Abstract
The invention concerns a cartridge for an inhalation device for delivering anaesthetic to a human or animal wherein anaesthetic in the cartridge is dispersed in an anaesthetic control release medium; an inhalation device for use with the cartridge and a formulation including at least one selected anaesthetic and anaesthetic control release medium.
Claims
1. An anaesthetic cartridge for use with an inhalation device for human or veterinary use to deliver an inhalational or volatilised anaesthetic to a patient, wherein said anaesthetic cartridge comprises: an adjustable stirrer or agitator; a non-volatile anaesthetic control release medium provided as an emulsion; and at least one selected inhalational or volatilised anaesthetic; wherein an amount of said non-volatile anaesthetic control release medium relative to said at least one selected inhalational or volatilised anaesthetic is such that when using said adjustable stirrer or agitator only the selected at least one inhalational or volatilised anaesthetic is delivered at a selected Minimum alveolar concentration (MAC), at a substantially constant or controllable rate, within the range of 0.25-4.0× Minimum alveolar concentration (MAC) thereby allowing for either i) induction and/or maintenance of anaesthesia or ii) sedation.
2. The anaesthetic cartridge according to claim 1 wherein said at least one selected inhalational or volatilised anaesthetic is dispersed or distributed in said non-volatile anaesthetic control release medium in a stable and chemically unaltered state.
3. The anaesthetic cartridge according to claim 1 wherein said emulsion is provided by one or more non-ionic surfactants selected from the group consisting of halogenated non-ionic surfactants, ethylene oxide based fluorocarbon surfactants, propylene oxide or ethylene oxide based hydrocarbon surfactants, partially fluorinated sulfosuccinate surfactants and branched hydrocarbon sulfosuccinate surfactants.
4. The anaesthetic cartridge according to claim 1 wherein said emulsion has a droplet size between 10-1000 nm.
5. The anaesthetic cartridge according to claim 1 wherein an anaesthetic content is between 0.25-44% by volume.
6. The anaesthetic cartridge according to claim 1 wherein said anaesthetic cartridge further comprises a gelling agent.
7. The anaesthetic cartridge according to claim 6 wherein the gelling agent comprises chiral, non-racemic bis-(α,β-dihydroxy ester)s.
8. The anaesthetic cartridge according to claim 1 wherein said non-volatile anaesthetic control release medium and said at least one selected inhalational or volatilised anaesthetic when mixed together in said anaesthetic cartridge have a surface area within the anaesthetic cartridge that is between 10-60 cm.sup.2.
9. The anaesthetic cartridge according to claim 8 wherein said surface area is 50 cm.sup.2.
10. The anaesthetic cartridge according to claim 1 wherein said at least one selected inhalational or volatilised anaesthetic is selected from one or more of the group consisting of: desflurane, isoflurane, halothane, enflurane, sevoflurane, and methoxyflurane.
11. The anaesthetic cartridge according to claim 1 wherein the anaesthetic cartridge works over a temperature range of 4° C. to 40° C.
12. The anaesthetic cartridge according to claim 11 wherein said anaesthetic cartridge works at a temperature of 20° C.
13. An inhalation device for human or veterinary use comprising: a mask for positioning over the face of a patient; a supply of breathable gas in fluid communication with said mask; and at least one anaesthetic cartridge according to claim 1; wherein said inhalation device is adapted or configured such that an anaesthetic released from said anaesthetic cartridge is mixed with said breathable gas before being delivered to said patient.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1) The invention will now be described by way of example only with reference to the following figures wherein:
(2) FIG. 1a shows the basic experimental testing chamber and set-up used to test the invention. Specifically, a 60 ml glass jar fitted with septum, N.sub.2 inlet and 1 ml syringe (open to air). Typically tests used a 3 ml sample or equivalent with respect to anaesthetic content. Headspace concentrations were sampled from gas flow out (no recirculation) and measured with a standard anaesthetic monitor using a balloon to provide a nitrogen atmosphere or with or 2 L min.sup.−1 N.sub.2 passed over or bubbled through sample;
(3) FIG. 1b shows a schematic of flow rig model 6, unless otherwise indicated surface area of formulation is 50 cm.sup.2, stirrer bar is 60 mm×10 mm(diam), inlet connector is connected to the gas supply, outlet connector is connected to anaesthetic monitor;
(4) FIG. 2 shows how the uncontrolled evaporation of sevoflurane leads to dangerously high concentrations in the carrier gas and demonstrates the limited timescale over which evaporation occurs. Sevoflurane concentration in N.sub.2 carrier gas flow after gas passed at 2 L min.sup.−1 over 3 ml liquid sevoflurane. (In the inset schematic orange represents the liquid anaesthetic);
(5) FIG. 3 shows that anaesthetic evaporation may be retarded by placing the liquid anaesthetic under a layer of water, that this prolongs the evaporation but that this system is also extremely sensitive to agitation leading to dangerously high concentrations in the carrier gas. Sevoflurane concentration in N.sub.2 carrier gas flow after gas passed at 2 L min.sup.−1 over 3 ml liquid sevoflurane in a phase separated sample with 3 ml water. Water (blue) forms the upper layer. Spikes in concentration at 30 and 36 minutes are due to shaking of the containment vessel;
(6) FIG. 4 shows the chemical structures of some example surfactant and polymeric stabilisers that may be used in the formulation, highlighting the functional groups useful for imparting some affinity with fluorocarbons. Structures of example classes of surfactant and polymeric stabilisers which may be used in the formulation. (a) fluorocarbon-ethylene oxide; (b) propylene oxide-ethylene oxide; (c) larger ethylene oxides with methoxy end-group functionality;
(7) FIG. 5 shows that mixing the anaesthetic with a surfactant solution gives the correct release profile of a higher initial level followed by a stable lower anaesthetic concentration over an extended time-course of one hour. Sevoflurane concentration in N.sub.2 carrier gas flow after gas passed at 2 L min.sup.−1 over a formulation containing 3 ml sevoflurane dispersed at 20 wt % in a surfactant solution. The inset shows the proposed emulsion structure of dispersed droplets of anaesthetic stabilised by a layer of surfactant adsorbed at the anaesthetic/water interface;
(8) FIG. 6 shows the chemical structures of example low molecular weight gelators that may be used to gel the anaesthetic;
(9) FIG. 7 shows a schematic representation of a two-stage formulation which combines the stable storage and transport properties of a gel, and is converted to an emulsion system by mixing with an aqueous solution of the stabiliser prior to use in the device. Schematic representation of two-stage formulation process incorporating both a gel (i) and an emulsion (iii);
(10) FIG. 8: shows a schematic diagram of the invention in use with a breathing system. F: fresh gas flow (oxygen/air or oxygen/nitrous oxide); R: reservoir bag; B: breathing tube; V: valve; M: facemask and DAD is the dispersion anaesthetic device of the invention;
(11) FIG. 9: Isoflurane release profile of a formulation containing 18 mL Isoflurane and 102 mL of aqueous solution of 25 wt. % Zonyl FSN-100 stirring at 400-500 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 1.8±0.2 vol. % (1.5 MAC) Isoflurane was attained;
(12) FIG. 10: Isoflurane release profile of a formulation containing 13 mL Isoflurane and 87 mL of aqueous solution of 13 wt. % Zonyl FSN-100 stirring at 260 rpm, under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 1.6±0.2 vol. % (1.3 MAC) Isoflurane was attained;
(13) FIG. 11: Isoflurane release profile of a formulation containing 9 mL Isoflurane and 91 mL of aqueous solution of 11 wt. % Zonyl FSN-100 stirring at 200 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 1.2±0.2 vol. % (1 MAC) Isoflurane was attained;
(14) FIG. 12: Isoflurane release profile of a formulation containing 12 mL Isoflurane and 98 mL of aqueous solution of 12 wt. % Zonyl FSN-100 stirring at 200 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 1.2±0.2 vol. % (1 MAC) Isoflurane was attained;
(15) FIG. 13: Isoflurane release profile of a formulation containing 4.5 mL Isoflurane and 95.5 mL of aqueous solution of 8 wt. % Zonyl FSN-100 stirring at 200 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 0.6±0.1 vol. % (0.5 MAC) Isoflurane was attained;
(16) FIG. 14: Isoflurane release profile of a formulation containing 2.5 mL Isoflurane and 77.5 mL of aqueous solution of 13 wt. % Zonyl FSN-100 stirring at 150 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 0.3±0.1 vol. % (0.25 MAC) Isoflurane was attained;
(17) FIG. 15: Isoflurane release profile of a formulation containing 15 mL Isoflurane and 85 mL of aqueous solution of 22 wt. % Zonyl FSN-100 stirring at 260-400 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 2.4±0.2 vol. % (2 MAC) Isoflurane was attained;
(18) FIG. 16: Isoflurane release profile of a formulation containing 30 mL Isoflurane and 100 mL of aqueous solution of 5 wt. % Chemguard S-550L-100 and 6 wt. % Capstone FS-63 and stirring at 300-750 rpm under Nitrogen flow rate of 4 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 2.4±0.2 vol. % (2 MAC) Isoflurane was attained;
(19) FIG. 17: Isoflurane release profile of a formulation containing 35 mL Isoflurane and 105 mL of aqueous solution of 19 wt. % Zonyl FSN-100 stirring at 375-1000 rpm under Nitrogen flow rate of 4 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 2.4±0.2 vol. % (2 MAC) Isoflurane was attained;
(20) FIG. 18: Sevoflurane release profile of a formulation containing 5.5 mL Sevoflurane and 84.5 mL of aqueous solution of 8 wt. % Zonyl FSN-100 stirring at 150 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 0.5±0.1 vol. % (0.25 MAC) Sevoflurane was attained;
(21) FIG. 19: Sevoflurane release profile of a formulation containing 7.5 mL Sevoflurane and 112.5 mL of aqueous solution of 4 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 and stirring at 250 rpm using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 1±0.2 vol. % (0.5 MAC) Sevoflurane was attained;
(22) FIG. 20: Sevoflurane release profile of a formulation containing 15 mL Sevoflurane and 105 mL of aqueous solution of 7 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 and stirring at 250 rpm using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 2±0.2 vol. % (1 MAC) Sevoflurane was attained;
(23) FIG. 21: Sevoflurane release profile of a formulation containing 26 mL Sevoflurane and 134 mL of aqueous solution of 10 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 and stirring at 300 rpm using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 3±0.2 vol. % (1.5 MAC) Sevoflurane was attained;
(24) FIG. 22: Sevoflurane release profile of a formulation containing 40 mL Sevoflurane and 120 mL of aqueous solution of 20 wt. % Zonyl FSN-100 stirring at 375 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 3.5±0.2 vol. % (1.75 MAC) Sevoflurane was attained;
(25) FIG. 23: Sevoflurane release profile of a formulation containing 50 mL Sevoflurane and 110 mL of aqueous solution of 18 wt. % Zonyl FSN-100 stirring at 312-375 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 4±0.2 vol. % (2 MAC) Sevoflurane was attained;
(26) FIG. 24: Sevoflurane release profile of a formulation containing 40 mL Sevoflurane and 100 mL of aqueous solution of 17 wt. % Zonyl FSN-100 stirring at 375-625 rpm under Nitrogen flow rate of 4 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 2±0.2 vol. % (1 MAC) Sevoflurane was attained;
(27) FIG. 25: Sevoflurane release profile of a formulation containing 50 mL Sevoflurane and 90 mL of aqueous solution of 22 wt. % Zonyl FSN-100 stirring at 375-625 rpm under Nitrogen flow rate of 4 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 3±0.2 vol. % (1.5 MAC) Sevoflurane was attained;
(28) FIG. 26: Sevoflurane release profile of a formulation containing 70 mL Sevoflurane and 90 mL of aqueous solution of 25 wt. % Zonyl FSN-100 stirring at 500-1000 rpm under Nitrogen flow rate of 4 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 4±0.2 vol. % (2 MAC) Sevoflurane was attained;
(29) FIG. 27: Sevoflurane release profile of a formulation containing 20 mL Sevoflurane and 110 mL of aqueous solution of 10 wt. % POLYFOX 159, the stirring rate was increased periodically by 50 rpm every 15 minutes to maintain a sustained Sevoflurane release of 2±0.2 vol. % after the first ten minutes for about 90 minutes under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 2±0.2 vol. % (1 MAC) Sevoflurane was attained;
(30) FIG. 28: Sevoflurane release profile of a 130 mL formulation containing 15 mL Sevoflurane and 115 mL of aqueous solution containing 5 wt. % Capstone FS-3100 and 3 wt. % of Polyfox 159 stirring at 230 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 1±0.1 vol. % (0.5 MAC) Sevoflurane was attained;
(31) FIG. 29: Sevoflurane release profile of a 130 mL formulation containing 15 mL Sevoflurane and 112.5 mL of aqueous solution containing 10 wt. % Polyfox 159 and 3 wt. % Capstone FS-3100 stirring at 250 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 2±0.2 vol. % (1 MAC) Sevoflurane was attained;
(32) FIG. 30: Sevoflurane release profile of a 130 mL formulation containing 18 mL Sevoflurane and 115 mL of aqueous solution containing 9 wt. % Capstone FS-3100 and 5 wt. % of Polyfox 159 under Nitrogen flow rate of 1 L min.sup.−1 and the stirring rate was increased gradually from 230-250 rpm using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 2±0.1 vol. % (1 MAC) Sevoflurane was attained;
(33) FIG. 31: Sevoflurane release profile of a 130 mL formulation containing 20 mL Sevoflurane and 110 mL of aqueous solution containing 1 wt. % Brij O20 and 12 wt. % Capstone FS-3100, stirring at 250 pm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 2±0.15 vol. % (1 MAC) Sevoflurane was attained;
(34) FIG. 32. Sevoflurane release profile of a formulation containing 5 mL Sevoflurane and 15 mL of 20 wt. % Brij O5 and 30 mL of 7 wt. % Tween 20 under Nitrogen flow rate of 1 L min.sup.−1 and stirring at 200 rpm using Flow-Rig Model 6 (S.A.=50 cm.sup.2), an average release of 0.5±0.1 vol. % (0.25 MAC) Sevoflurane was attained;
(35) FIG. 33: Sevoflurane release profile of two 130 mL formulations containing 20 mL Sevoflurane and 110 mL of aqueous solution containing 10 mL of 10 wt. % Brij O20 and 10 mL of Capstone FS-3100 stirring at 250 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(36) FIG. 34: Isoflurane release profile of two formulations containing 2.5 mL Isoflurane and 77.5 mL of aqueous solutions of 13 wt. % Zonyl FSN-100 stirring at 150 rpm under Nitrogen flow rate of 1 L min.sup.−1 using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(37) FIG. 35: Effect of Nitrogen flow rate on Sevoflurane release profile of a formulation containing 15 mL Sevoflurane and 105 mL of aqueous solutions of 7 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 and 4 L min.sup.−1 and stirring at 250 rpm using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(38) FIG. 36: Effect of stirring rate on Sevoflurane release profile of a formulation containing 15 mL Sevoflurane and 105 mL of aqueous solutions of 7 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 and stirring at 250 and 500 rpm using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(39) FIG. 37: Effect of stirring rate on Sevoflurane release profile of a formulation containing 15 mL Sevoflurane and 105 mL of aqueous solutions of 7 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 and different stirring speeds using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(40) FIG. 38: Sevoflurane release profile of a formulation containing 20 mL Sevoflurane and 120 mL of aqueous solutions of 7 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 and stirring speed of 315 rpm for 30 minutes and then at 250 rpm for another minutes and finally at 315 using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(41) FIG. 39: (a) Sevoflurane release profiles of 50 mL formulations containing 6 mL Sevoflurane and 34 mL of aqueous solutions of 6.5 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 and stirring at 250 rpm using Flow-Rig Models 4, 5, 6 and 7 with surface areas of 12.5, 20, 50 and 30 cm.sup.2, respectively. (b) Data at 10 and 30 min recast as function of surface area;
(42) FIG. 40: Sevoflurane release profiles of formulations containing 15 mL Sevoflurane and 105 mL of aqueous solutions of 7 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 and stirring at 250 rpm using Flow-Rig Model 6 vs. Model 7;
(43) FIG. 41: Sevoflurane release profiles of 60 and 120 mL formulations containing 7.5 and 15 mL Sevoflurane and 52.5 and 105 mL of aqueous solutions of 6.5 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 and stirring at 250 rpm using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(44) FIG. 42: Sevoflurane release profiles of different runs of a fixed composition formulation containing 20 mL Sevoflurane and 120 mL of aqueous solutions of 7 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 and (a) stirring at 250 rpm using Flow-Rig Model 6 (S.A.=50 cm.sup.2); (b) stirring speed of 250 rpm for 30 minutes and then at 315 rpm, the recycled formulation has been employed for 10 experiments;
(45) FIG. 43: Effect of temperature on Sevoflurane release profile of formulations containing 15 mL Sevoflurane and 55 mL of aqueous solutions of 9 wt. % Zonyl FSN-100 stirred at 375 rpm under Nitrogen flow rate of 1 L min.sup.−1 using a thermostatted glass flow cell (S.A.=20 cm.sup.2);
(46) FIG. 44: Effect of temperature on Sevoflurane release profile of a formulation containing 15 mL Sevoflurane and 55 mL of an aqueous solution of 9 wt. % Zonyl FSN-100 stirred at different rates under Nitrogen flow rate of 1 L min.sup.−1 using a thermostatted glass flow cell (S.A.=20 cm.sup.2). The formulations were stirred at 400, 350 and 200 rpm at 10, 20 and 40° C., respectively;
(47) FIG. 45: Sevoflurane release profile of two formulations containing 15 mL Sevoflurane and 105 mL of aqueous solutions of 7 and 20 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 and stirring at 250 rpm using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(48) FIG. 46: Sevoflurane release profile of a formulation containing 15 mL Sevoflurane and 105 mL of aqueous solutions of 7 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 and stirred using small 50×7 mm and large 60×10 mm bar magnets at 250 rpm using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(49) FIG. 47: Sevoflurane release profile of a formulation containing 50 mL sevoflurane and 110 mL of aqueous solutions of 15 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 as a function of stirring speed using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(50) FIG. 48: Isoflurane release profile of a formulation containing 20 mL Isoflurane and 100 mL of aqueous solutions of 16 wt. % Zonyl FSN-100 under Nitrogen flow rate of 1 L min.sup.−1 as function of stirring using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(51) FIG. 49a: Sevoflurane release profile of a formulation containing 70 mL Sevoflurane and 90 mL of aqueous solutions of 20 wt. % Zonyl FSN-100 under Nitrogen flow rate of 4 L min.sup.−1 as function of stirring using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(52) FIG. 49b: Isoflurane release profile of a formulation containing 50 mL Isoflurane and 70 mL of aqueous solution of 40 wt. % Zonyl FSN-100 under Nitrogen flow rate of 4 L min.sup.−1 as function of stirring using Flow-Rig Model 6 (S.A.=50 cm.sup.2);
(53) FIG. 50: Sevoflurane release profile of 65 mL formulation containing 10 mL Sevoflurane and 55 mL of aqueous solution of 30 wt. % Polyfox-159 under Nitrogen flow rate of 1 L/min and stirring at 200-500 rpm using Flow Rig Model 6 (S.A.=50 cm.sup.2); and
(54) FIG. 51: Appearance of Sevoflurane microemulsion-formulation (65 mL) containing 10 mL Sevoflurane and 55 mL of aqueous solution of 30 wt. % Polyfox-159.
(55) FIG. 52: Volatile fluorocarbon emulsion formed by shaking liquid HPFP in aqueous solution and surfactant solution, the increasingly hazy/opaque appearance of the liquid being indicative of emulsion formation.
(56) Table 1 shows that the model anaesthetic molecule 2H,3H-perfluoropentane (HPFP) may be formulated to provide a high content of volatile fluorocarbon liquid by shaking the liquid with an aqueous in a surfactant solution. The hazy/opaque appearance of the samples is indicative of emulsion formation;
(57) Table 2 shows the moderation of evaporation by formulation of the model anaesthetic liquid HPFP;
(58) Table 3 shows how the moderation of evaporation by formulation of the model anaesthetic liquid HPFP can be further controlled by flowing the carrier gas over and especially through the sample in the testing chamber;
(59) Table 4 shows how the concentration of volatile liquid in the carrier gas and the time taken to release all of the anaesthetic can be affected by the flow of carrier gas through the sample, and how the effects of formulation on retarding volatile release are maintained under these conditions;
(60) Table 5 shows Zonyl FSN-100 stabilised emulsions. Tested in flow rig 6 (50 cm.sup.2 surface area);
(61) Table 6 Sevoflurane emulsions stabilised by other surfactants. Tested in flow rig 6 (50 cm.sup.2 surface area) Abbreviations: Capstone FS-3100 (C); Polyfox 159 (P); Brij O20 (B);
(62) Table 7 Effect of stirring rate on release. Tested using formulation ZS2.0 at constant temperature and flow rate in flow rig 6 (50 cm.sup.2 surface area);
(63) Table 8 Release at 4 L min.sup.−1 flow rate. Zonyl FSN-100 stabilised emulsions tested in flow rig 6 (50 cm.sup.2 surface area). Flow rate=4 L min.sup.−1;
(64) Table 9 Emulsions stabilised by other surfactants tested in flow rig 6 (50 cm.sup.2 surface area). Flow rate=4 L min.sup.−1 Abbreviations: Capstone FS-3100 (C); Chemguard S-550L-100 (S);
(65) Table 10: Summary stirring rates used to generate release profile data presented in FIG. 47;
(66) Table 11: Summary stirring rates used to generate release profile data presented in FIG. 48;
(67) Table 12: Summary stirring rates used to generate release profile data presented in FIG. 49a; and
(68) Table 13: Summary stirring rates used to generate release profile data presented in FIG. 49b;
DETAILED DESCRIPTION OF THE INVENTION
(69) Sevoflurane was used as received from Abbott. 2H,3H perfluoropentane was used as received from Fluorochem UK. Zonyl FSO100 was used as received from DuPont. All water was deionised. Formulations of Sevoflurane, isoflurane or HPFP in surfactant solutions were prepared by vigorous shaking (by hand) of the required quantity of fluorocarbon with a pre-prepared aqueous surfactant solution at the proportions and concentrations described in the list of formulations described herein. The formulations described in Tables 1-4 were tested using testing chamber 1, the experimental set-up for which is described in FIG. 1a, by addition of an appropriate quantity of formulation to a 60 ml glass jar fitted with septum, N.sub.2 inlet and (needle free) 1 ml syringe (open to air) via a plastic tube from within which the outflow gas was continuously sampled and monitored for anaesthetic concentration. Typically a 3 ml sample was used, or an equivalent amount with respect to anaesthetic content. A balloon was used to provide a nitrogen atmosphere with no flow-through, or a continuous flow of nitrogen as a carrier gas was passed over or bubbled through the sample at a controlled flow-rate. Headspace fluorocarbon concentrations were sampled from gas outflow (no recirculation) and measured using a standard anaesthetic monitor (Capnomac Ultima, Datex Instrumentarium Inc., Heslinki, Finland), monitoring on either sevoflurane or isoflurane settings, depending on the anaesthetic in the formulation.
(70) Formulations described in tables 5 onwards were tested in the flow rig described in FIG. 1b, using different sample containers to vary the surface area where required, and using volumes as described in the tables (typically 30-120 ml). Nitrogen gas was passed through the sample chamber at a controlled flow rate, typically 1 L/min to 4 L/min, and the anaesthetic concentration in the outlet stream measured with a standard anaesthetic monitor (Capnomac Ultima, Datex Instrumentarium Inc., Heslinki, Finland), monitoring on either sevoflurane or isoflurane settings, depending on the anaesthetic in the formulation. In some instances a thermostatted cell consisting of a double-walled glass water-jacket was used, connected to a circulating water bath to maintain temperatures other that 20° C.
(71) Making the Emulsion
(72) The emulsions were prepared by mixing a known volume of anaesthetic with a known volume of dispersion medium. The dispersal medium, typically a surfactant solution, was pre-prepared at a known concentration of surfactant. The emulsions were formed by manual shaking of the two components for a fixed time of 60 s. More energetically intensive mixing methods, for example, high shear mixing, sonication or emulsification apparatus were not required to form the emulsions, although obviously these represent alternative preparation methods that could be employed.
(73) Emulsion Structure Use of the Inhalation Device
(74) The formation of an emulsion was determined by light-microscope imaging using an Olympus BX50 system microscope (Olympus, UK) fitted with JVC TK-C1380 colour video camera (JVC, Japan) and analysed using Image J software (Fiji, USA). Additional measurements were obtained from dynamic light scattering measurements using The Brookhaven ZetaPlus analyser (Brookhaven Instruments Ltd., USA). For light scattering measurements the emulsions were diluted by a factor of 20-50 depending on the emulsion concentration.
(75) Use of the Inhalation Device
(76) A typical inhalation device of the invention is shown in FIG. 8 it includes a supply of breathable air or gas, in this instance fresh air, and downstream thereof a releasable anaesthetic cartridge (DAD) which is connected to a conventional docking mechanism known to those skilled in the art. Although not shown, said cartridge comprises an adjustable stirring or agitation device whereby the release of anaesthetic from said cartridge can be controlled as herein described and with reference to the Figures. In the embodiment shown in FIG. 8 a reservoir bag is provided and a breathing tube is connected to a face mask. Further, in this embodiment of the invention said face mask includes a valve whereby commencement of anaesthesia can be controlled. In other embodiments of the invention said inhalation device may be connected to a supply or canister of breathable gas upstream of said releasable anaesthetic cartridge. Additionally or alternatively, said breathing tube may comprise a circular, closed system in which case a further breathing tube connects the mask with the supply of breathable gas. In this embodiment there is also provided, downstream of said face mask, filters or extractors for extracting from exhaled breath selected gases such as carbon dioxide or anaesthetic gas whereby exhaled gas can be suitably treated then recycled and reused and anaesthetic extracted from the exhaled breath may also be re-used. With the exception of the releasable anaesthetic cartridge, the configuration and components of the inhalation device are known to those skilled in the art. In use, a releasable anaesthetic cartridge is located within a corresponding connecting device and either this action of location releases anaesthetic from the cartridge or a separate valve is provided for this purpose. The mask is placed over the face of a patient and the device is ready to use. If a user wants to alter the amount of the anaesthetic released the adjustable stirrer is used to either raise or lower anaesthetic release as herein described. In the instance where a contained supply of breathable gas is used this is switched on before the face mask is placed over a patient.
(77) Results
(78) FIG. 2 shows the time dependence of the sevoflurane concentrations detected in the output carrier gas flow after addition of 3 ml sevoflurane to testing chamber 1, with carrier gas flow of 2 L min.sup.−1 through the sample environment headspace. Clinically dangerous concentrations of anaesthetic (13-15%) were recorded in the carrier gas outflow stream for the first 10 minutes, with a sudden drop observed around 15-16 minutes until zero anaesthetic concentration is recorded. This clearly demonstrates that more control of the evaporation process is required.
(79) FIG. 3 demonstrates that the speed of evaporation can be moderated somewhat by placing the anaesthetic under an equivalent volume of water. The anaesthetic was injected at the bottom of the containment vessel, and the natural immiscibility of the fluorocarbon and water prevents significant mixing of the two phases. 2 L min.sup.−1 carrier gas flow was used.
(80) FIG. 3 shows the initial measured sevoflurane concentration of 15% (too high for clinical use) decreases over the first ten minutes to a plateau value of around 8% which is maintained for approximately a further eight minutes before declining steadily to zero over the following ten minutes. The plateau value is closer to the required clinical concentration region than the un-moderated sevoflurane but is still higher than required and is not maintained for the target timescale. Also, gentle agitation of the sample causes a spike in concentration back to 15% which decays quickly back to zero over approximately two minutes. This spike is reproduced at 35 minutes, showing a lower maximum and quicker decay as the total anaesthetic content of the formulation declines. This demonstrates that a more robust formulation is required that is less sensitive to agitation and provides delivery over a longer timescale.
(81) Formulation of the liquid anaesthetic by vigorous shaking with water and an appropriate stabiliser forms a hazy or opaque dispersion which phase separates over time and is therefore characteristic of emulsion formation. Some example stabilisers are shown in FIG. 4. The volatile fluorocarbon liquid 2H,3H-perfluoropentane (HPFP), which is structurally similar to sevoflurane, was used to investigate the effect of formulation parameters on evaporation rates. Table 1 and the accompanying image report the formulation of HPFP in a 10 wt % solution of Zonyl-FSO100 in water. The dispersions were readily formed by 60 seconds of manual shaking, at HPFP concentrations of between 9 and 50% v/v HPFP (equivalent to 3-15% w/w). The release properties of these formulations are summarised in Tables 2 and 3, which report the fluorocarbon concentration recorded (monitoring as sevoflurane, and therefore representing only a relative value for HPFP) at a fixed time-point of 30 s, and also the time for the measured value to drop to zero. Table 2 reports these values for two example formulations, along with the values for an equivalent amount of the unformulated HPFP. Here, the evaporation was monitored under minimal gas flow through the sample (by attachment of a balloon to provide a small positive carrier gas pressure). These data demonstrate that whether or not the liquid is incorporated into an emulsion, higher volatile fluorocarbon levels and longer time to zero gas phase concentrations are recorded where there is a larger amount of the fluorocarbon to begin with. Comparing the measured values between the unformulated and formulated HPFP, significantly lower measured carrier gas concentrations are observed for the formulations, while the degree of suppression is fluorocarbon content dependent (a 50× reduction occurs for formulation J1 (5% v/v HPFP) compared to 17× for formulation J5 (29% v/v HPFP)). Table 2 also demonstrates a greater than fourfold increase in the time to zero measured concentration for formulation J1 compared to the equivalent amount of free fluorocarbon, and the 6× higher HPFP content of J5 extended the time to zero measured concentration to greater than the maximum recorded experiment time of 20 minutes.
(82) Repeating the experiment with formulation J5 (30% v/v HPFP) under 2 L min.sup.−1 carrier gas flow through and over the sample highlights further the influence of formulation; Table 3 includes data for both free HPFP and HPFP under water as comparators. At 30 s the measured equivalent sevoflurane concentration is reduced by a factor of just under two by a layer of water, and by a factor of four by formulation as an emulsion. The time to zero concentration is also significantly extended, by around 25% by the water alone, but by greater than 500% by the emulsification process (experiment terminated at 25 minutes). Table 3 also demonstrates that the release can be accelerated by flowing the carrier gas through rather than over the sample, with fourteen times higher fluorocarbon concentrations recorded at the 30 s time point and a greater than three-fold reduction in the time to zero measured concentration. These data are consistent with the results of a cumulative release calculation, which indicate that >99% of the volatile fluorocarbon is released from the formulation. Hence for equivalent fluorocarbon content, a higher gas-phase concentration results in a shorter time to zero concentration, and for an equivalent volume of formulation, a higher fluorocarbon content increases both of these parameters.
(83) The influence of gas-flow rate when using the rig shown in FIG. 1a is further demonstrated by the data in table 4 which shows the effect of gas flow rate through the sample for HPFP under water and a 30% HPFP emulsion formulation. These data show that the time to zero recorded HPFP concentration is decreased with increased flow rate, as is the concentration recorded at a fixed time point of 30 s. For the formulation the time to zero measured concentration halves from 0 to 2 L.sup.−1 gas flowed through.
(84) Sevoflurane Experiments
(85) FIG. 5 shows the time dependence of sevoflurane release from an emulsion formulation containing 20 wt % sevoflurane dispersed by shaking in a 10 wt % solution of Zonyl FSO-100. Comparing the overall shape of the profile to that in FIG. 2 it is evident that the retardation of the evaporation leads to an extended plateau region where a constant sevoflurane concentration in the carrier-gas is recorded. This plateau region is much lower in concentration than for either the free sevoflurane control sample (˜13%, FIG. 2) or the sevoflurane under water control sample (˜8%, FIG. 3). At <1% the concentration delivered from the formulation is lower than the required clinical window (˜4%), however optimisation of the formulation and gas-flow conditions can be used to obtain the desired concentration. The initial concentration is also lowered by formulation (˜5% sevoflurane during initialisation for the formulation, compared to ˜15% for the controls), obtaining a value much closer to the clinically required concentration of around 8%. The current formulation is also successful in delivering the anaesthetic over a one-hour timescale, and therefore is a clear lead candidate for optimisation towards a clinically viable dispersion.
(86) FIG. 6 gives the chemical structures of example low molecular weight organogelators: molecules that are known to gel organic and/or fluorocarbon liquids. Gelation of the anaesthetic therefore represents an alternative method to controlled anaesthetic release.
(87) FIG. 7 shows a schematic representation of a two stage formulation that combined the expected formulation robustness of a gelled anaesthetic for transportation and storage, which can be converted at the point of use into an emulsion by vigorous shaking with an aqueous solution of the emulsifier (surfactant solution).
(88) Sustained Isoflurane Release Formulations
(89) Sustained Isoflurane release at a constant rate (MAC) (vol %) for 1 hour has been achieved at 0.3% (MAC 0.25), 0.6% (MAC 0.5), 1.2% (MAC 1), 1.6% (MAC 1.33), 1.8% (MAC 1.5) and 2.4% (MAC 2) using the formulations described in table 5, under the conditions also described therein. Graphs for each individual release profile are shown in FIGS. 9-15.
(90) Sustained Isoflurane release at a constant rate (MAC) (vol %) for 1 hour has been achieved at 2.4% (MAC 2) using the formulations described in table 8, under the conditions also described therein. Graphs for each individual release profile are shown in FIGS. 16-17.
(91) Sustained Sevoflurane Release Formulations
(92) Sustained Sevoflurane release at a constant rate (MAC) (vol %) for 1 hour has been achieved at 0.5% (MAC 0.25), 1.0% (MAC 0.5), 2% (MAC 1), 3% (MAC 1.5), 3.5% (MAC 1.75) and 4% (MAC 2) using the formulations described in table 5, under the conditions also described therein. Graphs for each individual release profile are shown in FIGS. 18-23.
(93) Sustained Sevoflurane release at a constant rate (MAC) (vol %) for 1 hour has been achieved at 0.5% (MAC 0.25), 2% (MAC 1), 3% (MAC 1.5) and 4% (MAC 2) using the formulations described in table 8, under the conditions also described therein. Graphs for each individual release profile are shown in FIGS. 24-26 and FIG. 36 (1 l/min) and FIG. 41 (4 l/min).
(94) Sustained Mixed Surfactant Release Formulations
(95) Sustained mixed surfactant release formulations at a constant rate (MAC) (vol %) for 1 hour has been achieved at 2% (MAC 1) and 1.0% (MAC 0.5) using the formulations described in table 6, under the conditions also described therein. Graphs for each individual release profile are shown in FIGS. 27-32.
(96) Sustained Sevoflurane release at a constant rate (vol %) for 1 hour has been achieved at 0.5% (0.25 MAC) under Nitrogen flow rate of 1 L min.sup.−1 using a formulation containing 5 mL Sevoflurane and 15 mL of 20 wt. % Brij O5 and 30 mL of 7 wt. % Tween 20 and stirred at 200 rpm. The release profile is shown in FIG. 32. This figure demonstrates that hydrogenated surfactants could be used to stabilize Sevoflurane dispersions in aqueous solutions.
(97) Formulation Reproducibility
(98) Reproducibility of formulation performance is shown in FIGS. 33-34. The reproducibility of sample preparation has been demonstrated. FIGS. 33 and 34 show, for sevoflurane and isoflurane, respectively, data obtained from two replicate samples prepared independently.
(99) Effect of Carrier Gas Flow Rate on Sevoflurane Release Profile
(100) The effect of the carrier gas flow rate on the released Sevoflurane concentration has been investigated at two different flow rates of 1 L min.sup.−1 and 4 L min.sup.−1 Nitrogen, using fixed-composition formulations, fixed stirring rates and using the rig shown in FIG. 1b. The resulting Sevoflurane release profiles are given in FIG. 35. As shown, increasing the flow rate of the carrier gas results in a decrease in the concentration of the released Sevoflurane, but the level remains constant over the one hour time course. In this instance the level of release obtained is 0.5MAC which is suitable for sedation purposes. This demonstrates that a chosen cartridge may be used for either anaesthesia or sedation, depending on the clinical set-up and therefore flow rate.
(101) Emulsion Structure
(102) Emulsion structure was confirmed and evaluated by optical microscopy and subsequent image analysis. Micrographs for 1, 2 and 3% formulations showed a droplet size of 1.5 μm, 1.4 μm and 1.4 μm, respectively. These results and the droplet size of the other formulations are shown in tables 5, 6, 8 & 9.
(103) Effect of Stirring Rate on Sevoflurane Release Profile
(104) It has been demonstrated that stirring rate can be used to alter and control Sevoflurane release from the formulation.
(105) For a formulation that gives a steady release, e.g. at 2% with a stirring rate of 250 rpm, using a higher stirring rate 500 rpm causes an increase in the initial release. As shown in FIG. 36, the Sevoflurane is used more quickly at the higher stirring speed and the release level drops more quickly than at slower speeds.
(106) Different Stirring Rates within the Same Run
(107) Stirring rate can be used to control the release level of Sevoflurane, and the response to stirring is both rapid and reversible, as shown in FIG. 37. FIG. 38 shows that stirring rate can be used to provide different release regimes over a one hour time-course, or to maintain a 2% release profile with <0.1% drift over a longer timescale of 80 minutes (Compare to 250 rpm data in FIG. 36). The magnetic stirrer bar used was 10 mm (diameter) by 60 mm.
(108) Effect of Surface Area of Flow-Rig Models on Sevoflurane Release Profile
(109) The importance of using the correct surface area is demonstrated in FIG. 39(a), using a smaller amount of the 2% formulation (50 ml) to be able to compare all of the surface areas. At high surface areas the release is higher, but at low surface areas clinically required levels are not reached. Selected data points are recast in FIG. 39(b), to show that the effect of increasing surface area levels off at ˜somewhere between 20 and 40 cm.sup.2. A full comparison of data at 30 cm.sup.2 and 50 cm.sup.2 is shown in FIG. 40.
(110) Effect of Amount of Formulation Used on Sevoflurane Release Profile
(111) Increasing the amount of formulation present does not significantly increase the level of release, but extends the timescale over which the level of release is sustained. This is shown in FIG. 41 for the 2% formulation.
(112) Formulation Recycling
(113) The formulation can be used and recharged with Sevoflurane (compensating for loss of water) with no compromise in performance, as shown in FIG. 42. The data presented are for a fresh formulation, and one employed for up to 10 experiments.
(114) Effect of Temperature on Anaesthetic Release
(115) The effect of temperature on anaesthetic release from formulations using Sevoflurane stabilised by Zonyl-FSN-100 surfactant is shown in FIG. 43. Increasing the temperature increases the release level of the Sevoflurane in the carrier gas, however, this can be compensated for by adjusting the stirring rate as shown in FIG. 44 where Sevoflurane release profiles using a fixed-composition formulation under Nitrogen flow rate of 1 L min.sup.−1 at 10° C., 20° C. and 40° C. are stabilised at 1 MAC by stirring at 400, 350 and 200 rpm, respectively.
(116) Effect of Surfactant Concentration on the Release Profile
(117) The effect of surfactant concentration, in this case Zonyl FSN-100, in the employed formulation on anaesthetic i.e. Sevoflurane release profile has been investigated. FIG. 45 shows Sevoflurane release profile of two formulations contain 15 mL Sevoflurane and Zonyl FSN-100 concentration of 7 and 20 wt. %. As shown in this figure, the formulation with lower surfactant concentration gives rise to a higher Sevoflurane release. For example, the concentration of the released Sevoflurane form the formulation with 7 wt. % FSN-100 at 30 minutes was 2.1 vol. % while the corresponding released concentration from the formulation with 20 wt. % FSN-100 was 1.72 vol. %.
(118) Effect of Magnet Size on the Release Profile
(119) Changing the size of the stirrer bar alters the shear forces and the degree of mixing/agitation, resulting in a different release level as illustrated in FIG. 46.
(120) All-in-One Release Formulations
(121) Using the technology developed herein it is possible to provide formulations able to deliver different anaesthetic release amounts/vol % or MAC values depending upon the shearing forces, or stirring/agitation rate, to which the formulation is exposed.
(122) For example, a Sevoflurane formulation has been developed for use at 1 L/min carrier gas flow rate that can be made to deliver different anaesthetic release amounts/vol % or MAC values solely by changing the stirring rate; this provides for prolonged release of anaesthetic at any fixed level. In the examples shown the release levels are from 4MAC downwards.
(123) Formulations of this kind could therefore be used to provide the highest concentration of anaesthetic required for induction of anaesthesia, followed by a sustained release at a lower concentration to maintain anaesthesia, whilst maintaining the flexibility to increase and decrease the delivered concentration by adjusting the stirring rate in a controlled manner.
(124) Unless otherwise stated in the text, the data in these All-In-One Release Formulations were obtained at room temperature (20±2° C.) using flow rig model 6 (surface area 50 cm.sup.2), under a nitrogen flow rate of 1 L.sup.−1.
(125) An analogous formulation has been prepared for Isoflurane to, function at room temperature (20±2° C.) using flow rig model 6 (surface area 50 cm.sup.2), under a nitrogen flow rate of 1 L min.sup.−1.
(126) Two further formulations have been prepared which exemplify the same concept for use at a higher nitrogen flow rate of 4 L/min at room temperature (20±2° C.) using flow rig model 6 (surface area 50 cm.sup.2).
(127) Sevoflurane at 1 L/Min
(128) FIG. 47 shows the release for a formulation containing 50 ml Sevoflurane dispersed by manual shaking in 110 ml of an aqueous solution of 15 wt % Zonyl FSN-100. The stirring rate has been adjusted to obtain different release levels at constant flow rate, as summarised in table 10.
(129) The required induction level of 4MAC (anaesthetic release 8 vol %) has been maintained for 20 minutes to illustrate that the formulation could be used to rapidly induce and then maintain anaesthesia at the desired MAC/vol %. Any desired intermediate value between those explicitly demonstrated in FIG. 47 can be obtained by adjustment to the stirring of the system. As previously described, stirring rates are representative of the specific experimental set-up rather than absolute values; different stirring rates would be required using different apparatus or agitation methods, never the less, each individual cartridge can be calibrated to take this into account having regard to the shearing apparatus contained therein and/or method used. Notably, the principle concept i.e. to obtain controlled variation in release, of the amount of anaesthetic by changing the speed/manner of stirring holds across other stirring or agitation mechanisms. It should also be self-evident, based on the data herein that the timescales are indicative only of the experiment; the lower the release required the longer the fixed volume formulation will deliver a constant MAC. This is a general point that applies to all of the formulations where release is influenced by shearing/stirring rate.
(130) All-in-One Isoflurane Release Formulation for 1 L/Min
(131) FIG. 48 shows the release for a formulation containing 20 ml Sevoflurane dispersed by manual shaking in 100 ml of an aqueous solution of 16 wt % Zonyl FSN-100. The stirring rate has been adjusted to obtain different release levels at constant flow rate, as summarised in table 11.
(132) All-in-One Release Formulations for 4 L/Min
(133) FIG. 49a shows the analogous release behaviour to that presented in FIG. 47, but at a higher carrier gas flow rate of 4 L/min. The stirring rate data is summarised in Table 12. FIG. 49b) shows the analogous release behaviour to that presented in FIG. 48, but at a higher carrier gas flow rate of 4 L/min. The stirring rate data is summarised in Table 13.
(134) Emulsions Prepared Using Microemulsions
(135) FIG. 50 shows that the invention can be worked using a microemulsion. In the example given 10 mL Sevoflurane and 55 mL of aqueous solution of 30 wt. % Polyfox-159 produce a microemulsion that is optically transparent as shown in FIG. 51. The release profile of this microemulsuion shows the requisite controllable and constant rate for working the invention.
(136) Emulsions Prepared from Pre-Gelled Anaesthetic
(137) To illustrate the feasibility of storing the anaesthetic as a gel and then mixing with a surfactant solution to constitute the final formulation, samples of anaesthetic were pre-gelled using gelator G4, the structure for which is shown below. The gelator used (G4) contains two less CH2 groups in the hydrocarbon chain linking the two chiral centres.
(138) ##STR00001##
(139) Pre-gelation of the Sevoflurane was achieved by adding 0.15 g G4 to 1 ml Sevoflurane, heating to ca 70° C. and cooling in an ice bath. This heat-cool cycle was repeated twice to obtain a clear homogenous gel. On adding the required surfactant solution there is no mixing of the two phases but, on shaking, the sample appearance is the same as a control sample prepared from non-gelled anaesthetic, indicating that an emulsion is still formed. The samples were left to phase separate, and the liquid nature of the lower phase indicates that the gel is broken on mixing and the liquid anaesthetic is retained on phase separation.
CONCLUSION
(140) The formulation of a volatile fluorocarbon liquid such as an anaesthetic as a stabilised dispersion greatly reduces the measured concentration of that fluorocarbon in a stream of carrier gas passed over the formulation when compared to the concentrations measured over the bare fluorocarbon liquid, or the same fluorocarbon liquid with a layer of water above it. Hence, forming a dispersion reduces the dangerously high levels of anaesthetic delivered in the carrier gas. Over time, all (>99%) of the volatile anaesthetic is released from the formulation, and the remaining surfactant solution can then be recharged with anaesthetic and re-used. Under constant gas flow rates, after a short initiation period when higher levels of anaesthetic are released the concentration remains constant until all the anaesthetic is released from the formulation. Hence the desired profile for anaesthetic delivery has been demonstrated. The levels of anaesthetic recorded are within safe and appropriate clinical limits, and are reproducible from sample to sample. Hence the formulation allows controlled, prolonged delivery of an anaesthetic over a predictable timescale.
(141) The anaesthetic concentration in the carrier gas may be increased by flowing the carrier gas through the formulation, rather than through the head-space of the containment vessel. This also offers control of the concentration versus time release profile. Alternatively, the dispersion can be agitated to alter the rate of release of anaesthetic therefrom.
(142) Table 1 shows that the model anaesthetic molecule 2H,3H-perfluoropentane (HPFP) may be formulated to provide a high content of volatile fluorocarbon liquid by shaking the liquid with an aqueous in a surfactant solution. The hazy/opaque appearance of the samples is indicative of emulsion formation.
(143) TABLE-US-00001 TABLE 1 Formulation fluorocarbon content as volume and weight percentage of the volatile fluorocarbon liquid in formulations containing the model anaesthetic fluorocarbon HPFP in a surfactant solution. sample J0 J1 J2 J3 J4 J5 J6 J7 vol % HPFP 0 5 9 13 17 29 38 50 wt % HPFP 0 1.5 3 4 5 9 11 15
Table 2 shows the moderation of evaporation by formulation of the model anaesthetic liquid HPFP.
(144) TABLE-US-00002 TABLE 2 Release characteristics of the volatile fluorocarbon liquid 2H,3H perfluoropentane (HPFP) in different formulation conditions. 3 ml of HPFP was used either alone, under an equal volume of water or after mixing with a surfactant solution to provide a formulation containing 30 wt % HPFP. The HPFP was monitored using the sevoflurane setting on the anaesthetic monitor, hence the data is reported in units of sevoflurane % and represents a relative concentration only. Reported are the ‘sevoflurane’ concentrations recorded 30 seconds after mixing of the formulation and the time taken for the detected concentration to drop to zero. No N.sub.2 flow J1 J2 J3 J4 J5 J6 J7 Sevo % HPFP 1.9 2.0 2.8 2.9 @ 30 s only emulsion 0.04 .sup. 0.17 time to HPFP 135 140 335 900 0% emulsion 630 >1200* Sevo/s
Table 3 shows how the moderation of evaporation by formulation of the model anaesthetic liquid HPFP can be further controlled by flowing the carrier gas over and especially through the sample in the testing chamber.
(145) TABLE-US-00003 TABLE 3 Release characteristics of the volatile fluorocarbon liquid 2H,3H perfluoropentane (HPFP) in different formulation conditions. 3 ml of HPFP was used either alone, under an equal volume of water or after mixing with a surfactant solution to provide a formulation containing 30 wt % HPFP. 2 L min.sup.−1 nitrogen carrier gas was flowed either over or through each sample. The HPFP was monitored using the sevoflurane setting on the anaesthetic monitor, hence the data is reported in units of scvoflurane % and represents a relative concentration only. Reported data are the sevoflurane concentrations recorded 30 seconds after mixing of the formulation and the time taken for the detected concentration to drop to zero. HPFP 21 min-1 N.sub.2 HPFP under water 30% emulsion Over sevoflurane % @ 30 s 1.6 0.62 0.04 Through sevoflurane % @ 30 s — — 0.56 Over Time to 220 270 >1500 0% sevoflurane/s through Time to <220 210 570 0% sevoflurane/s
Table 4 shows how the concentration of volatile liquid in the carrier gas and the time taken to release all of the anaesthetic can be affected by the flow of carrier gas through the sample, and how the effects of formulation on retarding volatile release are maintained under these conditions.
(146) TABLE-US-00004 TABLE 4 Release characteristics of the a volatile fluorocarbon liquid 2H,3H perfluoropentane (HPFP) in different formulation conditions. 3 ml of HPFP was used under an equal volume of water. Nitrogen carrier gas was flowed through each sample at different flow rates. The HPFP was monitored using the sevoflurane setting on the anaesthetic monitor, hence the data is reported in units of sevoflurane % and represents a relative concentration only. Reported data are the sevoflurane concentrations recorded 30 seconds after mixing of the formulation and the time taken for the detected concentration to drop to zero. 3 ml HPFP under 3 ml H.sub.2O N2 flowrate J5 under same conditions through time to 0% N2 flowrate time to 0% sample/ % sevoflurane sevoflurane .sup.a/ through % sevoflurane sevoflurane/ L min.sup.−1 @ 30 s mins sample @30 s mins 0 L min.sup.−1 1.5 8.5 0 L min.sup.−1 0.04 20 1 L min.sup.−1 2.5 4.5 1 L min.sup.−1 — — 2 L min.sup.−1 2.3 3.5 2 L min.sup.−1 0.56 10 3 L min.sup.−1 2.2 3.0 3 L min.sup.−1 — — .sup.a monitored as sevoflurane
(147) TABLE-US-00005 TABLE 5 Zonyl FSN-100 stabilised emulsions. Tested in flow rig 6 (50 cm.sup.2 surface area) Formulation Details Test Conditions Character- Total Vol Vol % Concentration Carrier isation Release MAC vol of Anaes- Anaes- of surfactant gas flow Droplet level/ equiv- formula- thetic/ thetic in in aqueous stock rate/L Temp/ Stirring size (Av- vol % alent tion/ml ml formulation solution/wt % min.sup.−1 ° C. rate/rpm erage)/nm REF SEVO- 4 2 160 50 31.2 18 1 20 312-375 209 (±2) ZS4.01 FLURANE 3.5 1.75 160 40 25.0 20 1 20 375 118 (±2) ZS3.51 3 1.5 134 26 19.4 10.0 1 20 300 .sup. 259 (±0.6) ZS3.01 2 1 120 15 12.5 7.0 1 20 250 261 (±4) ZS2.01 1 0.5 120 7.5 6.3 4.0 1 20 250 239 (±5) ZS1.01 0.5 0.25 90 5.5 6.1 8 1 20 150 188 (±4)- ZS0.51 ISO- 2.4 2 100 15 15 22 1 20 260-400 225 (±2) ZI2.41 FLURANE 1.8 1.5 120 18 15 25 1 20 400-500 340 (±7) ZI1.81 1.6 1.33 100 13 13 13 1 20 260 360 (±7) ZI1.61 1.2 1 100 9 9 11 1 20 200 430 (±8) ZI1.21 1.2 1 110 12 11 12 1 20 200 208 (±7) ZI1.2b1 0.6 0.5 100 4.5 4.5 8 1 20 200 200 (±6) ZI0.61 0.3 0.25 80 2.5 3.1 13 1 20 150 153 (±2) ZI0.31
(148) TABLE-US-00006 TABLE 6 Sevoflurane emulsions stabilised by other surfactants. Tested in flow rig 6 (50 cm.sup.2 surface area) Formulation Details Test Conditions Character- Total Vol Vol % of Concentration Carrier isation Release vol of Sevo- Sevo- of surfactant gas flow Droplet level/ formula- flurane/ flurane in in aqueous stock rate/L Temp/ Stirring size (Av- Surfactant vol % MAC tion/ml ml formulation solution min.sup.−1 ° C. rate/rpm erage)/nm REF Capstone 2 1 130 15 11.5 3 wt % (C) + 1 20 250 142 (±2) CPS2.01 FS-3100 + 10 wt % (P) Polyfox 159 Capstone 2 1 130 18 13.8 9 wt % (C) + 1 20 230-250 245 (±5) CPS2.0b1 FS-3100 + 5 wt % (P) Polyfox 159 BrijO20 + 2 1 130 20 15.3 10 wt %(B) + 1 20 250 318 (±3) BCS2.01 Capstone 12 wt % (C) FS-3100 Polyfox 159 2 1 130 23 23.0 10 wt % P 1 20 50-250 200 (±1) PS2.01 Capstone 1 0.5 130 15 11.5 5 wt % (C) + 1 20 230 346 (±8) CPS1.01 FS-3100 + 3 wt % (P) Polyfox 159 Brij O5 (B); 0.5 0.25 50 5 10 20 wt % B + 1 20 200 626 (±17) BTS0.5 Tween 20 7 wt % T (T) Abbreviations: Capstone FS-3100 (C); Polyfox 159 (P); Brij O20 (B)
(149) TABLE-US-00007 TABLE 7 Effect of stirring rate on release. Tested using formulation ZS2.0 at constant temperature and flow rate in flow rig 6 (50 cm.sup.2 surface area) Formulation Details Test Conditions Total Vol Vol % Concentration Carrier vol of Sevo- Sevo- of surfactant gas flow Release MAC formula- flurane/ flurane in in aqueous stock rate/L Temp/ Stirring level/ equiv- tion/ml ml formulation solution/wt % min.sup.−1 ° C. rate/rpm vol % alent SEVO- ZS2.01 120 15 12.5 7.0 1 20 100 0.7 0.35 FLURANE 1 20 150 1.3(ave) 0.65 1 20 200 1.4(ave) 0.7 1 20 250 2.0 1 1 20 315 3.0 1.5 1 20 500 3.4(ave) 1.7
(150) TABLE-US-00008 TABLE 8 Release at 4 L min.sup.−1 flow rate. Zonyl FSN-100 stabilised emulsions tested in flow rig 6 (50 cm.sup.2 surface area). Flow rate = 4 L min.sup.−1 Formulation Details Test Conditions Character- Total Vol Concentration Concentration Carrier isation Release MAC vol of Anaes- of anaesthetic of surfactant gas flow Droplet level/ equiv- formula- thetic/ in formulation/ in aqueous stock rate/L Temp/ Stirring size (Av- vol % alent tion/ml ml vol % solution/wt % min.sup.−1 ° C. rate/rpm erage)/nm REF SEVO- 4 2.0 160 70 43.8 25 4 20 500-1000 256 (±5) ZS4.04 FLURANE 3 1.5 140 50 35.7 22 4 20 375-625 206 (±2) ZS3.04 2 1.0 140 40 28.6 17 4 20 375-625 384 (±5) ZS2.04 0.5 0.25 120 15 12.5 7 4 20 250 188 (±4) ZS0.54 = ZS2.01 ISO- 2.4 2.0 140 35 0.25 19 4 20 375-1000 884 (±5) ZI2.44 FLURANE
(151) TABLE-US-00009 TABLE 9 Emulsions stabilised by other surfactants tested in flow rig 6 (50 cm.sup.2 surface area). Flow rate = 4 L min.sup.−1 Formulation Details Test Conditions Character- Total Vol Concentration Concentration Carrier isation Release MAC vol of Sevo- of anaesthetic of surfactant gas flow Droplet level/ equiv- formula- flurane/ in formulation/ in aqueous stock rate/L Temp/ Stirring size (Av- vol % alent tion/ml ml vol % solution/wt % min.sup.−1 ° C. rate/rpm erage)/nm REF ISO- 2.4 2.0 130 30 23.0 5S + 6C 4 20 300-750 480 (±5) GCI2.44 FLURANE Abbreviations: Capstone FS-3100 (C); Chemguard S-550L-100 (S)
(152) TABLE-US-00010 TABLE 10 Summary stirring rates used to generate release profile data presented in FIG. 47. Sevoflurane level/vol MAC duration Stirring rate 8 (±0.2) 4 20 400-500 4 (±0.2) 2 30 315-400 3 (±0.2) 1.5 20 260-315 2 (±0.2) 1 20 225-250 1 (±0.2) 0.5 15 150 0.5 (±0.1) 0.25 40 100 0.25 (±0.1) 0.125 30 50
(153) TABLE-US-00011 TABLE 11 Summary stirring rates used to generate release profile data presented in FIG. 48. Isoflurane level/vol MAC duration Stirring rate 4.8 (±0.2) 4 20 315-375 2.4 (±0.2) 2 15 260-315 1.2 (±0.1) 1 15 225-250 0.6 (±0.1) 0.5 20 200 0.3 (±0.1) 0.25 20 150
(154) TABLE-US-00012 TABLE 12 Summary stirring rates used to generate release profile data presented in FIG. 49a. Sevoflurane level/vol % MAC duration/min Stirring rate/rpm 8 (±0.2) 4 20 550-750 4 (±0.2) 2 30 500-650 2 (±0.2) 1 20 350 1 (±0.2) 0.5 15 315 0.5 (±0.1) 0.25 40 200 0.25 (±0.1) 0.125 30 180
(155) TABLE-US-00013 TABLE 13 Summary of stirring rates used to generate release profile data presented in FIG. 49 b. Isoflurane level/ MAC duration/ Stirring rate/ vol % equivalent min rpm REF 4.8 (±0.2) 4 15 280-400 AIO_1_4 2.4 (±0.2) 2 15 240-300 1.2 (±0.1) 1 15 220-250 0.6 (±0.05) 0.5 20 200-250 0.3 (±0.05) 0.25 20 180-225
