Microporation of tissue for delivery of bioactive agents

• US 20040220456A1
• Filed: 02/06/2004
• Published: 11/04/2004
• Est. Priority Date: 12/30/1997
• Status: Active Grant

• Current Assignee: ​Passport Technologies, Inc.
• Original Assignee: Altea Therapeutics Corporation (Nitto Denko Corporation)
• Inventors: Eppstein, Jonathan A.
• Granted Patent: US 7,758,561 B2
• Time in Patent Office: Days
• US Class Current: 600/309
• CPC Class Codes: A61B 1/313 for introducing through surgical openings, e.g. laparoscopes
• CPC Class Codes: A61B 18/04 by heating by applying electromagnetic radiation A61B18/18; hyperthermia using electric or magnetic fields, radiation or ultrasound A61N
• CPC Class Codes: A61B 18/10 Power sources therefor
• CPC Class Codes: A61B 18/203 applying laser energy to the outside of the body
• CPC Class Codes: A61B 2017/00026 Conductivity or impedance, e.g. of tissue
• CPC Class Codes: A61B 2017/00172 Pulse trains, bursts, intermittent continuous operation
• CPC Class Codes: A61B 2017/00765 Decreasing the barrier function of skin tissue by radiated energy, e.g. using ultrasound, using laser for skin perforation
• CPC Class Codes: A61B 2018/00452 Skin
• CPC Class Codes: A61B 2018/00577 Ablation
• CPC Class Codes: A61B 2018/00642 with feedback, i.e. closed loop control
• CPC Class Codes: A61B 2018/00791 Temperature
• CPC Class Codes: A61B 5/14514 using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
• CPC Class Codes: A61B 5/150022 for capillary blood or interstitial fluid
• CPC Class Codes: A61B 5/150076 by heating
• CPC Class Codes: A61B 5/150083 by vibration, e.g. ultrasound
• CPC Class Codes: A61B 5/150091 by electricity
• CPC Class Codes: A61B 5/150099 by negative pressure, other than vacuum extraction into a syringe by pulling on the piston rod or into pre-evacuated tubes
• CPC Class Codes: A61B 5/150129 by cooling
• CPC Class Codes: A61B 5/150175 Adjustment of penetration depth
• CPC Class Codes: A61B 5/15136 by use of radiation, e.g. laser
• CPC Class Codes: A61K 41/0047 : Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
• CPC Class Codes: A61M 2037/0007 : having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
• CPC Class Codes: A61M 37/0092 : using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
• CPC Class Codes: A61N 1/0412 : Specially adapted for transcutaneous electroporation, e.g. including drug reservoirs
• CPC Class Codes: A61N 1/0428 : Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
• CPC Class Codes: A61N 1/0476 : Array electrodes (including any electrode arrangement with more than one electrode for at least one of the polarities)
• 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: A61N 1/327 : for enhancing the absorption properties of tissue, e.g. by electroporation
• CPC Class Codes: A61N 2007/0034 : Skin treatment

Abstract

A method of enhancing the permeability of a biological membrane, including the skin or mucosa of an animal or the outer layer of a plant to a permeant is described utilizing microporation of selected depth and optionally one or more of sonic, electromagnetic, mechanical and thermal energy and a chemical enhancer. Microporation is accomplished to form a micropore of selected depth in the biological membrane and the porated site is contacted with the permeant. Additional permeation enhancement measures may be applied to the site to enhance both the flux rate of the permeant into the organism through the micropores as well as into targeted tissues within the organism.

Claims

1-73. -73. (canceled)

74. A method of delivering a nucleic acid into an organism comprising steps of:

porating a biological membrane at a selected area of the organism to form at least one micropore 1-1000 μ

m in diameter in said biological membrane comprising the step of ablating the biological membrane by placing a heat conducting element in substantial physical contact with the selected area to deliver sufficient energy by conduction to said selected area of said biological membrane such that the temperature of tissue-bound water and other vaporizable substances in said selected area is elevated above the vaporization point of said water and other vaporizable substances, thereby removing the biological membrane in said selected area; and

contacting the selected area with a nucleic acid under conditions whereby the nucleic acid is taken up into the organism through the at least one micropore formed in the biological membrane.

75. The method of claim 74, wherein the nucleic acid is DNA.

76. The method of claim 74, wherein the nucleic acid is RNA.

77. A method for delivering a permeant into an organism comprising steps of:

porating a biological membrane at a selected area of the organism to form at least one micropore 1-1000 μ

m in diameter in said biological membrane, comprising the step of ablating the biological membrane by placing a heat conducting element in substantial physical contact with the selected area to deliver sufficient energy by conduction to said selected area of said biological membrane such that the temperature of tissue-bound water and other vaporizable substances in said selected area is elevated above the vaporization point of said water and other vaporizable substances, thereby removing the biological membrane in said selected area; and

contacting the selected area with a permeant, wherein the permeant is selected from the group consisting of insulin, interferon and heparin, under conditions whereby the permeant is taken up into the organism through the at least one micropore formed in the biological membrane.

78. A method of delivering a permeant associated with a carrier into an organism comprising steps of:

porating a biological membrane at a selected area of the organism to form at least one micropore 1-1000 μ

m in diameter in said biological membrane comprising the step of ablating the biological membrane by placing a heat conducting element in substantial physical contact with the selected area to deliver sufficient energy by conduction to said selected area of said biological membrane such that the temperature of tissue-bound water and other vaporizable substances in said selected area is elevated above the vaporization point of said water and other vaporizable substances thereby removing the biological membrane in said selected area; and

contacting the selected area with the carrier under conditions whereby the permeant associated with the carrier is taken up into the organism through the at least one micropore formed in the biological membrane;

wherein the carrier comprises liposomes, lipid complexes, microparticles, or polyethylene glycol compounds; and

optionally,

wherein the carrier is formulated to have a charge.

79. The method of claim 78, wherein the carrier comprises liposomes.

80. The method of claim 78, wherein the carrier comprises lipid complexes.

81. The method of claim 78, wherein the carrier is formulated to have a charge.

82. The method of claim 78, wherein the carrier comprises microparticles.

83. The method of claim 78, wherein the carrier comprises polyethylene glycol compounds.

84. An apparatus for delivering a dry powder formulation into an organism comprising:

a heat source, which, when put in substantial physical contact with a selected area of a biological membrane of the organism, is capable of porating the biological membrane at the selected area to form at least one micropore 1-1000 μ

m in diameter, by delivering sufficient energy to the selected area such that the temperature of tissue-bound water and other vaporizable substances in the selected area is elevated above the vaporization point of the water and other vaporizable substances, thereby removing the biological membrane in the selected area, and wherein the apparatus enables the dry powder formulation, when the dry powder formulation is put in contact with the selected area, to be taken up through the micropore into the organism, wherein the apparatus delivers the dry powder formulation into the organism.

85. The apparatus of claim 84, wherein the dry powder formulation comprises a peptide(s), protein(s), vaccine antigen, DNA or RNA.

86. The apparatus of claim 84, wherein the dry powder comprises adenovirus.

87. The apparatus of claim 84, wherein the dry powder formulation comprises microparticles.

88. The apparatus of claim 87, wherein said microparticles comprise a bioactive agent(s).

89. The apparatus of claim 88, wherein said bioactive agent(s) is selected from the group consisting of peptide(s), protein(s), vaccine antigen(s), DNA or RNA.

90. The apparatus of claim 89, wherein said DNA or RNA is naked, fragmented, encapsulated or coupled to another agent.

91. An apparatus for delivering a bioactive agent into an organism comprising:

a heat source, which, when put in substantial physical contact with a selected area of a biological membrane of the organism, is capable of porating the biological membrane at the selected area to form at least one micropore 1-1000 μ

m in diameter, by delivering sufficient energy to the selected area such that the temperature of tissue-bound water and other vaporizable substances in the selected area is elevated above the vaporization point of the water and other vaporizable substances, thereby removing the biological membrane in the selected area, and wherein the apparatus enables the bioactive agent, when the bioactive agent is put in contact with the selected area, to be taken up through the micropore into the organism, wherein said bioactive agent is put in contact with the selected area in a form selected from the group consisting of a tablet, a bio-erodable matrix and an adhesive polymer, wherein said bio-erodable matrix and adhesive polymer matrix are fabricated in a manner to allow the bioactive agent to be released into the organism via the mircropore, wherein the apparatus delivers the bioactive agent into the organism.

92. A system for stimulating an immune response in an organism wherein a permant is delivered into the organism comprising:

a heat source, which, when put in substantial physical contact with a selected area of a biological membrane of the organism, is capable of porating the biological membrane at the selected area to form at least one micropore 1-1000 μ

m in diameter and at a depth coincident with increased concentration of langerhans cells, by delivering sufficient energy to the selected area such that the temperature of tissue-bound water and other vaporizable substances in the selected area is elevated above the vaporization point of the water and other vaporizable substances, thereby removing the biological membrane in the selected area, and wherein the system enables the permant, when the permant is put in contact with the selected area, to be taken up through the micropore into the organism, wherein the system stimulates the immune response in the organism.

93. The system of claim 92, wherein the depth of the micropore is 180 microns to 250 microns.

94. The system of claim 92, wherein the organism is a human or an animal.

95. The system of claim 92, wherein the organism is a human.

96. The system of claim 92, wherein the permeant is a vaccine.

97. The system of claim 96, wherein the vaccine comprises DNA or RNA.

98. A process for introducing a permeant into an organism in order to stimulate an immune response in the organism, comprising delivering the permeant into the epidermis at a depth coincident with increased concentration of langerhans cells via micropores formed using the system of claim 92.

99. The process of claim 98, wherein the surface area of the selected area of the biological membrane is greater than the total areas of the micropores.

100. A system for delivering a dry powder formulation into an organism comprising:

a heat source, which, when put in substantial physical contact with a selected area of a biological membrane of the organism, is capable of porating the biological membrane at the selected area to form at least one micropore 1-1000 μ

m in diameter, by delivering sufficient energy to the selected area such that the temperature of tissue-bound water and other vaporizable substances in the selected area is elevated above the vaporization point of the water and other vaporizable substances, thereby removing the biological membrane in the selected area, and wherein the system enables the dry powder formulation, when the dry powder formulation is put in contact with the selected area, to be taken up through the micropore into the organism, wherein the system delivers the dry powder formulation into the organism.

101. The system of claim 100, wherein the dry powder formulation comprises a peptide(s), protein(s), vaccine antigen(s), DNA or RNA.

102. The system of claim 100, wherein the dry powder formulation comprises microparticles.

103. The system of claim 102, wherein said microparticles comprise a bioactive agent(s).

104. The system of claim 103, wherein said bioactive agent(s) is selected from the group consisting of peptide(s), protein(s), vaccine antigen(s), DNA or RNA.

105. The system of claim 104, wherein said DNA or RNA is naked, fragmented, encapsulated or coupled to another agent.

106. A system for delivering a bioactive agent into an organism comprising:

a heat source, which, when put in substantial physical contact with a selected area of a biological membrane of the organism, is capable of porating the biological membrane at the selected area to form at least one micropore 1-1000 μ

m in diameter, by delivering sufficient energy to the selected area such that the temperature of tissue-bound water and other vaporizable substances in the selected area is elevated above the vaporization point of the water and other vaporizable substances, thereby removing the biological membrane in the selected area, and wherein the system enables the bioactive agent, when the bioactive agent is put in contact with the selected area, to be taken up through the micropore into the organism, wherein said bioactive agent is put in contact with the selected area in a form selected from the group consisting of a tablet, a bio-erodable matrix and an adhesive polymer, wherein said bio-erodable matrix and adhesive polymer matrix are fabricated in a manner to allow the bioactive agent to be released into the organism via the mircropore, wherein the system delivers the bioactive agent into the organism.