# US 5,700,481 A · Transdermal drug delivery process > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,700,481 A - Document ID: US5700481A - Status: Granted - Kind: A - Application number: 08/614,376 - Filed: 1996-03-12 - Granted: 1997-12-23 - Earliest claimed: 1995-03-17 - Assignees: Takeda Chemical Industries, Ltd.; Advance Co., Ltd.; Teikoku Hormone Mfg. Co., Ltd. - Inventors: Katsumi Iga; Shigeo Yanai; Keiichiro Okabe; Masaki Itoh - Web page: https://patentgrep.com/patent/US5700481A ## CPC - A61N 1/044: {Shape of the electrode} - A61N 1/0436: {Material of the electrode} - A61N 1/30: Apparatus for iontophoresis, {i.e. transfer of media in ionic state by an electromotoric force into the body}, or cataphoresis - A61N 1/325: {for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body (electrodes for external use A61N1/0428)} - A61N 1/0448: {Drug reservoir} - A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B) ## Abstract A calcitonin, its derivative or a salt thereof is transdermally delivered by iontophoresis in which a substantially constant voltage in the range of 3 to 20 V is applied at an electric current of 0.05 to 0.5 mA/cm.sup.2. In this process, the calcitonin can be delivered transdermally with a higher absorptivity by applying a higher voltage for a short period (at a voltage of about 6 to 14 V for about 5 to 15 minutes) in the initial stage of the voltage application, and then applying a lower voltage for a long period (at a voltage of about 3 to 9 V for about 30 to 40 minutes). ## Claims ### Claim 1 A transdermal drug delivery process by iontophoresis for a calcitonin, its derivative having similar function or activity to the calcitonin or a salt thereof, which comprises the step of applying a substantially constant voltage within the range of 3 to 20 V at a current density of 0.05 to 0.5 mA/cm.sup.2, wherein the process comprises: (1) at least one cycle comprising: (1a) a precedent voltage application step of applying a substantially constant voltage for 1 to 30 minutes, and (1b) a succeeding voltage application step of applying a substantially constant voltage, which voltage is lower than the applied voltage of the precedent voltage application step (1a), for 15 to 100 minutes, or (2) at least one cycle comprising; (2a) a voltage application step of applying a substantially constant voltage in the range of 4 to 15 V for 1 to 30 minutes. (2b) a step of interrupting the voltage application for 1 to 30 minutes, and (2c) a voltage application step of applying a substantially constant voltage, which voltage is substantially the same as the applied voltage of the voltage application step (2a) and in the range of 4 to 15 V, for 1 to 30 minutes. where the current density in the voltage application steps (2a) and (2c) is maintained at 0.08 to 0.3 mA/cm.sup.2. ### Claim 2 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the voltage in the voltage application steps (1a) and (1b) is 4 to 15 V. ### Claim 3 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the current density in the voltage application steps (1a) and (1b) is 0.08 to 0.5 mA/cm.sup.2. ### Claim 4 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the current density in the voltage application steps (1a) and (1b) is 0.08 to 0.3 mA/cm.sup.2. ### Claim 5 (depends on 1) A transdermal drug delivery process according to claim 1, wherein a substantially constant voltage within the range of 4 to 15 V is applied at a current density of 0.08 to 0.3 mA/cm.sup.2 in the voltage application steps (1a) and (1b). ### Claim 6 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the process comprises the steps of: (1a) a precedent voltage application step of applying a substantially constant voltage in the range of 5 to 15 V for 1 to 30 minutes, and (1b) a succeeding voltage application step of applying a substantially constant voltage, which voltage is lower than the applied voltage of the precedent voltage application step and in the range of 1 to 10 V, for 15 to 100 minutes. ### Claim 7 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the applied voltage of the precedent voltage application step (1a) is 6 to 14 V. ### Claim 8 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the voltage application period of the precedent voltage application step (1a) is 5 to 20 minutes. ### Claim 9 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the applied voltage of the succeeding voltage application step (1b) is 3 to 9 V. ### Claim 10 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the voltage application period of the succeeding voltage application step (1b) is 20 to 60 minutes. ### Claim 11 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the process comprises the steps of; (1a) a precedent voltage application step of applying a substantially constant voltage in the range of 6 to 14 V for 5 to 15 minutes, and (1b) a succeeding voltage application step of applying a substantially constant voltage, which voltage is lower than the applied voltage of the precedent voltage application step (1a) and in the range of 3 to 9 V, for 30 to 40 minutes. ### Claim 12 (depends on 1) A transdermal drug delivery process according to claim 1, wherein a direct-current pulse voltage with a frequency of 0.1 to 200 kHz is applied. ### Claim 13 (depends on 1) A transdermal drug delivery process according to claim 1, wherein a direct-current pulse voltage with a frequency of 1 to 100 kHz is applied. ### Claim 14 (depends on 12) A transdermal drug delivery process according to claim 12, wherein the ratio of the voltage application period per cycle in the direct-current pulse voltage is 10 to 90%. ### Claim 15 (depends on 1) A transdermal drug delivery process according to claim 1, wherein a substantially constant voltage in the range of 4 to 15 V is applied at a current density of 0.08 to 0.3 mA/cm.sup.2 with the use of a direct-current pulse voltage having a frequency of 1 to 100 kHz and a ratio of a voltage applying period per cycle of 10 to 70%. ### Claim 16 (depends on 1) A transdermal drug delivery process according to claim 1, wherein a substantially constant voltage in the range of 6 to 14 V is applied for 5 to 15 minutes in the precedent voltage application step (1a), and subsequently a substantially constant voltage in the range of 3 to 9 V is applied for 30 to 40 minutes in the succeeding voltage application step (1b), with the use of a direct-current pulse voltage having a frequency of 1 to 100 kHz and a ratio of voltage application period per cycle of 10 to 70% and with maintaining a current density at 0.08 to 0.3 mA/cm.sup.2. ### Claim 17 (depends on 1) A transdermal drug delivery process according to claim 1, wherein a substantially constant voltage in the range of 6 to 14 V is applied for 5 to 15 minutes in the precedent voltage application step (1a), and then a substantially constant voltage in the range of 3 to 9 V is applied for 30 to 40 minutes in the succeeding voltage application step (1b), with a proviso that a direct-current pulse voltage having a frequency of 1 to 50 kHz and a ratio of a voltage applying period per cycle of 10 to 70% is used and the skin contact area of the iontophoresis is 1 to 50 cm.sup.2. ### Claim 18 (depends on 1) A transdermal drug delivery process according to claim 1, wherein wherein the process comprises (1) the steps of; (1a) the precedent voltage application step, (1c) a step of interrupting the voltage application for 1 to 30 minutes, and (1b) the succeeding voltage application step. ### Claim 19 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the process comprises (2) at least one cycle comprising; (2a) a voltage application step of applying a substantially constant voltages in the range of 6 to 14 V for 1 to 30 minutes, where the voltage is a direct-current pulse voltage with a frequency of 1 to 50 kHz having a ratio of a voltage applying period per cycle of 10 to 70%, and the area to be contacted by a skin in the iontophoresis is 1 to 50 cm.sup.2 and the current density is maintained at 0.1 to 0.3 mA/cm.sup.2, (2b) a step of interrupting the voltage application for 1 to 30 minutes, and (2c) a voltage application step of applying a substantially constant voltage, which voltage is the same as the applied voltage of the voltage application step (2a) and in the range of 6 to 14 V for 1 to 30 minutes, where the voltage is a direct-current pulse voltage with a frequency of 1 to 50 kHz having a ratio of a voltage applying period per cycle of 10 to 70%, and the area to be contacted by a skin in the iontophoresis is 1 to 50 cm.sup.2 and the current density is maintained at 0.1 to 0.3 mA/cm.sup.2. ### Claim 20 An apparatus for iontophoresis which is provided with: (i) an applicator comprising (ia) an electrode applicable with a direct-current voltage and (ib) an interface conductible to the electrode, capable of contacting a skin, possessing a calcitonin, its derivative having similar function or activity to the calcitonin or a salt thereof, transmittablly and capable of being supplied with a liquid for dissolving the calcitonin, its derivative or a salt thereof, (ii) an electric power supply for applying a direct-current voltage to the electrode, and (iii) a voltage stabilizing means for applying a substantially constant direct-current voltage in the range of 3 to 20 V supplied from the electric power supply to the electrode with maintaining a current density of 0.05 to 0.5 mA/cm.sup.2. ### Claim 21 A method of applying a voltage for enhancing transdermal absorption of a calcitonin with the use of an applicator comprising an electrode applicable with a direct-current voltage, and an interface conductible with the electrode, capable of contacting a skin, possessing a calcitonin, its derivative having similar function or activity to the calcitonin or a salt thereof transmittablly and capable of being supplied with a liquid for dissolving the calcitonin, its derivative or a salt thereof, wherein a substantially constant direct-current voltage in the range of 3 to 20 V is applied to the electrode with maintaining a current density at 0.05 to 0.5 mA/cm.sup.2, and wherein said process comprises: (1) at least one cycle comprising; (1a) a precedent voltage application step of applying a substantially constant voltage for 1 to 30 minutes, and (1b) a succeeding voltage application step of applying a substantially constant voltage, which voltage is lower than the applied voltage of the precedent voltage application step (1a), for 15 to 100 minutes, or (2) at least one cycle comprising; (2a) a voltage application step of applying a substantially constant voltage in the range of 4 to 15 V for 1 to 30 minutes, (2b) a step of interrupting the voltage application for 1 to 30 minutes, and (2c) a voltage application step of applying a substantially constant voltage, which voltage is substantially the same as the applied voltage of the voltage application step (2a) and in the range of 4 to 15 V, for 1 to 30 minutes, where the current density in the voltage application steps (2a) and (2c) is maintained at 0.08 to 0.3 mA/cm.sup.2. ### Claim 22 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the calcitonin derivative is a compound shown by the following formula (II) ##STR2## wherein X represents 2-aminosberic acid. ### Claim 23 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the voltage application steps (1a) and (1b) are conducted continuously, or intermittently with an interval of 1 second to 60 minutes. ### Claim 24 (depends on 1) A transdermal drug delivery process according to claim 1, wherein the process comprises a plurality of cycles comprising; (1a) a precedent voltage application step of applying a substantially constant voltage in the range of 5 to 15 V for 1 to 30 minutes, and (1b) a succeeding voltage application step of applying a substantially constant voltage, which voltage is lower than the applied voltage of the precedent voltage application step (1a) and in the range of 1 to 12 V, for 15 to 100 minutes. ### Claim 25 (depends on 20) An apparatus for iontophoresis according to claim 20, wherein the interface (ib) is treated with an adsorption-inhibitor. ### Claim 26 (depends on 25) An apparatus for iontophoresis according to claim 25, wherein the adsorption-inhibitor is a serum albumin or benzalkonium chloride.