Methods for inhibiting decrease in transdermal drug flux by inhibition of pathway closure

• US 7,438,926 B2
• Filed: 09/08/2001
• Issued: 10/21/2008
• Est. Priority Date: 09/08/2000
• Status: Expired due to Fees

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Cormier, Michel, Daddona, Peter, Matriano, James, Johnson, Juanita, Lin, Wei Qi
• Primary Examiner(s): GITOMER, RALPH J
• Application Number:
  US09/950,436
• Publication Number:
  US 20020102292A1
• Time in Patent Office: 2,600 Days
• Field of Search: 435/4, 435/975, 435/283.1, 424/449, 514/947
• US Class Current: 424/449
• CPC Class Codes: A61K 9/0021 Intradermal administration, e.g. through microneedle arrays, needleless injectors mechanical aspects A61M
• CPC Class Codes: A61K 9/703 characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
• CPC Class Codes: A61K 9/7084 Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches

Abstract

This invention relates to a method for inhibiting a decrease in the transdermal flux of an agent that is being transdermally delivered or sampled over a prolonged period of time wherein the delivery or sampling involves disrupting at least the stratum corneum layer of the skin to form pathways through which the agent passes. The desired result is achieved by co-delivering or co-sampling the agent with an amount of at least one anti-healing agent wherein the amount of the anti-healing agent is effective in inhibiting a decrease in the agent transdermal flux compared to when the delivery or sampling of the agent is done under substantially identical conditions except in the absence of the anti-healing agent(s).

Claims

1. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

2. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising one or more stratum corneum piercing microprotrusion which are capable of forming microslits in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

3. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent, and wherein the anti-healing agent is selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit cellular migration, and osmotic agents and mixtures thereof;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

4. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first agent under substantially identical conditions except in the absence of said at least one anti-healing agent, said anti-healing agent is selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit cellular migration, and osmotic agents and mixtures thereof and wherein said anticoagulant is selected from the group consisting of heparin having a molecular weight from 3000 to 12,000 daltons, pentosan polysulfate, citric acid, citrate salts, EDTA, and dextrans having molecular weight from 2000 to 10,000 daltons, aspirin and lyapolate sodium;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

5. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent, wherein the anti-healing agent is selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit cellular migration, and osmotic agents and mixtures thereof; and

wherein said anti-inflammatory agent is selected from the group consisting of hydrocortisone sodium phosphate, betamethasone sodium phosphate, and triamcinolone sodium phosphate;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

6. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent, wherein the anti-healing agent is selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit cellular migration, and osmotic agents and mixtures thereof; and

wherein the agent that inhibits cellular migration is laminin;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

7. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent, wherein the anti-healing agent is selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit cellular migration, and osmotic agents and mixtures thereof; and

wherein said osmotic agent is a biologically compatible salt of an osmotic agent;

-wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

8. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent, wherein said anti-healing agent is selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit cellular migration, and osmotic agents and mixtures thereof; and

wherein said osmotic agent, in solution, generates an osmotic pressure greater than about 2,000 kilopascals at 20°

C.;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

9. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent; and

wherein the first therapeutic agent is a therapeutic agent and said device delivers said therapeutic agent transdermally into the skin;

-wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

10. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first agent under substantially identical conditions except in the absence of said at least one anti-healing agent; and

wherein the first agent is a therapeutic agent and said device delivers said therapeutic agent transdermally into the skin, and wherein the agent comprises a macromolecular agent;

-wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

11. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first agent under substantially identical conditions except in the absence of said at least one anti-healing agent; and

wherein the first agent is a therapeutic agent and said device delivers said therapeutic agent transdermally into the skin, and wherein the macromolecular agent is selected from the group consisting of polypeptides, proteins, oligonucleotides, nucleic acids and polysaccharides;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

12. A mechanical device for causing transdermal flux of an agent comprising:

a patch comprising a microprotrusion array comprising one or more stratum corneum-piercing microprotrusions which are capable of disrupting the skin by the formation of microslits in the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first agent under substantially identical conditions except in the absence of said at least one anti-healing agent; and

wherein the first agent is a therapeutic agent and said device delivers said therapeutic agent transdermally into the skin;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

13. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first agent under substantially identical conditions except in the absence of said at least one anti-healing agent; and

wherein the first therapeutic agent is a body analyte that is transdermally sampled;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

14. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent; and

wherein the first agent is the body analyte glucose that is transdermally sampled;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

15. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array comprising one or more stratum corneum-piercing microprotrusions which are capable of disrupting the skin by the formation of one or more microslits in the stratum corneum of the skin which form one or more pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent; and

wherein the first therapeutic agent is a body analyte that is transdermally sampled;

-wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

16. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in Therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent; and

wherein the anti-healing agent is delivered;

(a) before any transdermal flux of the first agent;

(b) before and during transdermal flux of the first agent;

(c) during transdermal flux of the first agent;

or (d) during and after transdermal flux of the first agent;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

17. A mechanical device for causing A transdermal flux of a therapeutic agent comprising:

a patch comprising one or more stratum corneum piercing microprotrusion which are capable of forming microslits in at least the stratum corneum of the skin in order to form pathways therethrough;

said microprotrusion having a length of less than 0.5 mm; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first agent under substantially identical conditions except in the absence of said at least one anti-healing agent;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

18. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising one or more stratum corneum-piercing microprotrusions which are capable of disrupting the skin by the formation of one or more microslits in the stratum corneum of the skin which form one or more pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent; and

wherein the first agent is a body analyte that is transdermally sampled; and

wherein the microprotrusions and the reservoir are an integral element;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

19. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent; and

wherein the first therapeutic agent is selected from the group consisting of heparin having a molecular weight from 3000 to 12,000 daltons, pentosan polysulfate, citric acid, citrate salts, EDTA, and dextrans having molecular weight from 2000 to 10,000 daltons;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

20. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the therapeutic agent and said at least one anti-healing agent which are different from each other are dry-coated on said one or more microprotrusions; and

wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

21. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising a microprotrusion array capable of forming disruptions in at least the stratum corneum of the skin in order to form pathways therethrough; and

at least one reservoir comprising a first therapeutic agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent, and wherein the anti-healing agent is selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit cellular migration, and neutral osmotic agents and mixtures thereof;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

22. A mechanical device for causing transdermal flux of a therapeutic agent comprising:

a patch comprising one or more stratum corneum piercing microprotrusion which are capable of forming microslits in at least the stratum corneum of the skin in order to form pathways therethrough;

said first one reservoir comprising at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first agent under substantially identical conditions except in the absence of said at least one anti-healing agent;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

23. A mechanical device for causing transdermal flux of an agent comprising:

a patch comprising one or more stratum corneum piercing microprotrusion which are capable of forming microslits in at least the stratum corneum of the skin in order to form pathways therethrough, wherein the first agent is a therapeutic agent dry coated on one or more of said microprotrusions, wherein said device is capable of delivering said first agent transdermally into the skin, and at least one reservoir comprising a first agent and at least one anti-healing agent which are different from each other, said at least one reservoir is capable of being placed in agent transmitting relationship with the skin and said pathways, wherein the amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first agent under substantially identical conditions except in the absence of said at least one anti-healing agent;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.

24. A mechanical device for causing transdermal flux of an agent comprising:

a patch comprising one or more stratum corneum piercing microprotrusion which are capable of forming microslits in at least the stratum corneum of the skin in order to form pathways therethrough, wherein the first agent is a therapeutic agent dry coated on one or more of said microprotrusions, wherein said device is capable of delivering said first agent transdermally into the skin, and at least amount of said at least one anti-healing agent is effective in inhibiting a decrease in therapeutic agent transdermal flux when compared to the transdermal flux of said first therapeutic agent under substantially identical conditions except in the absence of said at least one anti-healing agent; and

wherein the first therapeutic agent and the anti-healing agent are the same compound and selected from the group consisting of heparin having a molecular weight from 3000 to 12,000 daltons, pentosan polysulfate, citric acid, citrate salts, EDTA, and dextrans having molecular weight from 2000 to 10,000 daltons;

wherein said anti-healing agent is provided in an amount sufficient to achieve a flux decrease of less than a 2-fold between 1 and 24 hours.