Methods of predicting dose of drug and program for predicting dose of drug

• US 7,925,520 B2
• Filed: 01/16/2008
• Issued: 04/12/2011
• Est. Priority Date: 01/16/2007
• Status: Expired due to Fees

• Current Assignee: Transcutaneous Technologies, Inc.
• Original Assignee: TTI Ellebeau, Inc. (Ease Asset Management Ltd.)
• Inventors: Nakamura, Naoki, Kogure, Kentaro, Kigasawa, Kaoru
• Primary Examiner(s): Sirmons; Kevin C
• Assistant Examiner(s): OSINSKI, BRADLEY JAMES
• Application Number:
  US12/015,449
• Publication Number:
  US 20080208106A1
• Time in Patent Office: 1,182 Days
• Field of Search: 604/890.1, 604/20, 604/21, 604/501, 705/2
• US Class Current: 705/2
• CPC Class Codes: A61N 1/0428 Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
• CPC Class Codes: A61N 1/0444 Membrane
• CPC Class Codes: A61N 1/0448 Drug reservoir
• CPC Class Codes: 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
• CPC Class Codes: G16H 20/10 relating to drugs or medications, e.g. for ensuring correct administration to patients

Abstract

A migration M of a drug ion in a membrane type iontophoresis device for administering the drug ion through a first ion exchange membrane is predicted on the basis of a migration C of the drug ion from the first ion exchange membrane to the outside of the device in the case where a voltage is applied to an electrode by using the device under such a condition that the first ion exchange membrane is not brought into contact with the skin of a living organism and a migration R of the drug ion to a liposome caused by mixing a liposome solution having a predetermined concentration and a drug solution containing a predetermined concentration of the drug ion.

Claims

1. A method of determining by a computer having at least one processor and at least one non-transitory processor-readable medium to store instructions executable by the at least one processor an amount of drug deliverable to a biological subject by an iontophoretic delivery device having a drug holding portion for holding a drug solution including drug ions of a first polarity, an electrode coupled to the drug holding portion and operable to apply an electrical potential of the first polarity to the drug solution held in the drug solution holding portion, and a first ion exchange membrane, having an exchange group of the first polarity, in contact with a front surface side of the drug solution holding portion, the method comprising:

determining a first drug migration parameter indicative of the migration of an amount of drug ions from the first ion exchange membrane to an outermost front surface side of the iontophoretic delivery device;

determining a second drug migration parameter indicative of the migration of an amount of the drug ions migrated from a volume of a drug ion solution to a plurality of liposomes in a volume of a liposome suspension after contacting the volume of the drug ion solution to the volume of the liposome suspension; and

determining by the at least one processor at least one of an iontophoretic drug ion delivery amount, iontophoretic drug ion delivery rate, an efficiency, and a dose based on the determined first drug migration parameter and the determined second drug migration parameter;

wherein the values of the first and the second drug migration parameters are such as to yield a finite value for at least one of an iontophoretic drug ion delivery amount, an iontophoretic drug ion delivery rate, an efficiency, and a dose.

2. The method according to claim 1, wherein determining the first drug migration parameter includes contacting a volume of physiological salt solution with the first ion exchange membrane, applying an electrical potential of the first polarity to the electrode for a time period, and measuring the amount of the drug ion that migrates from the drug solution holding portion to the volume of physiological salt solution.

3. The method according to claim 1, wherein determining the first drug migration parameter includes contacting a volume of physiological salt solution with the iontophoretic delivery including a 6.25 mM drug solution held in the drug holding portion, supplying a current of about 0.94 mA to the electrode for a period of about 60 minutes, and measuring the amount of the drug ion that migrated from the drug solution holding portion to the volume of physiological salt solution.

4. The method according to claim 1, wherein determining the second drug migration parameter includes mixing a one-to-one by volume mixture of a suspension of egg phosphatidylcholine liposomes with a drug solution, incubating the mixture for a time period, and measuring the amount of the drug ion carrier by the egg phosphatidylcholine liposomes.

5. The method according to claim 1, wherein determining the second drug migration parameter includes mixing a one-to-one by volume mixture of a suspension of liposomes with a drug solution, incubating the mixture for a time period, and measuring the amount of the drug ion carried by the liposomes.

6. The method according to claim 1, wherein determining the second drug migration parameter includes mixing a one-to-one by volume mixture of a 20 mM suspension of egg phosphatidylcholine liposomes with a 3 mM drug solution, incubating the mixture at about 37°

C. for a time period of about 18 hours, and measuring the amount of the drug ion carried by the egg phosphatidylcholine liposomes.

7. The method according to claim 1, wherein determining the second drug migration parameter includes mixing in a one-to-one volume ratio of a 20 mM suspension of egg phosphatidylcholine liposomes having an average particle diameter ranging from about 290 nm to about 490 nm with a 3 mM drug solution, incubating the mixture at 37°

C. for a time period of about 18 hours, and measuring the amount of the drug ion carried by the egg phosphatidylcholine liposomes.

8. At least one computer readable storage medium comprising instructions that, when executed on a computer, execute a method for determining an amount of drug deliverable to a biological subject by an iontophoretic delivery device having a drug holding portion for holding a drug solution including drug ions of a first polarity, an electrode coupled to the drug holding portion and operable to apply an electrical potential of the first polarity to the drug solution held in the drug solution holding portion, and a first ion exchange membrane, having an exchange group of the first polarity, in contact with a front surface side of the drug solution holding portion, the method comprising:

determining a first drug migration value indicative of the migration of an amount of drug ions from the first ion exchange membrane to an outermost surface side of the iontophoretic delivery device;

determining a second drug migration value indicative of the migration of an amount of the drug ions migrated from a volume of the drug ion solution to a plurality of liposomes in a volume of a liposome suspension after contacting the volume of the drug ion solution to the volume of the liposome suspension; and

determining at least one of an iontophoretic drug ion delivery amount, iontophoretic drug ion delivery rate, an efficiency, and a dose based on the determined first drug migration value and the determined second drug migration value;

wherein the values of the first and second drug migration parameters are such as to yield a finite value for the at least one of an iontophoretic drug ion delivery amount, an iontophoretic drug ion delivery rate, an efficiency, and a dose.

9. A method of predicting by a computer having at least one processor and at least one non-transitory processor-readable medium to store instructions executable by the at least one processor a migration M of a drug ion having a first polarity to an inside of a skin of a living organism via iontophoresis using an iontophoresis device having a drug solution holding portion for holding a drug solution containing the drug ion, a working side electrode for applying a voltage having the first polarity to the drug solution of the drug solution holding portion, and a first ion exchange membrane having the first polarity and placed in contact with the drug solution of the drug solution holding portion on a front surface side of the drug solution holding portion, the method comprising:

determining a migration C of the drug ion from the first ion exchange membrane to an outside of the iontophoresis device in a case where a voltage is applied to the working side electrode in the device under such a condition that the first ion exchange membrane is not brought into contact with the skin of the living organism;

determining a migration R of the drug ion to a liposome in a case where a liposome solution having a predetermined concentration and the drug solution containing a

deriving by the at least one processor a migration M of the drug ion to the inside of the skin of the living organism based on the determined migration C and migration R;

wherein the values of the migration C and migration R are such as to yield a finite value for the migration M.

10. The method according to claim 9 wherein determining the migration C includes contacting the first ion exchange membrane to a volume of physiological salt solution, applying a voltage to the working side electrode of the iontophoresis device, and measuring the amount of the drug ion that migrated from the first ion exchange membrane to the volume of physiological salt solution.

11. The method according to claim 9 wherein determining the migration R includes contacting a liposome solution having the predetermined liposome concentration to the drug solution containing the predetermined concentration of the drug ion and measuring the amount of the drug ion that migrated from the drug solution containing the predetermined concentration of the drug ion to liposomes in the liposome solution having the predetermined liposome concentration.

12. The method according to claim 9 wherein deriving the migration M of the drug ion to the inside of the skin of the living organism based on the determined migration C and migration R includes deriving the migration M of the drug ion on the basis of the following formula (1):

Log(M/C)=A₁ Log R+A₂ 

 

(1)

where C represents the migration of the drug ion from the first ion exchange membrane to the outside of the iontophoresis device in the case where a voltage is applied to the working side electrode in the iontophoresis device under such a condition that the first ion exchange membrane is not brought into contact with the skin of the living organism, R represents the migration of the drug ion to the liposome in the case where the liposome solution having the predetermined concentration and the drug solution containing the predetermined concentration of the drug ion are mixed, A_l and A₂ each represent a constant, and C, R and M/C are non-zero, finite values.

13. The method according to claim 9 wherein the iontophoresis device further includes:

a second ion exchange membrane having second polarity, the second ion exchange membrane being placed between the working side electrode and the drug solution holding portion; and

an electrolyte solution holding portion for holding an electrolyte solution, the electrolyte solution holding portion being placed between the working side electrode and the second ion exchange membrane.

14. A computer system, comprising:

a memory; and

a processing unit operable to execute a process of predicting a migration M of a drug ion having a first polarity to an inside of a skin of a living organism in an iontophoresis device having a drug solution holding portion for holding a drug solution containing the drug ion, a working side electrode for applying a voltage having the first polarity to the drug solution of the drug solution holding portion, and a first ion exchange membrane having the first polarity and placed in contact with the drug solution of the drug solution holding portion on a front surface side of the drug solution holding portion in a case where a voltage is applied to the working side electrode in a state where the first ion exchange membrane is brought into contact with the skin of the living organism, by;

determining a migration C of the drug ion from the first ion exchange membrane to an outside of the iontophoresis device in a case where a voltage is applied to the working side electrode in the device under such a condition that the first ion exchange membrane is not brought into contact with the skin of the living organism;

determining a migration R of the drug ion to a liposome in a case where a liposome solution having a predetermined concentration and the drug solution containing a predetermined concentration of the drug ion are mixed; and

determining the migration M of the drug ion to the inside of the skin of the living organism in the iontophoresis device based on the determined migration C and the determined migration R;

wherein the values of the migration C and the migration R are such as to yield a finite value for the migration M.