Composition comprising an agent providing a signal, an implant material and a drug

• US 20060177379A1
• Filed: 12/30/2005
• Published: 08/10/2006
• Est. Priority Date: 12/30/2004
• Status: Abandoned Application

• Current Assignee: Cinvention AG
• Original Assignee: Cinvention AG
• Inventors: Asgari, Soheil
• Application Number:
  US11/322,694
• Publication Number:
  US 20060177379A1
• Time in Patent Office: Days
• US Class Current: 424/9.300
• CPC Class Codes: A61K 47/6957 the form being a device or a kit, e.g. stents or microdevices
• CPC Class Codes: A61K 49/04 X-ray contrast preparations
• CPC Class Codes: A61K 49/18 characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
• CPC Class Codes: A61L 31/022 Metals or alloys
• CPC Class Codes: A61L 31/18 Materials at least partially X-ray or laser opaque

Abstract

The present invention relates to compositions or combinations of materials for non-degradable and degradable implantable medical devices with regard to the setup of their signal generating properties and control of their therapeutic effectiveness, as well as to a method for the control of degradation of degradable or partially degradable medical devices composed like this, based on their signal generation, and to a method for supervision of their therapeutic effectiveness and/or the release of therapeutically active ingredients from such devices.

Claims

1. A composition for use in an implantable medical device, comprising:

at least one first agent capable of causing a detection of signals by at least one of a physical measurement, a biological measurement, a chemical measurement, or a verification method;

at least one material for manufacture of at least one portion of the implantable medical device; and

at least one second agent capable of causing a therapeutic action in at least one of an animal organism or a human organism.

2. The composition of claim 1, wherein the second agent is capable of being released one of directly or indirectly into at least one of an animal organism or a human organism from the at least one portion of the implantable medical device.

3. The composition of claim 1, wherein the first agent has at least one additional property in addition to the causing the detection of the signals.

4. The composition of claim 1, wherein the first agent is capable of causing a detection of signals in the absence of at least one of a physical stimulus, a chemical stimulus, a biological stimulus, and a physiologically conditioned in-vivo change.

5. The composition of claim 1, wherein the first agent is capable of causing the detection of the signals in response to at least one of a physical stimulus, a chemical stimulus, or a biological stimulus.

6. The composition of claim 1, wherein the first agent is capable of causing a detection of signals in response to at least one of a physical change in-vivo, a chemical change in-vivo, a biological change in-vivo, or a physiologically-conditioned change in-vivo.

7. The composition of claim 1, wherein the at least one material comprises biologically degradable materials.

8. The composition of claim 1, wherein the at least one material comprises biologically non-degradable materials.

9. The composition of claim 1, wherein the at least one material comprises a combination of biologically non-degradable materials and biologically degradable materials.

10. The composition of claim 3, wherein the at least one additional property is capable of causing one of a direct therapeutic action or an indirect therapeutic action in at least one of an animal organism or a human organism.

11. The composition of claim 3, wherein the at least one additional property comprises a capability to provide at least one targeting group.

12. The composition of claim 3, wherein the first agent comprises a first unit and a second unit which are covalently bonded to each other, wherein the second unit has at least one property that is different from a property which causes the detection of the signals by at least one of a physical measurement, a biological measurement, a chemical measurement, or a verification method.

13. The composition of claim 12, wherein the at least one property comprises at least one of causing a therapeutic action in at least one of an animal organism or a human organism, or providing a targeting group.

14. The composition of claim 13, wherein the first agent further comprises a third unit that includes at least one of an agent capable of causing a therapeutic action in at least one of an animal organism or a human organism, or a targeting group.

15. The composition of claim 3, wherein the first agent comprises a first unit and a second unit which are non-covalently bonded to each other, and wherein the second unit has at least one property that is different than a property which is capable of causing the detection of the signals by at least one of a physical measurement, a biological measurement, a chemical measurement, or a verification method.

16. The composition of claim 15, wherein the at least one property provides at least one of a therapeutically active agent or a targeting group.

17. The composition of claim 16, wherein the first agent further comprises a third unit that includes at least one of a therapeutically active agent or a targeting group.

18. The composition of claim 1, further comprising at least one region exhibiting a concentration gradient in a local distribution of the first agent.

19. The composition of claim 1, wherein the composition is a coating capable of being applied on at least one portion of the implantable medical device, wherein the coating further comprises a first layer and a second layer, and wherein a concentration of the first agent in the first layer differs from a concentration of the first agent in the second layer.

20. The composition of claim 1, further comprising at least one adjuvant.

21. The composition of claim 20, wherein the adjuvant is a polymer.

22. The composition of claim 20, wherein the adjuvant is a non-polymeric material.

23. The composition of claim 20, wherein the adjuvant is an inorganic material.

24. The composition of claim 20, wherein the adjuvant is an organic material.

25. The composition of claim 20, wherein the adjuvant comprises an inorganic-organic composite material.

26. The composition of claim 20, wherein the adjuvant is biodegradable.

27. The composition of claim 20, wherein the adjuvant is non-degradable.

28. The composition of claim 20, wherein the adjuvant is partially biodegradable.

29. The composition of claim 20, wherein the adjuvant is capable of controlling a release of at least one of the first agent or the second agent when the composition is at least one of exposed to physiologic fluids or implanted into at least one of a human organism or an animal organism.

30. The composition of claim 1, further comprising a third agent capable of causing a detection of further signals by at least one of a further measurement method or a further verification method, wherein the first agent is approximately precluded from causing a detection of signals by the at least one of a further measurement method or a further verification method.

31. The composition of claim 30, wherein the first agent is capable of causing the detection of the signals by at least one of a conventional X-ray method, an X-ray-based split-image method including computer tomography, a neutron transmission tomography procedure, a radio frequency magnetization procedure including magnetic resonance tomography, a method based on radio nuclides including scintigraphy, a single photon emission computed tomography (SPECT) procedure, a positron emission computed tomography (PET) procedure, an ultrasonic-based method, a fluoroscopic method, a luminescence or fluorescence-based method including intravasal fluorescence spectroscopy, a Raman spectroscopy procedure, a fluorescence emission spectroscopy procedure, an electrical impedance spectroscopy procedure, a colorimetry procedure, an optical coherence tomography procedure, an electron spin resonance (ESR) procedure, a radiofrequency (RF) method, or a microwave laser method.

32. The composition of claim 31, wherein the third agent agent is capable of causing a detection of signals by at least one of a conventional X-ray method, an X-ray-based split-image method including computer tomography, a neutron transmission tomography procedure, a radio frequency magnetization procedure including magnetic resonance tomography, a method based on radio nuclides including scintigraphy, a single photon emission computed tomography (SPECT) procedure, a positron emission computed tomography (PET) procedure, an ultrasonic-based method, a fluoroscopic method, a luminescence or fluorescence-based method including intravasal fluorescence spectroscopy, a Raman spectroscopy procedure, a fluorescence emission spectroscopy procedure, an electrical impedance spectroscopy procedure, a colorimetry procedure, an optical coherence tomography procedure, an electron spin resonance (ESR) procedure, a radiofrequency (RF) method, or a microwave laser method.

33. The composition of claim 30, wherein at least one of the first agent or the third agent is selected from the group consisting of metals, metal oxides, metal carbides, metal nitrides, metal oxynitrides, metal carbonitrides, metal oxycarbides, metal oxynitrides, metal oxycarbonitrides, metal hydrides, metal alkoxides, metal halides, inorganic or organic metal salts including salts and chelates from the lanthanide group with atomic numbers 57-83 or from the transition metals with atomic numbers 21-29, 42 or 44, metal polymers, metallocenes, or other organometallic compounds including metal complexes with phthalocyanines.

34. The composition of claim 30, wherein at least one of the first agent or the third agent is selected from the group consisting of magnetic materials including those with paramagnetic, diamagnetic, super paramagnetic, ferrimagnetic or ferromagnetic properties;

semiconducting materials including those from the Groups II-VI, Groups III-V, or Group IV, having absorption properties for radiation in wavelength ranges approximately from gamma rays up to microwave radiation and/or emitting radiation properties.

35. The composition of claim 30, wherein at least one of the first agent or the third agent is selected from the group consisting of ionic and non-ionic halogenated agents including 3-acetylamino-2,4-6-triiodobenzoic acid, 3,5-diacetamido-2,4,6-triiodobenzoic acid, 2,4,6-triiodo-3,5-dipropionamidobenzoic acid, 3-acetyl amino-5-((acetyl amino)methyl)-2,4,6-triiodobenzoic acid, 3-acetyl amino-5-(acetylmethylamino)-2,4,6-triiodobenzoic acid, 5-acetamido-2,4,6-triiodo-N-((methylcarbamoyl)methyl)isophthalamic acid, 5-(2-methoxyacetamido)-2,4,6-triiodo-N-[2-hydroxy-1-(methylcarbamoyl)-ethyl]-isophthalamic acid, 5-acetamido-2,4,6-triiodo-N-methylisophthalamicacid, 5-acetamido-2,4,6-triiodo-N-(2-hydroxyethyl)isophthalamic acid, 2-[[2,4,6-triiodo-3[(1-oxobutyl)amino]phenyl]methyl]butanoic acid, beta-(3-amino-2,4,6-triiodophenyl)-alpha-ethylpropionic acid, or iopamidol, iotrolan, iodecimol, iodixanol, ioglucol, loglucomide, iogulamide, iomeprol, or iopentol.

36. The composition of claim 30, wherein at least one of the first agent or the third agent is selected from the group consisting of carbon species including carbides, fullerenes, fullerene-metal complexes, or endohedral fullerenes which contain rare earths including cerium, neodymium, samarium, europium, gadolinium, terbium, dysprosium or holmium, or halogenated fullerenes.

37. The composition of claim 30, wherein at least one of the first agent or the third agent is selected from the group consisting of anionic and/or cationic lipids, including halogenated anionic or cationic lipids.

38. The composition of claim 30, wherein at least one of the first agent or the third agent is selected from the group consisting of gases or in-vivo gas-forming substances including air, nitrogen, hydrogen, alkanes, or halogenated hydrocarbon gases including methyl chloride, perfluoroacetone, and perfluorobutane.

39. The composition of claim 38, wherein at least one of the gases or the in-vivo gas-forming substances are contained in at least one of microbubbles or microspheres.

40. The composition of claim 30, wherein at least one of the first agent or the third agent is selected from the group consisting of recombinant and non-recombinant nucleic acids, proteins, peptides, or polypeptides, including those which directly or indirectly induce the in-vivo formation or enrichment of signal-generating agents and those which contain coding sequences for the expression of signal-generating agents including metallo-protein complexes, dicarboxylate proteins, lactoferrin or ferritin, or those that regulate enrichment and/or homeostasis of physiologically available signal-generating agents such as the iron regulatory protein (IRP), transferrin receptor, or erythroid 5-aminolevulinate synthase.

41. The composition of claim 30, wherein at least one of the first agent or the third agent is provided in a form of at least one of polymeric nanoparticles, non-polymeric nanoparticles, or microparticles, wherein an average size of the polymeric nanoparticles, the non-polymeric nanoparticles, or the microparticles is between about 2 nm and 20 μ

m.

42. The composition of claim 41, wherein the average size of the polymeric nanoparticles, the non-polymeric nanoparticles, or the microparticles is between about 2 nm to 5 μ

m.

43. The composition of claim 30, wherein at least one of the first agent or the third agent is provided in a form of at least one of microspheres, macrospheres, micelles or liposomes, or encapsulated in polymeric shells.

44. The composition of claim 30, wherein at least one of the first agent or the third agent is provided in a form of biological vectors, including transfection vectors such as virus particles or viruses, including adeno viruses, adeno virus associated viruses, herpes simplex viruses, retroviruses, alpha viruses, pox viruses, arena-viruses, vaccinia viruses, influenza viruses or polio viruses.

45. The composition of claim 30, wherein at least one of the first agent or the third agent comprises at least one of cells, cell cultures, organized cell cultures, tissues, organs of any desired species, or non-human organisms, and wherein the at least one of the first agent or the third agent further comprises recombinant nucleic acids with coding sequences capable of producing at least one agent capable of causing the detection of the signals by at least one of a physical measurement, a biological measurement, a chemical measurement, or a verification method.

46. The composition of claim 30, wherein at least one of the first agent or the third agent is provided in a form of at least one of a solution, a suspension, an emulsion, a dispersion, or a solid material.

47. The composition of claim 30, wherein the first agent is bonded covalently to the third agent.

48. The composition of claim 30, wherein the first agent is bonded non-covalently to the third agent.

49. An implantable medical device comprising:

at least one first agent capable of causing a detection of signals by at least one of a physical measurement, a biological measurement, a chemical measurement, or a verification method;

at least one material for manufacture of at least one portion of the implantable medical device; and

at least one second agent capable of causing a therapeutic action in at least one of an animal organism or a human organism.

50. The implantable medical device of claim 49, wherein the at least one material comprises at least one polymer selected from the group consisting of polyurethane, collagens, albumin, gelatin, hyaluronic acid, starch, cellulose (methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulosephthalat, casein, dextrane, polysaccharides, fibrinogen, poly(D,L-lactide), poly(D,L-lactide-co-glycolide), poly(glycolides), poly(hydroxybutylate), poly(alkyl carbonates), poly(orthoesters), polyesters, poly(hydroxyvaleric acid), polydioxanone, poly(ethylene terephthalate), poly(malic acid), poly(tartronic acid), polyanhydrides, polyphosphohazenes, poly(amino acids).

51. The implantable medical device of claim 49, wherein the at least one material comprises at least one non-polymeric materials selected from the group consisting of ceramics, glasses, metals, alloys, bone, stone, minerals, or any mixture thereof.

52. The implantable medical device of claim 49, wherein the at least one material comprises a mixture of non-polymeric and polymeric materials.

53. The implantable medical device of claim 49, wherein the at least one material comprises magnesium or zinc.

54. The implantable medical device of claim 53, wherein the medical device is a stent.

55. The implantable medical device of claim 54, wherein the stent is at least partially coated with a coating comprising particles containing at least one of magnesium or zinc.

56. The implantable medical device of claim 49, wherein the first agent is present in a porous reticulated network which is capable of being loaded with the second agent.

57. A method for determining of the extent of release of a therapeutically active agent from an implantable medical device, comprising:

providing the implantable medical device comprising at least one first agent capable of causing a detection of signals by at least one of a physical measurement, a biological measurement, a chemical measurement, or a verification method, and at least one second agent capable of causing a therapeutic action in at least one of an animal organism or a human organism, wherein the medical device is capable of at least partially releasing the second agent together with the first agent after insertion of the device into at least one of a human organism or an animal organism;

determining a correlation between an amount of the second agent released and an amount of the first agent released;

detecting an extent of release of the first agent through the application of at least one of a non-invasive measurement or a verification method; and

determining an extent of release of the second agent by applying the correlation.

58. The method of claim 57, wherein the implantable medical device is at least partially degradable, and wherein the first and second agents are released during the at least partial degradation of the medical device.

59. The method of claim 57, wherein the implantable medical device is non-degradable.

60. The method of claim 57, wherein the first agent is covalently bonded to the second agent.

61. The method of claim 57, wherein the first agent is non-covalently bonded to the second agent.