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US-12622880-B2 - Therapeutic system for the topical, transdermal and transcutaneous application of carbon monoxide

US12622880B2US 12622880 B2US12622880 B2US 12622880B2US-12622880-B2

Abstract

The present invention discloses a therapeutic system for the topic, transdermal and transcutaneous application of carbon monoxide (CO), comprising: (i) an adhesive layer, (ii) a gas-permeable and liquid- and solid-impermeable membrane, (iii) a reaction chamber comprising a CO releasing molecule A, and (iv) a gas-impermeable backing layer, wherein the transdermal therapeutic system is configured that the CO releasing molecule A can be brought into contact with a CO release triggering compound B in the reaction chamber (iii). The therapeutic system can be used for the treatment of wounds, inflammatory diseases of the skin, and inflammatory diseases of subcutaneous skin tissue, joints and tendons.

Inventors

  • Lorenz Meinel
  • Matthias RUOPP
  • Wolfgang Schmehl
  • Marcus Otto GUTMANN

Assignees

  • JULIUS-MAXIMILIANS-UNIVERSITAET WUERZBURG

Dates

Publication Date
20260512
Application Date
20210312
Priority Date
20200313

Claims (20)

  1. 1 . A therapeutic system for the topical, transdermal and transcutaneous application of carbon monoxide (CO), said system comprising: (i) an adhesive layer, (ii) a gas-permeable and liquid- and solid-impermeable membrane, (iii) a reaction chamber comprising a CO releasing molecule A, and (iv) a gas-impermeable backing layer, wherein the therapeutic system is configured such that the CO releasing molecule A can be brought into contact with a CO release triggering compound B in the reaction chamber (iii), wherein the CO releasing molecule A is a molybdenum carbonyl compound, and wherein the reaction chamber (iii) is surrounded by a spacer made of silicone.
  2. 2 . The therapeutic system according to claim 1 , wherein the membrane (ii) is a lower membrane and the system additionally comprises a liquid- and solid-impermeable upper membrane (v) disposed between the reaction chamber (iii) and the backing layer (iv).
  3. 3 . The therapeutic system according to claim 1 , wherein the membrane is fabricated from an expanded polytetrafluoroethylene or silicone.
  4. 4 . The therapeutic system according to claim 1 , wherein the reaction chamber (iii) is a one-compartment reaction chamber and the therapeutic system further comprises a luer-lock connection (vii) or a septum (vii) that allows for addition of a CO release triggering compound B into the reaction chamber (iii).
  5. 5 . The therapeutic system according to claim 1 , wherein the reaction chamber (iii) is a two-compartment reaction chamber divided by a removable partition wall (viii), further wherein a first of said two compartments comprises the CO releasing molecule A, and a second of said two compartments comprises the CO-release triggering compound B.
  6. 6 . The therapeutic system according to claim 1 , wherein the adhesive layer is protected by a release liner during storage of the therapeutic system.
  7. 7 . The therapeutic system according to claim 1 , wherein the CO release triggering compound B is selected from the group consisting of a sulfur containing compound, a nitrogen containing compound, an oxidizing compound, an oxidizing metal salt, a non-oxidizing metal salt, and water.
  8. 8 . The therapeutic system according to claim 1 , wherein the CO release triggering compound B is selected from the group consisting of FeCl 3 , Ce(SO 4 ) 2 and H 2 O 2 , preferably FeCl 3 .
  9. 9 . The therapeutic system according to claim 1 , wherein the CO releasing molecule A is used in form of a powder or tablet and/or the CO release triggering compound B is used in form of an aqueous solution or suspension.
  10. 10 . A method for treating a wound, said method comprising the step of applying the therapeutic system according to claim 1 to the wound of a patient in need of such treatment.
  11. 11 . A method for treating an inflammatory disease of the skin, said method comprising the step of applying the therapeutic system according to claim 1 to an afflicted area of a patient's skin in need of such treatment.
  12. 12 . A method for treating an inflammatory disease of the subcutaneous skin tissue, tendons and/or joints, said method comprising the step of applying the therapeutic system according to claim 1 to an afflicted tissue of a patient in need of such treatment.
  13. 13 . A method for treating an inflammatory disease of the eye, said method comprising the step of applying the therapeutic system according to claim 1 to one or both eyes of a patient in need of such treatment.
  14. 14 . A kit comprising the therapeutic system according to claim 1 in combination with an injection device, wherein said injection device carries an aqueous solution of the CO release triggering compound B.
  15. 15 . The kit of claim 14 , wherein said injection device is a syringe.
  16. 16 . The therapeutic system according to claim 1 , wherein the membrane is fabricated from silicone.
  17. 17 . The therapeutic system according to claim 8 , wherein the CO releasing molecule A is Mo(CO) 3 (CNCH 2 CO 2 H) 3 and the CO release triggering compound B is FeCl 3 .
  18. 18 . The method according to claim 11 , wherein said inflammatory disease of the skin is dermatitis or eczema.
  19. 19 . The method according to claim 12 , wherein said inflammatory disease of the subcutaneous skin tissue, tendons and/or joints is gout and tendonitis.
  20. 20 . The system according to claim 1 , wherein said silicone spacer reinforces said reaction chamber while affording sufficient overall flexibility to said therapeutic system to enable application to an afflicted tissue site.

Description

PRIORITY This application corresponds to the U.S. National Phase of International Application No. PCT/EP2021/056296, filed Mar. 12, 2021, which, in turn, claims priority to European Patent Application No. 20162912.8 filed Mar. 13, 2020, the contents of which are incorporated by reference herein in their entirety. TECHNICAL FIELD The present invention is directed to a therapeutic system for the topic, transdermal and transcutaneous application of carbon monoxide and use thereof in the treatment of wounds and inflammatory diseases of the skin, subcutaneous tissue, tendons and joints, as well as of the eye. The present invention also concerns a kit comprising the transdermal therapeutic system and an injection device such as a syringe. BACKGROUND Chronic and non-healing wounds represent a substantial economic burden for the health system causing high annual costs. They also affect the quality of life of patients and often precede serious events such as limp amputations or even premature death. The most serious challenge to be avoided in the treatment of wounds is the infection of the wound. This is often done via topically applied antimicrobials such as silver particles and antibiotics. Silver nanoparticles, however, show genotoxic and cytotoxic effects on host cells and, like antibiotics, are aimed merely at the prevention of infections without supporting angiogenesis and proliferation and migration of fibroblasts, which are important for wound healing. In addition, the frequent application of antibiotics can lead to renal disease and the onset of contact dermatitis with further stress on the patient. In order to avoid such complications, the use of nitric oxide (NO) as gaso-transmitter for improved wound healing has been studied for years. NO, with its antimicrobial properties, such as the classic substances mentioned above, supports the prevention of wound infections, which can accelerate the healing process of the wound. In addition to prevention of infections, processes such as the aforementioned angiogenesis, proliferation of fibroblasts, and transport of chemokines and nutrients into the wound, are also critical for a successful closure of the wound. Carbon monoxide (CO) is an interesting candidate for improved wound healing properties over NO due to its antimicrobial and anti-inflammatory properties and its good tissue penetration properties. These properties make CO not only interesting as active agent for the treatment of open wounds, but also for the treatment of inflammatory diseases of the skin as well as subcutaneous tissue, joints and tendons, as well as of the eye. Systemic tests have shown, however, that CO is bound very rapidly by hemoglobin under CO-Hb formation. Therefore, high doses are necessary to achieve a therapeutic effect. This, however, enhances the risk of CO poisoning of the patient. Therefore, methods have been developed in recent years to transport CO targeted to the site of action. Steiger et al. developed oral delivery systems that release CO after activation with an activating fluid, allowing for the local release of CO gas in the stomach and intestines at the damaged sites (see for example: WO 2015/188941 A1; C. Steiger et al., “Oral drug delivery of therapeutic gases—Carbon monoxide release for gastrointestinal diseases”, Journal of Controlled Release, 189 (2014), 46-53; and C. Steiger et al., “Prevention of colitis by controlled oral drug delivery of carbon monoxide”, Journal of Controlled Release, 239 (2016), 128-136). Such oral systems, however, only function inside the patient and do not provide means of treating skin wounds or underlying tissue, tendons or joints. Problematic in the treatment of open wounds with CO releasing molecules (CORMs) is that the wound and thus also the organism is in direct contact with the CORM. Such molecules frequently show toxic side effects, particularly if they contain metals such as e.g. ruthenium or molybdenum. Therefore, direct contact with a CORM via the skin, let alone via an open wound, should be avoided. WO 95/35105 A1 discloses a transdermal therapeutic system for the systemic administration of CO using CO releasing molecules, such as iron pentacarbonyl. However, in the system according to WO 95/35105 A1, contact of the patient with the CO releasing molecule is not avoided—to the contrary, while release of the CO releasing molecule from the system is controlled by a polymer matrix, it is required that the CO releasing molecule enters the organism in order to release CO into the systemic cycle. The TTS according to WO 95/35105 A1 does not provide a means for activating CO release outside the patient's body and is not suitable to protect the patient from contact with the CO releasing molecule and toxic degradation products resulting therefrom. It is thus the object of the present invention to provide a simple and safe system for the topic, transdermal and transcutaneous application of CO, which is particularly useful for the treatm