent; and forming said polymer material into an insert for attachment within the oral cavity of a subject, with the therapeutic agent combined with the polymer, coated on the polymer or contained within a cavity of the polymer material .

The resorbable inserts of the invention may be formed for attachment to the mucosal membranes of the oral cavity or they be formed for attachment to a tooth or the teeth of a subject .

Preferably the polymer material is a thermoplastic and is formed into the insert by a thermal moulding or die extrusion process .

Preferably the process further comprises the step of providing a hydrogel coating to the insert. The hydrogel coating may comprise a second therapeutic agent.

Preferably the process further comprises the step of coating the insert with an outer coating of a polysaccharide .

Further preferred features and advantages of the present invention will appear from the following detailed description of some embodiments illustrated with reference to the accompanying drawings in which:

Figs. 1 (a to d) show rod shaped embodiments of the invention and their attachment to teeth;

Figs. 2 (a, b) show another embodiment of the invention and its attachment to teeth;

Figs . 3 (a, b) show another embodiment of the invention and its attachment to teeth by means of a dental brace; Figs. 4 (a, b) show another two embodiments of the invention comprising a loop structure; Figs. 5 show an alternative attachment of the insert of Fig. 3;

Fig. 6 shows an embodiment of the invention where the insert is part of a dental brace; and

Figs 7 to 9 show graphically the results of in vitro testing of inserts of the invention.

Examples of A Manufacturing Process

Solanyl® polymer pellets were combined with sodium fluoride powder, at up to 10% by weight of sodium fluoride and placed in the hopper of a single screw extruder of a conventional type, having a 25mm screw with a length to diameter ratio of 20:1. The temperature of the polymer as it passed through the extruder was ramped from 120 to 130 deg C. The metering zone pump operating at 3rpm delivered a pressure through the die head of 400psi. The softened or molten polymer/sodium fluoride mixture was extruded from the machine through a die having a single slit (0.3x8mm), at a rate of 62m/min, to produce a tape product, which was quenched by passing through a water bath at temperatures of between 10 and 50 deg C.

As an alternative to a tape product a multifilament yarn was produced by using the same method but with a die which has 30 holes of 0.54mm x 1.6mm rather than a single slit. Either the tape or the multifilament product can be further processed for example by knitting into a chosen form at this stage of manufacture if desired.

The fluoride-containing polymer tape was then coated with a hydrogel coating. The coating gel was prepared by first preparing an emulsion of chlorhexidine, as therapeutic agent, in boiling deionised water. This emulsion was then added to an appropriate quantity of powdered hydrogel to provide the desired slow release properties in the finished insert. Typically the amount of hydrogel used is from 2% to 10% by weight of the quantity of water used to disperse the chlorhexidine. The extruded tape of polymer material was then dipped into the hydrogel composition for about 30 seconds to 1 minute to coat it and the coated tape allowed to air-dry and set overnight. The adhesion of the hydrogel coating to the polymer material tape can be improved by first subjecting the tape to a gas plasma treatment, for example an argon, nitrogen or oxygen gas plasma treatment.

Finally the resorbable insert was completed by providing a polysaccharide coating to the tape by dipping it in a solution, typically of between 3% to 7% by weight of pullulan, as polysaccharide, and then drying. As with the hydrogel coating procedure, a plasma treatment can be employed to improve the adhesion of the polysaccharide coating.

The material produced by this method may then simply be cut into an appropriate length for attachment to the dentition of a user, by winding round a group of 4 upper or lower teeth (see Fig. 5) .

As an alternative to the tape or multifilament product described above a moulded product may be produced. For example, an extrusion process, from the melt, similar to that described above was used to produce a tape of 5cm width and lmm thickness from Solanyl® pellets. The melt

temperature used was lOOdeg C with the metering pump operating at lOrpm resulting in a processing torque of 450kg.m. The tape produced from this process was then compression moulded into sheets or films, of the desired thickness, by forming in a press at lOOdeg C and a pressure of 5-10 tonnes for 5 minutes. The resulting sheet or film is then hydrogel coated, plasma treated and then polysaccharide coated, as described above. The desired shape and size of implant is then punched out of the sheet or film.

In Vitro Testing of Inserts of the Invention

In order to demonstrate the ability of inserts of the invention to provide useful slow release of a therapeutic agent a number of in vitro experiments were carried out on test samples of film and tape products containing sodium fluoride as therapeutic agent. The test samples were made by extrusion and moulding processes in accord with those described above. The film and tape products studied and described here were made without hydrogel or other coatings being employed. The samples consisted of extruded or moulded Solanyl®/sodium fluoride mixtures. Fluoride release tests were carried out on samples of the products as follows : Each sample of tape or film product was conditioned for 24 hours prior to testing at 20 ⁰ C and 65% Relative Humidity. Samples were then placed in 50ml of phosphate buffer solution (9.88g per litre of phosphate buffered saline concentrate - Fisher Bioreagents BPE661-10) at pH7 and a temperature of 37° to model placement within the oral cavity. The release of fluoride from the sample into the phosphate buffer solution was measured using a fluoride with selective electrode (Cole Palmer 27540-14) .

Cumulative release of fluoride was then measured at periodic intervals.

The results of tests for various samples are described below with reference to figures 7, 8, 9.

A number of different embodiments all made by processes generally as described above or by similar thermal moulding process are shown in Figures 1 to 6.

Figure Ia shows an insert 1 of the invention in elevation. The insert 1 has the form of a rod 2 which is wider at each end 3,4 than in the middle 6 as shown in the three cross- section views of figure Ib. The middle 6 has a generally triangular cross-section.

Figure Ic shows the insert 1 in place between two molars 8,10 adjacent the gum 12, in elevation.

Figure Id shows a plan view.

The triangular cross-section of the middle 6 of the insert fits snugly in the space 14 between the molars 8,10 and the gum 12 and the wider ends 3,4 act to prevent accidental dislodging of the insert 1 in use. Over time the insert dissolves slowly in the oral fluids of a user, continuously providing a dose of the therapeutic agents employed.

Figure 2a shows an alternative embodiment of the insert 1 of the invention which takes the form of a curved plate 15. the curved plate 15 is shown attached to the side 16 of a molar tooth 8 by means of an acid etched resin 18.

The curved plate 15 conforms closely to the shape of the molar 8 (Fig. 2b, plan view) and is positioned so as to be clear of the biting surface 20 of the tooth 8.

Figure 3a shows in detail a molar tooth 8 which has an attached dental brace 22 consisting of a bracket 24 and wire 26. An insert 1 of the invention which in this case is a fibrous tape 28 is wound round the bracket 24 and wire 26. Figure 3b shows in partial plan view a row 30 of teeth 8 with the tape 28 wound round the wire 26 and brackets 24 of the dental brace 22.

Figure 4a shows an embodiment of the insert invention 1 which is in the form of an elasticated loop 32. The loop is shown in position around the base 34 of a molar tooth 8, adjacent the gum 12. The loop 32 passes between the spaces 14 between the tooth 8 around which it attached and adjacent teeth 10.

Figure 4b shows a similar loop with a bead 36 of insert material attached. This provides a greater reservoir of therapeutic agent (s) than the simple loop 32 of Figure 4a.

Figure 5 shows the tape 28 embodiment of Figure 3 attached directly to the dentition by being wound round a group of four molar teeth 8.

Figure 6 shows a dental brace 22 of the form shown in Figure 3 attached by brackets 24, to molar teeth 8. in this case one ' bracket 38 is itself an insert 1 of the invention, which dissolves slowly in use.

Figure 7 shows the results of in vitro testing as described above for fluoride release from three samples of

Solanyl®/sodium fluoride tapes as a graph. Each tape sample was βcm long by lmm wide. One tape containing 0.5% NaF by weight was of 0.15mm average thickness. The other two tapes contained 5% Naf (0.38mm thickness) and 10% NaF (0.39mm thickness) .

The graph of Figure 7 shows cumulative fluoride release for each sample. The tape containing 0.5% NaF shows a very low release over the five-week period illustrated. Both the 5% NaF and the 10% NaF containing tapes show a relatively steady (approximately linear) release curve on the graph. This indicates that fluoride was released steadily throughout the period of the experiment (5 weeks) . The 10% NaF containing tape had the highest rate of release (steepest curve) as expected. These results show that adjusting the concentration of therapeutic agent in the polymer can be used to adjust the release rate.

Figure 8 shows graphically the results obtained in an in vitro study of release of fluoride from lcm ² films of solanyl containing 8% -NaF. The films had an average thickness of 0.55mm. Three film samples were tested as shown on the graph of Figure 8 with consistent results obtained. The results show fluoride release for the first two weeks of the test at about 15ppm per week. Thereafter fluoride release ceases as shown by the substantially horizontal release rate curves from about two weeks onwards .

Figure 9 shows the effects that different types of processing can have on the release characteristics of a Solanyl®/NaF mixture. Pieces of film (lcm ² ) were tested in phosphate buffer as before. One sample was not sterilised. One was sterilised by gamma radiation and the third was

both sterilised and argon plasma treated as may be done to prepare a film for coating with a hydrogel layer.

The results indicate that the sterilisation method had little impact on the release of fluoride. However the plasma treatment did have an effect, moderating the fluoride release. It is thought that the plasma treatment may cause alterations in the surface properties of the polymer/NaF mixture resulting in the change of release rate observed.