Method for pressure mediated selective delivery of therapeutic substances and cannula

#This invention concerns selective delivery of therapeutic agents, such as drugs or genetic vectors, to specific organs, tissue compartments or cell types.

#Local delivery of therapeutic agents to target organs or tissues is a very desirable technique for delivering drugs with minimal side effects. U.S. Pat. No. 5,087,244 is an example of such targeted drug delivery, in which an endovascular catheter has a flexible balloon that is inflated to contact the internal walls of the vessel. A drug is then delivered through minute holes in the balloon, which is in intimate contact with the walls of the vessel. U.S. Pat. No. 5,282,785 discloses another endovascular drug delivery catheter, in which an expandable balloon brings a perforated drug delivery portion of the catheter into intimate contact with a radially restricted portion of the vessel wall, for transmural delivery of drugs through the contiguous catheter and lumen wall. See also U.S. Pat. No. 5,662,609, according to which a catheter with a pair of expandable balloons is used to isolate a portion of a blood vessel between the balloons for treatment via infusions, and U.S. Pat. No. 5,674,192, in which a single expandable balloon is used to contact a portion of vessel wall for treatment.

#U.S. Pat. Nos. 4,781,677 and 5,514,088 both disclose treatment of gallstones by direct infusion of a solvent (such as methyl tertiary butyl ether) into the gallbladder through a catheter positioned in that organ.

#FIG. 1 is a schematic view of the epithelial cells that line the gallbladder (A), the small bile ducts (B), and the liver (C).

#FIGS. 2A and 2C are schematic views of site specific delivery to the apical surface of an epithelial cell in a gall bladder at relatively low biliary pressures; FIGS. 2B and 2D show site specific delivery to the subepithelial space at higher biliary pressures.

#FIG. 3A is a schematic view of site specific delivery to the apical surface of a hepatocyte in the liver at relatively low, subthreshold hepatobiliary pressures, while FIG. 3B is a schematic view of delivery to the subepithelial layers once the threshold pressure is exceeded.

#The present invention is a method of specific delivery of agents (such as therapeutic or diagnostic drugs) into pressurized body cavities, such as the lumen of an organ, including a hollow viscus (e.g. gallbladder, small intestine) or a duct (e.g. the ducts of the salivary, parotid or hepatobiliary systems). The body cavities are anatomically, manometrically isolated (for example by occluding one or more ducts from the organ that communicate with the gastrointestinal tract). An agent to be delivered is then introduced by an infusion into the isolated body cavity either above or below a threshold pressure/flow/volume at which transepithelial delivery of the agent occurs. Hence agents delivered below this threshold are delivered preferentially to the cells of a superficial epithelial lining, while agents delivered above this threshold are also delivered to the subepithelial space (which can include periductular or even systemic vascular administration, for example through the sinusoids of the liver).

#Many cavitary organs in the body (such as the gall bladder, hepatobiliary ducts, parotid ducts, and gastrointestinal organs) contain epithelial cells that are lined by polarized epithelial cells. These cells are “polarized” in the sense that they have an apical surface facing the lumen, and a basal surface which is substantially isolated from the lumen by tight junctions between the epithelial cells. The surfaces of these polar cells are often specialized for unidirectional passage of biological substances through the cell, for example for delivery into the lumen.

#FIG. 1 shows schematic cross-sections of the histological architecture of several different classes of tissue, FIG. 1A shows the architecture common in gallbladder, large bile ducts and intestine, in which polarized epithelial cells 30 are joined to one another by tight junctions 32, which isolate the apical surfaces 34 of the cells 30 from a basal cellular surface 36 and a subepithelial space 38 having a lamina propria. The architecture of the small bile ducts in FIG. 1B illustrates that the epithelial cells (called cholangiocytes in these bile ducts) have a subepithelial space that is occupied by a capillary plexus, but does not have a lamina propria. FIG. 1C shows that in the liver, the subepithelial space 38 is occupied by the Space of Disse and the sinusoids of the liver, but no lamina propria.