Source: https://patents.google.com/patent/US6200302B1/en
Timestamp: 2018-08-19 07:28:31
Document Index: 506921343

Matched Legal Cases: ['art 15', 'art 15', 'art 15', 'art 15', 'art 15', 'art 15']

US6200302B1 - Hypodermic needle for percutaneous drug delivery - Google Patents
Hypodermic needle for percutaneous drug delivery Download PDF
US6200302B1
US6200302B1 US09270689 US27068999A US6200302B1 US 6200302 B1 US6200302 B1 US 6200302B1 US 09270689 US09270689 US 09270689 US 27068999 A US27068999 A US 27068999A US 6200302 B1 US6200302 B1 US 6200302B1
US09270689
Devices and methods are disclosed for the percutaneous administration of a composition to a desired in vivo location. The composition comprises a biologically active substance and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is preferably non-solid and a polymer, which is preferably capable of being transformed into a gel, thus allowing timed-released delivery of the substance. A preferred use for this invention is to provide local delivery of biologically active substances for the prevention of restenosis following angioplasty or other blood vessel injury.
This application is a divisional application of U.S. patent application Ser. No. 08/816,670, filed on Mar. 13, 1997, now issued as U.S. Pat. No. 5,893,839.
Studies have suggested a number of conditions which lead to vessel restenosis, including remodeling and intimal hyperplasia. These studies have indicated that vessel injury, such as endothelial denudation, injury to the vascular wall, and rupture of the vasa vasorum, can result as an unwanted consequence to an angioplasty thereby making the treated site susceptible to restenosis. Upon injury, the ensuing deposition of platelets, in connection with the vessel's healing mechanism, signals smooth muscle cell proliferation within the arterial wall. The deposition of platelets may lead to acute thrombosis in some circumstances. More significantly, the proliferation of smooth muscle cells is a process which frequently continues unabated and has therefore been widely implicated as a prominent factor in the resulting restenosis. No pharmacologic or mechanical intervention has heretofore proven sufficiently effective in preventing restenosis following angioplasties.
Yet another type of localized drug delivery is described in Edelman et al., Proc. Natl. Acad. Sci., 87:3773-3777 (1990). Edelman et al. discuss site-specific therapy following vascular interventions in which ethylene/vinyl acetate copolymer matrix is utilized to permit heparin delivery over time. In practice, however, the approach described by Edelman et al. is ill-suited for treating restenosis in vivo because the matrices must be surgically deployed. Because angioplasties and other intravascular interventions demonstrate value by producing desired results while obviating the need for open operation, the performance of an operation to improve the results of an intravascular intervention negates the clinical value of that interventional procedure.
The aforesaid problems are solved, in accordance with the present invention, by methods and devices for percutaneously administering sustained, timed-release localized drug delivery of biologically active substances to desired in vivo locations. One aspect of the present invention relates to the methods of drug delivery. Administration of compositions described herein is accomplished by delivering to the desired locus a composition comprising a biologically active substance and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is preferably a polymer, for example, a polysaccharide such as alginate. Although the carrier can be in the form of a solid, preferred carriers are non-solid. More preferably, the non-solid carrier is compatible with a cross-linker which converts the first composition into a less mobile gel or solid.
The methods of the present invention can be utilized with any desired in vivo locus, such as a vessel, organ, tissue or cavity that can be percutaneously treated. The desired locus can be treated under the methods of the present invention by delivering biologically active substances into, around, or adjacent to the locus, as desired. By way of example, in one embodiment the methods of drug delivery under the present invention can be utilized to treat a blood vessel or graft that has been subject to an endovascular procedure, for example, an angioplasty or stent placement, by providing biologically active substances substantially around the vessel or graft without intramurally entering the interior thereof. Specifically, biologically active substances, including, but not limited to, drugs such as heparin (including modified forms of heparin such as NAC-heparin) can be injected into a periadventitial area of the blood vessel or graft that has been subject to the angioplasty without traversing the endothelium and lumen of the vessel. For clarity of description, the term “periadventitial” is meant to include the adventitia of a vessel, as well as soft tissues near the adventitia. The biologically active substances are injected nonintramurally, meaning that the injection does not traverse the endothelium and lumen, although the substances may diffuse to an intramural location subsequent to the injection. Significantly, the methods under the present invention do not create further injury to blood vessels, particularly the lumen and endothelium, and therefore do not promote the onset of restenosis. In addition, the novel percutaneous methods of the present invention do not require a surgical procedure.
Although the characteristic features of this invention will be particularly pointed out in the claims, the invention itself, and the manner in which it may be made and used, may be better understood by referring to the following descriptions taken in connection with the accompanying drawings forming a part hereof, wherein reference numerals refer to like parts throughout the several views.
FIG. 11B represents a cross-sectional view of the tubular member depicted in FIG. 11A, taken along the line 11B—11B.
The following portion of the specification, taken in conjunction with the drawings, sets forth the preferred embodiments of the present invention. The embodiments of the invention disclosed herein include the best mode contemplated by the inventor for carrying out the invention in a commercial environment, although it should be understood that various modifications can be accomplished within the parameters of the present invention.
Alternative embodiments of devices 10 under the present invention are depicted in FIGS. 2-3 and 9. In FIG. 2, the piercing part 15 of the hypodermic needle 11 is oriented such that the lumen opening 16 faces substantially toward the interior of a circle or ellipse defined by the arc of the second section 14, termed “curved section” herein. Alternatively, FIG. 3 depicts an embodiment wherein the lumen opening 16 faces in a direction not lying within the plane of a circle or ellipse defined by the arc. It can readily be seen by one of ordinary skill in the art that the lumen opening 16 could alternatively face away from the interior of the circle or ellipse in a direction substantially in a plane defined by the circle or ellipse or in any other direction rotated around the hypodermic needle 11.
It can readily be seen that a tubular device 10 formed according to the present invention must have a gauge which offers sufficient rigidity to maintain the appropriate arc. In addition, it can be readily seen that the preferred gauge “g” of the device 10 will be dependent upon the viscosity of the injected composition. As such, a device 10 smaller than about 21 g would likely clog too easily, and may fail to retain the appropriate arc in use. A preferred device 10 of the present invention, therefore, has a gauge from about 21 g to about 18 g. More preferably, the tubular device 10 has a gauge from about 20 g to about 19 g.
Referring again to FIGS. 4-7 and FIG. 8, for treatment of a blood vessel or graft 31 according to an exemplary utility for the.present invention, the device 10 is preferably advanced under a patient's skin 30 such that the piercing part 15 of the device 10 moves around a first side 33 of the blood vessel or graft 31 to a first location 34 in the periadventitial area of the blood vessel or graft 31. The first location 34 is preferably opposite the blood vessel from the skin 30. Next, the composition is injected through the lumen opening 16 as the piercing part of the tubular device 10 is withdrawn from the first location 34 to a second location 35. A second location 35 is preferably between the blood vessel or graft 31 being treated and the patient's skin 30. Next, the device 10 is advanced such that the piercing part 15 moves around a second side of the blood vessel or graft 31 to a third location 37. This third location 37 is preferably near the first location 34. Next, the composition is injected through the lumen opening 16 as the piercing part 15 is withdrawn from the third location 37 to a fourth location 38 which is substantially the same as the second location 35. The device may then be withdrawn from the skin 30.
It is noted that the above method may be usefully performed using a linearly straight tubular device in accordance with the present invention. In a preferred embodiment, however, an inventive device 10 having a curved section 14 is used. A curved device 10 with the appropriate radius, as described hereinabove, can be advanced through a single puncture site around a blood vessel, closely hugging the perimeter of that vessel. As the device 10 is withdrawn, the polymer can be administered closely to the outer surface, the adventitia, of that blood vessel. Without removing the device 10 completely from the patient, the device 10 can be rotated 180° and advanced around the other side of the blood vessel, allowing introduction of the polymer on that side. It would be more difficult to remain close to the adventitia of the blood vessel if a straight tubular device were used. In this embodiment, the most preferred device 10 would be one having a radius and an arc length capable of delivering the composition closely to the deepest wall of the vessel or graft 31 from a single percutaneous puncture.
Although the pharmaceutically acceptable carrier of the present invention may be any of a wide variety of pharmaceutically acceptable carriers, a preferred carrier is a polymer. In addition, although solid carriers, including but not limited to microcapsules, that are capable of being injected by a tubular device 10 can be utilized under the present invention, the carrier is preferably “non-solid.” As used herein, the term “non-solid carrier” is intended to refer to a carrier which has physical characteristics similar to a liquid or a gel and which is capable of being injected through a tubular device 10. In a preferred embodiment, the pharmaceutically acceptable non-solid carrier is a liquid polymer capable of being cross-linked and thus converted into a gel or a solid upon being mixed with a suitable cross-linker. As used herein, the term “cross-linker” is meant to refer to a substance which, when mixed with a specific non-solid polymer, will cause the non-solid polymer to be converted to a gel or solid. In accordance with this embodiment, the cross-linker is preferably delivered into the periadventitial area simultaneously with or subsequent to the delivery of the first composition. Most preferably, the first composition and the cross-linker are delivered by injection through a tubular device 10 under the present invention.
In one preferred embodiment, the polymer is a polysaccharide.
More.preferably, the polymer is one capable.of being cross-linked when mixed with a cross-linker as noted above. One example of a polymer capable of being cross-linked is alginate, and preferred cross-linkers for use therewith include divalent cations such as calcium, for example in the form of calcium chloride or calcium gluconate. The desired effect may be obtained with regard to alginate by using as a cross-linker a wide variety of divalent cations. However, various divalent cations have different effects upon the gel, the substance carried therein, and the surrounding tissue. As such, the preferred divalent cations selected for a particular use will depend on the carrier being used, the substance being delivered, and the specific in vivo location of the delivery.
The term “alginate” as used herein is intended to designate a family of unbranched binary copolymers of 1-4-linked β-D-mannuronic acid (M) and α-L-guluronic acid (G). Alginates have widely varying compositions and sequences, depending on the organism and the tissue from which they are isolated. The monomers are arranged in a pattern of blocks along the chain, with homopolymeric regions (termed M and G blocks) interspersed with regions of alternating structure (MG blocks). Thus, when inventive methods are used to deliver a composition comprising a biologically active substance, as most preferably carried in a pharmaceutically acceptable non-solid polymer capable of being cross-linked, to a desired location such as the periadventitial area overlying the blood vessel or graft in vivo, a subsequent injection of a cross-linker causes the first non-solid composition to be converted to a gel or a solid, thereby advantageously becoming more apt to remain immobilized. Accordingly, a preferred method for treating a blood vessel or graft in vivo with the biologically active substance comprises a non-solid carrier and additionally comprises injecting a second non-solid composition into the first non-solid composition, wherein the second non-solid composition comprises a cross-linker, prior to withdrawing the piercing part 15 of the tubular device 10 from the skin.
Additionally contemplated by this invention are methods and devices for injecting the first composition and a cross-linker simultaneously. As seen in FIGS. 10-13, in a preferred method a tubular device 10 is used which has more than one lumen 12 a and 12 b, and is thus capable of injecting the first composition and the cross-linker simultaneously. For example, FIGS. 10A and 10B depict a first exemplary arrangement of a tubular member 10 which comprises two substantially semicircular (in cross-section) lumens 12 a and 12 b disposed side-by-side separated by a septum 40. Septum 40 isolates the two lumens 12 a and 12 b into separate chambers thereby permitting segregated simultaneous flow of different compositions, as desired, without premature mixing thereof. Septum 40 can terminate at or near the piercing part 15 so that the first composition and the cross-linker can be mixed after or just before they exit at least one lumen opening.
FIG. 10A illustrates the side-by-side lumens 12 a and 12 b in a linear tubular member 10, while FIG. 10B shows the side-by-side lumens 12 a and 12 b in a curved tubular member 10. As seen in FIG. 10B, a pair of trocars 22 a and 22 b can be disposed in corresponding lumens if desired, although placing a trocar in only one lumen is also possible. The trocars 22 a and 22 b for the side-by-side arrangement are preferably substantially configured in a D-shape so as to be particularly compatible with the semicircular lumens 12 a and 12 b. It will be appreciated that the two D-shaped trocars 22 a and 22 b can form a conical or pyramidal piercing portion 15, although each trocar can be configured to form a conventionally shaped piercing portion, which is particularly useful if only one trocar is desired.
FIGS. 11A-11B depict an alternative double-lumen arrangement comprising an outer lumen 12 a and an inner lumen 12 b. For convenience in manufacture and use, the outer and inner lumens 12 a and 12 b in cross-section can preferably be fixed along a line tangent to both lumens 12 a and 12 b, as best seen in FIG. 11B. However, the inner lumen 12 b can alternatively be wholly contained within a perimeter of the outer lumen 12 a if desired. The inner lumen 12 b is more readily conducive to receiving a trocar, if desired, than the outer lumen 12 a, which can be, for example, moon-shaped. By using a singular trocar with inner lumen 12 b while not utilizing .a trocar with outer lumen 12 a, the structural support provided by the singular trocar can be sufficient even in a double-lumen arrangement. It is emphasized for clarity of description that the alternative side-by-side and inner/outer double-lumen arrangements can be used in both linear and curved tubular members in accordance with the present invention. One of ordinary skill in the art will also appreciate that the alternative double-lumen arrangements can also be utilized with unitary tubular members comprising, for example, a hypodermic needle, or with cannula/trocar arrangements as described hereinabove. Also, the position of the lumen opening can vary as described above in conjunction with FIGS. 2-3.
Referring to FIG. 12, the septum 40 preferably fully extends to a top 41 of the hub 17, or axially adjacent thereto, for the side-by-side arrangement shown in FIGS. 10A and 10B. By extending the septum 40, isolation of the lumens 12 a and 12 b is optimized thereby protecting separated compositions from premature mixing as desired compositions are received by the lumens 12 a and 12 b, for example, through corresponding receiving portions in the hub 17 or directly. The hub 17 is also preferably provided with locking means such as a notch 42 that can fit with, for example, a predetermined closure, syringe or other object having, for example, a protrusion which aligns with or otherwise matches the notch 42. The locking means prevents an opportunity for an undesired syringe or cap to engage with an unintended lumen in the tubular member.
As seen in FIG. 13, a preferred hub 17 for use with the outer/inner lumens 12 a and 12 b shown in FIGS. 11A and 11B comprises a head portion 44 including receiving portions 46 a and 46 b which are adapted to receive a syringe, another source for desired compositions, or a closure. The receiving portion 46 b that corresponds to the inner lumen 12 b vertically extends from head 44 and, as noted above, can selectively retain a trocar if desired. The receiving portion 46 a that corresponds to the outer lumen 12 a extends horizontally or laterally from head 44 and is therefore substantially perpendicular relative to receiving portion 46 b. It will be appreciated that placement of a trocar is inconvenient in receiving portion 46 a, and hence outer lumen 12 a, because of this lateral placement.
As an illustration of a specific use of the inventive devices and methods, after a patient undergoes an angioplasty, stenting or other endovascular procedure of an artery, vein, or a graft, the patient's skin overlying that vessel will be sterilely prepped and draped if it is not already within the sterile field while the patient remains in the procedural suite. An inventive curved tubular member or device 10 is advanced through the skin overlying the vessel at the selected site, around the vessel to the portion of the vessel furthest from the skin. In accordance with the preferred constructed embodiment of the present invention, the inner trocar 22 of the device 10 is removed, and the first composition is injected as the trocar 22 is withdrawn. The device 10 is withdrawn to a location adjacent the skin, but not completely out of the patient. The device 10 is turned 180°, advanced around the other side of the vessel, and the first composition is introduced on this side of the vessel as well. A cross-linker is injected into the first composition, if needed, and the device 10 is completely removed from the patient. The patient can then be immediately discharged from the procedural suite with very little time having been spent undergoing time-consuming procedures and observation previously associated with the threat of restenosis. The polymer allows timed-release of the drug with predetermined optimal release kinetics. Since the administered drug would be in the soft tissues immediately surrounding the vessel, such as the adventitia, as opposed to the lumen and endothelium, the drug would not be washed quickly away, in contradistinction to the currently available intraluminal methods of drug administration.
While the preferred embodiments of the invention have been disclosed, it should be appreciated that the invention is susceptible to modification without departing from the spirit of the invention or the scope of the subjoined claims. As noted above, the present invention can be directed to any locus in the body, and is not limited to application to blood vessels and grafts. For example, the present invention can be used to percutaneously administer a biologically active substance and a carrier, preferably a non-solid carrier that is compatible with a crosslinker, into, around and/or adjacent to the desired locus, as desired, as perhaps to provide localized drug delivery to a tumor located within an organ.
1. A hypodermic needle for percutaneously delivering desired biologically active substances, the needle comprising a tubular member having a selected radius, the tubular member comprising:
(a) at least two lumens therethrough,
(b) a first section which lies along a longitudinal axis of the tubular member, and
(c) a second section fluidly connected to the first section; the second section lying substantially along an arc and terminating in a piercing part located off of the longitudinal axis which includes at least one lumen opening therein.
2. A hypodermic needle as defined in claim 1, wherein the tubular member has a gauge of from about 21 gauge to about 18 gauge.
3. A hypodermic needle as defined in claim 1, wherein the tubular member has a gauge of from about 20 gauge to about 19 gauge.
4. A hypodermic needle as defined in claim 1, wherein the piercing part is located off said longitudinal axis by a distance which is at least two times said radius.
5. A hypodermic needle as defined in claim 1, wherein the piercing part is located off the longitudinal axis by a distance which is at least several times said radius.
6. A hypodermic needle for percutaneously delivering at least two compositions simultaneously, the needle including a tubular member comprising:
(a) a first lumen capable of delivering a first composition;
(b) a second lumen capable of delivering a second composition;
(c) at least one lumen opening fluidly connected to the first and second lumens for outputting the compositions from the device;
(d) a piercing part; and
(e) a hub that includes (i) a first receiving portion that selectively permits inputting the first composition into the first lumen, (ii) a second receiving portion for selectively inputting the second composition into the second lumen, and (iii) a head portion, wherein the first receivingportion extends substantially vertically from the head portion and wherein the second receiving portion extends substantially horizontally from the head portion.
7. A hypodermic needle as defined in claim 6 wherein the first receiving portion is adapted to receive a trocar.
8. A hypodermic needle for percutaneously delivering desired biologically active substances, the needle including a tubular member comprising:
(a) an outer wall defining an internal cavity; and
(b) a partition dividing the internal cavity of said tubular member into two separate lumens, wherein the tubular member includes a first section which lies along a longitudinal axis of the tubular member, and a second section fluidly connected to the first section, and wherein the second section lies substantially along an arc and terminates in a piercing part located off of the longitudinal axis which includes at least one lumen opening therein.
US09270689 1997-03-13 1999-03-17 Hypodermic needle for percutaneous drug delivery Expired - Fee Related US6200302B1 (en)
US08816670 US5893839A (en) 1997-03-13 1997-03-13 Timed-release localized drug delivery by percutaneous administration
US09270689 US6200302B1 (en) 1997-03-13 1999-03-17 Hypodermic needle for percutaneous drug delivery
US6200302B1 true US6200302B1 (en) 2001-03-13
ID=25221320
US08816670 Expired - Lifetime US5893839A (en) 1997-03-13 1997-03-13 Timed-release localized drug delivery by percutaneous administration
US09270689 Expired - Fee Related US6200302B1 (en) 1997-03-13 1999-03-17 Hypodermic needle for percutaneous drug delivery
US (2) US5893839A (en)
WO (1) WO1998040118A1 (en)
US20050149080A1 (en) * 2003-11-10 2005-07-07 Angiotech International Ag Medical implants and anti-scarring agents
US5893839A (en) 1997-03-13 1999-04-13 Advanced Research And Technology Institute, Inc. Timed-release localized drug delivery by percutaneous administration
US4203436A (en) * 1977-04-05 1980-05-20 Lars Grimsrud Assembly for dividing a hollow hypodermic needle into two separated flow conduits
US5100668A (en) 1988-06-14 1992-03-31 Massachusetts Institute Of Technology Controlled release systems containing heparin and growth factors
Edelman et al., "Effect Of Controlled Adventitial Heparin Delivery On Smooth Muscle Cell Proliferation Following Endothelial Injury", Proc. Natl. Acad. Sci. USA, Medical Sciences, May 1990, vol. 87, pp. 3773-3777.
Hill-West, et al., "Inhibition Of Thrombosis And Intimal Thickening By in situ Photopolymerization Of Thin Hydroge Barriers", Proc. Natl. Acad. Sci. USA, Medical Sciences, Jun. 1994, vol. 91, pp. 5967-5971.
Rogers et al., "Controlled Release Of Heparin Reduces Neointimal Hyperplasia In Stented Rabbit Arteries: Ramifications For Local Therapy", Journal of Interventional Cardiology, Mar. 3, 1992, vol. 5, No. 3, 195-202.
Rogers, et al., "Inhibition Of Experimental Neointimal Hyperplasia And Thrombosis Depends On The Type Of Vascula Injury And The Site Of Drug Administration", Circulation, Sep. 1993, vol. 88, pp. 1215-1221.
Slepian, "Polymeric Endoluminal Paving: A Family Of Evolving Methods For Extending Endoluminal Therapeutic Beyond Stenting", Cardiology Clinics, Nov. 1994, vol. 12, No. 4, pp. 715-737.
US20050149158A1 (en) * 2003-11-10 2005-07-07 Angiotech International Ag Medical implants and anti-scarring agents
WO1998040118A1 (en) 1998-09-17 application
US5893839A (en) 1999-04-13 grant
US6206004B1 (en) 2001-03-27 Treatment method via the pericardial space
US20040068241A1 (en) 2004-04-08 Implantable medical device
US20030065303A1 (en) 2003-04-03 Methods and devices for treating diseased blood vessels
US20040243057A1 (en) 2004-12-02 Catheter for modified perfusion
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