HYDROFLUOROOLEFIN CRYOABLATION COMPOSITION TO A TISSUE

FIELD OF THE INVENTION

[0001] The invention relates generally to a cryoablation device for topical application of a hydrofluoroolefin cryoablation composition to a tissue of a patient, and more particularly to such a cryoablation device comprising (a) an aerosol-dispensing container comprising an internal chamber, a valve, a dispensing hole, and an actuator, and (b) a hydrofluoroolefin cryoablation composition comprising refrigerant trans-1,3,3,3- tetrafluoroprop-l-ene (HFO-1234ze) at 5% to 50% (weight/weight) and refrigerant 2,3,3,3- tetrafluoropropene (HFO-1234yf) at 15% to 50% (weight/weight), wherein the

hydrofluoroolefin cryoablation composition is stored within the internal chamber, and the aerosol-dispensing container is configured so that depressing the actuator reversibly opens the valve to allow the hydrofluoroolefin cryoablation composition to flow from the internal chamber, past the valve, and through the dispensing hole, thereby dispensing the

hydrofluoroolefin cryoablation composition from the aerosol-dispensing container.

BACKGROUND OF THE INVENTION

[0002] Topical cryoablation devices are used to destroy unwanted or diseased tissue on or near the surface of the skin. Typically, topical cryoablation devices treat unwanted tissue and/or diseased tissue including actinic keratosis, genital warts, lentigo, mulluscum contagiosum, seborrheic keratosis, skin tags, verruca plantaris, verruca vulgaris, verruca plana, age spots, benign lesions, anal lesions, penile lesions, vulva lesions, and plantar warts, among others. The compositions of the cryoablation formulations typically include a liquefied gas with a boiling point below 0 °C. The liquefied gas formulation is applied to the tissue and evaporates, which removes heat energy from the tissue and cools the tissue to temperatures below the freezing point of water (0 < °C). Typically, cryoablation devices achieve cytotoxic and lethal ice temperatures of -20 °C to -40 °C depending on the tissue type.

[0003] Current topical cryoablation devices are formulated with refrigerant blends that are flammable, costly, dangerous, and/or not environmentally friendly. The flammable blends are typically formulated from dimethyl ether, isobutane, propane, and/or pentane. Other cryoablation formulations include liquefied gases with high global warming potentials including 1,1-difluoroethane (HFC-152a), 1,1, 1-trifluoroethane (HFC-143a), 1, 1,1,2-tetrafluoroethane (HFC-134a), and/or pentafluoroethane (HFC-125). Pure liquid nitrogen, pure liquid nitrous oxide, and pure liquid argon are used in topical cryoablation devices as well, but since they achieve surface temperature less than -89 °C, they require a great deal of skill to keep the patient and practitioner safe.

[0004] Previous topical cryoablation devices include those disclosed in U.S.

Pat. No. 8,038,668, "Cryosurgical Device and Method for Cooling Surfaces"; U.S. Pat. No. 8,906,005, "Cryosurgical Systems and Methods of Using the Same"; U.S. Pat. No. D681,807, "Devices for Dispensing a Cryogenic Fluid"; U.S. Pat. No. 5,516,505, "Method for Using Cryogenic Agents for Treating Skin Lesions"; and U.S. Pat. No. 5,330,745, "Method for Using Cryogenic Agents for Treating Skin Lesions." Of these, U.S. Pat. No. 8,038,668 and U.S. Pat. No. 8,906,005 disclose devices for dispensing refrigerants from an aerosol container with a dispensing bud. These patents do not describe novel refrigerant blends or use of Joule- Thomson supercooling, which is achieved by a refrigerant moving rapidly from a high pressure environment of at least 30 psi (210 kPa) to a low pressure environment of 14 psi (97 kPa) or lower. U.S. Pat. No. D681,807 focuses on the dispensing packaging of a nonspecific refrigerant. U.S. Pat. No. 5,516,505 and U.S. Pat. No. 5,330,745 disclose a series of refrigerant blends that are either hydrofluorocarbon (HFC) based or flammable liquefied gases. Moreover, U.S. Pat. No. 5,516,505 does not disclose use of a cone to dispense the refrigerant onto tissue, and U.S. Pat. No. 5,330,745 does not disclose use of the Joule- Thomson supercooling through an aerosol valve to supercool a refrigerant blend.

BRIEF SUMMARY OF THE INVENTION

[0005] A cryoablation device for topical application of a hydrofluoroolefin cryoablation composition to a tissue of a patient is disclosed. The cryoablation device comprises (a) an aerosol-dispensing container comprising an internal chamber, a valve, a dispensing hole, and an actuator. The cryoablation device also comprises (b) a

hydrofluoroolefin cryoablation composition comprising refrigerant trans-1,3,3,3- tetrafluoroprop-l-ene (HFO-1234ze) at 5% to 50% (weight/weight) and refrigerant 2,3,3,3- tetrafluoropropene (HFO-1234yf) at 15% to 50% (weight/weight). The hydrofluoroolefin cryoablation composition is stored within the internal chamber. The aerosol -dispensing container is configured so that depressing the actuator reversibly opens the valve to allow the hydrofluoroolefin cryoablation composition to flow from the internal chamber, past the valve, and through the dispensing hole, thereby dispensing the hydrofluoroolefin cryoablation composition from the aerosol -dispensing container. [0006] In accordance with some embodiments, the hydrofluoroolefin cryoablation composition further comprises one or more refrigerants, in addition to HFO- 1234ze and HFO-1234yf, at 0.1% to 80% (weight/weight). In some examples of these embodiments, the one or more additional refrigerants comprise one or more of 1,1, 1,2,2- pentafluoroethane (HFC-125), difluoromethane (HFC-32), 1,1, 1,2-tetrafluoroethane (HFC- 134a), liquid nitrogen, liquid nitrous oxide, liquid argon, dimethyl ether, 1, 1-difluoroethane (HFC- 152a), liquid carbon dioxide, 1, 1,1-trifluoroethane (HFC- 143 a), difluoromethane (HFC-32), propane, isobutane, or butane. In some examples, the one or more additional refrigerants comprise one or more of HFC-125 at 15% to 40% (weight/weight), HFC-32 at 20% to 40% (weight/weight), or HFC- 134a at 10% to 25% (weight/weight). In some examples, the one or more additional refrigerants comprise each of HFC-125 at 15% to 40% (weight/weight), HFC-32 at 20% to 40% (weight/weight), and HFC-134a at 10% to 25% (weight/weight).

[0007] Also in accordance with some embodiments, the cryoablation device further comprises a dispensing straw having a proximal end and a distal end and a passage therebetween. The proximal end of the dispensing straw is configured for attachment to the actuator. The dispensing straw is configured for receiving the hydrofluoroolefin cryoablation composition from the actuator at the proximal end of the dispensing straw and dispensing the hydrofluoroolefin cryoablation composition from the distal end of the dispensing straw.

[0008] In some examples of these embodiments, the cryoablation device further comprises a dispensing bud attached to the distal end of the dispensing straw.

[0009] Also in some examples of these embodiments, the cryoablation device further comprises a cone comprising a cone body having (i) a proximal end having a proximal opening and (ii) a distal end having a distal opening, and defining a reservoir between the proximal opening and the distal opening. The cone body has a generally conical shape tapering toward the distal opening. The cone is configured for dispensing of the hydrofluoroolefin cryoablation composition from the aerosol-dispensing container into the reservoir.

[0010] In some cases of these examples, the cryoablation device supercools the hydrofluoroolefin cryoablation composition by the use of Joule-Thomson supercooling, in which the rapid expansion of the hydrofluoroolefin cryoablation composition through the aerosol valve from a high pressure environment within the aerosol can to a low pressure environment outside of the aerosol can results in a temperature decrease below the theoretical boiling point temperature of the hydrofluoroolefin cryoablation composition. Also in some cases, the cryoablation device further generates a refrigeration cycle during use, based on the cone acting as an expansion valve and evaporator to allow for evaporation of the

hydrofluoroolefin cryoablation composition dispensed into the reservoir of the cone, thereby removing heat energy from the distal end of the cone.

[0011] Also disclosed is a method for treating a tissue of a patient by use of the cryoablation device. The method comprises a step of dispensing the hydrofluoroolefin cryoablation composition from the cryoablation device onto the tissue of the patient.

[0012] In some examples the hydrofluoroolefin cryoablation composition is dispensed directly from the aerosol-dispensing container onto the tissue of the patient. Also in some examples the hydrofluoroolefin cryoablation composition is dispensed from the aerosol-dispensing container, through a dispensing straw, and onto the tissue of the patient. Also in some examples the hydrofluoroolefin cryoablation composition is dispensed from the aerosol-dispensing container, through a dispensing straw, into a dispensing bud, with the dispensing bud then being placed in contact with the tissue of the patient. Also in some examples the hydrofluoroolefin cryoablation composition is dispensed from the aerosol- dispensing container, into a cone, and onto the tissue of the patient, with the cone being in contact with the tissue of the patient. Also in some examples the hydrofluoroolefin cryoablation composition is dispensed from the aerosol-dispensing container, through a dispensing straw, into a cone, and onto the tissue of the patient, with the cone being in contact with the tissue of the patient.

[0013] In accordance with some embodiments, the patient comprises a human or an animal. Also in accordance with some embodiments, the tissue is an unwanted tissue and/or a diseased tissue. Also in accordance with some embodiments, the tissue of the patient is contacted with the hydrofluoroolefin cryoablation composition for a freeze time of 5-60 seconds following the dispensing. Also in accordance with some embodiments, the dispensing generates a refrigeration cycle through Joule-Thomson supercooling, in which the hydrofluoroolefin cryoablation composition rapidly expands through an aerosol valve from a high pressure environment within the aerosol can of at least 30 psi (210 kPa) to a low pressure environment outside of the aerosol can of 14 psi (97 kPa) or lower.

[0014] Exemplary embodiments include the following.

[0015] Embodiment 1 : A cryoablation device for topical application of a hydrofluoroolefin cryoablation composition to a tissue of a patient comprising: (a) an aerosol- dispensing container comprising an internal chamber, a valve, a dispensing hole, and an actuator; and (b) a hydrofluoroolefin cryoablation composition comprising refrigerant trans- 1,3,3,3-tetrafluoroprop-l-ene (HFO-1234ze) at 5% to 50% (weight/weight) and refrigerant 2,3,3, 3-tetrafluoropropene (HFO-1234yf) at 15% to 50% (weight/weight); wherein: the hydrofluoroolefin cryoablation composition is stored within the internal chamber; and the aerosol-dispensing container is configured so that depressing the actuator reversibly opens the valve to allow the hydrofluoroolefin cryoablation composition to flow from the internal chamber, past the valve, and through the dispensing hole, thereby dispensing the

hydrofluoroolefin cryoablation composition from the aerosol-dispensing container.

[0016] Embodiment 2: The cryoablation device of embodiment 1, wherein the hydrofluoroolefin cryoablation composition consists essentially of HFO-1234ze and HFO- 1234yf.

[0017] Embodiment 3 : The cryoablation device of embodiment 1 or 2, wherein the hydrofluoroolefin cryoablation composition does not comprise any refrigerants other than HFO-1234ze and HFO-1234yf.

[0018] Embodiment 4: The cryoablation device of embodiment 1, wherein the hydrofluoroolefin cryoablation composition further comprises one or more additional refrigerants at 0.1% to 80% (weight/weight).

[0019] Embodiment 5: The cryoablation device of embodiment 4, wherein the one or more additional refrigerants comprise one or more of 1,1, 1,2,2-pentafluoroethane (HFC-125), difluoromethane (HFC-32), 1, 1,1,2-tetrafluoroethane (HFC-134a), liquid nitrogen, liquid nitrous oxide, liquid argon, dimethyl ether, 1,1-difluoroethane (HFC- 152a), liquid carbon dioxide, 1,1,1-trifluoroethane (HFC-143a), difluoromethane (FIFC-32), propane, isobutane, or butane.

[0020] Embodiment 6: The cryoablation device of embodiment 4, wherein the one or more additional refrigerants comprise FIFC-125 and HFC-32.

[0021] Embodiment 7: The cryoablation device of embodiment 6, wherein the hydrofluoroolefin cryoablation composition comprises HFO-1234ze at 5% to 40%

(weight/weight), HFO-1234yf at 15% to 40% (weight/weight), HFC-125 at 15% to 40% (weight/weight), and HFC-32 at 20% to 40% (weight/weight).

[0022] Embodiment 8: The cryoablation device of embodiment 6, wherein the hydrofluoroolefin cryoablation composition comprises HFO-1234ze at 10% to 35%

(weight/weight), HFO-1234yf at 20% to 35% (weight/weight), HFC-125 at 20% to 35% (weight/weight), and HFC-32 at 25% to 35% (weight/weight). [0023] Embodiment 9: The cryoablation device of any one of embodiments 6-

8, wherein the hydrofluoroolefin cryoablation composition consists essentially of HFO- 1234ze, HFO-1234yf, HFC-125, and HFC-32.

[0024] Embodiment 10: The cryoablation device of any one of embodiments

6-9, wherein the hydrofluoroolefin cryoablation composition does not comprise any refrigerants other than HFO-1234ze, HFO-1234yf, HFC-125, and HFC-32.

[0025] Embodiment 11 : The cryoablation device of embodiment 4, wherein the one or more additional refrigerants comprise HFC-125, HFC-32, and HFC-134a.

[0026] Embodiment 12: The cryoablation device of embodiment 11, wherein the hydrofluoroolefin cryoablation composition comprises HFO-1234ze at 5% to 40% (weight/weight), HFO-1234yf at 15% to 40% (weight/weight), HFC-125 at 15% to 40% (weight/weight), HFC-32 at 20% to 40% (weight/weight), and HFC-134a at 10% to 25% (weight/weight).

[0027] Embodiment 13 : The cryoablation device of embodiment 11, wherein the hydrofluoroolefin cryoablation composition comprises HFO-1234ze at 10% to 35% (weight/weight), HFO-1234yf at 20% to 35% (weight/weight), HFC-125 at 20% to 35% (weight/weight), HFC-32 at 25% to 35% (weight/weight), and HFC-134a at 15% to 20% (weight/weight).

[0028] Embodiment 14: The cryoablation device of any one of embodiments

11-13, wherein the hydrofluoroolefin cryoablation composition consists essentially of HFO- 1234ze, HFO-1234yf, HFC-125, HFC-32, and HFC-134a.

[0029] Embodiment 15: The cryoablation device of any one of embodiments

11-14, wherein the hydrofluoroolefin cryoablation composition does not comprise any refrigerants other than HFO-1234ze, HFO-1234yf, HFC-125, HFC-32, and HFC-134a.

[0030] Embodiment 16: The cryoablation device of embodiment 4, wherein the one or more additional refrigerants comprise liquid nitrogen.

[0031] Embodiment 17: The cryoablation device of embodiment 16, wherein the hydrofluoroolefin cryoablation composition comprises HFO-1234ze at 10% to 45% (weight/weight) and HFO-1234yf at 20% to 45% (weight/weight).

[0032] Embodiment 18: The cryoablation device of any one of embodiments

1-17, wherein the aerosol-dispensing container is selected from the group consisting of a stainless steel aerosol can, an aluminum aerosol can, a plastic aerosol can, a polymer-based aerosol can, an aerosol bottle, a glass aerosol bottle, and a pressure container. [0033] Embodiment 19: The cryoablation device of any one of embodiments

1-18, wherein the actuator comprises an actuator insert comprising an orifice having a diameter of 0.005 inches to 0.009 inches (0.13 mm to 0.23 mm).

[0034] Embodiment 20: The cryoablation device of any one of embodiments

1-18, further comprising a dispensing straw having a proximal end, a distal end, and a passage therebetween, wherein: the proximal end of the dispensing straw is configured for attachment to the actuator; and the dispensing straw is configured for receiving the hydrofluoroolefin cryoablation composition from the actuator at the proximal end of the dispensing straw and dispensing the hydrofluoroolefin cryoablation composition from the distal end of the dispensing straw.

[0035] Embodiment 21 : The cryoablation device of embodiment 20, wherein the straw has a distal end opening of 0.005 inches to 0.009 inches (0.13 mm to 0.23 mm).

[0036] Embodiment 22: The cryoablation device of embodiment 20, wherein the cryoablation device dispenses the hydrofluoroolefin refrigerant composition from the distal opening of the straw as a vapor stream.

[0037] Embodiment 23 : The cryoablation device of any one of embodiments

20-22, wherein the dispensing straw comprises a tab, and the actuator of the aerosol- dispensing container has a groove, with the groove being configured to receive the tab.

[0038] Embodiment 24: The cryoablation device of embodiment 20, further comprising a dispensing bud attached to the distal end of the dispensing straw.

[0039] Embodiment 25: The cryoablation device of any one of embodiments

1-24, wherein the cryoablation device dispenses the hydrofluoroolefin refrigerant

composition from a pressure of 30 psi (210 kPa) to 190 psi (1300 kPa) within the internal chamber of the aerosol-dispensing container to a pressure of an ambient external environment of 14 psi (97 kPa) or lower, thereby supercooling the hydrofluoroolefin cryoablation composition below its boiling point through Joule-Thomson supercooling.

[0040] Embodiment 26: The cryoablation device of embodiment 25, further comprising a cone comprising a cone body having (i) a proximal end having a proximal opening and (ii) a distal end having a distal opening, and defining a reservoir between the proximal opening and the distal opening, wherein: the cone body has a generally conical shape tapering toward the distal opening; and the cone is configured for dispensing of the hydrofluoroolefin cryoablation composition from the aerosol-dispensing container into the reservoir. [0041] Embodiment 27: The cryoablation device of embodiment 26, wherein the cryoablation device generates a refrigeration cycle during use, based on the cone acting as an expansion valve and evaporator to allow for evaporation of the hydrofluoroolefin cryoablation composition dispensed into the reservoir of the cone, thereby removing heat energy from the distal end of the cone.

[0042] Embodiment 28: The cryoablation device of embodiment 26 or 27, wherein the cone further comprises heat transfer fins extending outwardly from the cone body.

[0043] Embodiment 29: The cryoablation device of any one of claims 26-28, wherein the cone further comprises surface-area enhancing features.

[0044] Embodiment 30: The cryoablation device of embodiment 29, wherein the surface-area enhancing features comprise two or more bulbous portions disposed in series from the proximal end to the distal end.

[0045] Embodiment 31 : The cryoablation device of any one of embodiments

26-30, wherein the proximal opening is larger than the distal opening.

[0046] Embodiment 32: The cryoablation device of any one of embodiments

26-31, wherein the cone further comprises a proximal covering configured to slow

evaporation of the hydrofluoroolefin cryoablation composition within the reservoir, the proximal covering having a plurality of proximal covering vents disposed therein, and the proximal covering being disposed over the proximal opening.

[0047] Embodiment 33 : The cryoablation device of any one of embodiments

26-32, wherein the cone has a straw hole configured to allow insertion of the distal end of the dispensing straw therethrough for dispensing of the hydrofluoroolefin cryoablation composition into the reservoir.

[0048] Embodiment 34: The cryoablation device of any one of embodiments

1-33, wherein the hydrofluoroolefin refrigerant composition has an evaporation time in a cone of 10 to 60 seconds.

[0049] Embodiment 35: A method for treating a tissue of a patient by use of the cryoablation device of any one of embodiments 1-34 comprising a step of dispensing the hydrofluoroolefin cryoablation composition from the cryoablation device onto the tissue of the patient.

[0050] Embodiment 36: The method of embodiment 35, wherein the patient comprises a human or an animal. [0051] Embodiment 37: The method of embodiment 35 or 36, wherein the tissue is an unwanted tissue and/or a diseased tissue.

[0052] Embodiment 38: The method of any one of embodiments 35-37, wherein the treating comprises cryoablation and/or treatment of one or more of actinic keratosis, genital warts, lentigo, mulluscum contagiosum, seborrheic keratosis, skin tags, verruca plantaris, verruca vulgaris, verruca plana, age spots, benign lesions, anal lesions, penile lesions, vulva lesions, angiomas, granuloma annulare, porokeratosis plantaris, keratoacanthoma, chondrodermatitis, epithelial nevus, leukoplakia, granuloma pyogenicum, pyogenic granuloma, small keloids, dermatofibroma, acrochordon, or plantar warts.

[0053] Embodiment 39: The method of any one of embodiments 35-38, wherein the tissue of the patient is contacted with the hydrofluoroolefin cryoablation composition for a freeze time of 5 to 60 seconds following the dispensing.

[0054] Embodiment 40: The method of any one of embodiments 35-39, wherein the dispensing generates a refrigeration cycle.

[0055] Embodiment 41 : The method of any one of embodiments 35-40, wherein the hydrofluoroolefin cryoablation composition is dispensed onto the tissue of the patient through a hole in a spray-protecting bandage.

BRIEF DESCRIPTION OF THE DRAWINGS

[0056] FIG. 1 shows an embodiment of a cryoablation device for topical application of a hydrofluoroolefin cryoablation composition to a tissue of a patient, comprising (a) an aerosol -dispensing container and (b) a hydrofluoroolefin cryoablation composition, in perspective view.

[0057] FIG. 2 shows the cryoablation device of FIG. 1, in front view.

[0058] FIG. 3 shows the cryoablation device of FIG. 1, in side view.

[0059] FIG. 4 shows the cryoablation device of FIG. 1, in side sectional view.

[0060] FIG. 5 shows the structure of trans-l,3,3,3-tetrafluoroprop-l-ene, also termed HFO-1234ze or trans-l,3,3,3-tetrafluoropropene.

[0061] FIG. 6 shows the structure of 2,3,3,3-tetrafluoropropene, also termed

HFO-1234yf.

[0062] FIG. 7 shows an embodiment of a dispensing straw configured for attachment to the actuator of the cryoablation device, in side view.

[0063] FIG. 8 shows an embodiment of a dispensing straw comprising a dispensing bud attached to the dispensing straw, in side view. [0064] FIG. 9A-E shows an embodiment of a cone comprising a cone body having (i) a proximal end having a proximal opening and (ii) a distal end having a distal opening, and defining a reservoir between the proximal opening and the distal opening, with the cone being shown in (A) perspective view, (B) top view, (C) first side view, (D) second side view, and (E) sectional view.

[0065] FIG. 10 shows an embodiment of a cone comprising two or more bulbous portions disposed in series from the proximal end to the distal end, with the cone being shown in (A) perspective view, (B) top view, (C) first side view, (D) second side view, and (E) sectional view.

[0066] FIG. 11 shows an embodiment of a cone comprising heat transfer fins that increase the surface area of the cone, thereby enhancing the ability of the cone to transfer heat and lower the temperature of tissue in contact with the cone, and having ergonomic indentations for enhanced gripping of the cone, with the cone being shown in (A) perspective view, (B) top view, (C) first side view, (D) second side view, and (E) sectional view.

[0067] FIG. 12 shows an embodiment of a cone having a straw hole near the top of the cone for connection of a dispensing straw, with the cone being shown in (A) perspective view, (B) top view, (C) first side view, (D) second side view, and (E) sectional view.

[0068] FIG. 13 shows an embodiment of a cone with a proximal covering configured to slow evaporation of the hydrofluoroolefin cryoablation composition within the reservoir and having a straw hole for connection of a dispensing straw and a plurality of proximal covering vents, with the cone with the proximal covering being shown in (A) perspective view, (B) top view, (C) first side view, (D) second side view, and (E) sectional view, each with the proximal covering attached to the cone, and (F) perspective view, with the proximal covering separated from the cone.

[0069] FIG. 14 shows another embodiment of a cryoablation device for topical application of a hydrofluoroolefin cryoablation composition to a tissue of a patient, comprising (a) an aerosol -dispensing container and (b) a hydrofluoroolefin cryoablation composition, and further comprising another embodiment of a dispensing straw configured for attachment to the actuator of the cryoablation device or another embodiment of a dispensing straw comprising a dispensing bud attached to the dispensing straw, in exploded view, in perspective view.

[0070] FIG. 15 shows the aerosol-dispensing container of the cryoablation device of FIG. 14, in perspective view. [0071] FIG. 16 shows the aerosol-dispensing container of the cryoablation device of FIG. 14, in front view.

[0072] FIG. 17 shows the aerosol-dispensing container of the cryoablation device of FIG. 14, in side view.

[0073] FIG. 18 shows the aerosol-dispensing container and the

hydrofluoroolefin cryoablation composition of the cryoablation device of FIG. 14, in side sectional view.

[0074] FIG. 19 shows the dispensing straw configured for attachment to the actuator of the cryoablation device of FIG. 14, in side view.

[0075] FIG. 20 shows the dispensing straw configured for attachment to the actuator of the cryoablation device of FIG. 14, in front view.

[0076] FIG. 21 shows the dispensing straw configured for attachment to the actuator of the cryoablation device of FIG. 14, in side sectional view.

[0077] FIG. 22 shows the dispensing straw of FIG. 21, enlarged, in side sectional view.

[0078] FIG. 23 shows the dispensing straw comprising a dispensing bud of

FIG. 14, in side view.

[0079] FIG. 24 shows the dispensing straw comprising a dispensing bud of

FIG. 14, in front view.

[0080] FIG. 25 shows the dispensing straw comprising a dispensing bud of

FIG. 14, in side sectional view.

[0081] FIG. 26 shows the dispensing straw comprising a dispensing bud of

FIG. 25, enlarged, in side sectional view.

[0082] FIG. 27 shows the device for topical application of a hydrofluoroolefin cryoablation composition to a tissue of a patient of FIG. 14, comprising the dispensing straw configured for attachment to the actuator of the cryoablation device of FIG. 14, in perspective view.

[0083] FIG. 28 shows the actuator of the cryoablation device of FIG. 14, comprising the dispensing straw configured for attachment to the actuator of the cryoablation device of FIG. 14, in front view.

[0084] FIG. 29 shows the actuator of the cryoablation device of FIG. 14, comprising the dispensing straw configured for attachment to the actuator of the cryoablation device of FIG. 14, in side sectional view.

[0085] FIG. 30 shows the device for topical application of a hydrofluoroolefin cryoablation composition to a tissue of a patient of FIG. 14, comprising the dispensing straw comprising a dispensing bud attached to the dispensing straw of FIG. 14, in perspective view.

[0086] FIG. 31 shows the actuator of the cryoablation device of FIG. 14, comprising the dispensing straw comprising a dispensing bud attached to the dispensing straw of FIG. 14, in front view.

[0087] FIG. 32 shows the actuator of the cryoablation device of FIG. 14, comprising the dispensing straw comprising a dispensing bud attached to the dispensing straw of FIG. 14, in side sectional view.

[0088] FIG. 33 shows an embodiment of a spray-protecting bandage, that has a central hole, and that can be applied to a tissue of a patient, including a tissue that is intended to be destroyed by topical cryoablation, such that the central hole encircles the tissue to be destroyed.

[0089] FIG. 34 shows a graph of temperature (°C) versus time (seconds) for evaporation of a composition comprising 50% HFO-1234ze (weight/weight) and 50% HFO- 1234yf (weight/weight), demonstrating uniform supercooling properties of the composition.

[0090] FIG. 35 shows a graph of temperature (°C) versus time (seconds) for evaporation of a composition comprising 7% HFO-1234ze (weight/weight), 20% HFO- 1234yf (weight/weight), 26% HFC-32 (weight/weight), 26% HFC-125 (weight/weight), and 21%) HFC-134a (weight/weight), demonstrating uniform supercooling properties of the composition.

DETAILED DESCRIPTION OF THE INVENTION

[0091] As shown in FIGS. 1-4, a cryoablation device 100 for topical application of a hydrofluoroolefin cryoablation composition to a tissue of a patient is disclosed. The cryoablation device 100 comprises (a) an aerosol-dispensing container 102 comprising an internal chamber 104, a valve 106, a dispensing hole 108, and an actuator 110. The cryoablation device 100 also comprises (b) a hydrofluoroolefin cryoablation composition 112 comprising refrigerant trans-1, 3,3, 3-tetrafluoroprop-l-ene (HFO-1234ze) at 5% to 50% (weight/weight) and refrigerant 2,3,3,3-tetrafluoropropene (HFO-1234yf) at 15% to 50% (weight/weight). The hydrofluoroolefin cryoablation composition 112 is stored within the internal chamber. The aerosol-dispensing container 102 is configured so that depressing the actuator 110 reversibly opens the valve 106 to allow the hydrofluoroolefin cryoablation composition 112 to flow from the internal chamber 104, past the valve 106, and through the dispensing hole 108, thereby dispensing the hydrofluoroolefin cryoablation composition 112 from the aerosol-dispensing container 102.

[0092] Without wishing to be bound by theory, it is believed that a

hydrofluoroolefin cryoablation composition 112 comprising refrigerant HFO-1234ze at 5% to 50% (weight/weight) and refrigerant HFO-1234yf at 15% to 50% (weight/weight), unexpectedly provides advantages of producing a uniform supercooling effect when used in methods for treating a tissue of a patient by use of the cryoablation device 100, based on dispensing the hydrofluoroolefin cryoablation composition 112 from the cryoablation device 100 onto the tissue of the patient, for example by providing effective cryoablation and/or treatment of one or more of actinic keratosis, genital warts, lentigo, mulluscum contagiosum, seborrheic keratosis, skin tags, verruca plantaris, verruca vulgaris, verruca plana, age spots, benign lesions, anal lesions, penile lesions, vulva lesions, angiomas, granuloma annulare, porokeratosis plantaris, keratoacanthoma, chondrodermatitis, epithelial nevus, leukoplakia, granuloma pyogenicum, pyogenic granuloma, small keloids, dermatofibroma, acrochordon, or plantar warts, without presenting the unfavorable environmental risks and safety risks associated with previous topical cryoablation compositions. As shown in FIG. 34, combining HFO-1234ze at 5%-50% and HFO-1234yf at 15%-50% results an azeotropic mixture with uniform supercooling properties. It was not predictable that combining HFO-1234ze at 5%- 50% and HFO-1234yf at 15%-50% would have this effect.

[0093] HFO-1234ze is a refrigerant. The structure of HFO-1234ze is shown in

FIG. 5. HFO-1234ze is commercially available, for example as Honeywell HFO-1234ze Solstice Propellant.

[0094] HFO-1234yf also is a refrigerant. The structure of HFO- 1234yf is shown in FIG. 6. HFO-1234yf is commercially available, for example as Honeywell HFO- 1234yf Solstice Propellant.

[0095] In accordance with some embodiments, the hydrofluoroolefin cryoablation composition 112 consists essentially of HFO-1234ze and HFO-1234yf, i.e. the hydrofluoroolefin cryoablation composition 112 includes HFO-1234ze and HFO-1234yf, and potentially additional compounds, but not additional compounds that would materially affect the cryoablation characteristics of the hydrofluoroolefin cryoablation composition 112. Also, in accordance with some embodiments, the hydrofluoroolefin cryoablation composition does not comprise any refrigerants other than HFO-1234ze and HFO-1234yf.

[0096] In accordance with some embodiments, the hydrofluoroolefin cryoablation composition 112 further comprises one or more refrigerants, in addition to HFO- 1234ze and HFO-1234yf, at 0.1% to 80% (weight/weight). In some examples of these embodiments, the one or more additional refrigerants comprise one or more of 1, 1,1,2,2- pentafluoroethane (HFC-125), difluoromethane (HFC-32), 1,1, 1,2-tetrafluoroethane (HFC- 134a), liquid nitrogen, liquid nitrous oxide, liquid argon, dimethyl ether, 1, 1-difluoroethane (HFC- 152a), liquid carbon dioxide, 1, 1,1-trifluoroethane (HFC- 143 a), difluoromethane (HFC-32), propane, isobutane, or butane. In some examples, the one or more additional refrigerants comprise one or more of HFC-125 at 15% to 40% (weight/weight), HFC-32 at 20% to 40% (weight/weight), or HFC- 134a at 10% to 25% (weight/weight). In some examples, the one or more additional refrigerants comprise each of HFC-125 at 15% to 40% (weight/weight), HFC-32 at 20% to 40% (weight/weight), and HFC-134a at 10% to 25% (weight/weight).

[0097] For example, the one or more additional refrigerants can comprise

HFC-125 and HFC-32. Thus, in some examples the hydrofluoroolefin cryoablation composition 112 comprises HFO-1234ze at 5% to 40% (weight/weight), HFO-1234yf at 15% to 40% (weight/weight), HFC-125 at 15% to 40% (weight/weight), and HFC-32 at 20% to 40% (weight/weight); i.e. the hydrofluoroolefin cryoablation composition 112 comprises each of HFO-1234ze, HFO-1234yf, HFC-125, and HFC-32, each in the amounts recited respectively. Also, in some examples the hydrofluoroolefin cryoablation composition 112 comprises HFO-1234ze at 10% to 35% (weight/weight), HFO-1234yf at 20% to 35%

(weight/weight), HFC-125 at 15%-35% (weight/weight), and HFC-32 at 25% to 35%

(weight/weight). Also, in some examples the hydrofluoroolefin cryoablation composition 112 consists essentially of HFO-1234ze, HFO-1234yf, HFC-125, and HFC-32, i.e. the

hydrofluoroolefin cryoablation composition 112 includes HFO-1234ze, HFO-1234yf, HFC- 125, and HFC-32, and potentially additional compounds, but not additional compounds that would materially affect the cryoablation characteristics of the hydrofluoroolefin cryoablation composition 112. In some examples the hydrofluoroolefin cryoablation composition 112 does not comprise any refrigerants other than HFO-1234ze, HFO-1234yf, HFC-125, and HFC-32.

[0098] Also, for example, the one or more additional refrigerants can comprise HFC-125, HFC-32, and HFC-134a. Thus, in some examples the hydrofluoroolefin cryoablation composition 112 comprises HFO-1234ze at 5% to 40% (weight/weight), HFO- 1234yf at 15% to 40% (weight/weight), HFC-125 at 15% to 40% (weight/weight), HFC-32 at 20% to 40% (weight/weight), and HFC-134a at 10% to 25% (weight/weight); i.e. the hydrofluoroolefin cryoablation composition 112 comprises each of HFO-1234ze, HFO- 1234yf, HFC-125, HFC-32, and HFC-134a each in the amounts recited respectively. Also, in some examples the hydrofluoroolefin cryoablation composition 112 comprises HFO-1234ze at 10% to 35% (weight/weight), HFO-1234yf at 20% to 35% (weight/weight), HFC-125 at 15%-35% (weight/weight), HFC-32 at 25% to 35% (weight/weight), and HFC-134a at 15% to 20%) (weight/weight). Also, in some examples the hydrofluoroolefin cryoablation composition 112 consists essentially of HFO-1234ze, HFO-1234yf, HFC-125, HFC-32, and HFC-134a, i.e. the hydrofluoroolefin cryoablation composition 112 includes HFO-1234ze, HFO-1234yf, HFC-125, HFC-32, and HFC-134a, and potentially additional compounds, but not additional compounds that would materially affect the cryoablation characteristics of the hydrofluoroolefin cryoablation composition 112. In some examples the hydrofluoroolefin cryoablation composition 112 does not comprise any refrigerants other than HFO-1234ze, HFO-1234yf, HFC-125, HFC-32, and HFC-134a.

[0099] Without wishing to be bound by theory, it is believed that a hydrofluoroolefin cryoablation composition 112 comprising refrigerant HFO-1234ze at 5% to 40% (weight/weight), HFO-1234yf at 15% to 40% (weight/weight), HFC-125 at 15% to 40% (weight/weight), HFC-32 at 20% to 40% (weight/weight), and HFC-134a at 10% to 25% (weight/weight), unexpectedly provides advantages of producing a uniform supercooling effect when used in methods for treating a tissue of a patient by use of the cryoablation device 100. This uniform supercooling effect is surprising, since it was not predictable that the combination of HFO-1234ze at 5% to 40% (weight/weight), HFO-1234yf at 15% to 40% (weight/weight), HFC-125 at 15% to 40% (weight/weight), HFC-32 at 20% to 40%

(weight/weight), and HFC-134a at 10% to 25% (weight/weight) would produce an azeotropic-like mixture with uniform supercooling properties, as shown in FIG. 35. For industrial refrigeration applications, blends of these refrigerants typically behave as a zeotropic mixture with evaporation characteristics performing in stages. Hence, the azeotropic supercooling of these hydrofluoroolefin cryoablation compositions is surprising.

[00100] In addition, without wishing to be bound by theory, a

hydrofluoroolefin cryoablation composition 112 comprising refrigerant HFO-1234ze at 5% to 40% (weight/weight), HFO-1234yf at 15% to 40% (weight/weight), HFC-125 at 15% to 40% (weight/weight), HFC-32 at 20% to 40% (weight/weight), and HFC-134a at 10% to 25% (weight/weight) provides further advantages for effective cryoablation and/or treatment by producing a shorter evaporation time, as shown in TABLE 1. The shorter evaporation time allows for shorter and safer treatments, yet again without presenting the unfavorable environmental risks and safety risks associated with previous topical cryoablation

compositions. If the evaporation time of the cryoablation composition is less than 5 seconds, then the device is not effective at tissue destruction. Meanwhile, cryoablation treatments with freeze-thaw cycles lasting longer than 2 minutes can be dangerous and affect healthy surrounding tissue.

[00101] Also, for example, the one or more additional refrigerants can comprise liquid nitrogen. Thus, in some examples the hydrofluoroolefin cryoablation composition 112 comprises HFO-1234ze at 10% to 45% (weight/weight) and HFO-1234yf at 20%) to 45%) (weight/weight), and also comprises liquid nitrogen.

[00102] Without wishing to be bound by theory, it is believed that the hydrofluoroolefin cryoablation composition 112 further comprising one or more refrigerants, such as HFC-125, HFC-32, HFC-134a, liquid nitrogen, liquid nitrous oxide, liquid argon, dimethyl ether, HFC-152a, liquid carbon dioxide, HFC-143a, HFC-32, propane, isobutane, or butane, at 0.1%> to 80%> (weight/weight), provides further advantages for effective

cryoablation and/or treatment by producing a shorter evaporation time, as shown in TABLE 1. This again allows for shorter and safer treatments, yet again without presenting the unfavorable environmental risks and safety risks associated with previous topical

cryoablation compositions. Again, if the evaporation time of the cryoablation composition is less than 5 seconds, then the device is not effective at tissue destruction. Meanwhile, cryoablation treatments with freeze-thaw cycles lasting longer than 2 minutes can be dangerous and affect healthy surrounding tissue.

[00103] With reference to FIGS. 1-4, as noted above the aerosol-dispensing container 102 is configured so that depressing the actuator 110 reversibly opens the valve 106 to allow the hydrofluoroolefin cryoablation composition 112 to flow from the internal chamber 104, past the valve 106, and through the dispensing hole 108, thereby dispensing the hydrofluoroolefin cryoablation composition 112 from the aerosol-dispensing container 102. In some examples, the valve 106 can comprise a spring cup 114, a spring 116, a gasket 118, and a vapor tap 120. Also, the valve 106 can have a dip tube 122 attached thereto, and the internal chamber 104 of the aerosol-dispensing container 102 can comprise a lower end 124, such that the dip tube 122 extends into the internal chamber 104 of the aerosol-dispensing container 102, toward the lower end 124 of the internal chamber 104. The dip tube 122 is open at both of its ends. In accordance with these examples, depressing the actuator 110 can displace the spring cup 114 and compress the spring 116, thereby opening the valve 106, allowing the hydrofluoroolefin cryoablation composition 112 to flow from the internal chamber 104, past the valve 106, e.g. around and/or through the valve 106, and through the dispensing hole 108. In accordance with these examples, upon release of the actuator 110, the spring 116 can extend, returning the spring cup 114 to its non-displaced position, thereby closing the valve 106, preventing the hydrofluoroolefin cryoablation composition 112 from flowing from the internal chamber 104. The gasket 118 on the valve 106 can provide a seal in the valve 106 to prevent outflow of the hydrofluoroolefin cryoablation composition 112 from the internal chamber 104 when the valve 106 is closed. The vapor tap 120 on the valve 106 can provide additional propellant force and control of mist particle size. The dip tube 122 attached to the valve 106 can allow the hydrofluoroolefin cryoablation composition 112 on the lower end 124 of the internal chamber 104 to flow through the valve 106. Other suitable configurations, for example as described above except without a vapor tap 120 and/or without a dip tube 122, among other suitable configurations, also can also be used.

[00104] The valve 106 can be, for example, a vertical valve that opens with vertical pressure on the valve, a tilt valve that opens with forward pressure on the valve, an "up/down" valve that can dispense in an upright or inverted position, a female valve that interfaces with a stem in the actuator 110, a male valve that interfaces with a slot or a channel in the actuator 110, a bag on valve that contains bag contents that do not mix with

propellants, a metering valve that dispenses an exact amount of contents, a high delivery valve, or a variable valve for multiple discharges, among other valves.

[00105] The dip tube 122 can be made from, for example, low density polyethylene (LDPE), medium density polyethylene (MDPE), polypropylene, or

polytetrafluoroethylene (Teflon), among other suitable materials that are compatible with the hydrofluoroolefin vapocoolant composition.

[00106] The gasket 118 can be, for example, an outer gasket. For example, as shown in FIG. 4, in some examples the cryoablation device 100 includes a valve cup 128. In accordance with these examples, the gasket 118 can be an outer gasket that forms a seal between the valve cup 128 and the aerosol-dispensing container 102. The gasket 118 also can be, for example, an inner gasket 142 that covers the dispensing hole in the valve. The gasket 118 can be made, for example, from buna, chlorobutyl, neoprene, butyl, or a fluoroelastomer, such as ZYTEL fluoroelastomer, among other materials.

[00107] The actuator 110 can be one that is suitable for allowing the hydrofluoroolefin cryoablation composition 112, during dispensing from the aerosol- dispensing container 102, to reach a tissue of a patient, before the hydrofluoroolefin cryoablation composition 112 has mostly or entirely evaporated. For example, the actuator 110 can comprise an actuator insert 130 comprising an orifice 126 having a diameter of 0.005 inches to 0.009 inches (0.13 mm to 0.23 mm). [00108] Furthermore, in some examples of these embodiments, the actuator 110 of the cryoablation device 100 comprises an orifice 126 having a diameter of 0.005 inches to 0.009 inches (0.13 mm to 0.23 mm), as discussed above. In accordance with these examples, this orifice 126 size between 0.005 inches to 0.009 inches (0.13 mm to 0.23 mm) produces an additional supercooling effect on the hydrofluoroolefin cryoablation composition 112 as shown in TABLE 1. Specifically, the additional supercooling of the hydrofluoroolefin cryoablation composition 112 varies between 5 °C to 25 °C lower than compared to a standard actuator orifice of 0.1 inch (2.54 mm), as shown in TABLE 1. It was not predictable that use of an orifice 126 size between 0.005 inches to 0.009 inches (0.13 mm to 0.23 mm) would provide this additional supercooling.

[00109] Also for example, the actuator 110 can be configured for dispensing the hydrofluoroolefin cryoablation composition 112 without breaking up flow of the hydrofluoroolefin cryoablation composition 112, e.g. based on the actuator insert 130 comprising a smooth bore. Also for example, the actuator 110 can comprise a non- mechanical break up ( MBU) actuator, e.g. again based on the actuator insert 130

comprising a smooth bore.

[00110] The vapor tap 120 on the valve 106 can provide additional propellant force and control of mist spray particle size and spray consistency. A safety release valve can be disposed on the bottom of the cryoablation device 100 in order to control the bursting of the cryoablation device 100 if internal pressures get too high.

[00111] The aerosol-dispensing container 102 can be an aerosol can, an aerosol bottle, or other suitable aerosol-dispensing container. Accordingly, in some examples the aerosol-dispensing container 102 is selected from the group consisting of a stainless steel aerosol can, an aluminum aerosol can, a plastic aerosol can, a polymer-based aerosol can, an aerosol bottle, a glass aerosol bottle, and a pressure container.

[00112] With reference to FIG. 7, in accordance with some embodiments the cryoablation device 100 further comprises a dispensing straw 200 having a proximal end 202, a distal end 204, and a passage 206 therebetween.

[00113] The proximal end 202 of the dispensing straw 200 is configured for attachment to the actuator 110. For example, the proximal end 202 can be sized to provide a complementary fit, e.g. a friction fit, with an orifice 126 of the actuator 110, such that the proximal end 202 of the dispensing straw 200 can be inserted into the orifice 126 of the actuator 110, and held in place by the actuator 110, among other suitable configurations. As will be appreciated, the dispensing straw 200 can have a form such that the proximal end 202 and distal end 204 are identically sized and shaped.

[00114] The dispensing straw 200 is configured for receiving the

hydrofluoroolefin cryoablation composition 112 from the actuator 110 at the proximal end 202 of the dispensing straw 200 and dispensing the hydrofluoroolefin cryoablation composition 112 from the distal end 204 of the dispensing straw 200. For example, when the proximal end 202 of the dispensing straw 200 is inserted into an orifice 126 of the actuator 110, the hydrofluoroolefin cryoablation composition 112 can flow from the orifice 126 of the actuator 110 into the dispensing straw 200 at the proximal end 202 thereof, through the passage 206 of the dispensing straw 200, and out from the dispensing straw 200 at the distal end 204 thereof.

[00115] The dispensing straw 200 can be used to control rate and direction of flow the hydrofluoroolefin cryoablation 112 during dispensing from the aerosol-dispensing container 102.

[00116] In some examples, the dispensing straw 200 has a distal end 204 with an opening of between 0.005 inches to 0.009 inches (0.13 mm to 0.23 mm). Use of this distal end 204 opening size between 0.005 inches to 0.009 inches (0.13 mm to 0.23 mm) produces an additional supercooling effect on the hydrofluoroolefin cryoablation composition 112 as shown in TABLE 1. This additional supercooling of the hydrofluoroolefin cryoablation composition 112 varies between 5 °C to 25 °C lower than compared to use of a distal end opening of a conventional straw of 0.05 inches (1.27 mm) and a standard actuator orifice of 0.1 inch (2.54 mm) as shown in TABLE 1, providing an advantage relative to use of distal end opening of a conventional straw and standard actuator orifice. In addition to the supercooling, this distal end 204 opening between 0.005 inches to 0.009 inches (0.13 mm to 0.23 mm) provides the hydrofluoroolefin cryoablation composition 112 as a vapor stream, compared to a distal end opening of a conventional straw of 0.05 inches (1.27 mm) or a standard actuator orifice of 0.1 inch (2.54 mm), which provide the hydrofluoroolefin cryoablation composition 112 as a liquid stream. This vapor stream is advantageous for precise and delicate applications. It was not predictable that use of an opening size between 0.005 to 0.009 inches (0.13 mm to 0.23 mm) would provide this additional supercooling and vapor stream.

[00117] With reference to FIG. 8, in some examples of these embodiments, the cryoablation device 100 further comprises a dispensing bud 208 attached to the distal end 204 of the dispensing straw 200. The dispensing bud 208 can comprise a porous matrix. The dispensing bud 208 can be used to provide the hydrofluoroolefin cryoablation composition 112 at higher temperatures relative to dispensing directly from the aerosol-dispensing container 102, due to the dispensing bud 208 having the ability to slow the evaporation rate of the hydrofluoroolefin cryoablation composition 112. Thus, for example, the dispensing bud 208 can be used as an applicator of the hydrofluoroolefin cryoablation composition 112, as dispensed from the aerosol -dispensing container 102 and through the dispensing straw 200, to a tissue of a patient, at a higher temperature than if the hydrofluoroolefin cryoablation composition 112 were applied directly from the aerosol-dispensing container 102 to the tissue.

[00118] In accordance with some embodiments, the cryoablation device 100 dispenses the hydrofluoroolefin refrigerant composition 112 from a pressure of 30 psi (210 kPa) to 190 psi (1300 kPa) within the internal chamber 104 of the aerosol-dispensing container 102 to a pressure of an ambient external environment of 14 psi (97 kPa) or lower, thereby supercooling the hydrofluoroolefin cryoablation composition 112 below its boiling point through Joule-Thomson supercooling.

[00119] With reference to FIGS. 9-13, in accordance with some embodiments the cryoablation device 100 further comprises a cone 300 comprising a cone body 302 having (i) a proximal end 304 having a proximal opening 306 and (ii) a distal end 308 having a distal opening 310, and defining a reservoir 312 between the proximal opening 306 and the distal opening 310. The cone body 302 has a generally conical shape tapering toward the distal opening 308. For example, the cone body 302 can have a convex cone geometry 314 at or near the distal end 308. The cone 300 is configured for dispensing of the hydrofluoroolefin cryoablation composition 112 from the aerosol-dispensing container 102 into the reservoir 312. The cone 300 can have a height, from the proximal end 304 to the distal end 308, of, for example, 25 mm to 100 mm, although other heights also can be suitable.

[00120] Without wishing to be bound by theory, it is believed that dispensing the hydrofluoroolefin cryoablation composition 112 from a high pressure environment of the internal chamber 104 of the aerosol-dispensing container 102 of at least 30 psi (210 kPa), to a low pressure ambient environment external to the aerosol-dispensing container 102 of 14 psi (97 kPa) or lower, e.g. into the reservoir 312 of the cone 300, by rapidly expanding the hydrofluoroolefin cryoablation composition 112 through the valve 106, results in a Joule- Thomson supercooling effect of the hydrofluoroolefin cryoablation composition 112 below its boiling point, and that this provides enhanced cryoablation properties when used for the destruction of unwanted tissue. Again without wishing to be bound by theory, it is believed that the cryoablation device 100 is acting as a refrigeration cycle, whereby the aerosol propulsion from the aerosol-dispensing container 102 is acting to supercool the

hydrofluoroolefin cryoablation composition 112 by Joule-Thomson conservation of enthalpy, and, after the filling of the cone 300 with the hydrofluoroolefin cryoablation composition 112, the cone 300 is acting as the expansion valve and evaporator. The Joule-Thomson effect occurs when there is a rapid drop in pressure from the internal environment of at least 30 psi (210 kPa) to the external environment of 14 psi (97 kPa) or lower when the hydrofluoroolefin cryoablation composition 112 passes through the aerosol valve 106, resulting in supercooling of the hydrofluoroolefin cryoablation composition 112 below its boiling point. This is shown in TABLE 1 for various exemplary cryoablation compositions. Specifically, the pressure drop from the internal pressure of at least 30 psi (210 kPa) to the ambient environment external pressure, approximately 14 psi (97 kPa), induces the Joule-Thomson supercooling effect on the temperatures of hydrofluoroolefin cryoablation compositions 112 at least 20 °C below their expected boiling points (TABLE 1).

[00121] The formulation of the hydrofluoroolefin cryoablation composition 112 affects evaporation time when the hydrofluoroolefin cryoablation composition 112 is dispensed directly onto a surface or into a cone 300, for a variety of spray applications, as shown in TABLE 1. For advantageous topical use of the cryoablation device 100,

evaporation times within the cone 300 of 5-60 seconds are desired. Evaporation times of the hydrofluoroolefin cryoablation compositions 112 are shown to vary with the formulation and are shown to be advantageous with mixtures containing combinations of HFO-1234ze, HFO- 1234yf, HFC-125, HFC-32, and/or HFC-134a, and also HFC-143a. (TABLE 1).

[00122] For reference, the variety of spray applications tested include the following: direct spray on a horizontal surface, direct spray on a vertical surface, direct spray through straw 200 on a horizontal surface, direct spray through a straw 200 on a vertical surface, direct spray through a 0.007 inch (0.18 mm) opening, spray through a straw 200 into a cone 300 with a 5 second spray, spray through a straw 200 into a cone 300 by achieving a 0.25 inch (0.64 mm) fill-height, spray through a 0.007 inch (0.18 mm) opening into a cone with a 5 second spray, and spray through a bud 208 (TABLE 1). Typically, healthcare practitioners will utilize a straw, cone, and buds for treating tissue. The cone and the bud are meant to protect the surrounding tissue from becoming damaged. The direct sprays represent the testing necessary to evaluate the performance of the cryoablation devices.

[00123] Accordingly, in some examples of these embodiments, the

cryoablation device 100 generates a refrigeration cycle during use, based on the supercooling of the hydrofluoroolefin cryoablation composition 112 as it is rapidly expanded out of the aerosol valve 106 and moves from an internal environment having a pressure of 30 psi (210 kPa) to 190 psi (1300 kPa) within the internal chamber 104 of the aerosol-dispensing container 102 to an ambient external environment having a pressure of 14 psi (97 kPa) or lower.

[00124] Also in some examples of these embodiments, the cryoablation device 100 further generates a refrigeration cycle during use, based on the cone 300 acting as an expansion valve and evaporator to allow for evaporation of the hydrofluoroolefin

cryoablation composition 112 dispensed into the reservoir 312 of the cone 300, thereby removing heat energy from the distal end 308 of the cone 300.

[00125] With reference to FIGS. 9-13, various embodiments of the cone 300, having various geometries, are provided.

[00126] As shown in FIG. 9A-E, in some examples the proximal opening 306 of the cone 300 is larger than the distal opening 310 thereof. For example, for a cone 300 having a height of 25 mm to 100 mm, the proximal opening 306 can have a diameter of 17 mm to 50 mm, and the distal opening 310 can have a diameter of 3 mm to 16 mm, although other heights and/or diameters also can be suitable. Having a proximal opening 306 that is larger than the distal opening 310 makes the cone 300 suitable for dispensing of the hydrofluoroolefin cryoablation composition 112 directly from the aerosol-dispensing container 102, through the proximal opening 306, and into the reservoir 312, without need for use of a dispensing straw 200, while also being suitable for generating a refrigeration cycle during use, as discussed above.

[00127] As shown in FIG. 10A-E, in some examples the cone 300 further comprises surface-area enhancing features 318. In some examples the surface-area enhancing features 318 comprise two or more bulbous portions disposed in series from the proximal end 304 to the distal end 308. For example, the cone can have a geometry that contains a series of bulb geometries 320 separated by convex cone geometries 314 between the proximal opening 306 and distal opening 310 that resemble an Allihn condenser, which increase the surface area of the cone 300 (FIG. 10A-E). This can enhance the ability of the cone 300 to transfer heat and lower the temperature of tissue in contact with the cone 300.

[00128] As shown in FIG. 11A-E, in some examples the cone 300 has a grip enhancing feature 322. For example, the cone 300 can have one or more ergonomic indents 324 on the cone 300 that can provide an enhanced grip on the cone 300 by a practitioner. In some examples, the cone 300 also can further comprise heat transfer fins 316 extending outwardly from the cone body 302. For example, the cone 300 can further comprise heat transfer fins 316 disposed perpendicular to the surface of the tissue being treated and parallel with the axis of the cone 300 (FIG. 11A-E).

[00129] As shown in FIG. 12A-E, in some examples the cone 300 has a straw hole 326 configured to allow insertion of the distal end 204 of the dispensing straw 200 through for dispensing of the hydrofluoroolefin cryoablation composition 112 into the reservoir 312. For example, the straw hole 326 can be sized to provide a complementary fit, e.g. a friction fit, with the distal end 204, such that the distal end 204 of the dispensing straw 200 can be inserted into the straw hole 326 of the cone 300, and held in place by the cone 300, among other suitable configurations. Also for example, the cone 300 can have a straw hole 326 in the cone body 302 near the proximal opening 306 of the cone 300 to allow the dispensing straw 200 to attach to the cone 300, in order to allow dispensing of the

hydrofluoroolefin cryoablation composition 112 into the cone 300 in a controlled manner (FIG. 12A-E)

[00130] As shown in FIG. 13A-F, in some examples the cone 300 further comprises a proximal covering 328 configured to slow evaporation of the hydrofluoroolefin cryoablation composition 112 from the reservoir 312, the proximal covering 328 having a plurality of proximal covering vents 330 disposed therein, and the proximal covering 328 being disposed over, and thereby covering, the proximal opening 306, thus allowing release of the hydrofluoroolefin cryoablation composition 112 from the reservoir 312 as the hydrofluoroolefin cryoablation composition 112 evaporates. For example, the cone 300 can comprise a proximal covering 328 with a straw hole 326, as discussed above, and a plurality of venting holes 330, the overall effect being slowing of evaporation of the hydrofluoroolefin cryoablation composition 112 (FIG. 13A-F).

[00131] Without wishing to be bound by theory, it is believed that the cone 300 can provide greater protection to the surrounding healthy tissue, longer evaporation times, and enhanced heat transfer based on the geometries as shown in FIGS. 9-13.

[00132] As shown in FIGS. 14-22, in some embodiments the cryoablation device 100 comprises a dispensing straw 200 that is configured for attachment to the actuator 110 of the aerosol-dispensing container 102 based on the dispensing straw 200 comprising a tab 210, and the actuator 110 having a groove 144, with the groove 144 being configured to receive the tab 210, as well as based on the proximal end 202 of the dispensing straw 200 being configured for attachment to the actuator 110. As noted above, the proximal end 202 of the dispensing straw 200 is configured for attachment to the actuator 110, for example based on the proximal end 202 being sized to provide a complementary fit, e.g. a friction fit, with the orifice 126 of the actuator 110, such that the proximal end 202 of the dispensing straw 200 can be inserted into the orifice 126 of the actuator 110, and held in place by the actuator 110, among other suitable configurations. In accordance with the embodiments of FIGS. 14- 22, the dispensing straw 200 can also comprise a tab 210. As shown in FIGS. 19-22, the tab 210 can be positioned at or near the proximal end 202 of the dispensing straw 200. Also in accordance with these embodiments, as shown in FIGS. 15-18, the actuator 110 can have a groove 144. The groove 144 can be positioned adjacent the orifice 126. As shown in FIGS. 27-29, like the proximal end 202 of the dispensing straw 200 and the orifice 126 of the actuator 110, the groove 144 of the dispensing straw 200 can be configured for attachment to the actuator 110 based on the groove 144 being configured to receive the tab 210, for example based on the tab 210 being sized to provide a complementary fit, e.g. a friction fit, with the groove 144 of the actuator 110, such that the tab 210 of the dispensing straw 200 can be inserted into the groove 144 of the actuator 110, and held in place by the actuator 110, among other suitable configurations. As the proximal end 202 of the dispensing straw 200 is inserted into the orifice 126 of the actuator 110, the tab 210 of the dispensing straw 200 also is inserted into the groove 144 of the actuator 110. The dispensing straw 200 comprising the tab 210 is thus held in place both at the proximal end 202 and the tab 210, providing additional stability for maintaining attachment of the dispensing straw 200 to the actuator 100 relative to attachment in the absence of the tab 210 and the groove 144.

[00133] In accordance with these embodiments, the dispensing straw 200 is configured for receiving the hydrofluoroolefin cryoablation composition 112 from the actuator 110 at the proximal end 202 of the dispensing straw 200 and dispensing the hydrofluoroolefin cryoablation composition 112 from the distal end 204 of the dispensing straw 200, as discussed above. The dispensing straw 200 can be used to control rate and direction of flow of the hydrofluoroolefin cryoablation composition 112 during dispensing from the aerosol-dispensing container 102, also as discussed above.

[00134] As best seen in FIG. 21 and FIG. 22, in some examples of these embodiments, the dispensing straw 200 has a distal end 204 with an opening 212 of between 0.005 inches to 0.009 inches (0.13 mm to 0.23 mm), as discussed above, which produces an additional supercooling effect on the hydrofluoroolefin cryoablation composition 112, and provides the hydrofluoroolefin cryoablation composition 112 as a vapor stream, also as discussed above. As shown in FIG. 21 and FIG. 22, the opening 212 can have an inner diameter that is smaller than an inner diameter of the passage 206 of the dispensing straw 202. As also shown, the opening 212 can have an inner diameter that decreases proximally from the distal end 204 of the dispensing straw 202, to reach an inner diameter of 0.005 inches to 0.009 inches (0.13 mm to 0.23 mm). The additional stability for maintaining attachment of the dispensing straw 200 to the actuator 100, based on the dispensing straw 200 being held in place both at the proximal end 202 and the tab 210, can decrease the likelihood of the dispensing straw 200 being expelled from the actuator 100 during dispensing of the hydrofluoroolefin cryoablation composition 112 from the dispensing straw 200.

[00135] As shown in FIG. 14 and FIGS. 23-26, in some examples of these embodiments, a dispensing straw 200 comprising a dispensing bud 208 attached to the distal end 204 of the dispensing straw 200 also can be attached to an aerosol-dispensing container 102 comprising an actuator 110 having a groove 144. As discussed above, a dispensing bud 208 can be used to provide the hydrofluoroolefin cryoablation composition 112 at higher temperatures relative to dispensing directly from the aerosol-dispensing container 102, due to the dispensing bud 208 having the ability to slow the evaporation rate of the

hydrofluoroolefin cryoablation composition 112. In some examples of these embodiments, as shown in FIGS. 30-32, the proximal end 202 of a dispensing straw 200 comprising a dispensing bud 208 attached to the distal end 204 of the dispensing straw 200 is configured for attachment to the actuator 110, for example based on the proximal end 202 being sized to provide a complementary fit, e.g. a friction fit, with the orifice 126 of the actuator 110, such that the proximal end 202 of the dispensing straw 200 can be inserted into the orifice 126 of the actuator 110, and held in place by the actuator 110, among other suitable configurations. As shown in FIGS. 30-32, the dispensing straw 200 can be provided without a tab 210.

[00136] Also disclosed is a method for treating a tissue of a patient by use of the cryoablation device 100.

[00137] The cryoablation device 100 is as described above. Accordingly, the cryoablation device 100 comprises (a) an aerosol-dispensing container 102 comprising an internal chamber 104, a valve 106, a dispensing hole 108, and an actuator 110. The cryoablation device 100 also comprises (b) a hydrofluoroolefin cryoablation composition 112 comprising refrigerant trans-1, 3,3, 3-tetrafluoroprop-l-ene (HFO-1234ze) at 5% to 50% (weight/weight) and refrigerant 2,3,3,3-tetrafluoropropene (HFO-1234yf) at 15% to 50% (weight/weight). The hydrofluoroolefin cryoablation composition 112 is stored within the internal chamber 104. The aerosol-dispensing container 102 is configured so that depressing the actuator 110 reversibly opens the valve 106 to allow the hydrofluoroolefin cryoablation composition 112 to flow from the internal chamber 104, past the valve 106, and through the dispensing hole 108, thereby dispensing the hydrofluoroolefin cryoablation composition 112 from the aerosol-dispensing container 102.

[00138] In accordance with some embodiments, the hydrofluoroolefin cryoablation composition 112 further comprises one or more refrigerants, in addition to HFO- 1234ze and HFO-1234yf, at 0.1% to 80% (weight/weight), as described above. Also, in accordance with some embodiments the cryoablation device 100 further comprises a dispensing straw 200 having a proximal end 202, a distal end 204, and a passage 206

therebetween, as described above. Also, in some examples of these embodiments, the cryoablation device 100 further comprises a dispensing bud 208 attached to the distal end 204 of the dispensing straw 200, as described above. Also, in accordance with some embodiments the cryoablation device 100 further comprises a cone 300 comprising a cone body 302 having (i) a proximal end 304 having a proximal opening 306 and (ii) a distal end 308 having a distal opening 310, and defining a reservoir 312 between the proximal opening 306 and the distal opening 310, also as described above.

[00139] The method comprises a step of dispensing the hydrofluoroolefin cryoablation composition 112 from the cryoablation device 100 onto the tissue of the patient. The dispensing can be carried out as described above. Accordingly, in some examples the hydrofluoroolefin cryoablation composition 112 is dispensed directly from the aerosol- dispensing container 102 onto the tissue of the patient. Also in some examples the

hydrofluoroolefin cryoablation composition 112 is dispensed from the aerosol-dispensing container 102, through a dispensing straw 200, and onto the tissue of the patient. Also in some examples the hydrofluoroolefin cryoablation composition 112 is dispensed from the aerosol-dispensing container 102, through a dispensing straw 200, into a dispensing bud 208, with the dispensing bud 208 then being placed in contact with the tissue of the patient. Also in some examples the hydrofluoroolefin cryoablation composition 112 is dispensed from the aerosol-dispensing container 102, into a cone 300, and onto the tissue of the patient, with the cone 300 being in contact with the tissue of the patient. Also in some examples the hydrofluoroolefin cryoablation composition 112 is dispensed from the aerosol-dispensing container 102, through a dispensing straw 200, into a cone 300, and onto the tissue of the patient, with the cone 300 being in contact with the tissue of the patient.

[00140] In some examples, the patient comprises a human or an animal. For example, the patient can be a human in need of treatment of a tissue by cryoablation. Also for example, the patient can be an animal in need of treatment of a tissue by cryoablation. [00141] In some examples, the tissue is an unwanted tissue and/or a diseased tissue.

[00142] In some examples the treating comprises cryoablation and/or treatment of one or more of actinic keratosis, genital warts, lentigo, mulluscum contagiosum, seborrheic keratosis, skin tags, verruca plantaris, verruca vulgaris, verruca plana, age spots, benign lesions, anal lesions, penile lesions, vulva lesions, angiomas, granuloma annulare, porokeratosis plantaris, keratoacanthoma, chondrodermatitis, epithelial nevus, leukoplakia, granuloma pyogenicum, pyogenic granuloma, small keloids, dermatofibroma, acrochordon, or plantar warts.

[00143] In some examples, the tissue of the patient is contacted with the hydrofluoroolefin cryoablation composition 112 for a freeze time of 5-60 seconds following the dispensing.

[00144] In some of these examples the hydrofluoroolefin cryoablation composition 112 is dispensed for 1-10 seconds from the aerosol-dispensing container 102, through a dispensing straw 200, into a cone 300, and onto the tissue of the patient, and then is allowed to evaporate for 10 to 60 seconds while the hydrofluoroolefin cryoablation composition 112 remains in contact with the tissue of the patient. In these examples, the cone 300 becomes filled with the hydrofluoroolefin cryoablation composition 112, and the hydrofluoroolefin cryoablation composition 112 contacts the tissue of the patient, during the dispensing. The hydrofluoroolefin cryoablation composition 112 also evaporates from the cone 300. The hydrofluoroolefin cryoablation composition 112 thereby achieves supercooling and tissue destruction.

[00145] Also in some of these examples, the hydrofluoroolefin cryoablation composition 112 is dispensed for 2-10 seconds from the aerosol-dispensing container 102, through a dispensing straw 200, and into a dispensing bud 208, while the dispensing bud 208 is not in contact with the tissue of the patient. The dispensing bud 208 is then placed in contact with the tissue of the patient for 10-60 seconds. In these examples, the dispensing bud 208 becomes filled with the hydrofluoroolefin cryoablation composition 112 during the dispensing. Following the dispensing, the hydrofluoroolefin cryoablation composition 112 also evaporates from the dispensing bud 208, and the dispensing bud 208 contacts the tissue of the patient. The hydrofluoroolefin cryoablation composition 112 thereby achieves supercooling and tissue destruction.

[00146] In some examples, the dispensing generates a refrigeration cycle, as discussed above. [00147] With reference to FIG. 33, in some examples, the hydrofluoroolefin cryoablation composition 112 is dispensed onto the patient's tissue through a hole 402 in a spray-protecting bandage 400.

[00148] While this invention has been described in conjunction with the specific embodiments outlined above, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, the preferred embodiments of the invention as set forth above are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the invention.

INDUSTRIAL APPLICABILITY

[00149] The devices, compositions, and methods disclosed herein are useful for cryoablation of tissues of patients, e.g. human and/or animal patients.

TABLE 1 : Surface temperatures measured by a K-type thermocouple with various cryoablation compositions and spray applications compared to their theoretical boiling points.

* N.D.: Not determined.