WO2002090436A2

WO2002090436A2 - Bioactive biomimetic elastomers

Info

Publication number: WO2002090436A2
Application number: PCT/EP2002/005221
Authority: WO
Inventors: David Woolfson; Karl Malcolm; David Jones; Sean Gorman
Original assignee: Xiomateria Limited
Priority date: 2001-05-09
Filing date: 2002-05-09
Publication date: 2002-11-14
Also published as: AU2002341225A1; WO2002090436A3

Abstract

The present invention relates to a silicone elastomer which is formed by vulcanising avulcanisable polysiloxane using a crosslinking agent, in the presence of at least one beneficial agent. The crosslinking agent comprises a silane in which at least one oxygen bonded substitutent is selected from a functionalised or unfunctionalised, substituted or unsubstituted straight or branched chain C5-25alkyl, alkenyl, alkynyl or cyclic alkyl moiety; substituted or unsubstituted aryl; or substituted or unsubstituted acyl, in which the moiety bonded to the carboxyl group is a functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain (C4-25alkyl, alkenyl, or alkynyl; or substituted or unsubstituted aryl. These silicone elastomers permit delivery of the beneficial agent(s) to the surface.

Description

BIOACTIVE BIOMIMETIC ELASTOMERS

The present invention relates to bioactive biomimetic elastomers.

As used herein, the term "bioactive" is intended to mean the ability to deliver one or more agents having beneficial activity in vivo, for example, one or more therapeutic or prophylactic agents and/or one or more device protective agents such as agents that enhance the biocompatibility of silicone elastomers such as those elastomers disclosed in our International patent application No. PCT/EPOO/11252, the contents of which are incorporated herein by reference, which agents are beneficial in the treatment or prevention of disease in humans or animals. It will be appreciated that the therapeutic or prophylactic agents are directly beneficial in the treatment or prevention of disease in humans or animals, respectively, whilst the device protective agents are usually beneficial in the treatment or prevention of disease in humans or animals by prolonging the useful life, in vivo, of medical devices comprising said elastomers.

As used herein, the term "biomimetic" as applied to a non-biological surface is intended to embrace properties that are substantially similar to human or animal epithelial tissue in vivo. Thus, human or animal epithelial body surfaces are protected by constant renewal through the production and shedding of mucous, which also provides surface lubrication. Biomimetic surface properties, therefore, include resistance to surface microbial growth and infection, resistance to surface deposition of solid material, such as, for example, the deposition of complex inorganic salts, and/or lubricity.

The use of medical devices for temporary or permanent implantation in humans or animals is common, with tens of millions of such devices used annually throughout the world. By the term "medical device" is meant any device having a structural, for example, a "mechanical" function, which device is suitable for temporary or permanent implantation in, or for attachment in or on, the human or animal body, the device being selected from, but by no means limited to, urinary tract devices (including ureteral stents and urinary catheters), ocular devices (including contact lenses), orthopaedic devices, respiratory devices, cardiovascular devices, dental devices, neurological devices, gastrointestinal devices, audiology devices, surgical devices, including surgical gloves, foot care devices, wound healing devices, condoms and the like. In addition, the term "medical device" is intended, in the present invention, to comprise devices having drug delivery functions, in addition to the aforementioned structural (or mechanical) functions. By drug delivery is meant any device arranged to permit drug delivery therefrom, the device being selected from, but by no means limited to, subcutaneous implants, pessaries, suppositories, intravaginal devices, intrauterine devices, intrarectal devices, transdermal devices, wound care devices and the like.

Such medical devices are typically manufactured from one or more biocompatible polymers, collectively referred to as "biomaterials". Silicone elastomer is the most common biomaterial presently used in the production of such devices. However, in common with all presently lαiown biomaterials, silicone elastomer is prone to biofilm formation and, in the case of silicone urinary devices, to encrustation with complex inorganic salts.

When used as biomaterials for the production of medical devices, all presently known silicone elastomers suffer from the disadvantage of an inherent lack of lubricity. In addition, when implanted in a living human or animal body, they are prone to surface attachment of microorganisms and, in certain cases, deposition and attachment of material of biological origin, such as naturally occurring complex inorganic salts. The description which follows, makes reference to indwelling catheters in particular but is by no means to be considered limited thereto.

The number of patients who use an indwelling catheter, either for long periods or indefinitely, to manage their incontinence or because of bladder outlet obstruction, is estimated at 10 - 12% of hospital patients and 4% of community patients. Significant levels of bacteriuria are found within 72 hours in long-term catheterised patients. In addition, the most common cause of recurrent catheter blockage, requiring hospital treatment, is encrustation on the catheter surface and in its lumen. The major components of the blocking encrustation are struvite (magnesium ammonium phosphate) and hydroxyapatite (calcium phosphate). These minerals are precipitated from urine under alkaline conditions caused by the release of ammonia from urinary urea by urease-producing bacteria in the urine and on the catheter surface.

Device-related infection, in general, is a major life-threatening problem with all types of medical devices, due to the formation of a microbial biofilm on the biomaterial itself. When this occurs, systemic antibiotic treatment is unable to eradicate the infection and invasive surgery may be necessary to remove and replace the medical device.

It is an object of the present invention to provide a bioactive biomimetic elastomer whose constantly exuding, renewable liquid surface carries in solution or otherwise dispersed therein, one or more additional agents that have beneficial activity in vivo when used in association with biomimetic silicone elastomers, such as those as disclosed in International application No. PCT/EPOO/11252. Such additional agents may include therapeutic and/or prophylactic agents and/or a device protective agent, for example, a biocompatibility enhancer such as lecithin or other surface active agents, or a mixture thereof. Whilst the present invention finds immediate utility in the field of medical devices, it is not so limited. Thus, the present invention will also be useful where the elastomers of the present invention form structural tubing for use in the field of food/agriculture. One example would be the tubing through which drinks are transferred to dispenser taps.

It is believed that such additional agents may act directly by targeted in vivo delivery to an accessible internal or external site at the location of the medical device or, alternatively, may act beneficially by preventing infection or other deleterious effects due to the presence, in vivo, of the medical device by, for example, preventing or reducing the adherence of microorganisms to the medical device. Equally, a combination of such possible mechanisms of action are also envisaged.

Accordingly, in a first aspect, the present invention provides a silicone elastomer comprising, in addition, at least one beneficial agent. Specifically, the silicone elastomer of the present invention is formed by vulcanising a vulcanisable polysiloxane, or a mixture thereof, in the presence of at least one beneficial agent and in the presence of a crosslinking agent, or a mixture thereof, the crosslinking agent or the mixture thereof including a silane having at least three, and preferably four, oxygen-bonded substituents, at least one of said oxygen-bonded substituents, which may be the same or different, being selected from functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C₅-_25; (C₅-₂₅) alkyl; functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain (Cs-₂₅)alkenyl or alkynyl; functionalised or unfunctionalised, substituted or unsubstituted, saturated or unsaturated cyclic alkyl (C₅-₂₅); substituted or unsubstituted aryl; or substituted or unsubstituted acyl in which the moiety bonded to the carboxyl group is a functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_4-25 alkyl; functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C _{- 5} alkenyl or alkynyl; or substituted and unsubstituted aryl; and, if necessary, a condensation catalyst.

Preferably, the at least one beneficial agent comprises a therapeutic and/or prophylactic agent, and/or a device protective agent (which includes a biocompatability enhancer), or a mixture thereof. Said beneficial agent must have sufficient solubility in the higher alcohol or exudate, so that an effective amount of the beneficial agent is released from said elastomer of the present invention. In addition, said beneficial agent must be compatible with the vulcanisable polysiloxane, i.e., chemically inert therewith. Said beneficial agent should, preferably, have a solubility in the alcohol exudate provided by said silicone elastomer of at least 1.1, preferably 1.25, more preferably 1.45, times greater than its solubility in silicone oil, measured at 37 degrees Celsius.

By the term "therapeutic agent' is meant any substance or mixture of substances; or any pro-substance or mixture of pro-substances, that are beneficial in the treatment of a disease state in humans or animals.

By the term "pro-substance" is meant anything which is converted, in vivo, into an active agent, be it an active therapeutic agent or an active prophylactic agent or an active device protective agent.

By the term "prophylactic agent' is meant any substance or mixture of substances, or any pro-substance or mixture of pro-substances, that are beneficial in the prevention of a disease state in humans or animals.

Examples of suitable classes of therapeutic and/or prophylactic agents include, but are not limited to, cytotoxic agents, anti-migratory agents for the prevention of cell migration; cardiovascular agents such as anticoagulants and anti- tlirombogenics, anti-continence agents, anti-inflammatory agents, anti-spasmodic agents, growth factors and related promoters of tissue regrowth, anti-proliferative agents, antimicrobial agents (including antibacterial, antifungal, anti-protozoal, antiviral agents), anthelmintics, anti-parasitics, local anaesthetics, neurological agents, agents for use in the eye, ear, nose or throat and agents that act on the lower urinary tract or on the urogenital tract.

By the term "device protective agent" is meant any substance or mixture of substances, or any pro-substance or mixture of pro-substances, that beneficially maintains and/or improves and/or prolongs the intended function and/or biocompatibility of the medical device, for example, agents making the medical device surface more hydrophilic, for example, polyethylene glycols; naturally occurring biocompatibility enhancers such as lecithin, anti-infective agents, anti- proliferative agents, surface active agents or a mixture thereof. For example, such device protective agents can have utility in inhibiting, preferably substantially preventing, deposition of foreign matter in, or on, the medical device.

In a second aspect, the present invention provides a medical device comprising the silicone elastomer according to the first aspect of the present invention.

Preferably, the medical device is adapted to release the at least one beneficial agent over, in vivo, at least 2 days, preferably at least 3 days, more preferably at least 4 days, still more preferably more than 4 days.

In a third aspect, the present invention provides a polysiloxane vulcanisable composition comprising a vulcanisable polysiloxane or a mixture thereof; at least one beneficial agent; a crosslinking agent, or a mixture thereof, the crosslinldng agent or the mixture thereof including a silane having at least three, and preferably four, oxygen-bonded substituents, at least one of said oxygen-bonded substituents, which may be the same or different, being selected from functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C₅-C₂₅ alkyl; functionalised or unfunctionalised, substituted or unsubstituted C_5-25 alkenyl or alkynyl; functionalised or functionalised, substituted or unsubstituted, saturated or unsaturated, cyclic alkyl (C₅-₂₅); substituted or unsubstituted aryl; or substituted or unsubstituted acyl, in which the moiety bonded to the carboxyl group is a functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_4-25 alkyl; functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_4-25 alkenyl or alkynyl; or substituted or unsubstituted aryl; and, if necessary, a condensation catalyst.

In its broadest aspect, therefore, at least one of the oxygen-bonded substituents is as defined above but all remaining oxygen-bonded substituents, which may be the same or different, are not so limited and may be selected firom functionalised or unfunctionalised, substituted or unsubstituted, straight, cyclic or branched chain Cι-₂₅ alkyl, alkenyl or alkynyl; substituted or unsubstituted aryl; or substituted or unsubstituted acyl, in which the moiety bonded to the carboxyl group is a functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain Cι_-25 alkyl, C_2-25 alkenyl, C_3-25 cyclic alkyl or C_2-25 alkynyl; or substituted or unsubstituted aryl.

Preferably, each (i.e. all three or all four) of said oxygen-bonded substituents, which may be the same or different, is selected from functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_5-25 alkyl, C₅-₂-₅ alkenyl, C₅-₂₅ alkynyl or C₅-₂₅ cyclic alkyl; substituted or unsubstituted aryl; or substituted or unsubstituted acyl, in which the moiety bonded to the carboxyl group is a functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_4-25 alkyl, alkenyl or alkynyl; or substituted or unsubstituted aryl. More preferably, each (i.e. all three or all four) of said oxygen-bonded substituents, which may be the same or different, is selected from functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_8-25 alkyl, C_8-25 alkenyl, C_8-25 alkynyl or C_8-25 cyclic alkyl; substituted or unsubstituted aryl; or substituted or unsubstituted acyl, in which the moiety bonded to the carboxyl group is a functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_8-25 alkyl, alkenyl or alkynyl; or substituted or unsubstituted aryl.

As used herein, the term "aryl" is intended to embrace substituted or unsubstituted monocyclic or polycyclic aromatic hydrocarbon or heterocyclic radicals. Preferred monocyclic aromatic radicals are selected from phenyl, substituted phenyl radicals such as, but not limited to, tolyl, xylyl, mesityl, cumenyl (isopropylphenyl) and substituted phenylene derivatives such as, but not limited to, benzyl, benzhydryl, cinnamyl, phenethyl, styryl and trityl. Preferred polycyclic aromatic radicals include, but are not limited to, substituted or unsubstituted naphthalene and anthracene radicals, of which napthyl is most preferred.

As used herein, the term "acyl" is intended to embrace all radicals of the structural formula

R - C -

I I o in which R, being the moiety bonded to the carboxyl group, is a functionalised or unfunctionalised, substituted or unsubstituted, saturated straight or branched chain Cι-₂₅ alkyl; a functionalised or unfunctionalised, substituted or unsubstituted, uήsaturated, straight or branched chain C₂..25 moiety (including alkenyl and alkynyl); or is a substituted or unsubstituted aryl.

As used herein, the term "functionalised" indicates the presence of one or more reactive chemical moieties such as, but not limited to, halide, hydroxyl, carboxyl, carbonyl, anhydride, cyano, ester, ether, sulphide, thiocyanate, thioether, alkene, alkyne and various conjugated groups and the term "unfunctionalised" indicates their absence. In a further aspect of the invention, there is provided use of such bioactive biomimetic elastomers according to the first aspect of the invention in medical devices for permanent or temporary implantation in, or for attachment in or on, the human or animal body.

In a still further aspect of the present invention, there is provided use of silicone elastomers according to the first aspect of the invention for the manufacture of medical devices for temporary or permanent implantation in, or for attachment in or on, the human or animal body, in which the silicone elastomers act as bioactive biomimetic elastomer biomaterials.

In a yet further aspect of the present invention, there is provided use of silicone elastomers according to the first aspect of the invention for the manufacture of drug delivery devices, including medical devices that also have an additional use as a drug delivery device, for permanent or temporary implantation in, or for attachment in or on, the human or animal body, in which the silicone elastomer is provided with one or more beneficial agents that are beneficial in vivo when used in association with the silicone elastomer, the one or more additional agents being carried, either in solution or otherwise dispersed, in the constantly exuding, renewable liquid surface disclosed in International patent application No. PCT/EPOO/11252.

Beneficial Agents

One or more therapeutic and/or one or more prophylactic agents and/or one or more device protective agents will be present in any medical device prepared from silicone elastomers according to the first aspect of the invention. Such beneficial agents may include therapeutic and/or prophylactic agents acting as drug substances for the treatment or prevention of human or animal diseases, and/or device protective agents for the improvement or modification of the performance of a medical device, for example, by improving the ability of said device to withstand the attachment of microorganisms to any part of the device. Examples of suitable therapeutic or prophylactic agents for use in the invention include, but are by no means limited to, antimicrobial agents, antispasmodic agents, agents that aid in the dissolution or dispersal of blood clots and agents such as a surface active agent that inhibits or reduces surface attachment of foreign matter in, or on, the medical device. Such agents may also include those intended to enhance the biocompatability of a medical device prepared from silicone elastomers according to the first aspect of the invention, for example, lecithin.

The surface active agent suitable for use in the present invention may be selected from nonionic, anionic and cationic surface active agents and mixtures thereof. Suitable surface active agents include, but are not limited to, polyoxyethylene derivatives of the sorbitan esters (T weens), sorbitan esters (Spans), Macrogol monomethyl ethers, polyethylene glycols and derivatives thereof, phospholipids (lecithins) and derivatives thereof, poloxamers, gelatin and other proteins, quaternary ammonium compounds, bile salts and derivatives thereof, sodium lauryl sulphate, sodium oleate and other metal salts of anionic surfactants.

GENERAL METHOD OF MANUFACTURE OF BIOMIMETIC SILICONE ELASTOMERS

A polysiloxane vulcanisable composition is prepared by thoroughly blending a hydroxyl-terminated vulcanisable polysiloxane, containing about 25 parts by weight (per 100 parts by weight of the polysiloxane starting material) of diatomaceous earth as the filler, with 1-25, preferably 2-25, more preferably 2-15, most preferably 2-12, parts by weight (per 100 parts by weight of the vulcanisable polysiloxane starting material) of a crosslinking agent or agents as defined in the present invention or, alternatively, 1-25, preferably 2-25, more preferably 2-15, most preferably 2-12, parts by weight (per 100 parts by weight of the vulcanisable polysiloxane) of a mixture of a crosslinking agent(s) as defined in the present invention with a conventional crosslinking agent (such as tetramethoxysilane, tetraethoxy silane, tetrapropoxy silane or tetra-n-butoxy silane). A further 0.1-150 parts by weight per 100 parts by weight of the vulcanisable polysiloxane, and preferably 1-40 parts by weight, of at least one beneficial agent (an additional agent) are added into the elastomer mix thus formed. Entrapped air is removed from the mix by an appropriate means, for example, by allowing the mix to stand for several hours. A suitable catalyst, typically stannous octoate (0.25 to 2.5, preferably 0.25 to 1.25, more preferably 0.5 to 1.0 parts by weight per 100 parts by weight of the vulcanisable polysiloxane) is then added rapidly with gentle stirring. Vulcanisation, for example at 80°C for 2 minutes (see Table 1), yields the bioactive silicone elastomer of the first aspect of the invention (Materials B, C ,D, F, G, H, and I). Greater amounts of the catalyst may be added, if a quicker cure time is desired. Vulcanisation conditions (time and temperature) may also be altered in a conventional manner.

A bioactive silicone elastomer, for drug delivery device applications, including those where drug delivery is in addition to a medical device function, may be produced by rapidly processing the catalysed mixture using, for example, single or multiple extrusion, or injection moulding processes. Thus, a range of novel bioactive silicone elastomers of the present invention were prepared by extruding a mixture of the required amounts of a vulcanisable polysiloxane or a mixture thereof, a crosslinking agent or a mixture thereof, a condensation catalyst or a mixture thereof, and at least one beneficial agent such as a therapeutic or prophylactic agent or a device protective agent (biocompatibility enhancer) or a mixture thereof, between two flat glass plates separated by spacers of 2 mm thickness, with curing at 80°C for 2 minutes, according to Table 1 (Materials B,

C, D, F, G, H and I).

Data for a silicone elastomer produced using tetrapropoxy silane, a crosslinldng agent lαiown in the art, and not containing an additional agent, is included for comparative purposes (Material A). Data for a silicone elastomer not containing a beneficial agent, is also included for comparative purposes (Material E). The parts by weight of crosslinldng agent used in each case is given per 100 parts by weight of the vulcanisable polysiloxane, together with the curing time required to produce a solid silicone elastomer at 80°C (curing temperature) and the parts by weight of condensation catalyst used per 100 parts by weight of the vulcanisable polysiloxane. In each case, the crosslinking agent(s) used for each of Materials A- J is a liquid at room temperature.

GENERAL METHODOLOGY: SURFACE ENCRUSTATION

Sections (50 mm x 10 mm x 2 mm) of material were suspended in an artificial urine model for 14 days [Tunney M.M., Bonner M.C., Keane P.F., Gorman S.P. 1996. Development of a model for assessment of biomaterial encrustation in the upper urinary tract. Biomaterials 17, 1025 - 1029.]. The artificial urine was changed on a daily basis to simulate conditions in the urinary tract and maintained at 37°C. Sections of each material were then removed for assessment of encrustation by image analysis to provide the % material surface coverage of encrustation. Material sections were placed in 0.005% w/v of benzalkonium chloride at pH 4.5 for 15min in an orbital incubator operating at 37°C and 1 OOthrows/min.

GENERAL METHODOLOGY: % KILL

Escherichia coli isolated from microbial biofilm on retrieved ureteral stents was grown to stationary phase in Mueller Hinton Broth at 37°C [Keane P.F., Bonner

M.C., Johnston S.R., Zafar A., Gorman S.P. 1994. Characterisation of biofilm and encrustation on stents in vivo. Br. J. Urol, 73, 687 - 691.]. The bacterial cells were then washed and standardised in sterile phosphate buffered saline (PBS, pH 7.3, O.OlmM) to the required density, expressed as colony forming units (cfu) ml^"1. Discs of the novel silicone elastomer were contacted with the standardised bacterial culture under shaking conditions (100 rpm, 37°C) for 4 hours. The discs were removed and washed to release non-adherent bacteria. Silicone discs with adhered bacteria were immersed in 0.005%) (w/v) benzalkonium chloride-based catheter maintenance liquid for 15min at 37°C. Subsequently, discs were then placed in phosphate buffered saline (PBS) (10ml) and adherent bacteria dislodged by low power sonication and vortexing. The number of remaining viable bacteria/mm² silicone elastomer was calculated following serial dilution and plating of samples onto Mueller Hinton Agar and incubation at 37°C for 24-48 hours.

Table 1 : Formulations

Alcohol starting Crosslinking Agent Parts by weight of Cure time catalyst cone, (parts by material for Beneficial Agent crosslinking, beneficial (minutes) weight of stannous octoate crosslinking SR* (ratio of solubility in agent (per 100 parts by per 100 parts by weight of the agent/by-product alcohol starting material to weight of the vulcanisable polysiloxane) solubility in silicone oil) vulcanisable polysiloxane)

A propan-1-ol tetra(propyloxy)silane 2.5 2 0.50

B propan-1-ol tetra(propyloxy) silane and 1.00 2 0.75 and tetra(oleyloxy) silane 6.23 oleyl alcohol nalidixic acid 0.5 S =1.6

C propan-1-ol tetra(propyloxy) silane and 0.50 2 0.75 and tetra(oleyloxy) silane 8.30 oleyl alcohol benzalkonium chloride 2.5 SR =2.3

D propan-1-ol tetra(propyloxy) silane and 0.50 2 0.75 and tetra(oleyloxy) silane 8.30 oleyl alcohol benzalkonium chloride 5 SR =2.3

E propan-1-ol tetra(propyloxy) silane and 0.50 2 0.75 and tetra(oleyloxy) silane 8.30 oleyl alcohol

F propan-1-ol tetra(propyloxy) silane and 0.50 2 0.75 and tetra(oleyloxy) silane 8.30 oleyl alcohol econazole 0.5 1.8

G propan-1-ol tetra(propyloxy) silane and 0.50 2 0.75 and tetra(oleyloxy) silane 8.30 oleyl alcohol nystatin 1.0

SR =3.4

H propan-1-ol tetra(propyloxy) silane and 0.50 2 0.75 and tetra(oleyloxy) silane 8.30 oleyl alcohol nalidixic acid 1.0 SR =1.6

I propan-1-ol tetra(propyloxy) silane and 0.50 2 0.75 and tetra(oleyloxy) silane 8.30 oleyl alcohol

5-fluorouracil 1.0 SR = >5

J Propan-1-ol Tetra(propyloxy) silane and 0.50 2 0.75 and tetra(oleyloxy) silane 8.30

Oleyl alcohol oxybutynin 10 ^ ^' Estimated from weight measurements and visual observation S.R * indicates that the solubility in the alcohol starting material is greater than in silicone oil, thereby giving better release in the exudate. The S.R. values are determined by dissolving the solid in the respective liquids at 37°C, until the solution just loses clarity (or solubility is exceeded) and the weight differences due to dissolved solid is determined.

It will be appreciated that, in the silicone elastomers of the present invention, the higher chain alcohol starting material given in column 1 of Table 1 becomes the alcohol exudate or constantly exuding renewable liquid surface. Thus, the higher chain alcohol becomes the transport medium for carrying the at least one beneficial agent to the surface, in vivo, of the medical device, the at least one beneficial agent being dissolved or otherwise dispersed in this exudate.

Example 1

The in vitro delivery (dissolution characteristics) of a therapeutic agent from novel biomimetic silicone elastomers of the invention prepared according to the General Method of Manufacture was determined as follows.

Thus, four identical rectangular strips of the silicone elastomer of the present invention (30 mm length x 10 mm breadth) and thickness 2.5 mm were prepared. The strips were tested in vitro for their release characteristics in 10 ml of aqueous solution containing a surfactant (2%> (w/v) polyoxyethylene sorbitan monolaurate) to maintain sink conditions. Each strip was placed upright in a sealed 20 ml glass sample vial containing the dissolution medium, maintained at a constant temperature of 37°C. The contents of the flask were gently agitated in an orbital incubator in order to prevent the occurrence of a hydrostatic layer on the surface of the strip. After 24 hours, the dissolution medium was removed and replaced with fresh dissolution medium of identical volume. This process was repeated at each successive 24 hour period until a total time of 5 days had elapsed. At the end of each 24 hour period, a sample of the dissolution medium was analysed for its beneficial agent content by high performance liquid chromatography.

The data obtained for Material B (Table 1) and containing nalidixic acid (an antibiotic agent for the treatment of infection) as the therapeutic agent, is shown in Table 2a, showing that effective drug release was obtained with Material B. Furthermore, Material B provided enhanced release of active compared with conventional TPOS (tetra (propyloxy silane)) cured silicone (i.e., a material similar to Material A, but containing 0.5 parts nalidixic acid per 100 parts by weight of vulcanisable polysiloxane).

The in vitro delivery of oxybutynin (an antispasmodic agent for the treatment of uninary incontinence) from Material J (Table 1) was also investigated. Table 2b shows the data obtained, showing that effective drug release is also obtained with Material J.

Table 2a Cumulative release of nalidixic acid from material B over 5 days

Table 2b Cumulative release of oxybutynin from Material J over 5 days

Example 2 The effect of incorporation of the non-antibiotic antibacterial agent (benzalkonium chloride) into the silicone elastomers of the invention to form Materials C and D was determined against microbial biofilm on the material surfaces. Thus, Escherichia coli isolated from microbial biofilm on retrieved ureteral stents was grown to stationary phase in Mueller Hinton Broth at 37°C. The bacterial cells were then washed and standardised in sterile phosphate buffered saline (PBS, pH 7.3, O.OlmM) to the required density, expressed as colony forming units (cfu) ml^" ¹. Discs (diameter 2 cm) of either Material C or D, and discs of comparative Material E, were contacted with the standardised bacterial culture under shaking conditions (100 rpm, 37°C) for 4 hours. The discs were removed and washed to release non-adherent bacteria. Discs of the test materials with adhered bacteria were then immersed in an aqueous medium for 15min at 37°C to facilitate drug release. Subsequently, discs were placed in PBS (10ml) and adherent bacteria dislodged by low power sonication and vortexing. The number of remaining viable bacteria/cm² silicone elastomer was calculated following serial dilution and plating of samples onto Mueller Hinton Agar and incubation at 37°C for 24-48 hours. The data obtained indicates that incorporation of benzalkonium chloride into Materials C and D killed all or nearly all bacteria adhered to the material, when compared to comparative Material E.

Table 3 Antibacterial effect of Benzalkonium chloride incorporation into novel silicone elastomers of the present invention on Escherichia coli initial bacterial challenge in biofilm (surface area, mode of growth: 5xl0⁵cfu/cm²)

Example 3

The effect of incorporation of an antifungal agent (Econazole) into the silicone elastomers of the invention to form Material F was determined against Candidal biofilm on the material surfaces. Thus, the yeast Candida albicans, isolated from microbial biofilm on endotracheal tubes retrieved from patients, was grown to stationary phase in Mueller Hinton Broth at 25°C. The yeast cells were then washed and standardised in sterile phosphate buffered saline (PBS, pH 7.3, O.OlmM) to the required density, expressed as colony forming units (cfu) ml^"1. Discs (diameter 2 cm) of Material F and discs of comparative Material E were contacted with the standardised yeast culture under shaldng conditions (100 rpm, 37°C) for 4 hours. The discs were removed and washed to release non-adherent Candida. Discs of the test materials with adhered Candida were then immersed in an aqueous medium for 15min at 37°C to facilitate drug release. Subsequently, discs were placed in PBS (10ml) and adherent Candida dislodged by low power sonication and vortexing. The number of remaining viable Candida/ 'cm² silicone elastomer was calculated following serial dilution and plating of samples onto Sabouraud Dextrose Agar and incubation at 37°C for 24-48 hours. The data obtained indicates that incorporation of Econazole into Material F killed approximately 90% of Candida adhered to the material, when compared to Comparative Material E.

Table 4 Antifungal effect of Econazole incorporation into novel silicone elastomer on Candida albicans yeast in biofilm (surface) mode of growth

Example 4

The effect of incorporation of an antifungal agent (Nystatin) into the silicone elastomers of the invention to form Material G was determined against Candidal biofilm on the material surfaces using the methodology of Example 3. The data obtained indicates that incorporation of Nystatin into Material G killed approximately 99% of Candida adhered to the material, when compared to Comparative Material E.

Table 5 Antifungal effect of Nystatin incorporation into novel silicone elastomer on Candida albicans yeast in biofilm (surface) mode of growth

Example 5

The persistence of activity of an antibiotic (Nalidixic Acid) incorporated into the silicone elastomers of the invention to form Material H was determined against the bacterium Escherichia coli isolated from microbial biofilm on a ureteral stent retrieved from a patient using Escherichicia coli cultured according to the methodology of Example 2, the required density being about lxl 0⁵ colony forming units (cfu) ml^"1. The surface of Nutrient Agar (supplied by Oxoid Limited, UK) plates was spread with 1 ml of this standardised culture and discs (diameter 1 cm) of Material H, and discs of Comparative Material E, were placed centrally on the surface of these inoculated agar plates with one disc per plate. Incubation followed at 37°C for 24 hours and the diameter of zones of growth inhibition arising around the discs were measured in mm. The discs were removed and replaced onto newly inoculated agar plates, as described above, with incubation for a period of 24 hours at 37°C as before. Again, zones of growth inhibition were measured where these resulted. This procedure was continued over successive days with transfer of discs of Material H and E until no further zones of growth inhibition were observed. The data obtained indicates that incorporation of Nalidixic Acid into Material H resulted in substantial inhibition of Escherichia coli with continuing persistence of this antibacterial activity over time illustrating the continuing delivery of the antibiotic. Material E showed no such activity.

Table 6 Antibacterial effect of Nalidixic Acid incorporation into novel silicone elastomer on Escherichia coli bacteria illustrating persistence of inhibitory activity over time

The date of Table 6 confirm that silicone elastomers of the present invention and medical devices incorporating said silicone elastomers are suitable for delivery of at least one beneficial agent over, in vivo, at least 2 days, preferably at least 4 days, more preferably more than 4 days.

Example 6

The release of a cytotoxic agent (5-fluorouracil) incorporated into the silicone elastomers of the invention to form Material I was compared with the release of the same weight of 5-fluorouracil incorporated into elastomer formulation A of Table 1. An elastomer sample of each material (5 cm x 5 cm) was suspended by a thread in an individual closed flask containing the dissolution medium (pH 7.2, phosphate buffered saline, 250 ml) maintained at a constant temperature of 37 °C. The contents of the flask were gently agitated in order to prevent the occurrence of a hydrostatic layer on the surface of the sample. Each experiment was performed in triplicate. After 24 hours, each sample was removed and suspended in a flask of fresh dissolution medium of identical volume by a method identical to that previously described. This process was repeated at each successive 24 hour period until a total time of 4 days had elapsed. At the end of each 24 hour period, a sample of the dissolution medium was analysed for its drug content by high performance liquid chromatography, using the method described in Woolfson et al. Pharmaceutical Research , 11_, pages 1315-1319 (1994), incorporated herein by reference in its entirety. There was no detectable release from the elastomer formulation containing 5-fluorouracil derived from material A. For material I, the mean daily release rates determined over a 3 day period were 7.3 μg (day 1), 6.9 μg (day 2), 6.1 μg (day 3).

Example 7

The incorporation of a suitable device protective agent, specifically a surface active agent, into the silicone elastomers of the present invention provide release to the elastomer surface such that the surface exudates are emulsified. Such emulsified surface exudates are then readily removed along with attached encrusting deposits and microorganisms. The removal of attached material from the silicone elastomers of the present invention may be further optimised by application of a catheter maintenance solution to the elastomer surface in vivo. Such catheter maintenance solutions act on the emulsified surface exudate of the elastomer to allow cleaning of the surface and removal of unwanted attached material.

The effect of incorporation of a device protective agent, specifically a surfactant (or surface active agent) into the silicone elastomers on the activity of a catheter patency or maintenance solution containing benzalkonium chloride was determined against microbial biofilm and encrustation. The biomimetic silicone elastomers were cured in the presence of a surface active agent (l%w/v). These materials were then coated with bacteria and encrusted deposits as described in the General Methodologies above, prior to being subjected to 15min contact with benzalkonium chloride (0.005%w/v at pH 4.5) catheter maintenance solution at 37°C. The data obtained (Table 7) showed that the incorporation of a surface active agent into the novel silicones increased the removal of both bacteria and encrusted deposits from the silicone surface when in contact with the benzalkonium chloride catheter patency solution compared to silicone elastomer without incorporated surfactant.

Table 7 Effect of 15min contact with Benzalkonium chloride (0.005%o (w/v)) patency solution on surface encrustation and biofilm on the novel silicone elastomer with incorporated surface active agents.

Claims

Claims:

1. A silicone elastomer comprising, in addition, at least one beneficial agent, the silicone elastomer being formed by vulcanising a vulcanisable polysiloxane, or a mixture thereof, in the presence of at least one beneficial agent and in the presence of a crosslinking agent, or a mixture thereof, the crosslinking agent or the mixture thereof including a silane having at least three; and preferably four, oxygen- bonded substituents, at least one of said oxygen-bonded substituents, which may be the same or different, being selected from functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C₅-C₂₅ alkyl; functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C₅,₂₅ alkenyl or alkynyl; functionalised or unfunctionalised, substituted or unsubstituted, saturated or unsaturated cyclic alkyl (C₅-₂₅); substituted or unsubstituted aryl; or substituted or unsubstituted acyl in which the moiety bonded to the carboxyl group is a functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_4-25 alkyl; functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_4-25 alkenyl or alkynyl; or substituted and unsubstituted aryl; and, if necessary, a condensation catalyst.

2. A silicone elastomer according to Claim 1, in which the at least one beneficial agent comprises a therapeutic and/or a prophylactic agent, and/or a device protective agent, or a mixture thereof.

3. A silicone elastomer according to Claim 1 or 2, in which the at least one beneficial agent has a solubility in the alcohol exudate provided by said silicone elastomer of at least 1.1, preferably 1.25, more preferably 1.45, times greater than its solubility in silicone oil, measured at 37 degrees Celsius.

4. A medical device comprising the silicone elastomer according to any one of Claims 1-3 or Claim 6 or Claim 7.

5. A polysiloxane vulcanisable composition comprising a vulcanisable polysiloxane or a mixture thereof; at least one beneficial agent; a crosslinking agent, or a mixture thereof, the crosslinldng agent or the mixture thereof including a silane having at least three, and preferably four, oxygen-bonded substituents, at least one of said oxygen-bonded substituents, which may be the same or different, being selected from functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C₅-C₂₅ alkyl; functionalised or unfunctionalised, substituted or unsubstituted C_5-25 alkenyl or alkynyl; functionalised or unfunctionalised, substituted or unsubstituted, saturated or unsaturated, cyclic alkyl (C_5-25); substituted or unsubstituted aryl; or substituted or unsubstituted acyl, in which the moiety bonded to the carboxyl group is a functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C _-25 alkyl; functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_4-25 alkenyl or alkynyl; or substituted or unsubstituted aryl; and, if necessary, a condensation catalyst.

6. A silicone elastomer according to any one of Claims 1 to 3 or a polysiloxane vulcanisable composition according to Claim 5, in which each (i.e. all three or all four) of said oxygen-bonded substituents, which may be the same or different, is selected from functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_5-25 alkyl, C_5-25 alkenyl, C_5-25 alkynyl or C_5-25 saturated or unsaturated cyclic alkyl; substituted or unsubstituted aryl; or substituted or unsubstituted acyl, in which the moiety bonded to the carboxyl group is a functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_4-25 alkyl, alkenyl or alkynyl; or substituted or unsubstituted aryl.

7. A silicone elastomer or a polysiloxane vulcanisable composition according to Claim 6, in which each (i.e. all three or all four) of said oxygen-bonded substituents, which may be the same or different, is selected from functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_8-25 alkyl, C_8-25 alkenyl, C_8-25 alkynyl or C_8-25 saturated or unsaturated cyclic alkyl; substituted or unsubstituted aryl; or substituted or unsubstituted acyl, in which the moiety bonded to the carboxyl group is a functionalised or unfunctionalised, substituted or unsubstituted, straight or branched chain C_8- alkyl, alkenyl or alkynyl; or substituted or unsubstituted aryl.

8. Use of silicone elastomers according to any one of Claims 1-3 or Claims 6 -7 in medical devices for permanent or temporary implantation in, or for attachment in or on, the human or animal body.

9. Use of silicone elastomers according to any one of Claims 1-3 or Claims 6-7 for the manufacture of medical devices for temporary or permanent implantation in, or for attachment in or on, the human or animal body, in which the silicone elastomers act as bioactive biomimetic elastomer biomaterials.

10. Use of silicone elastomers according to any one of Claims 1-3 or Claims 6-7 for the manufacture of drug delivery devices, including medical devices that also have an additional use as a drug delivery device, for permanent or temporary implantation in, or for attachment in or on, the human or animal body, in which the at least one beneficial agent is carried in solution or otherwise dispersed, to a constantly exuding, renewable liquid surface of the drug delivery device.