Method of producing a delivery device

Abstract

A method of producing a delivery device for delivering a chemical compound includes i) providing an interpenetrating polymer substrate (IP substrate) having a first continuous polymer comprising rubber and a second polymer having hydrogel or a hydrogelable precursor, where the second polymer is interpenetrating in the first polymer; ii) providing the chemical compound and a loading solvent for the chemical compound; and iii) loading the IP substrate with the chemical compound by subjecting the IP substrate to the loading solvent having the chemical compound under conditions where the loading solvent at least partially swells the second polymer. The chemical compound, the second polymer and the loading solvent are selected such that the work of adhesion (W.sub.hc) between the second polymer and the chemical compound during at least a part of the loading is at least about 0 J/m.sup.2.

Claims

1. A method of producing a delivery device for delivering a chemical compound, the method comprising i) providing an interpenetrating polymer substrate (IP substrate) comprising a first continuous polymer comprising rubber and a second polymer comprising hydrogel, where the second polymer is interpenetrating in the first polymer; ii) providing the chemical compound and a loading solvent for the chemical compound, the loading solvent comprising CO.sub.2; and iii) loading the IP substrate with the chemical compound by subjecting the IP substrate to the loading solvent comprising the chemical compound under conditions where the loading solvent at least partially swells the second polymer, and wherein the chemical compound, the second polymer and the loading solvent are selected such that the work of adhesion (W.sub.hc) between the second polymer and the chemical compound during at least a part of the loading is at least 10 J/m.sup.2.

2. The method of claim 1, wherein the work of adhesion between the chemical compound and the second polymer during at least a part of the loading is as follows: 100 J/m.sup.2W.sub.hc15 J/m.sup.2.

3. The method of claim 1, wherein the rubber is a silicone rubber.

4. The method of claim 1, wherein the second polymer is a homopolymer polymerised from a monomer selected from an acrylate monomer or a vinyl polymer, styrene; oxygen-, phenyl, amino and nitrogen-containing acrylic and methacrylic derivatives; functionalized methacrylates; alkyl substituted acrylates and methacrylates; carbohydrides and fluorinated monomers, urethanes; mono- and di-functional alcohols; carboxylic acids; amines; isocyanates; epoxides; aromatics carrying alkyl group(s), sulfonated aromatics, aromatic resins, imidazol, imidazol derivatives; pyrazoles and quaternary ammonium monomers.

5. The method of claim 1, wherein the second polymer is a copolymer, polymerised from monomers comprising silanes, an acrylate monomer or a vinyl polymer, styrene; oxygen-, phenyl, amino and nitrogen-containing acrylic and methacrylic derivatives, functionalized methacrylates; alkyl substituted acrylates and methacrylates; carbohydrides and fluorinated monomers, urethanes; mono- and di-functional alcohols; carboxylic acids; amines; isocyanates; epoxides; aromatics carrying alkyl group(s), sulfonated aromatics, aromatic resins, imidazol, imidazol derivatives; pyrazoles and/or quaternary ammonium.

6. The method of claim 1, wherein the second polymer is poly(2-hydroxyethyl methacryate) (PHEMA).

7. The method of claim 1, wherein the second polymer has a max water swelling at 25 C. of about 10-10000% by mass of its dry mass.

8. The method of claim 1, wherein the second polymer has a max water swelling at 25 C. w/w of its dry mass which is higher than the max. water swelling at 25 C. w/w of the first continuous polymer.

9. The method of claim 1, wherein the IP substrate has a max water swelling at 25 C. of about 5-5000% by mass of its dry mass.

10. The method of claim 1, wherein the IP substrate comprises a continuous matrix of the first polymer and a plurality of interpenetrating paths of the second polymer.

11. The method of claim 1, wherein the IP substrate comprises a continuous matrix of the first polymer and a plurality of interpenetrating paths of the second polymer, the IP substrate has a surface and the plurality of interpenetrating paths of the second polymer coincides with said surface.

12. The method of claim 1, wherein the IP substrate is or comprises an Interpenetrating Polymer Network (IPN), the IPN being produced by providing a virgin substrate of the first continuous polymer, subjecting the virgin substrate to an extracting treatment comprising extraction of residuals, swelling the extracted virgin substrate with a solvent comprising monomers for the second polymer and polymerizing the monomers to form the IPN.

13. The method of claim 1, wherein the chemical compound, the first continuous polymer and the loading solvent are selected such that the work of adhesion (W.sub.sc) between the first continuous polymer and the chemical compound during at least a part of at the loading is at least about 10 J/m.sup.2.

14. The method of claim 1, wherein the work of adhesion for the chemical compound-first continuous polymer (W.sub.sc) during at least a part of the loading is higher than the work of adhesion between the chemical compound and the second polymer (W.sub.hc).

15. The method of claim 1, wherein the first continuous polymer during at least a part of the loading is swelled with the loading solvent, the relative swelling of the first continuous polymer by the loading solvent is at least about 0.2 times the relative swelling of the second polymer by the loading solvent.

16. The method of claim 1, wherein the loading solvent comprises a co-solvent which in a liquid phase can dissolve or disperse the chemical compound.

17. The method of claim 1, wherein the loading solvent comprises an organic co-solvent selected from an alcohol.

18. The method of claim 1, wherein the chemical compound is a drug, a compound for human nutrition, a compound for microbiologic nutrition, a fragrance compound, a flavor compound and/or a color compound.

19. The method of claim 1, wherein the method comprises loading the IP substrate with a plurality of chemical compounds simultaneously or in overlapping or separate steps.

20. The method of claim 1, wherein the chemical compound is not a salt.

21. The method of claim 1, wherein the chemical compound has a molar mass of up to about 90000 g/mol.

22. The method of claim 1, wherein the loading of the IP substrate with the chemical compound comprises arranging the IP substrate in a reaction chamber and at least partially swelling the second polymer with the loading solvent under conditions wherein at least a part of the loading solvent is in a sub-critical phase or supercritical phase.

23. The method of claim 1, wherein the loading of the IP substrate with the chemical compound comprises swelling the second polymer with the loading solvent comprising the chemical compound at a temperature of at least about 10 C. and an elevated pressure.

24. The method of claim 1, wherein the loading of the IP substrate with the chemical compound comprises swelling the second polymer with the loading solvent comprising the chemical compound for a period of at least about 30 minutes.

25. The method of claim 1, wherein the loading of the IP substrate with the chemical compound comprises swelling the second polymer with the loading solvent comprising the chemical compound at an elevated pressure for a preselected period, followed by lowering the pressure to about one standard atmosphere.

26. The method of claim 1, wherein the loading solvent does not dissolve the first continuous polymer or the second polymer during loading of the chemical compound.

27. The method of claim 1, wherein the loading solvent comprises a first fluid and a second fluid, wherein the first fluid during loading is in a sub-critical stage or supercritical stage and the second fluid is or comprises a co-solvent for the chemical compound, which in liquid stage can dissolve the chemical compound.

28. The method of claim 27, wherein the method comprises: arranging the IP substrate in a reactor; feeding the first fluid to the reactor; feeding the second fluid with the chemical compound dissolved to the reactor; and swelling the IP substrate with the first fluid and at least a part of the second fluid of the loading solvent to load the IP substrate with the chemical compound.

29. The method of claim 1, wherein the delivery device is a baby nipple for adding pharmaceuticals during feeding, teething devices; a catheter or shunt for any body fluid; a drug delivery patch; a nicotine patch; a wound care product; a surgical film; a prophylactic device, a glove or a intravenous bag; a contact lens; an implant; or a diagnostic device.

30. A method of producing a delivery device for delivering a chemical compound, the method comprising: selecting the chemical compound and a loading solvent comprising at least 50% by mass of CO.sub.2; providing an interpenetrating polymer substrate by a method comprising providing a first continuous polymer comprising rubber and swelling the first continuous polymer with a solvent comprising monomers for a hydrogel and polymerizing the monomers to form the interpenetrating polymer substrate; loading the interpenetrating polymer substrate with the chemical compound by subjecting the interpenetrating polymer substrate to the chemical compound dissolved in said loading solvent at a temperature of at least about 10 C. and at an elevated pressure, where the loading solvent at least partially swells the hydrogel, wherein the monomers for the hydrogel are selected by a method comprising determining the work of adhesion (W.sub.hc) between at least a one hydrogel and the chemical compound at a temperature of between 10 and 80 C. and identifying a hydrogel for which the determined work of adhesion (W.sub.hc) is between 15 J/m.sup.2 and 100 J/m.sup.2 and selecting the monomers to be monomers for said identified hydrogel.

Description

EXAMPLES

(1) The invention will be explained more fully below in connection with a preferred embodiment.

(2) Some preferred embodiments have been shown in the foregoing, but it should be stressed that the invention is not limited to these, but may be embodied in other ways within the subject-matter defined in the following claims.

Example 1

(3) An interpenetrating polymer substrate (IP substrate) was produced comprising a first continuous polymer of silicone (PDMS) and a second polymer of PHEMAhydrogel interpenetrating in the first polymer.

(4) A 16 ml custom made stainless steel high-pressure reactor (Abeto, Denmark) was loaded with 4.0 ml ethanol, 2000 L HEMA (2-hydroxyethyl methacrylate) and 60 L EGDMA (ethyleneglycol dimethacrylate) and 15 discs in the given order. Discs ( 10 mm) were stamped out from a 1 mm silicone sheet. The silicone sheet was injection molded Elastosil LR3003 (10 Shore A) silicone elastomer supplied by Wacker Silicones (Germany). The reactor was closed and pressurized with CO.sub.2 to approximately 56 bars at room temperature and heated to 75 C. When the temperature approached 75 C., CO.sub.2 was added the reactor to approximately 200 bars. After three hours of impregnation 500 L 0.15 M DEPDC (diethyl peroxydicarbonate) in hexane solution and CO.sub.2 was added to the reactor to ensure a polymerization pressure of approximately 300 bars. After two hours of polymerization the reactor was allowed to return to ambient temperature before the pressure was slowly decreased. The IPNs were cleaned in ethanol. This procedure ensured a PHEMA content of about 17-30% by mass.

(5) The example was repeated with silicone discs of up to 5 mm in thickness.

Example 2

(6) Loading of Ceragenin CSA-13

(7) 6 IPN discs (010 mm, thickness 1-2 mm) obtained from Example 1 and with about 20% PHEMA (total mass about 1.3266 g) was loaded with about 500 mg Ceragenin CSA-13. The loading solvent was 2.00 ml 99.8% EtOH supplied by Merck (Germany) and N48 CO.sub.2 (supplied by Air Liquid Denmark A/S (Denmark)). The Ceragenin CSA-13 was initially dissolved in the 2.00 ml 99.8% EtOH and injected into a reactor of 16 ml comprising the discs. The pressure was raised to about 300 bars by injecting CO.sub.2 and the temperature was raised to about 75 C. The discs were treated at this pressure and temperature under stirring (1100 rpm) for 21 hours and 50 minutes, where after the pressure was reduced, the discs were withdrawn and allowed to cool down.

(8) It was observed that a large amount of the Ceragenin CSA-13 had been loaded into the discs and it is expected that the major part of the loaded Ceragenin CSA-13 will be releasable from the delivery device. Test has shown that the Ceragenin CSA-13 can be released in sufficient amounts to provide a significant microbiological effect.

Example 3

(9) Loading of Sulfamethizole

(10) 2.5 g sulfamethizole (Unikem) was mixed with 60 ml sodium thiosulfate solution (12 ml 0.1 M was diluted to 60 ml using deionized water).

(11) Drug loading was performed by placing 10 discs obtained from Example 1 in a 16 ml reactor. 2.00 ml of the above sulfamethizole mixture and 2.00 ml 99.8% EtOH supplied by Merck (Germany) was fed to the reactor. The discs were kept under stirring during the treatment time. The pressure in the reactor was initially raised to about 100 bars and with a temperature of about 44 C. Thereafter the temperature was raised to 75 C. and the pressure increased to 300 bars with CO.sub.2 (N48 CO.sub.2 supplied by Air Liquid Denmark A/S). After a loading time of approximately 16 hours the pressure was slowly decreased and the discs were withdrawn.

(12) It was found that the major amount of sulfamethizole loaded into the discs would be released when soaked in phosphate buffer solution at pH 4.5 over a period of about 14 days.

Example 4

(13) Loading of Miconazole Test 1

(14) Loading of discs with and without pHEMA using scCO2:

(15) a) 10 PDMS (Polydimethylsiloxane) (silpuran 6000/40 supplied by Wacker) discs within the same mass range were used per high pressure vessel for loading drug into PDMS. 10 IPNs discs of similar size and shape as the PDMS discs (PDMS loaded with about 20% by mass of PHEMA as in Example 1) were placed in each high pressure vessel for loading drug into the IPN discs.
b) Approximately 1 g of miconazole nitrate was added to each high pressure vessel.
c) The reactors were properly closed and placed in water baths with stirring at 75 C. The reactors were then coupled to a scCO.sub.2 system. scCO.sub.2 was applied at 350 bars until the pressure inside the reactors also reached 350 bars. The pressure remained at 350 bars throughout the procedure. The reaction was left for equilibration for 2 hours.
d) The pressure was released, and the discs loaded with miconazole nitrate were gently cleaned with ethanol, and stored protected from light.

(16) It was observed that the amount of miconazole nitrate releasable from the IPN discs was much higher than the amount releasable from the PDMS discs.

Example 5

(17) Loading of Miconazole Test 2

(18) Loading of PDMS discs with and without pHEMA using scCO.sub.2 and methanol:

(19) a) 10 PDMS (Polydimethylsiloxane) discs within the same mass range were used per high pressure vessel for loading drug into PDMS. 10 IPNs discs of similar size and shape as the PDMS discs (PDMS loaded with about 20% by mass of PHEMA as in Example 1) were placed in each high pressure vessel for loading drug into the IPN discs.
b) 10 ml of the supernatant of a centrifuged saturated solution of miconazole nitrate in methanol was added to each high pressure vessel.
c) The reactors were properly closed and placed in water baths with stirring at 75 C. The reactors were then coupled to a scCO.sub.2 system. scCO.sub.2 was applied at 350 bars until the pressure inside the reactors also reached 350 bars. This pressure was maintained throughout the procedure. The reaction was left for equilibration for 2 hours.
d) The pressure was released, and the discs loaded with miconazole nitrate were gently cleaned with ethanol, and stored protected from light.

(20) It was observed that the amount of miconazole nitrate releasable from the IPN discs was much higher than the amount releasable from the PDMS discs.

Example 6

(21) Loading of Silver Lactate

(22) 800 mg IPN (18% PHEMA) obtained as described in Example 1 was introduced into a 16 ml reactor together with 200 mg silver lactate, 2.00 ml 99.9% EtOH (Merck) and pressure was raised using CO.sub.2 (N48) to 300 bars and the temperature was set to 75 C. The treatment was continued for 24 hours under stirring of the IPN.

(23) 1.4 g IPN (18% PHEMA) obtained as described in Example 1 was introduced into a 16 ml reactor together with 200 mg silver lactate, 1.6 ml 99.9% EtOH (Merck)) and pressure was raised using CO.sub.2 (N48) to 100 bars and the temperature was set to 75 C. The treatment was continued for 24 hours under stirring of the IPN.

Example 7

(24) Loading of Surfactants

(25) 30 g IPN (18% PHEMA) obtained as described in Example 1 was introduced into a 1 l reactor together with 5 ml demineralized water and 4.3 ml codamol GTCC. Pressure was raised using CO.sub.2 (N48) to 70 bars and the temperature was set to 15 C. The treatment was continued for 1 hour under stirring of the IPN.

(26) 30 g IPN (18% PHEMA) obtained as described in Example 1 was introduced into a 1 l reactor together with 5 ml demineralized water and 422 ml Gradamol PC. Pressure was raised using CO2 (N48) to 70 bars and the temperature was set to 15 C. The treatment was continued for 1 hour under stirring of the IPN.

Example 8

(27) Loading of Dye

(28) In every batch 1-2 discs from Example 1 were cut and put in a reactor. 1-2 g of dye was added. The reactor was then filled with 3 liters of CO.sub.2 (N48). The pressure was about 43 bars and the temperature 18 C. No additives were used. The treatment was carried out for 1 h. After the treatment the discs were washed with solvent (acetone) to remove excess dye.

(29) TABLE-US-00001 Batch Dyes used: A Blue S0509B B Oracet yellow ghs C Oracet red BG

Example 9

(30) Loading of Fragrance

(31) In every batch 1-2 discs from Example 1 were cut and put in a reactor. 0.5-2 g of fragrance was added. The reactor was then filled with CO.sub.2 (N48) to a pressure of 70 bars and the temperature was set to 10 C. In some batches citronella oil was added, in other batches no additives were used. The treatment was carried out for 30-60 minutes. After the treatment the discs were washed with solvent (acetone) to remove excess fragrance.

(32) TABLE-US-00002 Batch Fragrance Additive A Cappuccino Test ID: 070906AJ0001 B Cappuccino Test ID: 070907AJ0002 C Coffee 1% (w/w) Citronella of Test ID: silicone rubber mass 070910AJ0003a D Coffee 3% (w/w) Citronella of Test ID: silicone rubber mass 070910AJ0003b

Example 10

(33) Loading of Kitotifen Fumarate

(34) 40 identical IPN contact lenses were obtained as described in WO 2008/052568 Example 1. 10 contact lenses had a total mass of 235.4 mg.

(35) 200 mg kitotifen fumarate, 2 ml 99.9% EtOH, and 10 of the above contact lenses were put in a reactor and treated with CO.sub.2 (N48) under stirring according to the below scheme.

(36) TABLE-US-00003 Treatment Pressure Temperature time Batch Bars C. CO2 state Hours A 80 35 Near 5 supercritical (subcritical) B 300 75 Supercritical 1 C 100 10 Liquid 3 D 60 25 Liquid/gas 20

(37) The release of kitotifen from the samples to a PBS-buffer was measured by UV-spectroscopy and compared with the release from samples loaded in PBS-buffer.

Example 11

(38) Determination of Work of Adhesion

(39) At 1 bar and 25 C. the respective work of adhesion between sulfamethizole and the two polymers PDMS and PHEMA of the IPN of Example 1 was determined with respectively EtOH and water as loading solvents.

(40) The results were as follows

(41) TABLE-US-00004 Work of adhesion Wsc (J/m.sup.2) Work of adhesion Whc (J/m.sup.2) Loading s = PDMS h = PHEMA solvent c = sulfamethizole c = sulfamethizole Water 57.7309 38.3326 EtOH 6.3434 3.8908

(42) Work of adhesion between sulfamethizole and the two polymers PDMS and PHEMA of the IPN of Example 1 was determined with varying volume fractions of EtOH in a loading solvent of EtOH and scCO.sub.2.

(43) The determination was determined at 300 bars and 75 C.

(44) TABLE-US-00005 ETOH Work of adhesion Work of adhesion part of Wsc (J/m.sup.2) Whc (J/m.sup.2) loading scCO.sub.2 part of s = PDMS h = PHEMA solvent loading solvent c = sulfamethizole c = sulfamethizole 0.0000 1.0000 14.1969 29.8588 0.0625 0.9375 11.2585 25.3418 0.1250 0.8750 8.714 21.2182 0.1875 0.8125 6.5641 17.4885 0.2500 0.7500 4.8092 14.1531 0.3125 0.6875 3.4498 11.2126 0.3750 0.6250 2.4864 8.6675 0.4375 0.5625 1.9195 6.5181 0.5000 0.5000 1.7497 4.7652 0.5625 0.4375 1.9773 3.4091 0.6250 0.3750 2.6029 2.4503 0.6875 0.3125 3.6271 1.8894 0.7500 0.2500 5.0502 1.7267 0.8125 0.1875 6.8727 1.9629 0.8750 0.1250 9.0953 2.5985 0.9375 0.0625 11.7183 3.6338 1.0000 0.0000 14.7422 5.0694

(45) The results are shown in the table above.

Example 12

(46) Loading of Silicone without Hydrogel

(47) A silicone disc ( 10 mm) was stamped out from a 1 mm silicone sheet. The silicone sheet was injection molded Elastosil LR3003 (10 Shore A) silicone elastomer supplied by Wacker Silicones (Germany). The disc was subjected to residual extraction treatment for 32 hours in liquid CO.sub.2 at approximately 30 bars and 15 C. About 10% by mass of the silicone was extracted.

(48) Loading with Fluorescein in Supercritical CO.sub.2

(49) The disc was introduced into a 2.65 ml reactor together with 2.5 ml fluorescein solution in water (0.01 mg fluorescein per ml), pressure was raised using CO2 (N48) to 300 bars and the temperature was set to 25 C. The treatment was continued for 2-24 hours under stirring of the IPN.

(50) The fluorescein treated disc was studied in a laser scanning confocal microscope (LSCM) and no loading of fluorescein could be observed.

Example 13

(51) Production of an IPN Substrate

(52) An interpenetrating polymer substrate (IP substrate) was produced comprising a first continuous polymer of silicone (PDMS) and a second polymer of PHEMAhydrogel interpenetrating in the first polymer.

(53) A silicone disc ( 10 mm) was stamped out from a 1 mm silicone sheet. The silicone sheet was injection molded Elastosil LR3003 (10 Shore A) silicone elastomer supplied by Wacker Silicones (Germany). The disc was subjected to residual extraction treatment for 32 hours in liquid CO.sub.2 at approximately 30 bars and 15 C. About 10% by mass of the silicone was extracted.

(54) A 2.65 ml high-pressure reactor was loaded with 984 l 99.9% EtOH (Merck), 100 L HEMA and 16 L EGDMA and the silicone disc in the given order. The reactor was closed and pressurized with CO.sub.2 to approximately 50 bars at room temperature and heated to 75 C. When the temperature approached 75 C., CO.sub.2 was added to the reactor to approximately 200 bars. After three hours of impregnation 50 L 0.15 M DEPDC in hexane solution and CO.sub.2 was added to the reactor to ensure a polymerization pressure of approximately 300 bars. After 18 hours of polymerization the reactor was allowed to return to ambient temperature before the pressure was allowed to return to ambient temperature before the pressure was slowly decreased.

(55) Fluorescein Loading of IPN Substrate in Water at Ambient Pressure

(56) The disc was placed in an aqueous solution with 0.02 mg/ml fluorescein at 25 C. and ambient pressure for two weeks in order to reach an equilibrium water content.

(57) The fluorescein treated IPN substrate was studied in a laser scanning confocal microscope (LSCM) at different times during the loading and it could be observed that there was a diffusion gradient into the samples which increased in depth as a function of time.

Example 14

(58) Production of an IPN Substrate

(59) An interpenetrating polymer substrate (IP substrate) was produced as in example 13.

(60) Fluorescein Loading of IPN Substrate in Water in Supercritical CO2

(61) The disc was introduced into the 2.65 ml reactor together with 2.5 ml fluorescein solution in water (0.01 mg fluorescein per ml), pressure was raised using CO.sub.2 (N48) to 300 bars and the temperature was set to 25 C.

(62) The treatment was continued for 2 hours under stirring of the IPN.

(63) The fluorescein loaded IPN was studied in a laser scanning confocal microscope (LSCM) and it was observed that fluorescein was loaded into the IPN substrate to a depth of about 35-40 m. The fluorescein was distributed with a homogeneous background distribution comprising a fine network and with domain of higher concentration. The domains of higher concentration of fluorescein were interconnected by the fine network and the fine network was stretching to the surface of the IPN disc. The concentration of fluorescein in the network domains was significantly higher than the background concentration of fluorescein.

Example 15

(64) Production of an IPN Substrate

(65) An interpenetrating polymer substrate (IP substrate) was produced as in example 13.

(66) Fluorescein Loading of IPN Substrate in Water+EtOH in Supercritical CO2

(67) The IPN substrate was introduced into the 2.65 ml reactor together with 1 ml fluorescein solution in water (0.01 mg fluorescein per ml) and 1 ml 99.9% EtOH (Merck), pressure was raised using CO.sub.2 (N48) to 300 bars and the temperature was set to 25 C.

(68) The treatment was continued for 2 hours under stirring of the IPN.

(69) The fluorescein loaded IPN was studied in a laser scanning confocal microscope (LSCM) and it was observed that fluorescein was loaded into the IPN substrate to a depth of about 60-70 m. Also here it was observed that the fluorescein was distributed with a homogeneous background distribution comprising a fine network and with domain of higher concentration. The domains of higher concentration of fluorescein were interconnected by the fine network and the fine network was stretching to the surface of the IPN disc.

Example 16

(70) Production of IPN Substrate

(71) 5 silicone discs ( 10 mm) were stamped out from a 2 mm silicone sheet. The silicone sheet was injection molded Silpuran 6000 (40 Shore A) silicone medical grade elastomer supplied by Wacker Silicones (Germany). The disc was subjected to residual extraction treatment for 2 hours in liquid CO.sub.2 at approximately 30 bars and 15 C. About 1% by mass of the silicone was extracted.

(72) A 16 ml high-pressure reactor was loaded with 4 ml 99.9% EtOH (Merck), 2.00 ml HEMA and 60 L EGDMA and the silicone discs in the given order. The reactor was closed and pressurized with CO.sub.2 to approximately 50 bars at room temperature and heated to 75 C. When the temperature approached 75 C., CO.sub.2 was added to the reactor to approximately 250 bars. After 20 minutes of impregnation 500 L 0.15 M DEPDC in hexane solution and CO.sub.2 was added to the reactor to ensure a polymerization pressure of approximately 360 bars. After 2.5 hours of polymerization the reactor was allowed to return to ambient temperature before the pressure was slowly decreased. The IPNs were cleaned in ethanol.

(73) Fluorescein Loading of IPN Substrate in Water+EtOH in Supercritical CO2

(74) One of the IPN substrates was introduced into a 2.65 ml reactor together with 1 ml fluorescein solution in water (0.02 mg fluorescein per ml) and 1 ml 99.9% EtOH (Merck), pressure was raised using CO.sub.2 (N48) to 300 bars and the temperature was set to 25 C.

(75) The treatment was continued for 2 hours under stirring of the IPN.

(76) The fluorescein loaded IPN was studied in a laser scanning confocal microscope (LSCM) and it was observed that the fluorescein was homogeneously distributed in a fine network. It appeared that the IPN did not comprise domains of higher concentration as the loaded IPN in examples 14 and 15. It is believed that due to the IPN of the medical grade silicone (Silpuran 6000) the hydrogel is distributed in a much finer network that when using non-medical silicone, such as Elastosil LR3003. Due to the very fine distribution of the network, high concentration domains cannot be observed.

(77) It is anticipated that by selecting the structure and fineness degree (determined by the cross-linking homogeneity of the PDMSsubstrate material) of the hydrogel network in the silicone substrate, the release profile can be adjusted accordingly. A very fine network may provide that the chemical compound in the fine structure far from the surface of the IPN will have to travel relatively far in the hydrogel. This effect may be used to provide a desired release profile, such as a long and relatively stable release profile. Also it is expected that this effect can be used to provide a desired release profile where high concentrations of hydrogel can function to prolong the effective diffusion path and hence prolong the release.

Example 17

(78) Loading of Sodium Stibogluconate (Pentostam)

(79) 2.5 ml of a Sodium stibogluconate solution with a concentration of 10 mg/ml and using demineralized water is prepared.

(80) 3 IPN disks prepared according to example 1, having 25 mass % HEMA, and a diameter of 10 mm and a thickness of 2 mm is obtained.

(81) Drug loading is performed by placing the 3 discs in a 2.5 ml reactor. TT reactor is filled up with the above Sodium stibogluconate solution (about 2.5 ml). The discs are (optional) kept under stirring during the treatment time. The pressure in the reactor is raised to about 300 bars using CO.sub.2 (N48 CO.sub.2 supplied by Air Liquid Denmark A/S) and with a temperature of about 5 C. After a loading time of 4-24 hours the pressure is slowly decreased and the discs are withdrawn.

Example 18

(82) Loading of N-Methylglucamine Antimoniate

(83) 2.5 ml of a N-Methylglucamine antimoniate solution with a concentration of 10 mg/ml and using 99.8% EtOH supplied by Merck (Germany) is prepared.

(84) 3 IPN disks prepared according to example 1, having 25 mass % HEMA, and a diameter of 10 mm and a thickness of 2 mm is obtained.

(85) Drug loading is performed by placing the 3 discs in a 2.5 ml reactor. About 2.5 ml of the above N-Methylglucamine antimoniate solution is fed to the reactor (the reactor is filled up with the N-Methylglucamine antimoniate solution). The discs are kept under stirring during the treatment time. The pressure in the reactor is initially raised to about 100 bars using CO.sub.2 (N48 CO.sub.2 supplied by Air Liquid Denmark A/S) and with a temperature of about 45 C. Thereafter the temperature is raised to about 75 C. and the pressure is increased to 300 bars using further CO.sub.2. After a loading time of approximately 3 hours the pressure is slowly decreased and the discs are withdrawn.

Example 19

(86) Loading of Amphotericin

(87) 2.5 ml of an Amphotericin solution with a concentration of 10 mg/ml and using DMSO is prepared.

(88) 3 IPN disks prepared according to example 1, having 25 mass % HEMA, and a diameter of 10 mm and a thickness of 2 mm is obtained.

(89) Drug loading is performed by placing the 3 discs in a 16 ml reactor. 2.5 ml of the above Amphotericin solution is fed to the reactor. The discs are kept under stirring during the treatment time. The pressure in the reactor is initially raised to about 100 bars using CO.sub.2 (N48 CO.sub.2 supplied by Air Liquid Denmark A/S) and with a temperature of about 45 C. Thereafter the temperature is raised to about 75 C. and the pressure is increased to 300 bars using further CO.sub.2. After a loading time of approximately 2 hours the pressure is slowly decreased and the discs are withdrawn.