WO2016025850A1

WO2016025850A1 - Pericardial drug delivery device and method of use

Info

Publication number: WO2016025850A1
Application number: PCT/US2015/045305
Authority: WO
Inventors: Stephanie Toy; Mark Ka Lai LEE; Scott R. Gibson; Mallory HOLLAND
Original assignee: Amgen Inc.
Priority date: 2014-08-15
Filing date: 2015-08-14
Publication date: 2016-02-18

Abstract

A pericardial drug delivery device includes a delivery cannula (102) with a proximal end and a distal end and a drive. The distal end of the cannula includes an elongated tip with a first tip end and a second tip end disposed along a tip axis, and a hollow, arcuate retractor (136) transverse to the tip axis with a first retractor end attached to the second tip end and second retractor end attached to the proximal end of the delivery cannula. The drive is coupled to the distal end of the cannula to move the distal end in a distal direction into the pericardium. As an alternative to the hollow, arcuate retractor, the pericardial drug delivery device may include a pair of jaws (332) having open and closed states. Methods are also disclosed of using a pericardial drug delivery device to enlarge a pericardial space and deliver a drug therein.

Description

PERICARDIAL DRUG DELIVERY DEVICE AND METHOD OF USE

Cross-Reference to Related Application

[0001] The priority benefit of U.S. Provisional Patent Application No. 62/037,743, filed August 15, 2014, is claimed, and the entire contents thereof are expressly incorporated herein by reference.

Background

[0002] This patent is directed to a drug delivery device, and, in particular, to a drug delivery device used to deliver a drug into the pericardial space and/or the heart.

[0003] The pericardium encloses the whole heart, creating a small and relatively isolated fluid- filled compartment which provides a unique space that holds a vast potential for localized drug delivery of a number of agents to the heart. Localized drug delivery carries the potentials for increased effectiveness of treatments while reducing the quantities needed. Compounds introduced into the pericardial fluid can access coronary arteries with intramural concentrations, provide greater consistency than endoluminal delivery, and have prolonged coronary exposure.

[0004] It may be necessary to deliver drugs to the cardiac muscle for several indications, including myocardial infarction. This may be achieved by delivering the drugs to the pericardial space about the heart. The pericardial space can be difficult to access, however, and serious complications can occur when an attempt is made to access the space. For instance, there is a risk of perforation of the heart. This can result in hemopericaridium and/or injury to epicardial vessels.

[0005] As set forth in more detail below, the present disclosure sets forth an improved drug delivery device embodying advantageous alternatives to the conventional devices and methods for delivering drugs into the pericardial space. This drug delivery device may be used to deliver drugs to the cardiac muscle for myocardial infarction or any other indication that may benefit from more direct access to the heart.

Summary

[0006] According to an aspect of the present disclosure, a pericardial drug delivery device includes a needle having an internal passage and a distal end configured for insertion into a patient adjacent the pericardium. The pericardial drug delivery device also includes a pericardium retractor movable relative to the needle and configured to pull a section of the pericardium into the internal passage of the needle to enlarge the pericardial space beneath the section of the pericardium.

Additionally, the pericardial drug delivery device includes a delivery cannula extending through the needle and configured for insertion through the pericardium to deliver a drug to the enlarged pericardial space.

[0007] According to another aspect of the present disclosure, a pericardial drug delivery device includes a delivery cannula with a proximal end and a distal end, and a drive. The distal end of the cannula includes an elongated tip with a first tip end, a second tip end, and a hollow, arcuate retractor, the first tip end and the second tip end being disposed along a tip axis, the hollow, arcuate retractor being transverse to the tip axis and having a first retractor end attached to the second tip end and a second retractor end attached to the proximal end of the delivery cannula. The drive is coupled to the distal end of the cannula to move the distal end in a distal direction into the pericardium.

[0008] According to another aspect of the present disclosure, a method of delivering a drug to cardiac tissue via the pericardial space includes introducing a delivery cannula having a distal cannula end comprising a tip with a first tip end, a second tip end, and a hollow, arcuate retractor, the first tip end and the second tip end being disposed along a tip axis, the hollow arcuate retractor being transverse to the tip axis with a first retractor end attached to the second tip end and a second retractor end. The method also includes advancing the tip into the pericardium from a point external to the heart, advancing the retractor into the pericardium to expand the pericardial space, and administering a drug through the retractor.

[0009] According to a further aspect of the present disclosure, a pericardial drug delivery device includes a delivery cannula with a proximal end and a distal end, the distal end comprising an elongated tip with a tip end and a hollow, helical retractor attached to the elongated tip. The device also includes a drive coupled to the distal end to move the distal end in a distal direction into the pericardium.

[0010] According to a still further aspect of the present disclosure, a method of delivering a drug to cardiac tissue via the pericardial space includes introducing a delivery cannula having a distal cannula end comprising an elongated tip with a first tip end and a hollow, helical retractor attached to the elongated tip. The method also includes advancing the elongated tip into the pericardium from a point external to the heart, advancing the retractor into the pericardium to expand the pericardial space, and administering the drug through the retractor.

[0011] According to yet another aspect of the present disclosure, a pericardial drug delivery device includes a delivery cannula with a proximal end and a distal end, and a pair of jaws having an open state wherein inner surfaces of the pair of jaws are spaced from each other and a closed state wherein the inner surfaces of the pair of jaws are closer to each other than in the open state. The distal end of the delivery cannula depends from the inner surface of one of the pair of jaws. The device also includes an elongated control rod having a proximal end and a distal end attached to at least one of the pair of jaws, the control rod having a first position relative to the pair of jaws corresponding to the open state and a second position relative to the pair of jaws corresponding to the closed state.

[0012] According to a further aspect of the present disclosure, a method of delivering a drug to cardiac tissue via the pericardial space includes introducing a delivery cannula with a proximal end and a distal end, and a pair of jaws with inner surfaces, the distal end of the delivery cannula depending from the inner surface of one of the pair of jaws. The method also includes advancing the cannula and the pair of jaws to the pericardium from a point external to the heart, closing the pair of jaws on a section of the pericardium, the distal end of the cannula advancing into through the pericardium as the pair of jaws are closed, withdrawing the delivery cannula and the pair of jaws to expand the pericardial space, and administering the drug through the cannula.

[0013] According to a still further aspect of the present disclosure, a method of treating a heart condition in a patient having need of such treatment includes introducing and advancing any of the foregoing drug delivery devices into the pericardium from a point external to the heart, expanding the pericardial space, and administering a drug through the cannula.

Brief Description of the Drawings

[0014] It is believed that the disclosure will be more fully understood from the following description taken in conjunction with the accompanying drawings. Some of the figures may have been simplified by the omission of selected elements for the purpose of more clearly showing other elements. Such omissions of elements in some figures are not necessarily indicative of the presence or absence of particular elements in any of the exemplary embodiments, except as may be explicitly delineated in the corresponding written description. None of the drawings are necessarily to scale.

[0015] Fig. 1 is a perspective view of an embodiment of a pericardial drug delivery device in combination with a needle used to introduce the pericardial drug delivery device into the patient, the needle illustrated in cross-section;

[0016] Fig. 2 is an enlarged, perspective view of a distal end of the pericardial drug delivery device of Fig. 1;

[0017] Fig. 3 is a perspective view of the pericardial drug delivery device and a partial cross- sectional view of the needle of Fig. 1, advanced toward the pericardium;

[0018] Fig. 4 is a perspective view of the pericardial drug delivery device and a partial cross- sectional view of the needle of Fig. 1, with a tip disposed at the distal end of the device advanced through the pericardium;

[0019] Fig. 5 is a perspective view of the pericardial drug delivery device and a partial cross- sectional view of the needle of Fig. 1, with the pericardium drawn onto a helical retractor disposed at the distal end of the device;

[0020] Fig. 6 is an enlarged perspective view of the pericardium and helical retractor as illustrated in Fig. 5;

[0021] Fig. 7 is a schematic diagram of an alternative embodiment of the pericardial drug delivery device;

[0022] Fig. 8 is a perspective view of another embodiment of a pericardial drug delivery device in combination with a needle to introduce the pericardial drug delivery device into the patient, the needle illustrated in cross-section;

[0023] Fig. 9 is an enlarged, side view of a distal end of the pericardial drug delivery device of Fig. 8 with its jaws open; and

[0024] Fig. 10 is a perspective view of the pericardial drug delivery device and a partial cross- sectional view of the needle of Fig. 8, with the pericardium drawn into the jaws of the device and the pericardium pierced by a distal end of a drug delivery cannula.

Detailed Description of Various Embodiments

[0025] A drug delivery device is described herein for use in administering a drug into the pericardial space, for example. In particular, the device is well suited to be used in a minimally- invasive procedure for accessing the heart, expanding a portion of the pericardial space and administering a drug at least to the portion of the pericardial space that has been expanded. The device may be used to pass other materials into the pericardial space as well.

[0026] In one embodiment, a pericardial drug delivery device comprises a needle having an internal passage and a distal end configured for insertion into a patient adjacent the pericardium; a pericardium retractor movable relative to the needle and configured to pull a section of the pericardium into the internal passage of the needle to enlarge the pericardial space beneath the section of the pericardium; and a delivery cannula extending through the needle and configured for insertion through the pericardium to deliver a drug to the enlarged pericardial space.

[0027] According to another embodiment, the delivery cannula has a distal end and a proximal end, the distal end of the delivery cannula defining the pericardium retractor.

[0028] According to another embodiment, the distal end of the delivery cannula has a hollow linear shaft and a hollow arcuate shaft, the hollow linear shaft defining a distal tip of the distal end of the delivery cannula, and the hollow arcuate shaft being arranged proximal to the hollow linear shaft.

[0029] According to another embodiment, the hollow arcuate shaft defines a helix.

[0030] According to another embodiment, the helix has a plurality of turns of constant diameter.

[0031] According to another embodiment, a stop is disposed between the hollow arcuate shaft and the proximal end of the delivery cannula, the stop having an outer diameter greater than an outer diameter of the helix.

[0032] According to another embodiment, the delivery cannula has a longitudinal axis, the hollow linear shaft and the proximal end of the delivery cannula being disposed along the longitudinal axis, and the helix traversing about the longitudinal axis.

[0033] According to another embodiment, a drive is coupled to the delivery cannula and configured to move the distal end of the delivery cannula in at least one of a distal direction for insertion through the pericardium and a proximal direction to pull the pericardium into the internal passage of the needle. [0034] According to another embodiment, the pericardium retractor comprises at least two jaws having an open state wherein inner surfaces of the at least two jaws are spaced from each other and a closed state wherein the inner surfaces of the at least two jaws are closer to each other than in the open state.

[0035] According to another embodiment, an elongated control rod has a proximal end and a distal end attached to at least one of the at least two jaws, the control rod having a first position relative to the at least two jaws corresponding to the open state and a second position relative to the at least two jaws corresponding to the closed state.

[0036] According to another embodiment, the delivery cannula has a distal end and a proximal end, the distal end of the delivery cannula depending from the inner surface of one of the at least two jaws.

[0037] According to another embodiment, the distal end of the delivery cannula is defined by a rigid or semi-rigid needle and the proximal end of the delivery cannula is defined by a flexible catheter.

[0038] According to another embodiment, the rigid or semi-rigid needle is transverse to the inner surface of the one of the at least two jaws.

[0039] According to another embodiment, an outer perimeter of each of the inner surfaces is defined by a gripping edge, each gripping edge having one or more teeth depending toward the other one of the at least two jaws.

[0040] According to another embodiment, a scissors linkage includes the at least two jaws and at least two links, each link being attached at a first end to the distal end of the elongated control rod and at a second end to one of the at least two jaws.

[0041] In a further embodiment, a pericardial drug delivery device comprises a delivery cannula with a proximal end and a distal end, the distal end comprising an elongated tip with a first tip end, a second tip end, and a hollow, arcuate retractor, the first tip end and the second tip end being disposed along a tip axis, the hollow, arcuate retractor being transverse to the tip axis and having a first retractor end attached to the second tip end and a second retractor end attached to the proximal end of the delivery cannula; and a drive coupled to the distal end to move the distal end in a distal direction into the pericardium.

[0042] According to another embodiment, the elongated tip is hollow. [0043] According to another embodiment, the hollow, arcuate retractor defines a helix.

[0044] According to another embodiment, the helix has a plurality of turns of constant diameter.

[0045] According to another embodiment, the proximal end of the delivery cannula comprises an elongated hollow shaft with a first end attached to the second retractor end, and a second end coupled to the drive.

[0046] According to another embodiment, the delivery cannula has a longitudinal axis, and the elongated tip and the elongated shaft are disposed along the longitudinal axis.

[0047] According to another embodiment, the hollow, arcuate retractor defines a helix, the helix traversing about an axis disposed along the longitudinal axis.

[0048] According to another embodiment, the drive comprises a spring coupled to the proximal end of the cannula, the spring optionally being a Belleville spring.

[0049] According to another embodiment, a stop is disposed between the second retractor end and the proximal end of the cannula.

[0050] In a further embodiment, a method of delivering a drug to cardiac tissue via the pericardial space comprises introducing a delivery cannula having a distal cannula end comprising a tip with a first tip end, a second tip end, and a hollow, arcuate retractor, the first tip end and the second tip end being disposed along a tip axis, the hollow, arcuate retractor being transverse to the tip axis with a first retractor end attached to the second tip end and a second retractor end; advancing the tip into the pericardium from a point external to the heart; advancing the retractor into the pericardium to expand the pericardial space; and administering the drug through the retractor.

[0051] According to another embodiment, advancing the tip into the pericardium comprises actuating a spring coupled to the distal cannula end to move the distal cannula end in a distal direction.

[0052] According to another embodiment, advancing the retractor into the pericardium comprises rotating the delivery cannula about a longitudinal axis of the delivery cannula.

[0053] According to another embodiment, the tip is hollow, and the method further comprises administering the drug through the hollow tip. [0054] According to another embodiment, introducing the delivery cannula comprises introducing the delivery cannula via a subxiphoid approach.

[0055] According to a still further embodiment, a pericardial drug delivery device comprises a delivery cannula with a proximal end and a distal end, the distal end comprising an elongated tip with a tip end and a hollow, helical retractor attached to the elongated tip; and a drive coupled to the distal end to move the distal end in a distal direction into the pericardium.

[0056] According to another embodiment, the elongated tip is hollow.

[0057] According to another embodiment, the proximal end of the delivery cannula comprises an elongated hollow shaft attached to the hollow, helical retractor and the drive.

[0058] According to another embodiment, the drive comprises a Belleville spring coupled to the proximal end of the cannula.

[0059] According to further embodiment, a method of delivering a drug to cardiac tissue via the pericardial space comprises introducing a delivery cannula having a distal cannula end comprising an elongated tip with a first tip end and a hollow, helical retractor attached to the elongated tip; advancing the elongated tip into the pericardium from a point external to the heart; advancing the retractor into the pericardium to expand the pericardial space; and administering a drug through the retractor.

[0060] According to a still further embodiment, a pericardial drug delivery device comprises a delivery cannula with a proximal end and a distal end; a pair of jaws having an open state wherein inner surfaces of the pair of jaws are spaced from each other and a closed state wherein the inner surfaces of the pair of jaws are closer to each other than in the open state, the distal end of the delivery cannula depending from the inner surface of one of the pair of jaws; and an elongated control rod having a proximal end and a distal end attached to at least one of the pair of jaws, the control rod having a first position relative to the pair of jaws corresponding to the open state and a second position relative to the pair of jaws corresponding to the closed state.

[0061] According to another embodiment, the distal end of the cannula includes a rigid or semi-rigid needle and the proximal end of the cannula includes a flexible catheter. [0062] According to another embodiment, the rigid or semi-rigid needle is transverse to the inner surface of the one of the pair of jaws.

[0063] According to another embodiment, an outer perimeter of each of the inner surfaces is defined by a gripping edge, each edge having one or more teeth disposed thereat and depending toward the other one of the pair of jaws.

[0064] According to another embodiment, the drug delivery device comprises a scissors linkage including the pair of jaws and two links, each link attached at a first end to the distal end of the elongated control rod and at a second end to one of the pair of jaws.

[0065] According to a further embodiment, a method of delivering a drug to cardiac tissue via the pericardial space comprises introducing a delivery cannula with a proximal end and a distal end, and a pair of jaws with inner surfaces, the distal end of the delivery cannula depending from the inner surface of one of the pair of jaws; advancing the cannula and the pair of jaws to the pericardium from a point external to the heart; closing the pair of jaws on a section of the pericardium, the distal end of the cannula advancing into through the pericardium as the pair of jaws are closed;

withdrawing the delivery cannula and the pair of jaws to expand the pericardial space; and administering a drug through the cannula.

[0066] According to another embodiment, introducing the delivery cannula comprises introducing the delivery cannula via a subxiphoid approach.

[0067] According to another embodiment, any of the foregoing pericardial drug delivery devices further comprising a drug to treat a heart condition.

[0068] According to another embodiment, the heart condition is selected from the group consisting of hypertrophy, hypertension, chronic heart failure, acute heart failure, congestive heart failure, acute decompensatory failure, pericardial pericarditis and cardiomyopathy.

[0069] According to another embodiment, the heart condition is cardiac failure or autoreactive pericardial pericarditis.

[0070] According to another embodiment, the drug is TIMP-3 or an APJ agonist.

[0071] According to another embodiment, the drug is selected from the group consisting of esmolol, solatol, atenolol, ibutalide, procainamide, digoxin, amiodarone, arachadonic acid, nitroglycerin, TIMP 3, an APJ agonist and L-arginine. [0072] According to a still further embodiment, a method of treating a heart condition in a patient having need of such treatment comprises introducing and advancing any of the foregoing pericardial drug delivery devices into the pericardium from a point external to the heart; expanding the pericardial space; and administering a drug through the cannula.

[0073] Referring first to Figs. 1 and 2, an embodiment of a pericardial drug delivery device 100 according to the present disclosure is illustrated. The delivery device 100 includes a delivery cannula 102 and a drive 104 coupled to the delivery cannula 102. It should be understood that the delivery cannula 102 may be rigid, e.g., made or formed of metal, or flexible. The drive 104 is used to rapidly advance the delivery cannula 102 to pierce or puncture the pericardium 210, the pericardium 210 then being drawn up the delivery cannula 102 to expand the pericardial space 230 at least in the region adjacent to the distal end 112 of the delivery cannula 102 that is disposed in the pericardial space 230.

[0074] As is illustrated in Fig. 1, the device 100 is introduced into a patient using a needle 110 having a distal end 112 with a leading edge 114 shaped (e.g., beveled) so that the leading edge 114 may be used to puncture tissue structures on the approach to the heart. According to certain embodiments, the needle 110 may have a distal end 112 similar to a Touhy or Huber-type needle, for example. The introduction of the needle 110 may be by a subxiphoid approach, as pericardial access via the subxiphoid approach presently is considered to be the safest. The needle 110 has a passage 116 in which the device 100 is disposed and along which the device 100 advances in response to the action of the drive 104. A proximal end 118 of the needle 110 may be attached to a knob 120 or other device for manipulating the needle 110, and possibly actuating the drive 104.

[0075] According to certain embodiments, the needle 110 may have having a secondary passage 122, as is illustrated in Fig. 1. The secondary passage 122 may extend from the distal end 112 to the proximal end 118, similar to the passage 116. The needle 110 may be described as a dual-lumen needle, and additional secondary passages may be included to define a multi-lumen needle. The secondary passage 122 may be used for the introduction of procedural leads, such as for conductive mapping of cardiac tissue for example. [0076] The delivery cannula 102 has a distal end 130 and a proximal end 132. As seen in greater detail in Fig. 2, the distal end 132 includes an elongated tip 134 and a hollow, arcuate retractor 136. According to at least one embodiment, the elongated tip 134 may be a hollow linear shaft that defines the distal tip of the distal end 132 of the delivery cannula 102. The elongated tip 134 may have a blunt first tip end 138 and a second tip end 140 disposed along a tip axis 142 as illustrated, but according to other embodiments the blunt tip end 134 may be replaced with a beveled or other shape (e.g., similar to a Touhy or Huber-type needle) end. While the elongated tip 134 may be relatively straight between the ends 138, 140 as is illustrated, the elongated tip 134 may also be bent or have a certain degree of curvature between the ends 138, 140, in which case the tip axis 142 may be defined by a line that is parallel or collinear with a line connecting the ends 138, 140. The arcuate retractor 136 is transverse to the tip axis 142 with a first retractor end 144 attached to the second tip end 140 and second retractor end 146 attached to the proximal end 132 of the delivery cannula 102.

[0077] In particular and with respect to Fig. 1, the proximal end 132 of the delivery cannula 102 may include an elongated hollow shaft 148 with a first end 150 attached to the second retractor end 146, and a second end 152 coupled to the drive 104. The delivery cannula 102 may be described as having a longitudinal axis 154, and the tip 134 and the shaft 148 may be disposed along the longitudinal axis 154, as illustrated (i.e., the tip axis 142 may be collinear with the longitudinal axis 154). It will be recognized that if the shaft 148 is capable of bending or deflecting under load, then this relationship may appear only when the loading is removed.

[0078] The delivery cannula 102 may be hollow, in whole or in part, such that a passage 156 (see Fig. 2) is defined by an inner surface of a wall of the cannula 102. According to certain embodiments, the cannula 102 may be hollow from a point at or adjacent the proximal end 132 of the cannula, along the shaft 148 and the retractor 136, and into the elongated tip 134; according to other embodiments, the elongated tip 134 may not be hollow or may be only partially hollow. The passage 156 (see Fig. 2) may thus extend between the distal and proximal ends 130, 132 of the cannula 102 through which a drug may be administered. According to other embodiments, procedural tools such as electric mapping leads, which may be used to map damaged cardiac tissue for more precise delivery of therapy, may be advanced through the passage 156 as well.

[0079] According to certain embodiments, the elongated tip 134 and retractor 136 may each have one or more apertures 158, 160 in fluid communication with the passage 156 through which a drug, fluid or procedural tool (e.g., a lead) may exit the elongated tip 134 and/or retractor 136. The one or more apertures 158 in the tip 134 may be disposed through a surface 162 of the tip 134 between the first tip end 138 and the second tip end 140. By virtue of the placement of the apertures 158, the drugs, fluids, leads, etc. may exit the tip 134 in a direction transverse to the tip axis 142. The apertures 160 in the retractor 136 may also be disposed through a surface 164 of the retractor 136 and similarly allow egress in a direction transverse to the axis 142.

[0080] As illustrated, the hollow, arcuate retractor 136 may define a helix. The helix may have a plurality of turns 170 of constant outer diameter Dl. As illustrated, the helix 136 includes three turns with an outer diameter Dl of 2mm, as measured across the turn. In addition, where the hollow, arcuate retractor 136 defines a helix, the helix may traverse about (e.g., wrap around) an axis 172 disposed along the longitudinal axis 154 of the cannula 102. As illustrated, the axis 172 thus is also collinear with the tip axis 142.

[0081] The helix 136 may be adapted to permit the cannula 102 to puncture the pericardium, but avoid puncturing other cardiac structures and causing damage. More generally, the helix 136 and the drive 104 may be adapted as a system to permit the operation of the drive 104 to advance the cannula 102 to permit the tip 134 to puncture the pericardium while avoiding puncturing other cardiac structures. The two structures may work together, such that the drive 104 advances the tip 134 while the helix 136 deflects like a spring to absorb force and energy applied to the tip 134 by the drive 104 such that the result is that the tip 134 punctures the pericardium but does not puncture cardiac muscle or other structures. It will be recognized that

consideration of the rigidity (or flexibility) of other portions of the cannula 102 (e.g., the tip 134 or the shaft 148) also may need to be considered in addition to the flexibility of the helix 136, although this need not be the case according to all embodiments.

[0082] A stop 180 may be disposed between the second retractor end 144 and the proximal end 132 of the cannula 102. In at least one embodiment, the stop 180 is disposed about the second retractor end 146. The stop 180 may be used to control the distance to which the distal end 132 of the cannula 102 advances into the pericardial space, or alternatively how far the pericardium may be advanced along the retractor 136. Consequently, the stop 180 may be used to limit the risk of puncture of other heart structures. To achieve this functionality, some embodiments of the stop 180 may have an outer diameter D2 which is greater the outer diameter Dl of the turns 170 of the helix 136, or at least greater than an outer diameter D3 of the second retractor end 146. The stop 180 may be fixedly attached to an outer surface 182 of the cannula 102 (Fig. 2), or the stop 180 may include an adjustable fastener that would permit the stop 180 to be moved relative to the helix 136 to define a user-controlled penetration depth and then secured (at least temporarily) to the outer surface 182 of the cannula 102.

[0083] As illustrated in Fig. 2, the stop 180 may include a dish-shaped wall 184 with a first surface 186 facing the helix 136 and a second surface 188 facing the proximal end 132 of the cannula 102, although the dish- shaped nature of the wall 184 is not required according to all embodiments. The stop 180 may have an outer edge 190 that defines a perimeter and the outer diameter D2 of the stop 180. The outer diameter D2 of the stop 180 may be, for example, larger than the diameter Dl of the turns 170 of the helix 136; for example, the stop 180 may have a diameter of 3 mm.

[0084] The delivery cannula 102, including the elongated tip 134, the retractor 136 and the shaft 148, may be made of a drug and tissue compatible material, such as stainless steel or nickel titanium alloy. It will be recognized that the entire cannula 102 may be made of the same material, or different sections of the cannula 102 may be made of different materials (e.g., different materials used to make the tip 134 and the retractor 136, or the tip 134/retractor 136 and the shaft 148, for example). It also will be recognized that the different sections of the cannula 102 may be attached using a joining process, or the cannula 102 may be made as a single structure (i.e., integrally).

[0085] The drive 104 is coupled to the distal end 130 of the cannula 102 to move the distal end 130 in a distal direction (i.e., in the direction of the distal end 130, as opposed to the proximal end 132) into the pericardium. As illustrated, the drive 104 is coupled to the proximal end 132 (e.g., to the shaft 148), which is attached to the retractor 136 and tip 134 at the distal end 130, and is thereby coupled to the distal end 130. The drive 104 may include a spring 200 that is coupled to the proximal end 132 of the cannula 102. In particular, the spring 200 may be, inter alia, a Belleville spring as is illustrated. The device 104 may be configured to move the distal end 130 of the delivery cannula 102 in the distal and/or proximal directions, and/or rotate the distal end 130 of the delivery cannula 102 the clockwise and/or counterclockwise directions. In some embodiments, the device 104 may include an electronic motor controllable via a user interface by a surgeon.

[0086] A method of delivering a drug to cardiac tissue via the pericardial space (which has been exaggerated for ease of illustration), such as may be carried out using the device 100 and as is illustrated in Figs. 3-6, may include the following steps.

Initially, the delivery cannula 102 having a distal cannula end 130 and including a tip 134 with a first tip end 138 and a second tip end 140 disposed along a tip axis 142 (see Figs. 2 and 3) and a hollow, arcuate retractor 136 transverse to the tip axis 142 with a first retractor end 144 attached to the second tip end 140 and a second retractor end 146 (again, see Figs. 2 and 3) may be introduced (see Fig. 3). The tip 134 may be advanced into the pericardium 210 from a point external to the heart 220 (see Fig. 4), and the retractor 136 may be advanced into the pericardium 210 to expand the pericardial space 230 (see Figs. 5 and 6). A drug may then be administered through the cannula 102 and ultimately the retractor 136, as indicated by the arrows in Figs. 5 and 6.

[0087] The action of introducing the delivery cannula 102 may include introducing the delivery cannula 102 via a subxiphoid approach. According to a subxiphoid approach, the needle 110 would be inserted between the xiphoid process and the left costal margin at a 30-degree angle to the skin and directed toward the left shoulder. The needle 110 then may be advanced toward the heart under ultrasound guidance, for example.

[0088] The action of advancing the tip 134 into the pericardium 210 may include actuating a spring 200 (see Fig. 1) coupled to the distal cannula end 130 to move the distal cannula end 130 in a distal direction. The action of advancing the retractor 136 into the pericardium 210 also may include actuating the spring 200 coupled to the distal cannula end 130 to move the distal cannula end 130 in a distal direction, however this may be avoided in certain embodiments. According to these

embodiments, the action of advancing the retractor 136 into the pericardium 210 may include rotating the delivery cannula 102 (and potentially the needle 110) about the longitudinal axis 154 of the delivery cannula 102 in a first rotational direction, thereby causing a section of the pericardium 210 to slide along, and be pulled away from the remainder of the heart, by the turns 170 of the helix 136 of the hollow, arcuate retractor 136. In at least one embodiment, pulling a section of the pericardium 210 away from the remainder of the heart with the hollow, arcuate retractor 136 may involve pulling the section of the pericardium 210 into the internal passage 116 of the needle 110, as illustrated in Figs. 5 and 6. By pulling the section of the pericardium 210 away from the remainder of the heart with the hollow, arcuate retractor 136, the pericardial space 230 beneath the section of the pericardium 210 may be enlarged or expanded.

[0089] Where the tip 134 is hollow (as is illustrated), the method may include administering the drug through the hollow tip 134 in addition to administering the drug through the retractor 136. The drug is expelled from the hollow tip 134 and/or the retractor 136 into the enlarged pericardial space 230. It will be recognized that if the cannula 102 has apertures 158 in the tip 134, the drug must still pass through the retractor 136, such that the drug is administered through the retractor 136. Of course, if apertures 160 are provided in the retractor 136, then the drug may only pass through and be administered through the retractor 136.

[0090] Upon completion of drug delivery, the method may include rotating the delivery cannula 102 about the longitudinal axis 154 in a second rotational direction, opposite the first rotational direction, so that the pericardium 210 slides back down the turns 170 of the helix 136 of the hollow, arcuate retractor 136.

[0091] As a further alternative embodiment, a pressure sensor 240 may be coupled to or otherwise associated with the tip 134. In particular, the pressure sensor 240 may be fitted on or attached to the end 138 of the tip 134. See, e.g., Fig. 2. As illustrated in Fig. 7, the pressure sensor 240 may be coupled to a controller 250, and may provide or transmit a signal to the controller 250 that the controller 250 may use to determine if an indication should be provided to the user via an output device 252 coupled to the controller 250 that the tip 134 has pierced the pericardium 210. The controller 250 or other circuitry may provide power to the sensor 240.

[0092] According to the illustrated embodiment, the controller 250 may include at least one processor 254 and memory 256, the processor 254 programmed to carry out the actions that the controller 250 is adapted to perform and the memory 256 including one or more tangible non-transitory readable memories having executable instructions stored thereon, which instructions when executed by the at least one processor 254 may cause the at least one processor 254 to carry out the actions that the controller 250 is adapted to perform. Alternatively, the controller 250 may include other circuitry that carries out the actions that the controller 250 is adapted to perform. The output device 252 may be any of a number of different output devices that provide, by way of example and not by way of limitation, an audible, visible or tactile indication to the user (e.g., a light emitting diode (LED), a video monitor, a speaker, or a vibration generator).

[0093] The sensor 240 may provide a signal to the controller 250 that the pressure is increasing as the tip 134 abuts the pericardium 210 and then as the pericardium 210 resists the further motion of the tip 134. The sensor 240 may provide a further signal to the controller 250 that the pressure has suddenly decreased once the pericardium 210 has been pierced by the tip 134. The controller 250 may be adapted to receive these signals from the sensor 240 (either directly or via circuitry and/or additional processors), and to determine that the pericardium 210 has been pierced based on the change in the signal from the sensor 240. The controller 250 may then activate the output device 252 to indicate to the user that the pericardium 210 has been pierced.

[0094] As a further alternative embodiment, a pericardial drug delivery device 300 is illustrated in Figs. 8-10. The pericardial drug delivery device 300 may be introduced to the patient using a needle 310 having a distal end 312 with a leading edge 314 shaped (e.g., beveled) so that the leading edge 314 may be used to puncture tissue structures. As was the case relative to the embodiment illustrated in Figs. 1-6, the needle 310 may have a distal end 312 similar to a Touhy or Huber-type needle, for example. The introduction of the needle 310 may be by subxiphoid approach, as pericardial access via the subxiphoid approach presently is considered to be the safest. The hollow needle 310 may have one or more passages, at least one passage 316 in which the device 300 is disposed and along which the device 300 advances from a proximal end 318 of the needle 310 to the distal end 312.

[0095] The drug delivery device 300 includes a delivery cannula 330, a pair of jaws 332, 334 and an elongated control rod 336. The delivery cannula 330 has a distal end 338 and a proximal end 340. The pair of jaws 332, 334 have an open state wherein inner surfaces 342, 244 of the jaws 332, 334 are spaced from each other (see Figs. 8 and 9) and a closed state wherein the inner surfaces 342, 344 of the jaws 332, 334 are closer to each other than in the open state (see Fig. 10; the inner surfaces 342, 344 are also most clearly illustrated in Fig. 10). The distal end 338 of the delivery cannula 330 depends from the inner surface 344 of one of the pair of jaws 334. The elongated control rod 336 has a distal end 346 attached to the pair of jaws 332, 334 and a proximal end 348 adapted to be manipulated by the user, for example through a knob or handle 350. The control rod 336 has a first position relative to the jaws 332, 334 corresponding to the open state, and a second position relative to the jaws 332, 334 corresponding to the closed state.

[0096] More particularly, as is best illustrated in Fig. 9, the distal end 338 of the cannula 330 may be defined by a rigid or semi-rigid needle 360 and the remainder of the cannula 330 may be defined by a flexible catheter 362. According to certain embodiments, the rigid or semi-rigid needle 360 may be disposed transversely (e.g., orthogonally) to the inner surface 342 of the one of the pair of jaws 332, which inner surface 342 may be planar as illustrated (see Fig. 10). An outer perimeter 364, 366 of one or both (as illustrated) of the inner surfaces 342, 344 may have a gripping edge 368, 370 that depends therefrom and that may define a cup-shaped structure with the inner surfaces 342, 344. Each edge 368, 370 may have one or more teeth 372 that are disposed along the edge 368, 370 and that depend toward the other of the pair of jaws 332, 334 (and in particular, the inner surface 342, 344 thereof).

[0097] The motion of the jaws 332, 334 between the open and closed states may be achieved using a number of different mechanisms. As illustrated, the drug delivery device 300 includes a scissors linkage 380 that couples the pair of jaws 332, 334 to the control rod 336. The linkage 380 includes the jaws 332, 334 (or more particularly elongated ends 382, 384 of the jaws 332, 334) and two additional links 386, 388. The elongated ends 382, 384 are further defined by arms 390, 392 as explained in greater detail below.

[0098] The jaws 332, 334 are pivotally attached at a first pivot 396 with the inner surfaces 342, 344 of the jaws 332, 334 disposed distally of the pivot 396 and the ends 382, 384 (and arms 390, 392) associated with each jaw 332, 334 disposed proximally of the pivot 396. The link 386 has a first end 398 that is pivotally attached at a second pivot 400 to the end 384 of the jaw 334, and the link 388 has a first end 402 that is pivotally attached at a third pivot 404 to the end 382 of the jaw 332. Specifically, the first end 398 of link 386 is attached to the arm 392 that defines the end 384 of the jaw 334, while the first end 402 is attached to the arm 390 that defines the end 382 of the jaw 332. Second ends 406, 408 of the links 386, 388 are pivotally attached to the distal end 346 of the control rod 336 at a fourth pivot 410.

[0099] Lateral movement of the second and third pivots 400, 404 toward each other causes the jaws 332, 334 to move from the open to the closed position, while lateral movement of the second and third pivots 400, 404 away from each other causes the jaws 332, 334 to move from the closed position to the open position. As illustrated, the first pivot 396 is fixedly attached or secured to a frame 412, while the second, third, and fourth joints 400, 404, 410 are not fixedly attached or secured to the frame 412 and are thus movable relative to the frame 412. Consequently, a force applied to the knob 350 in a direction along a longitudinal axis 414 will cause the fourth pivot 410 to move relative to the first pivot 396, which in turn will cause the second and third pivots 400, 404 to move laterally (inwardly or outwardly) relative to each other.

[00100] Specifically, as the rod 336 is moved from the first position to the second position (i.e., in the direction of the proximal end 318 of the needle 310), the pivots 400, 404 move laterally inward toward each other. In a similar fashion, as the rod 336 is moved from the second position to the first position (i.e., in the direction of the distal end 312 of the needle 310), the pivots 400, 404 move laterally outward or away from each other. According to certain embodiments, the rod 336 may be biased (by a spring or other resilient member) toward the first position, such that the jaws 332, 334 are normally in the open state and a force must be applied to the knob 350 to move the jaws 332, 334 to the closed state.

[00101] It will be recognized that the moveable jaws 332, 334, control rod 336 and scissor linkage 380 are exemplary, and not intended to limit the disclosure of the alternative embodiment. For example, while the inner surfaces 342, 344 of the jaws 332, 334 move relative to each other and (pivotally) to the frame 412, it is possible to have one of the jaws is fixedly attached or secured to the frame 412 while the second jaw moves relative to the first jaw and the frame between the open and closed states. Furthermore, other linkages may be substituted for the scissor linkage 380; for example, a gear train may be substituted for the linkage illustrated. In addition, while the linkage 380 is directly responsive to a manual input applied through the rod 336, the jaws 332, 334 may be automated instead, such that motion of the rod between the first and second positions activates a micromotor or other device move the jaws 332, 334 between the open and closed states, or the input may be automated, such that the rod moves between the first and second positions by virtue of a motor that is actuated by a push button, for example. Furthermore, while certain embodiments would require the control rod 336 to be rigid or semi-rigid to cause the jaws 332, 334 to open and close, the control rod 336 may be flexible instead (like a cord) such that movement of the control rod 336 between the first and second positions causes motion from the open state to the closed state, but the jaws 332, 334 return to the open state from the closed state according to a biasing mechanism (such as a spring or other resilient member).

[00102] The embodiment of the drug delivery device 300 illustrated in Figs. 8-10 may be used in a method of delivering a drug to cardiac tissue via the pericardial space, although other devices may also be used to carry out this method. In particular, the method includes introducing a delivery cannula 330 with a distal end 338 and a proximal end 340, and a pair of jaws 332, 334 with inner surfaces 342, 344, the distal end 338 of the delivery cannula 330 (and more particularly, the needle 360) depending from the inner surface 344 of one of the pair of jaws 334, and advancing the cannula 330 and pair of jaws 332, 334 to the pericardium 210 from a point external to the heart 220. The method may further include closing the pair of jaws 332, 334 on a section of the pericardium 210 (see Fig. 10), the distal end 338 of the cannula 330 (and more particularly, the needle 360) advancing into the pericardium 210 as the pair of jaws 332, 334 are closed, withdrawing the delivery cannula 330 and pair of jaws 332, 334 to pull a section of the pericardium 210 into the internal passage 316 of the needle 310 thereby expanding or enlarging the pericardial space 230 beneath the section of the pericardium 210, and administering a drug through the cannula 330 into the enlarged pericardial space 230. According to certain

embodiments, introducing the delivery cannula 330 may include introducing the delivery cannula 330 via a subxiphoid approach.

[00103] The devices and methods described herein may provide one or more advantages relative to existing devices for drug delivery to the pericardial space, including improved safety, accuracy, consistency and efficiency. The same structures are used to access the pericardial space and to administer the drug into the pericardial space, simplifying device design and use. The device reduces the risks of perforation of cardiac tissue and other structures of the heart by improving the accuracy of the movement of the drug delivery device into the pericardial space and minimizing the risk of contact between the cutting surfaces of the drug delivery device and other cardiac tissues and structures. Improvements in accuracy may also lead to

improvements in procedure efficiency, shortening the time of the procedure.

Improvements in accuracy may also lead to better localization of the treatment. In fact, the device may be designed to allow for introduction of a procedural lead, such as may be used for conductive mapping of cardiac tissue, permitting assessment of the extent of damage following a myocardial infarction or other similar event and thus the scope of the necessary treatment. Simplification of the procedure also may lead to reductions in the amount of time required to train to perform the method or use the device. The reduced invasiveness of the procedure using the above device or according to the above method may also result in faster healing and reduced hospital stay.

[00104] It should be understood that the device described herein can be used with any drug for treating a heart condition. The heart condition can comprise, e.g. cardiac failure or autoreactive pericardial pericarditis. The drugs to be used can be those for treating various heart conditions, for example apelin or TIMP-3.

[00105] TEVIPs are endogenous tissue inhibitors of metalloproteinases (TIMPs) which are involved in many natural process. TIMP-3 is expressed by various cells or and is present in the extracellular matrix; it inhibits all the major cartilage-degrading metalloproteases, and may play a role in role in many degradative diseases of connective tissue, including rheumatoid arthritis and osteoarthritis, as well as in cancer and cardiovascular conditions. The amino acid sequences of various versions of TIMP-3, and the nucleic acid sequences of a DNA that encode these versions of TIMP-3, are disclosed in U.S. Patent No. 6,562,596 and U.S. Provisional Application No. 62/042,574, the disclosures of which are incorporated by reference herein.

[00106] Additionally, an APJ large molecule agonist e.g., apelin or modified apelin peptides could be used with the device . More information relating to such molecules can be found in PCT Publication No. PCT/US2013/075773, the disclosure of which is incorporated by reference herein.

[00107] In this regard, treatment of autoreactive pericardial pericarditis via intrapericardial injection of triamcinolone has resulted in symptomatic improvement and prevented effusion recurrence in approximately 93%. Maisch et al., European Heart Journal 23: 1503-1508 (2002).

[00108] Animal studies have been conducted that demonstrate the benefits of application of a therapeutic to the pericardial area. Nitric oxide donors, which could promote local vasodilation, were successfully applied to the pericardial area and demonstrated a systemic effect. Waxman et al., J. Am Coll Cardio. 33:2073-2077 (1999). Further, adenoviral-mediated gene transfer applied to the pericardium induced sustained VEGF165 expression in the myocardium. Lazarous et al.,

Cardiovasc. Res. 44:294-302 (1999). The benefits include: increased collateral vessel development, increased regional myocardial blood flow, improved myocardial function in the ischemic regions, and/or increased myocardial vascularity. In a study by Lazarous .et al., Cardiovasc. Res. 36:78-85 (1997), bFGF injected into the peri- infarct region in a pig MI model resulted in improvements in left ventricular function, reductions in left ventricular remodeling and an increase in vessel density. Pericardial administration of bFGF resulted in substantial cardiac bFGF delivery, as 19% of the substance was present in the heart compared with 0.5% using traditional intravenous administration. In a rabbit model, the presence of bFGF in the intrapericarial sac enhanced new epicardial small-vessel growth. Landau et al., Am. Heart J. 129:924- 931 (1995). Relative to cardioprotective agents, intrapericardial delivery of omega- 3 polyunsaturated fatty acids can dramatically reduce both infarct sizes and ventricular arrhythmias associated with ischemia. Even a single intrapericardial injection of bFGF in a porcine model of MI resulted in functionally significant myocardial angiogenesis. Laham et al., J. Pharmacol. Exp. Ther. 292:795-802 (2000).

Intrapericardial delivery of numerous antiarrhythmic agents has been undertaken, e.g., esmolol, solatol, atenolol, ibutalide, procainamide, digoxin, amiodarone, arachadonic acid, nitroglycerin and L-arginine. All have been shown to have electrophysiological effects when delivered to the pericardial space in various animal models. Given that these agents have been successfully applied to the pericardial sac with single injections, prolonged delivery of these agents using the device described herein might prove to be even more beneficial.

[00109] Additional cardiac disorders that may be treated using the delivery device can comprise, for example, any disorder affecting contractility of the heart or other heart functions. Additionally, various embodiments relate to any form of heart disease or disorder accompanied by heart dysfunction, e.g., hypertrophy,

hypertension, heart failure (chronic or acute), congestive heart failure, acute decompensatory failure, or cardiomyopathy.

[00110] Although the preceding text sets forth a detailed description of different embodiments of the invention, it should be understood that the legal scope of the invention is defined by the words of the claims set forth at the end of this patent. The detailed description is to be construed as exemplary only and does not describe every possible embodiment of the invention because describing every possible embodiment would be impractical, if not impossible. Numerous alternative embodiments could be implemented, using either current technology or technology developed after the filing date of this patent, that would still fall within the scope of the claims defining the invention.

[00111] It should also be understood that, unless a term is expressly defined in this patent using the sentence "As used herein, the term ' ' is hereby defined to mean..." or a similar sentence, there is no intent to limit the meaning of that term, either expressly or by implication, beyond its plain or ordinary meaning, and such term should not be interpreted to be limited in scope based on any statement made in any section of this patent (other than the language of the claims). To the extent that any term recited in the claims at the end of this patent is referred to in this patent in a manner consistent with a single meaning, that is done for sake of clarity only so as to not confuse the reader, and it is not intended that such claim term be limited, by implication or otherwise, to that single meaning. Finally, unless a claim element is defined by reciting the word "means" and a function without the recital of any structure, it is not intended that the scope of any claim element be interpreted based on the application of 35 U.S.C. § 112, sixth paragraph.

Claims

We claim:

1. A pericardial drug delivery device comprising:

a needle having an internal passage and a distal end configured for insertion into a patient adjacent the pericardium;

a pericardium retractor movable relative to the needle and configured to pull a section of the pericardium into the internal passage of the needle to enlarge the pericardial space beneath the section of the pericardium; and

a delivery cannula extending through the needle and configured for insertion through the pericardium to deliver a drug to the enlarged pericardial space.

2. The pericardial drug delivery device of claim 1, the delivery cannula having a distal end and a proximal end, the distal end of the delivery cannula defining the pericardium retractor.

3. The pericardial drug delivery device of claim 2, the distal end of the delivery cannula having a hollow linear shaft and a hollow arcuate shaft, the hollow linear shaft defining a distal tip of the distal end of the delivery cannula, and the hollow arcuate shaft being arranged proximal to the hollow linear shaft.

4. The pericardial drug delivery device of claim 3, the hollow arcuate shaft defining a helix.

5. The pericardial drug delivery device of claim 4, the helix having a plurality of turns of constant outer diameter.

6. The pericardial drug delivery device of claim 4, comprising a stop disposed between the hollow arcuate shaft and the proximal end of the delivery cannula, the stop having an outer diameter greater than an outer diameter of the helix.

7. The pericardial drug delivery device of any one of claims 4 or 6, the delivery cannula having a longitudinal axis, the hollow linear shaft and the proximal end of the delivery cannula being disposed along the longitudinal axis, and the helix traversing about the longitudinal axis.

8. The pericardial drug delivery device of claims 3 to 7, comprising a drive coupled to the delivery cannula and configured to move the distal end of the delivery cannula in at least one of a distal direction for insertion through the pericardium and a proximal direction to pull the pericardium into the internal passage of the needle.

9. The pericardial drug delivery device of claim 1, the pericardium retractor comprising at least two jaws having an open state wherein inner surfaces of the at least two jaws are spaced from each other and a closed state wherein the inner surfaces of the at least two jaws are closer to each other than in the open state.

10. The pericardial drug delivery device of claim 9, comprising an elongated control rod having a proximal end and a distal end attached to at least one of the at least two jaws, the control rod having a first position relative to the at least two jaws corresponding to the open state and a second position relative to the at least two jaws corresponding to the closed state.

11. The pericardial drug delivery device of any one of claims 9 to 10, the delivery cannula having a distal end and a proximal end, the distal end of the delivery cannula depending from the inner surface of one of the at least two jaws.

12. The pericardial drug delivery device of claim 11, the distal end of the delivery cannula being defined by a rigid or semi-rigid needle and the proximal end of the delivery cannula being defined by a flexible catheter.

13. The pericardial drug delivery device of claim 12, the rigid or semirigid needle being transverse to the inner surface of the one of the at least two jaws.

14. The pericardial drug delivery device of any one of claims 9 to 13, an outer perimeter of each of the inner surfaces being defined by a gripping edge, each gripping edge having one or more teeth depending toward the other one of the at least two jaws.

15. The pericardial drug delivery device of any one of claims 10 to 14, comprising a scissors linkage including the at least two jaws and at least two links, each link being attached at a first end to the distal end of the elongated control rod and at a second end to one of the at least two jaws.

16. A pericardial drug delivery device comprising: a delivery cannula with a proximal end and a distal end, the distal end comprising an elongated tip with a first tip end, a second tip end, and a hollow, arcuate retractor, the first tip end and the second tip end being disposed along a tip axis, the hollow, arcuate retractor being transverse to the tip axis and having a first retractor end attached to the second tip end and a second retractor end attached to the proximal end of the delivery cannula; and a drive coupled to the distal end to move the distal end in a distal direction into the pericardium.

17. The drug delivery device of claim 16, wherein the elongated tip is hollow.

18. The drug delivery device of any one of claims 16 to 17, wherein the hollow, arcuate retractor defines a helix.

19. The drug delivery device of claim 18, wherein the helix has a plurality of turns of constant diameter.

20. The drug delivery device of any one of claims 16 to 19, wherein the proximal end of the delivery cannula comprises an elongated hollow shaft with a first end attached to the second retractor end and a second end coupled to the drive.

21. The drug delivery device of claim 20, wherein the delivery cannula has a longitudinal axis, and the elongated tip and the elongated shaft are disposed along the longitudinal axis.

22. The drug delivery device of claim 21, wherein the hollow, arcuate retractor defines a helix, the helix traversing about an axis disposed along the longitudinal axis.

23. The drug delivery device of any one of claims 16 to 22, wherein the drive comprises a spring coupled to the proximal end of the cannula, the spring optionally being a Belleville spring.

24. The drug delivery device of any one of claims 16 to 23, further comprising a stop disposed between the second retractor end and the proximal end of the cannula.

25. A method of delivering a drug to cardiac tissue via the pericardial space, the method comprising: introducing a delivery cannula having a distal cannula end comprising a tip with a first tip end, a second tip end, and a hollow, arcuate retractor, the first tip end and the second tip end being disposed along a tip axis, the hollow, arcuate retractor being transverse to the tip axis with a first retractor end attached to the second tip end and a second retractor end; advancing the tip into the pericardium from a point external to the heart; advancing the retractor into the pericardium to expand the pericardial space; and administering the drug through the retractor.

26. The method of claim 25, wherein advancing the tip into the pericardium comprises actuating a spring coupled to the distal cannula end to move the distal cannula end in a distal direction.

27. The method of any one of claims 25 to 26, wherein advancing the retractor into the pericardium comprises rotating the delivery cannula about a longitudinal axis of the delivery cannula.

28. The method of any one of claims 25 to 27, wherein the tip is hollow, and the method further comprises administering the drug through the hollow tip.

29. The method of any one of claims 25 to 28, wherein introducing the delivery cannula comprises introducing the delivery cannula via a subxiphoid approach.

30. A pericardial drug delivery device comprising: a delivery cannula with a proximal end and a distal end, the distal end comprising an elongated tip with a tip end and a hollow, helical retractor attached to the elongated tip; and a drive coupled to the distal end to move the distal end in a distal direction into the pericardium.

31. The drug delivery device of claim 30, wherein the elongated tip is hollow.

32. The drug delivery device of any one of claims 30 to 31, wherein the proximal end of the delivery cannula comprises an elongated hollow shaft attached to the hollow, helical retractor and the drive.

33. The drug delivery device of any one of claims 30 to 32, wherein the drive comprises a Belleville spring coupled to the proximal end of the cannula.

34. A method of delivering a drug to cardiac tissue via the pericardial space, the method comprising: introducing a delivery cannula having a distal cannula end comprising an elongated tip with a first tip end and a hollow, helical retractor attached to the elongated tip; advancing the elongated tip into the pericardium from a point external to the heart; advancing the retractor into the pericardium to expand the pericardial space; and administering the drug through the retractor.

35. A pericardial drug delivery device comprising: a delivery cannula with a proximal end and a distal end; a pair of jaws having an open state wherein inner surfaces of the pair of jaws are spaced from each other and a closed state wherein the inner surfaces of the pair of jaws are closer to each other than in the open state, the distal end of the delivery cannula depending from the inner surface of one of the pair of jaws; and an elongated control rod having a proximal end and a distal end attached to at least one of the pair of jaws, the control rod having a first position relative to the pair of jaws corresponding to the open state and a second position relative to the pair of jaws corresponding to the closed state.

36. The drug delivery device of claim 35, wherein the distal end of the cannula includes a rigid or semi-rigid needle and the proximal end of the delivery cannula includes a flexible catheter.

37. The drug delivery device of claim 36, wherein the rigid or semi-rigid needle is transverse to the inner surface of the one of the pair of jaws.

38. The drug delivery device of any one of claims 36 to 37, wherein an outer perimeter of each of the inner surfaces is defined by a gripping edge, each edge having one or more teeth disposed thereat and depending toward the other one of the pair of jaws.

39. The drug delivery device of any one of claims 36 to 38, further comprising a scissors linkage including the pair of jaws and two links, each link attached at a first end to the distal end of the elongated control rod and at a second end to one of the pair of jaws.

40. A method of delivering a drug to cardiac tissue via the pericardial space, the method comprising: introducing a delivery cannula with a proximal end and a distal end, and a pair of jaws with inner surfaces, the distal end of the delivery cannula depending from the inner surface of one of the pair of jaws; advancing the cannula and the pair of jaws to the pericardium from a point external to the heart; closing the pair of jaws on a section of the pericardium, the distal end of the cannula advancing into through the pericardium as the pair of jaws are closed; withdrawing the delivery cannula and the pair of jaws to expand the pericardial space; and administering the drug through the cannula.

41. The method of claim 40, wherein introducing the delivery cannula comprises introducing the delivery cannula via a subxiphoid approach.

42. The drug delivery device of claim 16, 30 or 35, further comprising a drug to treat a heart condition.

43. The drug delivery device of claim 42, wherein the heart condition is selected from the group consisting of hypertrophy, hypertension, chronic heart failure, acute heart failure, congestive heart failure, acute decompensatory failure, pericardial pericarditis and cardiomyopathy.

44. The drug delivery device of claim 42, wherein the heart condition is cardiac failure or autoreactive pericardial pericarditis.

45. The drug delivery device of claim 44, wherein the drug is TIMP-3 or an APJ agonist.

46. The drug delivery device of claim 42, wherein the drug is selected from the group consisting of esmolol, solatol, atenolol, ibutalide, procainamide, digoxin, amiodarone, arachadonic acid, nitroglycerin, TIMP-3, an APJ agonist and L- arginine.

47. A method of treating a heart condition in a patient having need of such treatment comprising: introducing and advancing the drug delivery device of claim 16, 30 or 35 into the pericardium from a point external to the heart; expanding the pericardial space; and administering a drug through the cannula.