COMPOSITIONS I - I AND PRODUCTS AND USES THEREOF

Abstract

A curable composition apportioned between at least one Part A and at least one Part B, the Parts sealed within barrier means in manner to prevent contamination thereof, the composition comprising:

(i) one or more alkenyl-containing prepolymers having at least one alkenyl moiety per molecule,

(ii) one or more SiH-containing prepolymers having at least one SiH unit per molecule, and additionally:

(iii) a catalyst for curing by addition of alkenyl-containing prepolymer (i) to SiH-containing prepolymer (ii),

wherein the at least one Part A and at least one Part B are provided within or upon at least two respective receptacles or supports and are adapted to be dispensed or released therefrom in cooperative manner facilitating intimate contact and curing thereof, wherein the receptacle(s) or support(s) for at least one of Part A and Part B is thermally stable at elevated temperature of 123 C for a period in excess of 18 hours,

methods for preparing the composition, methods for sterilisation thereof, medical and non-medical use thereof, a device incorporating the composition, and a precursor therefor including its sterilisable precursor composition, in particular a terminally sterilisable or terminally sterile composition for medical use, particularly in wound therapy, more particularly as a wound packing material which can be shaped and configured to the shape of a wound, most particularly for application in negative pressure wound therapy (NPWT).

Claims

1-59. (canceled)

60. A wound therapy system comprising: a first receptacle in which at least one part A is sealed; a second receptacle in which at least one part B is sealed; a curable composition, apportioned between the at least one Part A and the at least one Part B, the composition comprising: one or more alkenyl-containing prepolymers including at least one, or at least two, alkenyl moiety per molecule, one or more SiH-containing prepolymers including at least one, or at least two, SiH unit per molecule, a catalyst facilitating curing by addition of alkenyl-containing prepolymer to SiH-containing prepolymer, and a blowing agent configured to evolve gas as part of or during a curing reaction; wherein the first receptacle and the second receptacle are configured to dispense or release the at least one Part A and the at least one Part B of the curable composition in cooperative manner facilitating intimate contact and curing thereof; wherein each of the first receptacle, the second receptacle, the at least one Part A, and the at least one the Part B are thermally stable at elevated temperature of at least 123? C. for a period in excess of 18 hours, allowing the at least one Part A and the at least one Part B to be kept sealed within the first and second receptacles, respectively, without degrading or interacting with the first and second receptacles; and wherein the curable composition is configured to form during the curing as a porous foam.

61. The system of claim 60, wherein at least one of the first receptacle or the second receptacle comprises materials selected from the group consisting of polycarbonates, polypropylene, polymethylpentene, cyclic olefin copolymers, metal foil, glass, solid phase silicone polymer and the like and from composites, laminates and combinations thereof.

62. The system of claim 60, wherein the one or more alkenyl-containing prepolymers and the one or more SiH-containing prepolymers include silicones comprising siloxanes and modified siloxanes, polyurethanes (PU) comprising polyester and polyether urethanes, elastomeric polyether polyesters, polyglycolic acid, polyacetates comprising ethyl vinyl acetate, polyacrylate, polyacid derivatives of polysaccharides comprising carboxyalkylcellulose, carboxyalkylchitosan and copolymers thereof, and their hybrids comprising copolymers, entangled systems and mixtures thereof.

63. The system of claim 60, wherein the one or more alkenyl-containing polymers and the one or more SiH-containing polymers comprise polyorganosiloxanes, and wherein the curing comprises curing between organohydrogensiloxane units and organoalkenylsiloxane units incorporated into polymeric, coplymeric, entagled, and mixed polymer systems.

64. The system of claim 60, further comprising a device configured to dispense the curable composition, the device comprising a mixing head configured to receive two or more cartridges comprising the at least one Part A and the at least one Part B.

65. The system of claim 64, wherein the device further comprises a double-barreled syringe configured to be loaded with polymers.

66. The system of claim 60, wherein the first and second receptacles are configured to be thermally stable during dry-heat sterilization.

67. The system of claim 60, wherein the blowing agent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, n-hexanol, n-octanol, benzyl alcohol, 4-butanediol, 1,5-pentanediol, 1,7-heptanediol, silane including at least one silanol group, polysilane including at least one silanol group, water, and combination thereof.

68. The system of claim 60, wherein the at least one Part B does not comprise water, steam or air.

69. The system of claim 60, wherein the porous foam comprises 70% to 90% free internal volume.

70. The system of claim 60, wherein the porous foam is resiliently deformable.

71. A method for treating a wound, the method comprising: providing a curable composition apportioned between at least one Part A and at least one Part B, the composition comprising: one or more alkenyl-containing prepolymers including at least one, or at least two, alkenyl moiety per molecule, one or more SiH-containing prepolymers including at least one, or at least two, SiH unit per molecule, a catalyst facilitating curing by addition of alkenyl-containing prepolymer to SiH-containing prepolymer, and a blowing agent configured to evolve gas as part of or during a curing reaction, wherein the Part A is sealed within a first receptacle, and wherein the Part B is sealed within a second receptacle; heating the first receptacle and the second receptacle at an elevated temperature of 123? C. or higher for a period of 18 hours or longer, wherein the at least one Part A and the at least one part Part B are terminally sterile and kept sealed within the first receptacle and the second receptacle without degrading or interacting with the first receptacle and the second receptacle, respectively, during or after heating; dispensing the at least one Part A and the at least one Part B of the curable composition directly or indirectly into the wound; and causing the curable composition to form as a porous foam.

72. The method of claim 71, further comprising combining the at least one Part A and the at least one Part B subsequent to dispensing.

73. The method of claim 71, further comprising sealing the wound including the porous foam and applying negative pressure to the wound.

74. The method of claim 71, wherein heating is conducted in a conventional oven or autoclave.

75. The method of claim 71, wherein a sterility level of the curable composition after heating corresponds to a sterility assurance level (SAL) of 10.sup.?6 such that the theoretical probability of there being a viable microorganism present is equal to or less than 1?10.sup.?6.

76. The method of claim 71, wherein at least one of the first receptacle or the second receptacle comprises materials selected from the group consisting of polycarbonates, polypropylene, polymethylpentene, cyclic olefin copolymers, metal foil, glass, solid phase silicone polymer and the like and from composites, laminates and combinations thereof.

77. The method of claim 71, wherein the one or more alkenyl-containing prepolymers and the one or more SiH-containing prepolymers include silicones comprising siloxanes and modified siloxanes, polyurethanes (PU) comprising polyester and polyether urethanes, elastomeric polyether polyesters, polyglycolic acid, polyacetates comprising ethyl vinyl acetate, polyacrylate, polyacid derivatives of polysaccharides comprising carboxyalkylcellulose, carboxyalkylchitosan and copolymers thereof, and their hybrids comprising copolymers, entangled systems and mixtures thereof.

78. The method of claim 71, the one or more alkenyl-containing polymers and the one or more SiH-containing polymers comprise polyorganosiloxanes; and curing by addition of the alkenyl-containing polymer to the SiH-containing polymer further comprises curing between organohydrogensiloxane units and organoalkenylsiloxane units incorporated into polymeric, coplymeric, entagled, and mixed polymer systems.

79. The method of claim 71, wherein each of the at least one Part A, the at least one Part B, the first receptacle and the second receptacle are thermally stable at the elevated temperature of 123? C. for the period in excess of 18 hours.

80. The method of claim 71, wherein the blowing agent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol, n-hexanol, n-octanol, benzyl alcohol, 4-butanediol, 1,5-pentanediol, 1,7-heptanediol, silane including at least one silanol group, polysilane including at least one silanol group, water, and combination thereof.

81. The method of claim 71, wherein the porous foam comprises 70% to 90% free internal volume.

82. The method of claim 71, wherein the porous foam is resiliently deformable.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0270] Embodiments of the invention will now be illustrated in non limiting manner with reference to the Figures in which

[0271] FIGS. 1A-2B illustrate a NPWT foam filler wound dressing;

[0272] FIGS. 3A-C and 7, 8, 9 and 10 illustrate the use and application of a dispensable sterile foam filler wound dressing onto a patient;

[0273] FIGS. 4A, 5 and 6 illustrate the a kit including a sealant composition and wound dressing;

[0274] FIGS. 11A to 15B illustrate the use and application of an embodiment of a wound cover kit, apparatus and sealant onto a patient.

[0275] FIGS. 16 to 17 are graphs showing time and temperature of receptacles or supports.

[0276] Referring now to FIG. 1, in conventional foam based NPWT the wound cavity (1) is filled or covered with a porous foam packing material (2), that may need to be cut to shape (2x shown as 2a) and covered over and sealed with an adhesive flexible sheet (a drape, 3) that is fairly impermeable to fluids.

[0277] Referring to FIG. 2, a vacuum line (4) is inserted (5) under or through the drape (3) into the wound site (1), in various embodiments this is received in a aperture or groove in the foam (6), or wrapped in gauze. The distal end (not shown) of vacuum line (4) is connected to a vacuum source (commonly a pump, not shown). The wound cavity, enclosed by the drape and tissue, contracts under the force of atmospheric pressure and compresses the packing material or dressing visibly. The system is however prone to vacuum leakage.

[0278] In FIG. 3A, a sterile foamable composition is shown (10) being dispensed from syringe (11) into wound site (1). In FIG. 3B, the composition cures once dispensed to form a foamed block (12) contacting the wound bed (1). In FIG. 3C, a drape (3) is placed thereover and sealed in place in conventional manner. Vacuum line (4) is inserted (5) through the drape (3) in conventional manner whereupon vacuum may be initiated via vacuum line (4). The wound cavity behaves in corresponding manner as described in relation to FIG. 2. This system improves the fit of the foam filler, and reduces the stresses placed on the adhesive sealing drape.

[0279] FIG. 4A illustrates a composition for use as a NPWT sealant. The sealant (20) is used by applying to skin about or around a wound site (1), or to disintegrating skin. Adhesive or non-adhesive drape (3) is applied, with optional dressing (not shown) over the wound (1) and in contact with the sealant (20) and the sealant is allowed to cure in contact with the drape. Vacuum line (4) is inserted through an aperture (5) in the drape (3) in conventional manner whereupon vacuum may be initiated via vacuum line (4). The sealant improves the quality of the negative pressure transmitted to the wound bed. FIG. 5 shows a variant of FIG. 4, in which the pump (8) is removably connected (5a) through aperture (5b) in the drape (3).

[0280] FIG. 6 shows a further variant in which preformed drape (33 incorporating integral vacuum line sheath (34) and aperture (5) is positioned over sealant (30) applied via syringe (11). In this case the drape (33) incorporates an adhesive backing (39), and sealant is therefore either dispensed about the wound in conventional manner as shown in step 3, or sealant (33) is dispensed to the edges of the adhered drape (33) as shown in step 4.

[0281] FIGS. 7 to 10 show a further variant to FIGS. 3A to 3C, in which the drape (3) is placed over the wound site (1) before composition (10) is dispensed from syringe (11) through aperture (5). The composition foams and cures to form a foamed block (12) including button (13) projecting through aperture (5). Button (13) is broken off to provide an aperture into the foam body. FIG. 10 shows vacuum line (4) coupled to aperture (5) and connected to vacuum pump (8) in conventional manner.

[0282] FIGS. 11 to 15 show variants to FIGS. 4a, 5 and 6, relating to dispensing sealant 20 to seal combination dressings/drapes (2a, 3) including integral port (5) for vacuum line (4). For these combination dressings (2a, 3) it is necessary to dispense the sealant (20) to the region of skin (1a) which will underly the perimeter portion of the drape (3) surrounding the dressing portion (2a), as shown in FIG. 15. In the case that it is difficult to prejudge where this perimeter portion will contact the skin (1a), dispensing about the edge of the combination dressing (2a, 3) is advantageous, as in FIGS. 11 and 12. Alternatively sealant (20) may be dispensed at the edge of the drape at positions where leakages can be observed or are suspected.

[0283] Alternatively sealant (20) may be dispensed directly to the combination dressing, also illustrated in FIG. 15, as a gasket (2), and the dressing then applied over the wound. In all cases, adhesive tape strips (3a) can be overlaid to ensure both adhesion and seal are satisfactory. In all cases, curing, sealing and operation of the vacuum are as previously described.

[0284] The invention may be carried into practice in various ways, and embodiments thereof will now be described by way of example only.

COMPARATIVE EXAMPLE

Example CE1

[0285] Preparation of Composition

[0286] RTV-2 polydimethylsiloxane composition Cavi-Care is a commercially available (Smith & Nephew, Catalogue number 4563) RTV-2 Pt catalysed foamable silicone elastomer having 30-105 seconds rise time, packaged as Parts A and B in a double foil laminate sachet laminated to either face with a PE, folded along the longitudinal axis, both parts of the sachet having a dispensing nozzle and a common tear notch in the folded edge. Part A contains predominantly two vinyl functionalised polydimethylsiloxanes and a platinum based catalyst. Part B contains predominantly vinyl functionalised polydimethylsiloxanes and a silicone based cross linking system. Both mixtures are clear to hazy moderately viscous liquids with a fill weight of 10.0-11.5 g. When mixed together the two chemical mixtures react to form a soft white, non absorbent foam dressing.

[0287] The sachet itself is made up of a laminate, used for the back and front, with a nominal thickness between 100 and 200 micron. It comprises 4 layers:

TABLE-US-00002 PETP (polyethylene terephthalate) 12 ?m ALU (aluminium) 9 ?m OPA (biaxially oriented polymide) 15 ?m LLDPE (linear low density polyethylene) 75 ?m

[0288] Sterilisationin an Oven

[0289] A Memmert oven was allowed to thermally equilibrate at the desired temperature (90? C., 100? C., 110? C., 120? C., 121? C., 123? C., 125? C., 127? C., 130? C., 136? C.). In each case a virgin pack of Cavi-Care was placed in the oven for 30 minutes (121? C. and 136? C. for 15 minutes), autoclaved using a liquid cycle , removed and the packaging integrity assessed.

[0290] After sterilisation the following were determined and compared with unsterilised polymer:

[0291] Subjective Assessment of Pack Integrity

[0292] A seal failure was observed when more than 2 crimps were separated when tested with the package tester.

[0293] 121? C./15 min: Packaging severely rippled and creased on the surface;

[0294] 136? C./15 min: Packaging soft and packaging heat seal failed;

[0295] 90? C. and 100? C./30 minutes: packaging integrity maintained;

[0296] 110? C./30 min: Part A inflated;

[0297] 120? C./30 min: Packaging soft but no silicone leakage;

[0298] 121? C./30 min: Packaging softseals delaminated in parts;

[0299] 123? C./30 min: Packaging softseals delaminated in parts;

[0300] 125? C./30 min: Packaging softpossible seals failure at top of pack;

[0301] 127? C./30 min: Packaging failedsmall amount of silicone leakage;

[0302] 130? C./30 min: Packaging failedcatastrophic seal failure with loss of containment of the silicones from both Part A and Part B.

[0303] The above investigations yielded the following:

[0304] At 127? C. the packaging demonstrated catastrophic failure, the prepolymer leaking out of the packaging;

[0305] At 110? C. the Part A packaging inflates, volatiles have been vaporised and put stress on the packaging allowing the possibility of contamination.

[0306] The Vicat softening temperature for typical low density poly(ethylenes) is reported as 88-100? C. (S. L Aggarwal, Polymer Handbook, ed. J. Brandrup and E. H. Immergut, Wiley Interscience, 2.sup.nd edn., 1975, ch. V, pp 20-21.) with optical melting points for a series of selected poly(ethylenes) spanning the range 104.2? C. to 135.8? C.

[0307] The existing Cavi-Care packaging is therefore not suitable for use in an assessment where it will be subject to temperatures and cycle hold times in the range of 134? C. for 6 hours through to 123? C. for 24 hours as determined in the following examples.

[0308] Sterilisationin an Autoclave

[0309] Cavi-Care was autoclaved using a liquid cycle (121? C. and 136? C. for 15 minutes).

[0310] 121? C. After autoclaving at 121? C. for 15 minutes the packaging was severely rippled and creased on the surface.

[0311] After autoclaving at 136? C. for 15 minutes the packaging was soft and the packaging heat seals had failed.

[0312] Brookfield Viscosity

[0313] The effect of autoclaving on Cavi-Care prepolymer viscosity showed no substantial change.

[0314] Curing

[0315] The foam density and compressibility was evaluated with foam made by hand mixing parts A and B together using the spatulas and pots supplied with each Cavi-Care pack.

[0316] Foam Density and Compressibility

[0317] The effect of autoclaving on Cavi-Care cured foam density showed no change.

[0318] Sterility

[0319] Sterility was not investigated for Cavi-Care as the packaging disintegrated and this was therefore not a viable productthis type of sterilisation is not appropriate for a liquid non-aqueous system. If using heat for sterilisation, then a dry heat at 160 C can be used to properly sterilise the prepolymers. This type of sterilisation will be challenging for any packaging that is used.

Example 1Thermally Stable Composition

[0320] Preparation of Composition

[0321] Example 1.1Cavi-Care (see Comparative Example CE1 above) was repackaged by filling in sealed vials under argon, glass borosilicate vials and PP lid (stable to 140? C.) (Fischer Scientific, supplied by Schott-Duran, catalogue no. BTF-682-030H).

[0322] Example 1.2Rhodorsil RTFoam 3240 A/B (Bluestar Silicones) is a RTV-2 Pt catalysed foamable polydimethylsiloxane elastomer having 7.5 minutes rise time. This was packaged by filling in sealed vials under argon, glass borosilicate vials and PP lid (stable to 140? C.) (Fischer Scientific, supplied by Schott-Duran, catalogue no. BTF-682-030H).

[0323] Example 1.3Rhodorsil NPWT was made by reformulating 1.2 to deliver faster rise time and cure, and foam properties differing in delivering lower volume, reduced density and increased tensile strength, although similar pore architecture. This was packaged by filling in sealed vials under argon, glass borosilicate vials and PP lid (stable to 140? C.) (Fischer Scientific, supplied by Schott-Duran, catalogue no. BTF-682-030H).

[0324] Sterilisation

[0325] As the Example 1 compositions do not contain a substantial amount of water, dry heat sterilisation conditions were examined. Time was allowed for chamber and samples to reach the target temperature before recording hold time. The hold time was therefore the time elapsed with contents at the target temperature.

[0326] The composition Example 1.2 was heated in an oven using a dry heat cycle at:

[0327] S1a121? C. for 1 hour;

[0328] S1b160? C. for 100.5 minutes;

[0329] As this regime reduces the number of packaging options available significantly lower temperatures were sought for the Example 1.2 composition:

[0330] S2134? C. for 2.5 hours;

[0331] Example 1.3, Rhodorsil NPWT, was heated in an oven using a dry heat cycle at:

[0332] S3134? C. for 6 hours.

[0333] S4123? C. for 24 hours performed with inspection at 6 hour intervals

[0334] The following were determined and compared with unsterilised polymer:

[0335] Subjective Assessment of Pack Integrity

[0336] Packaging was intact and substantially unaffected by the sterilisation regime. No visible thermal damage or degradation.

[0337] Brookfield Viscosity

[0338] In all cases, parts A and B were of same or comparable viscosity.

[0339] Curing

[0340] After sterilisation each part was then mixed and foamed with a non-sterilised corresponding part and resultant foam properties observed.

[0341] Foam Density and Compressibility

[0342] The foam densities and compressibilities were evaluated with foam made by hand mixing parts A and B together using spatulas and pots supplied with each Cavi-Care pack.

[0343] Foam properties and rise time were same or comparable to unsterilised foam.

[0344] Example 1.3 Part A foamed with sterilised Part B and part B foamed with sterilised Part A each delivered foams with rise time of 2 to 3.25 minutes and substantially unaltered volume (a reduction of 8 to 10%).

[0345] Sterility Testing

[0346] The methodology employed was as follows:

[0347] D-value determination: Bacillus atrophaerus biological indicator (BI) wires (spore wires inoculated with Bacillus atrophaerus ATCC 9372, manufactured by Raven Labs, labelled population 3.4?10.sup.6 cfu/wire, labelled dry heat d-value at 160? C. is 1.4 minutes) were used. Biological indicator population was verified. Biological indicator D-value was verified. Composition to be tested was placed into respective capillaries, corresponding to the components to be packaged into respective receptacles as hereinbefore defined. Each capillary received a BI wire and was heat sealed thereby being made airtight. Population and D-value of capillaries was determined based on Raven method LW1-3100 Revision 3 for metal carriers (disinfect capillary outer surface, expose wire (Tween 80/glass beads), vortex, refrigerate, vortex, sonicate, dilute, heat-shock, cool, serial dilute, culture (Difco TSA/TSB, agar) and incubate, read at 24 hr, 48 hr (also 72 hr for thermally challenged spores) average the 48 hr counts and use to calculate the mean number of spores per BI). Log reduction was assessed based on population results from pre and post exposure.

[0348] Sterility

[0349] Sterility testing methodology described above was employed. The results were as follows:

[0350] Population Determination per capillary: 1.2A and 1.2B pre and post exposure (log reduction); nnr (number of negative replicates after 7 days incubation)

TABLE-US-00003 S1a/ S1b/ Pre/ ?10.sup.6 cfu ?10.sup.6 cfu S2/ Capillary ?10.sup.6 cfu (lr) (lr) nnr Control Bl's 12.665 16.200 (6.4036) 4/10 1.2A 9.6676 8.9400 (6.2863) 0/10 1.2B 9.5276 7.9800 (6.2863) 3/10 Lr = log reduction Nnr = number of negative replicates after 7 days incubation

[0351] Population Determination per capillary: 1.3A and 1.3B pre and post exposure (log reduction); nnr (number of negative replicates after 7 days incubation)

TABLE-US-00004 S4/Nnr S4/Nnr S4/Nnr S4/Nnr Capillary Pre/?10.sup.6 cfu S3/nnr (6 hrs) (12 hrs) (18 hrs) (24 hrs) Control 25.800 10/10 10/10 BI's 1.3A 1.1025 10/10 0/5 0/5 2/5 5/5 1.3B 9.8875 10/10 2/5 4/5 5/5 5/5

[0352] S1atotal survival (variation in counts within error margin);

[0353] S1btotal kill (at least 6 log reduction)effective sterilisation;

[0354] S2zero/partial kill (A, B and controls);

[0355] S3total kill (at least 6 log reduction);

[0356] S4total kill (at least 6 log reduction) at 24 hours (Parts A and B)

[0357] total kill (at least 6 log reduction) at 18 hours (Part B)

[0358] fractional kill at 18 hours (Part A)

[0359] fractional kill at 12 hours (Part B)

[0360] total survival at 12 hours (Part A)

[0361] fractional kill at 6 hours (Part B)

[0362] total survival at 6 hours (Part A)

DISCUSSION

[0363] As can be seen clearly from the above, compositions 1.2 and 1.3 exposed to 134? C. for 6 hours (S3), 123? C. for 24 hours (S4) and 160? C. for 100.5 minutes (S1b) exhibited total kill (=6 log reduction) in comparison to their counterparts autoclaved at 134? C. for 2.5 hours (S2) and 121? C. for 1 hour (S1a).

Example 2Thermally Stable Composition in Presence of Soft Packaging

[0364] Composition 1.3 was provided in a number of samples according to Example 1. Vials were contaminated each with a disc or ring of soft polymeric packaging materials found in tubing, stoppers, seals and the like, and subject to the heating regime according to Example 1 S3. Control vials uncontaminated were also subject to the S3 regime.

[0365] Subjective visual assessment and foaming investigation were conducted (Part A foamed with contaminated Part B, Part B foamed with contaminated Part A and contaminated Parts A and B foamed).

[0366] Of the 9 materials investigated:

[0367] contamination of vials by 3 translucent materials gave visually unchanged samples closely matching the rise time and rise volume profile of uncontaminated samples: Colourless: cured Elastosil LR 3003/50 (Wacker), cured Silpuran 6600/50 (Wacker), White: cured Thermolast MT Series TM5MED (Kraiburg TPE);

[0368] contamination of vials by 2 translucent white materials gave visually unchanged samples deviating slightly from the rise time and rise volume profile of uncontaminated samples: cured Thermolast MT/LF Series TM5 LFT (Kraiburg TPE) and Saint-Gobain Peroxide Silicone Tubing (Saint-Gobain);

[0369] contamination of vials by 4 dark grey or black colored materials gave visually discolored darkened samples each of which either suffered an 11% to 30% increase in rise volume profile compared to uncontaminated samples, or suffered a 20 to 30 second increase in rise time: cured FM480 (Helvoet Pharma), cured FM257 (Helvoet Pharma), BSCF plunger stoppers (BD), NSCF plunger stoppers (BD)

[0370] Certain silicone rubber, peroxide silicone and styrene block copolymer materials are suitable as soft packaging materials for the compositions and methods disclosed herein, subject to individual testing as in Example 2

[0371] Certain bromobutyl and butadiene containing materials are considered unsuitable as soft packaging materials for compositions and methods disclosed herein, subject to individual testing as in Example 2.

COMPARATIVE EXAMPLE

Example CE2 Thermally Unstable Composition in Presence of Hard Packaging (Lids) and Enclosed Atmosphere

[0372] Compositions 1.1 and 1.3 were provided in a number of samples according to Example 1. Borosilicate glass vials were sealed with a number of lids as shown in Table 3:

[0373] temperature resistant lid fitted with PTFE coated silicone seal1.3 a) air headspace b) argon purge and headspace

[0374] Aluminium screw cap lid with black rubber seal

[0375] Polypropylene wadless lid.

[0376] Samples were subject to thermal cycle S4 as hereinbefore defined or of 130? C. for 24 hours (S5).

TABLE-US-00005 Composition/ Headspace/ heat cycle lid purge result 1.1/S5 or S4 PTFE coated silicon Air/none A - heavily seal (Fischer discolored, Scientific, supplied failed to foam, by Schott-Duran, or inadequate catalogue no. BTF- foaming 675-010C) B - ok 1.3/S4 PTFE coated Minimal/ A - heavily silicone seal Argon discolored (Fischer Scientific, B - ok supplied by Schott- Duran, catalogue no. BTF-675-010C). 1.1 S4 Polypropylene (not Air/none A - no temperature rated) discoloration, foamed but reduced rise volume B - ok 1.3/S3 aluminium screw Air/none A - heavily cap with black discolored rubber seal B - ok 1.3/S3 aluminium screw Argon/ A - discolored cap with black Argon B - ok rubber seal 1.3/S3 aluminium screw none/Argon B - minor cap with black discoloration rubber seal

Example 3Thermally Stable Composition in Presence of Hard Packaging (Wadless Lids) and Enclosed Atmosphere

[0377] Samples of 1.3 were subject to S3 heating cycle as follows:

[0378] Fisher 30 ml bottle (Fisher Scientific Catalogue no. BTF-605-030W) with polypropylene lid (not temperature rated)a) air headspace b) argon purge and headspace

[0379] Sterilin 30 ml bottle (Chromacol code 11912-001) with wadless lida) air headspace b) argon purge and headspace

[0380] Schott Duran 25 ml bottle (Fisher Scientific Catalogue no. BTF-682-030H) with blue polypropylene lid (rated to 140? C.)a) air headspace b) argon purge and headspace

[0381] Following the cycle the samples displayed no black or coloured residue. The lids on the Sterilin bottles had melted, and caused catastrophic failure of inverted samples with loss of containment.

[0382] The Fischer lids had retained a seal but showed signs of a pressure build-up and had suffered permanent deformation.

[0383] The Schott Duran lids showed no outward signs of stress. 25 ml Schott Duran glass bottles with blue polypropylene lids (25/ISO thread, lid related autoclavable to 140 C, Fischer Scientific Catalogue no: BTF-682-030H) moulded from a single piece of polypropylene part with no additional elastomeric components, were shown to provide containment for the silicone prepolymers through the S3 heat sterilisation cycle, even when the bottles were inverted.

[0384] There was no loss of liquid containment and no visible degradation with this system following heating. As such this range of containers was selected as the most appropriate packaging system.

Example 4Thermally Stable Composition in Presence of Hard Packaging (Lids) and Enclosed Atmosphere

[0385] Example 1 highlighted the thermal stability of the composition under suitable sterilisation conditions, and also the requirement that the composition be provided in containment packaging which is thermally stable per se. Examples 2 and CE2 and 3 highlighted the additional requirement that the composition be provided in specific containment packaging which ensures that the composition is not contaminated by thermal sterilisation in presence of certain materials. This Example provides a detailed assessment of 1.1, 1.2 and 1.3 when heat treated at 123? C. for 24 hours (S4) and at 134? C. for 6 hours (S3) within a carefully contained packaging environment.

[0386] Pre-polymers A & B were dispensed into separate 100 ml bottles made of clear borosilicate glass (Schott Duran) with blue polypropylene lids (rated autoclavable to 140? C., Fisher Scientific, Product Code BTF-682-071Q). In each case 100 ml of pre-polymer was contained in each vessel. This fill volume afforded a reasonably modest headspace whilst providing sufficient separation between the upper surface of the pre-polymer and the lower surface of the lid such that the two did not make direct contact whilst under thermal load. Inert atmosphere conditions were imposed degassing with argon, sparging the pre-polymer and purging the headspace.

[0387] The influence of these heating conditions on the appearance of the pre-polymers and on selected functional performance characteristics of the foam curing process was assessed.

[0388] After heat treatment discrete changes in the visual appearance of 1.1 Part A and 1.2 Part B were observed. In the case of 1.1, some darkening occurred and in the case of 1.2 suspended agglomerates of a cloudy gel like species formed which settled on standing for 8 weeks. No visual changes were observed in either Part of 1.3 following either of the heat treatment regimes.

[0389] Discrete changes in functional performance were observed for the heat treated pre-polymers of 1.1, 1.2 and 1.3 when compared to their unheated controls. Subject to the desired performance requirements of the system these changes can be considered acceptable following treatment at both S4 and S3.

[0390] Preferably the conditions of S3 would be recommended for the heat sterilization of RTV-2 platinum catalysed addition cure silicone foam pre-polymers as these conditions were found to have the smallest effect on the visual appearance of the prepolymers and the smallest effect on the performance of the foaming reactions during cure.

[0391] The samples were allowed to stand for 8 weeks following heat treatment before the foaming reactions were assessed. To ensure thorough mixing following this hold period all samples were agitated by hand and then placed on a motorized roller to ensure thorough mixing of the contents.

[0392] For each composition both pre-polymer components (Part A and Part B) were transferred to a double barrelled mixing system (Double-Cartridge Prefilled Delivery System (S-System), MedMix Systems Ag). In each case a 25 ml 1:1 double barrelled cartridge was used. A cap was applied to the cartridge and the cartridge positioned vertically within a dye (typically a 150 ml Sterilin pot) on an electronic balance. One chamber was filled with Part A to 10 g?0.5 g. An equal volume of Part B was then filled into the opposing chamber and the height level of the menisci matched by eye.

[0393] The cartridge pistons were inserted, expelling the air headspace, so that they were flush with the surface of the pre-polymers. In this position they were locked and the unit placed in an internally dry container submerged within a water bath at 25? C. The units were allowed to thermally equilibrate at 25? C. for a minimum of 1 hour before use.

[0394] The assessment reactions were run in a laboratory with ambient temperature 20? C.?2? C. Any apparatus which would make direct contact with the chemicals during the dispensing or foaming steps was allowed to thermally equilibrate in this environment for a minimum of 1 hour (typically mixing heads and 150 ml Sterilin pots).

[0395] At point of use each cartridge had the tip cap removed, a 16 element helical static mixer applied and it was inserted into a ratcheted dispenser. The material was rapidly ejected into a transparent 150 ml Sterilin pot and a timer started at the point all of the material had been ejected from the dispensing unit.

[0396] Rise time was measured as the time taken to reach the maximum rise height. In the majority of cases this moment was punctuated by a bubble collapse running through the upper foam structure, this resulted in a slight but definite drop in the top surface of the foam.

[0397] Volume was measured using a liquid displacement method once a minimum of 10 minutes had been allowed to elapse after the rise time measurement. The headspace was filled with water and the volume of liquid measured in a 250 ml measuring cylinder. The silicone foam was then demoulded from the Sterilin pot, the Sterilin pot filled with water and the volume of liquid measured in a 250 ml measuring cylinder. The foam volume was calculated as the liquid displacement.

[0398] All foaming experiments were run in triplicate (n=3).

[0399] The results are shown in Table 4.1

TABLE-US-00006 TABLE 4.1 Parts A and B treated, containment in glass bottles with PP lids. Liquids sparged and headspaces purged with argon. Percentage change in the mean rise times and mean foam volumes of heat treated samples relative to their unheated controls. Foam Foam Rise time Rise time volume volume S4 S3 S4 S3 1.1 ?23% +10% ?30% ?18% 1.2 ?8% ?4% ?20% ?10% 1.3 +8% +12% ?10% ?8%

[0400] Some changes in visual appearance were noticed including 1.1 Part A darkening of the clear component, 1.2 Part B presence of suspended agglomerates in a cloudy gel. Properties of Parts A and B subject to S3 conditions were closest to the control properties. Both S3 and S4 conditions were considered acceptable, S3 conditions were recommended for heat sterilisation of RTV-2 prepolymers.

[0401] EXAMPLE 5Thermally Stable Sealant Compositions

[0402] Silpuran 2400/18 A/B (Wacker) is an addition-curing RTV-2 silicone rubber curing to a blue coloured silicone of low hardness. It has application in flexible moulding applications for prosthetics.

[0403] Silpuran 2400/18 pre-polymers A & B were dispensed into separate 100 ml bottles made of clear borosilicate glass (Schott Duran) with blue polypropylene lids (rated autoclavable to 140? C., Fisher Scientific, Product Code BTF-682-071 Q). In each case 100 ml of pre-polymer was contained in each vessel. This fill volume afforded a reasonably modest headspace whilst providing sufficient separation between the upper surface of the pre-polymer and the lower surface of the lid such that the two did not make direct contact whilst under thermal load. Inert atmosphere conditions were imposed degassing with argon, purging the headspace.

[0404] Materials were subject to heat treatment at 134? C. for 6 hours (S3) and 123? C. for 24 hours (S4). The samples were allowed to cool and conditioned overnight at a temperature of 20? C.?2? C. Viscosity was measured using a Brookfield Programmable RVDV-II+ Viscometer fitted with Spindle 7. A set speed of 100 rpm was used for Parts A and for Parts B. The spindle and temperature probe were thoroughly cleaned (using ethanol) and allowed to dry before each reading.

TABLE-US-00007 % change in viscosity relative to the un-heated control Silpuran 2400/18 A Silpuran 2400/18 B 123? C., 24 hrs/cP 11.36%* 23.91%* 134? C., 6 hrs/cP 9.09%* 17.39%* *Viscometer set speed 100 rpm

[0405] Curing was achieved by placing a 250 ml glass bottle with extra wide neck (Fisher Scientific, Product Code BTF-630-090N) on an electronic balance. In each case 100.00 g?0.10 g of Part A was weighed into the container. To this 100.00 g?0.30 g of the corresponding Part B was weighed directly into the container. Using a spatula the system was mixed by hand for 5 minutes and transferred to an oven pre-heated at 120? C. The system was cured at 120? C. for 1 hour. Samples were removed from the oven, allowed to cool and conditioned overnight at a temperature of 20? C.?2? C.

[0406] There were no significant differences in the visual appearance or in the surface tack (as gauged by touch) between the cured control sample and the cured samples made from pre-polymers subject to the S3 and S4 heating cycles.

[0407] Penetration was measured using a Setamatic Penetrometer with automatic release, timing device and standard 47.5 g plunger. The instrument was fitted with a hollow plastic cone with a stainless steel tip of mass 15 g. A dwell time of 60 seconds was used. All measurements were recorded in triplicate (n=3).

TABLE-US-00008 Relative mass Mean of parts penetration/ A B 1/10 mm Silpuran 2400/18 A/B - control 50.0% 50.0% 51 (SD 1) Silpuran 2400/18 A/B - 134? C., 50.0% 50.0% 118 (SD 1) 6 hrs Silpuran 2400/18 A/B - 123? C., 50.0% 50.0% 87 (SD 1) 24 hrs

[0408] Subject to the desired performance requirements of the system these changes can be considered acceptable following treatment at both S3 and S4.

Example 6Thermally Stable Sealant Compositions

[0409] Example 6a

[0410] Mepiseal? (Molnlycke), a commercially available RTV-2 polyorganosiloxane sealant composition, was obtained as sold in a double barrel dispensing syringe dispensing 3 ml of composition. The cartridge has an integrated mixing head and integrated twist tip seal. The units are packaged within a secondary plastic bag. The composition is indicated for sealing a NPWT drape, and has an indicated cure time of 9 minutes.

[0411] Syringes incorporating composition were subject to S3 thermal sterilisation cycle and S4 thermal sterilisation cycle. Of these, 3 removed from their secondary pouches and 3 remaining in their secondary pouches were subject to S3. After 2.5 hours the plunger and piston were seen to have melted in all samples regardless of whether they were in the polymer pouches or not. After 6 hours no further change in the state of the syringes was observed. Other than the plungers, the remaining external components appeared intact. The pouches had not burst, although they had bonded to parts of the syringe inside. Upon opening one of these pouches it was observed that where the syringe had melted, direct contact could be made with the prepolymers. The prepolymers were no longer sealed in the syringe but were exposed. The viability and functional properties of the silicone prepolymers could not be assessed as it was not possible to dispense these from the syringe.

[0412] A further 4 samples were subject to S4 thermal sterilisation, 2 in their secondary pouches and 2 removed from their secondary pouches. After 24 hours the plungers did not fully melt however warping of the plungers was observed and the plungers moved freely in the barrel and no longer formed a seal. When compared to a non-heat sterilised Mepiseal? syringe, it was observed that a colour change had occurred in the silicone prepolymers after being heat treated at both temperatures.

[0413] Manual kinetic time for the non-heat treated sample was 12 minutes and 20 seconds. The S4 heat treated composition was dispensed and allowed to cure and manual kinetic time tested by finger touch to the dispensed composition. If composition is found to transfer to the finger this indicates that the manual kinetic point has not been reached and the composition has not (fully) cured.

[0414] The experiment to determine manual kinetic time for the S4 heat treated sample was aborted after 72 hours as the manual kinetic point had not been reached.

[0415] The composition was therefore shown to be thermally unstable at S4 conditions, the mildest terminal sterilisation conditions which we had been able to achieve, as a result of failure of the packaging under S3 and S4 conditions. Packaging failure allowed exposure to air and moisture, due to rupture of the seal and this in turn led to contamination of the composition.

[0416] Example 6b

[0417] Mepiseal? (Molnlycke), as in Example 7a was dispensed into 2 borosilicate glass vials and enclosed in manner according to Example 4 above and subject to S3 thermal sterilisation cycle. The composition was then mixed in standard manner and the manual kinetic time recorded. The manual kinetic time was considered acceptable following treatment at S3.

[0418] This indicates that the Mepiseal? composition is thermally stable to conditions providing terminal sterility, if provided in thermally stable packaging in the absence of excess air.

Example 8Thermally Stable Adhesive Compositions

[0419] Silpuran 2111 A/B (Wacker) is a commercially available 2-part, addition-curing silicone composition curing to a soft, tacky silicone adhesive. It is suitable for use in wound dressings.

[0420] Silpuran 2111 pre-polymers A & B were dispensed into separate 100 ml bottles made of clear borosilicate glass (Schott Duran) with blue polypropylene lids (rated autoclavable to 140? C., Fisher Scientific, Product Code BTF-682-071Q). In each case 100 ml of pre-polymer was contained in each vessel. This fill volume afforded a reasonably modest headspace whilst providing sufficient separation between the upper surface of the pre-polymer and the lower surface of the lid such that the two did not make direct contact whilst under thermal load. Inert atmosphere conditions were imposed degassing with argon, purging the headspace.

[0421] Materials were subject to heat treatment at 134? C. for 6 hours (S3) and 123? C. for 24 hours (S4). The samples were allowed to cool and conditioned overnight at a temperature of 20? C.?2? C. Viscosity was measured using a Brookfield Programmable RVDV-II+ Viscometer fitted with Spindle 7. A set speed of 100 rpm was used for Parts A and a set speed of 50 rpm was used for Parts B. The spindle and temperature probe were thoroughly cleaned (using ethanol) and allowed to dry before each reading.

TABLE-US-00009 % change in viscosity relative to the un-heated control Silpuran 2111 A Silpuran 2111 B 123? C., 24 hrs 0.36%* 1.47%.sup. 134? C., 6 hrs 2.00%* ?0.15%.sup. *Viscometer set speed 100 rpm .sup.Viscometer set speed 50 rpm

[0422] Curing was achieved by placing a 250 ml glass bottle with extra wide neck (Fisher Scientific, Product Code BTF-630-090N) on an electronic balance. In each case 100.00 g?0.10 g of Part A was weighed into the container. To this 100.00 g?0.30 g of the corresponding Part B was weighed directly into the container. Using a spatula the system was mixed by hand for 5 minutes and transferred to an oven pre-heated at 120? C. The system was cured at 120? C. for 1 hour. Samples were removed from the oven, allowed to cool and conditioned overnight at a temperature of 20? C.?2? C.

[0423] There were no significant differences in the visual appearance or in the surface tack (as gauged by touch) between the cured control sample and the cured samples made from pre-polymers subject to the S3 and S4 heating cycles.

[0424] Penetration was measured using a Setamatic Penetrometer with automatic release, timing device and standard 47.5 g plunger. The instrument was fitted with a hollow plastic cone with a stainless steel tip of mass 15 g. A dwell time of 60 seconds was used. All measurements were recorded in triplicate (n=3).

TABLE-US-00010 Relative mass Mean of parts penetration/ A B 1/10 mm Silpuran 2111 A/B - control 50.0% 50.0% 200 (SD 3) Silpuran 2111 A/B - 134? C., 6 hrs 50.1% 49.9% 206 (SD 3) Silpuran 2111 A/B - 123? C., 24 hrs 50.0% 50.0% 211 (SD 4)

[0425] Subject to the desired performance requirements of the system these changes can be considered acceptable following treatment at both S3 and S4.

Example 9 Thermally Stable NPWT Foamable Compositions

[0426] The cured foamed Example 1.2 composition Rhodorsil RT Foam 3240 was able to transmit a negative pressure with pressure drop, however this was not totally reproduceable. In some cases the transmitted pressure would be acceptable for NPWT.

[0427] The modified Example 1.3 composition, Rhodorsil NPWT, delivered a cured foam which was able to transmit negative pressure for NPWT.

[0428] Certain embodiments provide a route to sterile RTV-2 compositions at temperatures below that of the accepted standard dry heat cycle which removes packaging constraints and thereby provides a route to commercially viable packaging.

[0429] It will be appreciated that various embodiments and applications of the composite are envisaged and are not limited to the embodiments and applications hereinbefore described but may be varied in construction, detail and application within the scope of the appended claims.