Transluminal drug delivery methods and devices

Abstract

Transluminal drug delivery method and device embodiments can include a urethral suppository formulated to prevent or treat diseases of the urethra and surrounding organs, such as interstitial cystitis or urethritis, by enhancing the absorption of a therapeutic agent of the suppository into body tissues without adversely affecting the natural defense mechanisms of these tissues. Adverse effects on the glycosaminoglycan (GAG) barrier can be mitigated or eliminated by the presence of a suitable polysaccharide in the suppository.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an embodiment of a combination of a carrier base material, an anesthetic agent, a buffering agent, and a polysaccharide in liquid form being poured into a suppository mold cavity chamber.

FIG. 2 is a diagrammatic view of an embodiment of a combination of a carrier base material, an anesthetic agent, a buffering agent, and a polysaccharide in liquid form being poured into a suppository mold cavity embodiment showing the layers formed within the mold cavity chamber.

FIG. 3 is a perspective view of a urethral suppository embodiment.

FIG. 4 is a side view in partial section of a distal portion of a delivery catheter disposed within a urethra of a patient and a urethral suppository being advanced distally within the delivery catheter.

FIG. 5 is a side view in partial section of the urethral suppository disposed within the urinary tract of the patient with the delivery catheter withdrawn.

FIG. 6 is a graph showing the effect of lidocaine concentration on pH with the incremental addition of sodium bicarbonate to a fluid volume of 10 ml of water.

FIG. 7 is a graph showing the effect of lidocaine concentration on pH with the incremental addition of sodium bicarbonate to a fluid volume of 5 ml of water.

FIG. 8 is a graph showing the effect of fluid volume on pH with the addition of sodium bicarbonate to a solution containing 30 mg of lidocaine.

FIG. 9 is a graph showing the effect of fluid volume on pH with the addition of sodium bicarbonate to a solution containing 45 mg of lidocaine.

FIG. 10 is a graph showing the effect of fluid volume on pH with the addition of sodium bicarbonate to a solution containing 60 mg of lidocaine.

FIG. 11 is a graph showing the results of lidocaine absorption as a result of intravesical instillation and as a result of urethral suppository administration with plasma lidocaine concentration plotted against time, with a 100 mg dose administered both intravesically and by suppository.

FIG. 12 is a graph showing the data of FIG. 11 for urethral suppository administration of lidocaine replotted on a different scale.

FIG. 13 is a graph showing the mean arterial blood pressure (MAP) after urethral and suppository lidocaine administration.

FIG. 14 is a graph showing % of patients experiencing improvement in their symptoms of pain (red, n=24) or urgency (yellow, n=19) as rated by a PORIS questionnaire 30 minutes after having a suppository with 10 mg lidocaine, 5000 units heparin, with buffer and base.

FIG. 15 is a graph showing % of patients experiencing improvement in their symptoms of pain (n=4) as rated by a PORIS questionnaire 30 minutes after having a suppository with 10 mg lidocaine, 5000 units heparin with THAM (tris) buffer in place of bicarbonate and base.

FIG. 16 is a graph showing duration of pain relief of % of patients over time when contacted 24 hours after the initial treatment (n=33). The median duration of relief was 4 hours.

FIG. 17 is a cross-section of a urethral suppository according to the present invention showing multiple layers.

FIG. 18 is a schematic representation of a two-layer suppository according to the present invention showing inner space for suppository material created by insert.

FIG. 19 is a schematic representation of a three-layer suppository according to the present invention showing inner space for suppository material created by insert.

FIG. 20 is a perspective view of a suppository being dipped into a container of melted suppository material to create an outer layer of a multilayer suppository using a dipping process.

FIG. 21 is a representation of a multilayer suppository according to the present invention that employs different geometries in the layers.

Claims

1. A urethral suppository comprising: (a) a carrier base material;(b) a therapeutic agent; and(c) a buffering agent;

2. The urethral suppository of claim 1 wherein the suppository has a substantially uniform composition.

3. The urethral suppository of claim 1 wherein the carrier base material has a melting point such that the suppository is substantially melted at body temperature.

4. The urethral suppository of claim 1 wherein the carrier base material is a water soluble carrier base.

5. The urethral suppository of claim 1 wherein the carrier base material is at least one material selected from the group consisting of paraffin, theobroma oil, modified theobroma oil products, gelatins, glycerinated gelatins, polyethylene glycols (PEGs), glycerols, hydrogenated vegetable oils, cocoa butter, methyl butyl ketone (MBK), celluloses, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, polyphosphourethanes, polyoxyl stearate, ethylene oxide polymers, and fatty acid bases.

6. The urethral suppository of claim 5 wherein the carrier base material comprises methyl butyl ketone.

7. The urethral suppository of claim 5 wherein the carrier base material comprises methyl butyl ketone and paraffin.

8. The urethral suppository of claim 1 wherein the therapeutic agent is an anesthetic agent.

9. The urethral suppository of claim 8 wherein the anesthetic agent is present in a quantity sufficient to prevent or ameliorate a urinary tract disorder.

10. The urethral suppository of claim 9 wherein the urinary tract disorder is interstitial cystitis.

11. The urethral suppository of claim 9 wherein the urinary tract disorder is urethritis.

12. The urethral suppository of claim 8 wherein the anesthetic agent is at least one anesthetic agent selected from the group consisting of lidocaine, benzocaine, bupivacaine, articaine, cocaine, etidocaine, flecainide, mepivacaine, pramoxine, prilocaine, procaine, chloroprocaine, oxyprocaine, proparacaine, ropivacaine, tetracaine, dyclonine, dibucaine, chloroxylenol, cinchocaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, propoxycaine, pyrrocaine, risocaine, rodocaine, and pharmaceutically acceptable derivatives and bioisosteres thereof, and combinations thereof.

13. The urethral suppository of claim 12 wherein the anesthetic agent is at least one anesthetic agent selected from the group consisting of lidocaine, prilocaine, benzocaine, mepivacaine, etidocaine, articaine, bupivacaine, procaine, and tetracaine.

14. The urethral suppository of claim 13 wherein the anesthetic agent is lidocaine.

15. The urethral suppository of claim 1 wherein the buffering agent is present in a quantity such that the buffering agent buffers the suppository at a pH that ensures that a sufficient portion of an anesthetic agent that is present in the suppository is present in an uncharged state so that the anesthetic agent can cross cell membranes of cells surrounding the urethra.

16. The urethral suppository of claim 15 wherein the buffering agent maintains the pH of the suppository in a range of from about 7 to about 12.

17. The urethral suppository of claim 16 wherein the buffering agent maintains the pH of the suppository in a range of from about 7 to about 9.

18. The urethral suppository of claim 1 wherein the buffering agent is at least one buffer selected from the group consisting of sodium bicarbonate buffer, calcium bicarbonate buffer, tris(hydroxymethyl)aminomethane (Tris or THAM), MOPS (3-(N-morpholino)propanesulfonic acid) buffer, HEPES (N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) buffer, ACES (2-[(2-amino-2-oxoethyl)amino]ethanoesulfonic acid) buffer, ADA (N-(2-acetamido)2-iminodiacetic acid) buffer, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bicine (N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris (bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO (3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N′-(3-propanesulfonic acid), buffer, HEPPSO (N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid) buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolamine buffer, imidazole buffer, glycine buffer, ethanolamine buffer, phosphate buffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer, PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid) buffer, POPSO (piperazine-N,N′-bis(2-hydroxypropaneulfonic acid) buffer; TAPS (N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer, TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, tricine (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanol buffer, and combinations thereof.

19. The urethral suppository of claim 18 wherein the buffering agent is selected from the group consisting of sodium bicarbonate buffer and tris(hydroxymethyl)aminomethane buffer.

20. The urethral suppository of claim 19 wherein the buffering agent is sodium bicarbonate buffer.

21. The urethral suppository of claim 19 wherein the buffering agent is tris(hydroxymethyl)aminomethane buffer.

22. The urethral suppository of claim 1 further comprising a polysaccharide.

23. The urethral suppository of claim 22 wherein the polysaccharide is present in the suppository in a sufficient quantity to prevent or ameliorate a urinary tract disorder.

24. The urethral suppository of claim 23 wherein the urinary tract disorder is interstitial cystitis.

25. The urethral suppository of claim 23 wherein the urinary tract disorder is urethritis.

26. The urethral suppository of claim 22 wherein the polysaccharide is at least one polysaccharide selected from the group consisting of hyaluronic acid, hyaluronan, chondroitin sulfate, pentosan polysulfate, dermatan sulfates, heparin, heparan sulfates, keratan sulfates, dextran sulfates, and carrageenan.

27. The urethral suppository of claim 26 wherein the polysaccharide is heparin.

28. The urethral suppository of claim 1 wherein the suppository is from about 10 mg to about 1000 mg in weight.

29. The urethral suppository of claim 1 wherein the suppository is from about 400 mg to about 600 mg in weight.

30. The urethral suppository of claim 1 wherein the therapeutic agent is an anesthetic agent, and wherein the suppository comprises from about 1 mg to about 100 mg of anesthetic agent.

31. The urethral suppository of claim 30 wherein the suppository comprises from about 30 mg to about 60 mg of anesthetic agent.

32. The urethral suppository of claim 1 wherein the suppository comprises from about 0.5 mg to about 100 mg of buffering agent.

33. The urethral suppository of claim 32 wherein the suppository comprises from about 1 mg to about 20 mg of buffering agent.

34. The urethral suppository of claim 33 wherein the suppository comprises from about 0.5 mg to about 100 mg of buffering agent.

35. The urethral suppository of claim 1 wherein the suppository is in a configuration selected from the group consisting of a cylinder, a cone, and an ellipsoid.

36. The urethral suppository of claim 1 wherein the suppository is an elongated structure with a transverse dimension of from about 1 mm to about 10 mm.

37. The urethral suppository of claim 1 wherein the suppository is an elongated structure with a transverse dimension of from about 3 mm to about 6 mm.

38. The urethral suppository of claim 1 wherein the suppository is an elongated structure with a length of from about 5 mm to about 50 mm.

39. The urethral suppository of claim 38 wherein the suppository is an elongated structure with a length of from about 15 mm to about 35 mm.

40. The urethral suppository of claim 1 wherein the suppository comprises a quantity of buffering agent that comprises from about 1 percent to about 30 percent by weight of the overall weight of the suppository.

41. The urethral suppository of claim 1 further comprising a quantity of a suspending agent sufficient to prevent active ingredients within the suppository from aggregating.

42. The urethral suppository of claim 41 wherein the suspending agent is silica.

43. The urethral suppository of claim 1 further comprising a therapeutically effective quantity of an antibacterial agent or an antifungal agent to treat bacterial or fungal cystitis.

44. A method for manufacturing a urethral suppository comprising the steps of: (a) combining a therapeutic agent and a buffering agent in a liquid carrier base material until the therapeutic agent and the buffering agent have dissolved or been suspended in the liquid carrier base material; and(b) forming the liquid carrier base material, therapeutic agent, and buffering agent mixture into a suppository that is configured to be deployed within the urethra of a patient.

45. The method of claim 44 wherein the method further comprises combining a polysaccharide with the liquid carrier base material.

46. The method of claim 45 wherein the polysaccharide comprises at least one polysaccharide selected from the group consisting of hyaluronic acid, hyaluronan, chondroitin sulfate, pentosan polysulfate, dermatan sulfates, heparin, heparan sulfates, keratan sulfates, dextran sulfates, and carrageenan.

47. The method of claim 44 wherein the step of forming the mixture into a suppository results in a finished suppository having a weight of from about 10 mg to about 1000 mg.

48. The method of claim 44 wherein the therapeutic agent is an anesthetic agent.

49. The method of claim 48 wherein the anesthetic agent is lidocaine.

50. The method of claim 44 wherein the quantity of buffering agent combined with the therapeutic agent in the liquid base material is sufficient to produce a pH of from about 7 to about 12 in the finished suppository.

51. A method of treating at least a portion of the urinary tract of a patient comprising the steps of: (a) providing the urethral suppository of claim 1;(b) deploying the urethral suppository within the patient's urethra; and(c) allowing the suppository to at least partially disintegrate and release the therapeutic agent and the buffering agent to treat at least a portion of the urinary tract of the patient.

52. The method of claim 51 wherein disintegration of the suppository comprises melting of the carrier base material of the suppository.

53. The method of claim 51 wherein disintegration of the suppository comprises dissolving the carrier base material of the suppository.

54. The method of claim 51 wherein the therapeutic agent is an anesthetic agent.

55. The method of claim 54 wherein the anesthetic agent is lidocaine.

56. The method of claim 54 wherein treating at least a portion of the urinary tract of the patient comprises treatment of interstitial cystitis.

58. The method of claim 54 wherein treating at least a portion of the urinary tract of the patient comprises treatment of urethritis.

59. The method of claim 54 wherein the urethral suppository is deployed within the urethra of the patient in order to desensitize the urethra prior to insertion of instrumentation into the urethra.

60. The method of claim 54 wherein treating at least a portion of the urinary tract of the patient comprises treatment of pain associated with the urethra or bladder.

61. The method of claim 51 wherein the urethral suppository further comprises a polysaccharide and wherein the polysaccharide replaces or repairs the glycosaminoglycan barrier lining the urinary tract of the patient after insertion of the suppository into the urethra of the patient.

62. The method of claim 51 wherein the step of deploying the urethral suppository within the patient's urethra further comprises use of a water-based lubricant.

63. A urethral suppository comprising a plurality of distinct layers, each layer comprising a carrier base material, a therapeutic agent, and a buffering agent, wherein at least one of the identity of the carrier base material in a layer, the identity of the therapeutic agent in a layer, the identity of the buffering agent in a layer, the quantity of the carrier base material in a layer, the quantity of the therapeutic agent in a layer, the quantity of the buffering agent in a layer, and the shape of a layer varies between at least two of the layers of the suppository.

64. The urethral suppository of claim 63 wherein the urethral suppository comprises two layers.

65. The urethral suppository of claim 63 wherein the urethral suppository comprises three layers.

66. The urethral suppository of claim 63 wherein the urethral suppository comprises four layers.

67. The urethral suppository of claim 63 wherein the therapeutic agent in at least one layer of the urethral suppository is an anesthetic agent.

68. The urethral suppository of claim 63 wherein the therapeutic agent in all layers of the urethral suppository is an anesthetic agent.

69. The urethral suppository of claim 63 wherein the therapeutic agent in at least two layers of the urethral suppository is an anesthetic agent, and wherein the anesthetic agents in two layers of the urethral suppository are different anesthetic agents.

70. The urethral suppository of claim 69 wherein the anesthetic agent in one layer of the urethral suppository is a first anesthetic agent with a rapid onset and the anesthetic agent in another layer of the urethral suppository is a second anesthetic agent with a slower onset than the onset of the anesthetic agent with a rapid onset, but with a longer half-life than the half-life of the anesthetic agent with a rapid onset, the layer including the first anesthetic agent being located closer to the surface of the urethral suppository than the layer including the second anesthetic agent.

71. The urethral suppository of claim 70 wherein the first anesthetic agent is lidocaine and the second anesthetic agent is tetracaine.

72. The urethral suppository of claim 63 wherein the therapeutic agent in one layer of the urethral suppository is an anesthetic agent, and wherein the therapeutic agent in another layer of the urethral suppository is a therapeutic agent other than an anesthetic agent, the layer including the anesthetic agent being located closer to the surface of the urethral suppository than the layer including the therapeutic agent other than an anesthetic agent.

73. The urethral suppository of claim 72 wherein the anesthetic agent is lidocaine.

74. The urethral suppository of claim 72 wherein the therapeutic agent other than an anesthetic agent is selected from the group consisting of an anti-infection agent, an anti-incontinence agent, an anti-inflammatory agent, and an anti-cancer agent.

75. The urethral suppository of claim 63 wherein the urethral suppository includes therein at least two layers differing in the composition or quantity of the carrier base material in the layers.

76. The urethral suppository of claim 75 wherein the two layers differ in the concentration of an agent that regulates melting time.

77. The urethral suppository of claim 76 wherein the agent that regulates melting time is paraffin.

78. The urethral suppository of claim 63 wherein the shape of a layer varies between at least two of the layers of the suppository.

79. The urethral suppository of claim 78 wherein at least one of the layers of the suppository is shaped to focus the effect of the suppository in a specific section of the suppository.

80. The urethral suppository of claim 63 wherein one or more of the layers further includes a polysaccharide.

81. The urethral suppository of claim 70 wherein more than one layer includes a polysaccharide, and at least one of the identity of the polysaccharide in a layer and the quantity of the polysaccharide in the layer varies between at least two of the layers of the suppository.

82. The urethral suppository of claim 63 wherein at least one of the layers includes a suspending agent.

83. The urethral suppository of claim 63 wherein at least one of the layers includes a therapeutically effective quantity of an antibacterial agent or an antifungal agent.

84. A method for manufacturing a multilayered suppository comprising the steps of: (a) combining a therapeutic agent and a buffering agent in a liquid carrier base material until the therapeutic agent and the buffering agent have dissolved or been suspended in the liquid carrier base material; and(b) forming the liquid carrier base material, therapeutic agent, and buffering agent mixture into one or more layers of a multi-layered suppository that is configured to be deployed within the urethra of a patient.

85. A method of treating at least a portion of the urinary tract of a patient comprising the steps of: (a) providing the multilayered urethral suppository of claim 63;(b) deploying the multilayered urethral suppository within the patient's urethra; and(c) allowing the multilayered suppository to disintegrate and release the therapeutic agent and the buffering agent from at least one of the layers of the multilayered suppository to treat at least a portion of the urinary tract of the patient.

86. The method of claim 85 wherein disintegration of the suppository comprises melting of the carrier base material of at least one layer of the suppository.

87. The method of claim 85 wherein disintegration of the suppository comprises dissolving the carrier base material of at least one layer of the suppository.

88. The method of claim 85 wherein treating at least a portion of the urinary tract of the patient comprises treatment of interstitial cystitis.

89. The method of claim 85 wherein treating at least a portion of the urinary tract of the patient comprises treatment of urethritis.

90. The method of claim 85 wherein the urethral suppository is deployed within the urethra of the patient in order to desensitize the urethra prior to insertion of instrumentation into the urethra.

91. The method of claim 85 wherein treating at least a portion of the urinary tract of the patient comprises treatment of pain associated with the urethra or bladder.

92. The method of claim 85 wherein the step of deploying the urethral suppository within the patient's urethra further comprises use of a water-based lubricant.

93. A depot for luminal drug delivery comprising: (a) a carrier base material;(b) a therapeutic agent; and(c) a buffering agent;

94. The depot of claim 93 wherein the depot has a substantially uniform composition.

95. The depot of claim 93 further comprising a polysaccharide.

96. The depot of claim 93 . wherein the carrier base material has a melting point such that the depot is substantially melted at body temperature.

97. The depot of claim 93 wherein the therapeutic agent is an anesthetic agent.

98. The depot of claim 97 wherein the anesthetic agent is lidocaine.

99. The depot of claim 93 wherein the carrier base material comprises a water soluble carrier base.

100. The depot of claim 93 wherein the carrier base material comprises methyl butyl ketone.