Patent Application
20080057104
a is an illustration of an embodiment of an implantable lead with a distal end including an osmotic pump carrying a MMP inhibitor.
a is an illustration of an embodiment of an implantable lead with a distal end including a controlled pump having a reservoir carrying a MMP inhibitor.
b is an illustration of an embodiment of an implantable lead with a distal end including a matrix having a MMP inhibitor the delivery of which is controlled by electrophoresis.
LV myocardial remodeling that occurs in various settings of congestive heart failure (CHF) has historically been attributed to intrinsic changes in the cardiac myocyte. However, it is now recognized that changes also occur within the extracellular matrix (ECM) of the myocardium, contributing to the remodeling process. The myocardial ECM contains a fibrillar collagen network, a basement membrane, proteoglycans and glycosaminoglycans, and bioactive signaling molecules. The myocardial fibrillar collagens, such as collagen types I and III, ensure structural integrity of the adjoining myocytes, provide the means by which myocyte shortening is translated into overall LV pump function, and are essential for maintaining alignment of the myofibrils within the myocyte through a collagen-integrin-cytoskeletal myofibril relation (e.g., see Sackner-Bernstein, Curr. Cardiol. Rep., 2:112 (2000) and Burlew and Weber, Cardiol. Clin., 18:435 (2000)). The ECM forms a continuum between different cell types within the myocardium and provides a structural supporting network to maintain myocardial geometry during the cardiac cycle. Native ECM is continuously formed and then degraded by matrix metalloproteinases (MMPs) which along with their natural antagonists, the tissue-inhibiting metalloproteinases, regulate and determine the matrix turnover in living tissue.
MMPs play a pivotal role in normal tissue remodeling processes, such as tissue morphogenesis and wound healing (Woessner, In: Matrix Metalloproteinases, Parks (eds.), Academic Press, San Diego, Calif., pp. 1-14 (1998); Woessner and Nagase, In: Matrix Metalloproteinases and TIMPs, Oxford University Press, New York, N.Y., pp. 1-10 (2000); Vu and Werb, Genes Dev., 14:2123 (2000); Nelson et al., J. Clin. Oncol., 18:1135 (2000); Birkedal-Hansen et al., Crit. Rev. Oral. Biol. Med., 4:197 (1993); McDonnell et al., Biochem. Soc. Trans., 27:734 (1999)). This proteolytic system degrades a wide spectrum of ECM proteins and is constitutively expressed in a large number of cell and tissue types. Although MMPs likely play important roles in normal tissue remodeling, increased MMP expression has been identified in pathological processes, such as tumor angiogenesis and metastasis, rheumatoid arthritis, vascular neointimal hyperplasia, and plaque rupture (Nelson et al., J. Clin. Oncol., 18:1135 (2000); Birkedal-Hansen et al., Crit. Rev. Oral. Biol. Med., 4:197 (1993); McDonnell et al., Biochem. Soc. Trans., 27:734 (1999)). The MMPs constitute a family of zinc-dependent enzymes with over 20 members (Woessner, 1998; Woessner and Nagase, 2000).
There are two principal types of MMPs: those that are secreted into the extracellular space and those that are membrane bound (Table 1). The secreted MMPs are classified into several families based on their domain structure: matrilysin (minimal domain, MMP-7), collagenase (hemopexin domain, MMP-1, MMP-8, MMP-13), gelatinase (fibronectin domain, MMP-2, MMP-9), stromelysin (hemopexin domain, MMP-3, MMP-10, MMP-11), metalloelastase (MMP-12). The secreted MMPs constitute the majority of known MMPs and are released into the extracellular space in a latent or proenzyme state (proMMP). Activation of these latent MMPs is required for proteolytic activity, which can be achieved through enzymatic cleavage of the propeptide domain. Serine proteases, such as plasmin, as well as other MMP species can convert proMMPs to active enzymes (Woessner and Nagase, 2000; Murphy, Matrix Biol., 15:511 (1997)). Rapid amplification of MMP activity can thus occur after an initial enzymatic step. The cleavage of the propeptide domain results in a conformational change and exposure of the catalytic domain to the ECM substrate. There is a significant degree of homology within the catalytic domain of MMPs, and substrate specificity (see Table 2) is determined by the large extracellular binding domain at the C-terminus of the enzyme (Woessner, 1998; Woessner and Nagase, 2000; Knauper and Murphy, In: Matrix Metalloproteinases, Parks Ltd. (eds.), Academic Press, San Diego, Calif., pp. 199-218 (1998)).
Activated MMPs undergo autocatalysis, resulting in lower molecular weight forms and, ultimately, in inactive protein fragments (Woessner and Nagase, 2000; Murphy et al., 1997). Another control point of MMP activity is through the presence of an endogenous class of low-molecular-weight molecules called TIMPs (Edwards et al., Int. J. Obes. Relat. Metab. Disord., 20:9 (1996); Woessner and Nagase, 2000; Baker et al., J. Clin. Invest., 101:1478 (1998); Greene et al., J. Biol. Chem., 271:30375 (1996); Li et al., Cardiovasc. Res., 42:162 (1999)). Different TIMP species have been identified and bind to activated MMPs in a 1:1 stoichiometric ratio. Certain TIMPs bind to proMMPs and thereby form MMP:TIMP complexes. TIMP-2 forms a complex with membrane-type MMPs and that this complex enhances the activation of proMMP (Murphy et al., 1997). In addition to binding to MMPs, TIMPs appear to influence cell growth and metabolism in vitro (Baker et al., J. Clin. Investig., 101:1478 (1998); Greene et al., 1996).
Xenopus collagenase-4
Xenopus MMP;
Gallus domesticus
The transmembrane domain family (MT-MMPs) includes MMP-14 through MMP-17. Because MT-MMPs are membrane bound, they provide a focalized area for ECM proteolytic degradation. During trafficking to the cell membrane, MT-MMPs undergo intracellular activation through a proprotein convertase pathway (Murphy et al., 1997; Miyamori et al., Biochem. Biophys. Res. Commun., 267:796 (2000)). Thus, unlike other classes of MMPs, MT-MMPs are proteolytically active once inserted into the cell membrane. MT-MMPs contain a substrate recognition site for other MMP species and so constitute an important pathway for activation of other MMPs within the ECM (Woessner and Nagase, 2000; Murphy et al., 1997). MT1-MMP degrades fibrillar collagens and a wide range of ECM glycoproteins and proteoglycans. Moreover, MT1-MMP proteolytically processes the proforms of the gelatinase MMP-2 and the interstitial collagenase MMP-13. The MT-MMPs do not appear to be under the influence of local inhibitory control because the tissue inhibitors of the MMPs (TIMPs) apparently fail to effectively bind to MT-MMPs (Miyamori et al., 2000). MT-MMPs appear to be expressed in both normal and diseased cells (Miyamori et al., 2000; Shimada et al., Eur. J. Biochem., 262:907 (1999); Kajita et al., FEBS Lett., 457:353 (1999); Llano et al., Cancer Res., 59:2570 (1999); Velasco et al., Cancer Res., 60:877 (2000); Goldberg et al., Proc. Natl. Acad. Sci. USA, 86:8207 (1989)). A number of cell types within the myocardium express MT-MMPs, which include fibroblasts, vascular smooth muscle, and cardiac myocytes.
LV regional myocardial dysfunction and remodeling that occur immediately after MI can persist long after the acute insult (Pfeffer et al., Circulation, 81:1161 (1990); Chareonthaitawee et al., J. Am. Coll. Cardiol., 25:567 (1995); St. John Sutton et al., Circulation, 96:3294 (1997); Jugdutt et al., Clin. Cardiol., 10:641 (1987); St. John Sutton et al., Circulation, 101:2981 (2000); Jugdutt, J. Am. Coll. Cardiol., 25:1718 (1995)). The summation of cellular and extracellular events that occur in the post-MI period results in changes in LV geometry and has been called “infarct expansion.” Past studies have demonstrated that a structural determinant of infarct expansion is extracellular remodeling (Pfeffer et al., 1990; St. John Sutton et al., 2000; Jugdutt, 1995). MMPs have been implicated in tissue remodeling (Sun et al., Cardiovasc. Res., 46:250 (2000). For instance, increased MMP expression has been reported in patients with end-stage heart failure and in several animal models of developing LV dysfunction (Thomas et al., Circulation, 97:1708 (1998); Thomas et al., Circulation, 97:1708 (1998); Li et al., Circulation, 98:1728 (1998); Spinale et al., Circulation, 102:1944 (2000); Coker et al., Am. J. Physiol., 277:777 (1999); Peterson et al., Cardiovasc. Res., 46:307 (2000); Spinale et al., Circ. Res., 85:364 (1999); Li et al., Cardiovasc. Res., 46:298 (1999); Peterson et al., Circulation, 103:2303 (2001); Rohde et al., Circulation, 99:3063 (1999)). Increased interstitial MMP activity has been demonstrated to occur directly within the ischemic myocardium (Etoh et al., Am. J. Physiol., 281:987 (2001)).
Experimental studies using pharmacological compounds that inhibit all MMPs (broad-spectrum inhibitors) have been demonstrated to directly affect LV remodeling after MI (Rohde et al., 1999; Mukherhee et al., Circulation, 107:618 (2003); Creemers et al., Circ. Res., 89:201 (2001)). However, whether broad-spectrum MMP inhibition is necessary to favorably modulate LV remodeling after MI remains unclear. Moreover, early MMP inhibition may adversely affect normal wound-healing responses (Creemers et al., 2001; Heymans et al., 1999; Ducharme et al., 2000).
The invention provides for methods, devices and systems having the devices, useful to prevent, inhibit or treat post-infarct expansion and/or ventricular remodeling, or enhance the efficacy of post-infarct pacing, or any combination thereof. The methods, devices, and systems employ one or more inhibitors of one or more MMPs. In one embodiment, one or more broad spectrum inhibitors of MMPs are employed. In another embodiment, one or more selective inhibitors of one more MMPs are employed. In one embodiment, one or more broad spectrum inhibitors of MMPs are delivered during device delivery (acute delivery). In another embodiment, one or more selective inhibitors of one or more MMPs are delivered during device delivery (acute delivery). In yet another embodiment, one or more broad spectrum inhibitors of MMPs are delivered chronically. In a further embodiment, one or more selective inhibitors of one or more MMPs are delivered chronically. For example, a stent may be employed that delivers a MMP inhibitor upon stent placement (acute delivery) and which optionally may contain a MMP inhibitor, either the same or a different MMP inhibitor, for sustained release which is present in a sustained release formulation coated on the stent (chronic delivery). Alternatively, a stent may contain a MMP inhibitor for sustained release which is present in a sustained release formulation. In this embodiment, a catheter or lead may be employed to deliver a MMP inhibitor during or soon after an infarct (acute delivery). In another embodiment, a catheter or lead may be employed to deliver a MMP inhibitor during or soon after an infarct in the absence of stent placement or in conjunction with stent placement, which stent may contain a drug that is not a MMP inhibitor or may be a stent that does not itself deliver a drug.
There are three major components to most endogenous MMP inhibitors (TIMPs): the zinc binding group ZBG, the peptidic backbone and the pocket occupying side chain. Most MMPs inhibitors are classified according to their ZBG. Inhibitors interactions at active-site zinc play a role in defining the binding mode and relative inhibitor potency. MMP inhibitors generally contain an effective zinc binding group (e.g., hydroxamic acid, carboxylic acid, or sulfhydryl group) that is either generally substituted with a peptide-like structure that mimics the substrates that they cleave or appended to smaller side chains that may interact with specific subsites (e.g., P1′, P2′, P3′) within the active site.
Exemplary MMP inhibitors useful in the devices, methods and systems of the invention include but are not limited to TIMPs and compounds disclosed in U.S. Pat. Nos. 6,890,937, 6,750,233, 6,541,489, 6,872,727, 6,794,511, 6,750,228, 6,747,027, 6,716,844, 6,656,954, 6,638,952, 6,624,144, 6,583,299, 6,492,367, 6,476,027, 6,451,791, 6,448,250, 6,130,254, 6,087,559, 6,013,649, 5,990,158, 5,804,593, 5,948,780, 5,270,958, 5,240,958, 4,595,700, 6,420,408, 6,350,885, 6,265,432, and 6,116,910, in U.S. published applications 20040138260, 20060074108, and 20010049449 and in Wada, Curr. Topics in Med. Chem., 4:1255 (2004) and Skiles et al., Curr. Med. Chem., 11:2911 (2004)), the disclosures of which are incorporated by reference herein. Other exemplary MMP inhibitors include but are not limited to batimistat (BB-94), marimistat (BB-2516), prinomastat (AG3340), N-formylhydroxylamine (retrohydroxamate) biaryl ethers, e.g., ABT-770, BAY129566, minocylcine, doxocycline, tetracycline, doxycycline, methacycline, oxytetracycline, demeclocycline, 6-demethyl-6-deoxy-4-de(dimethylamino)tetracycline, 6-deoxy-5-hydroxy-4-de(dimethylamino)tetracycline, retinoids, antioxidants, e.g., glutathione, N-acetyl cysteine, glutathione ethyl ester, BMS-275291, R032-3555 (Trocade), bryostatin, HMG CoA reductase inhibitors, e.g., statins, ONO-4817 (Shimoyama et al., Med. Sci. Monit., 12:BR51 (2006)), allylisothiocyanate, GM 6001 (Dwiovedi et al., Am. J. Path., 168: 69 (2006), gallocatechin-3-gallate, tricyclic sulfonamides, heteroaromatics, 2-substituted oxazoles (Sheppart et al., Bioorg. Med. Chem. Lett., 8:3251 (1998), and thiol group-containing amide or peptidyl amide based MMPIs disclosed in WO 95/12389 and WO 96/11209. In one embodiment, a selective MMP inhibitor is employed. In one embodiment, the selective MMP inhibitor inhibits MMP-2, e.g., the inhibitor is/has a hydroxamic acid. In another embodiment, the selective MMP inhibitor inhibits MMP-8, e.g., the inhibitor is/has a carboxylic acid, thiadazin, barbiturate ring, phosphonic acid, peptidic thiol or hydroxamic acid such as a peptidic hydroxamic acid or malenic acid based hydroxamic acid, including BB94. In another embodiment, the selective MMP inhibitor inhibits MMP-13, e.g., the inhibitor is/has a hydroxamic acid, such as CGS 270237A, or a sulfone hydroxamic acid, or hemopexin. In one embodiment, the MMP inhibitor is one in one of Tables 5-12 in Skiles et al., Curr. Med. Chem., 11:2911 (2004), the disclosure of which is incorporated by reference herein.
Referring now to the drawings, there are shown in the Figures various implantable devices configured to carry and deliver one more inhibitors of one or more MMPs to a local area within a body. Those areas in the body that would benefit from the one or more inhibitors of the one or more MMPs include those areas that experience remodeling after infarct and those areas that experience trauma during surgical implantation of a device.
The implantable devices include, but are not limited to, cardiac rhythm management (CRM) device leads, stents, catheters, mechanical heart valves, atrial septal defect (ASD) devices, heart patches and ventricular restraint devices (VRD). Some of these devices, such as leads, heart patches, stents and catheters, may be implanted at or near an infarct resulting from an ischemia event. Devices such as stents, catheters, heart patches and leads may be implanted in or near the heart in reaction to an ischematic event or other cardiac event or disorder. Devices such as stents, heart patches or leads may be used for acute or chronic delivery, or both, and catheters may be used for acute delivery of MMP inhibitors.
Various methods of medicating the implantable devices are described below. While each of these methods is described in association with particular embodiments of the invention, it is understood that the various methods of medicating may be used with other embodiments, depending on the composition of the device. For example, methods of medicating devices having components made of silicone rubber are described in association with CRM device leads. Such methods may, however, be equally applicable to VRDs and cardiac patches. Also, methods of medicating metallic and polymeric components are also described in association with CRM device leads. These methods may find application in other devices such as stents, valves and heart patches.
Device coating may be accomplished by dipping the device in a solution or by spraying the device, or other methods of applying a coating to a device.
Non-thrombogenic and anti-thrombogenic coatings for devices have been developed, e.g., devices coated with polymers having pendant zwitterionic groups, specifically phosphorylcholine (PC) groups, generally described in WO 93/01221, or those described in WO 98/30615. The polymers coated onto the device have pendant crosslinkable groups which are subsequently crosslinked by exposure to suitable conditions, generally heat and/or moisture. Specifically a trialkoxysilylalkyl group reacts with pendant groups of the same type and/or with hydroxyalkyl groups to generate intermolecular crosslinks, which may lead to reduced thrombogenicity. Other drug coatings are described in Topol and Serruys in Circulation, 98:1802, (1998) and McNair et al., Proceedings of the International Symposium on Controlled Release Bioactive Materials, pp. 338-339 (1995) (hydrogel polymers having pendant phosphorylcholine groups). The hydrophilic/hydrophobic ratio of the (hydrophilic) phosphorylcholine monomer 2-methacryloyloxyethyl phosphorylcholine (HEMA-PC) and a hydrophobic comonomer may be modified. Crosslinking may be achieved by incorporating a reactive monomer 3-chloro-2-hydroxypropylmethacrylate. Release rates of drugs are influenced by the molecular size, solute partitioning and degree of swelling of the polymer.
Other coatings include polyurethanes. The polyurethanes may be modified to control compatibility with lipophilic or hydrophilic drugs. A polyurethane coated device may be contacted with a drug in a solvent which swells the polyurethane, whereby drug is absorbed into the polyurethane. Selection of a suitable solvent takes into account the swellability of the polyurethane and the solubility of the drug in the solvent.
Coatings for implantable devices may include an undercoat having a particulate drug and polymer matrix, and an overlying topcoat which partially covers the undercoat. The top coat may be discontinuous in situ, in order to allow for release of the drug from the undercoat. The polymer of the undercoat is, for example, hydrophobic biostable elastomeric material such as silicones, polyurethanes, ethylene vinyl acetate copolymers, polyolefin elastomers, polyamide elastomers and EPDM rubbers. The top layer may be formed of non-porous polymer such is as fluorosilicones, polyethylene glycols, polysaccharides and phospholipids.
Polymers having metal chelating activities may also have MMP inhibitory activity, e.g., polymers capable of chelating divalent metals. Those polymers are generally polymers of unsaturated carboxylic acids although sulphonated anionic hydrogels may be used. One example of a monomer for forming a sulphonated anionic hydrogel is N,N-dimethyl-N-methacryloyloxy-ethyl-N-(3-sulphopropyl) ammonium betaine. Other examples of polymers are acrylic acid based polymers modified with C10-30-alkyl acrylates crosslinked with di- or higher-functional ethylenically unsaturated crosslinking agents. In one embodiment, a device is coated with a crosslinkable polymer of 2-methacryloyloxyethyl-2′-trimethyl ammoniumethylphosphate inner salt and dodecyl methacrylate with crosslinking monomer.
Curing of a crosslinkable polymer may involve exposure to irradiation, chemical curing agents, catalysts or, more usually raised temperature and/or reduced pressure to acceptable condensation based cross-linking reactions. Drying a liquid composition usually involves raised temperature and/or reduced pressure for a time sufficient to reduce the amount of solvent remaining on the device to undetectable levels or levels at which it will not interfere with subsequent processing steps, or with release of the drug in use, or be toxic to a patient in whom the device is implanted.
In one embodiment, the coating on the outer wall of the device includes an inner layer of an amphiphilic polymer and adhered to the inner layer a crystalline MMP inhibitor. Provision of the crystalline MMP inhibitor may also confer useful release characteristics on the device. The crystalline material may be controlled for a particle size, for instance, to confer desired release characteristics which complement the release of absorbed drug from a polymer coating.
In one embodiment, the coating on at least the outer wall of the device has an inner layer where the polymer is amphiphilic and the topcoat has a non-biodegradable, biocompatible semipermeable polymer. The semipermeable polymer is selected so as to allow permeation of the MMP inhibitor through the top layer when the device is in an aqueous environment. In such an environment, the semipermeable polymer may, for instance, be swollen, and it is in this form that it should allow permeation of the active MMP inhibitors. A topcoat may confer desirable controlled release characteristics. Its use is of particular value where coating comprises crystalline MMP inhibitor adhered to an inner layer of amphiphilic polymer. The topcoat in such an embodiment has several functions. It provides a smooth outer profile, minimizes loss of the MMP inhibitor during delivery, provides a biocompatible interface with the blood vessel after implantation and controls release of MMP inhibitor from the stent into the surrounding tissue in use. A topcoat is preferably substantially free of the MMP inhibitor prior to implantation of the device. A topcoat may be formed of a second cross-linked amphiphilic polymer. The second amphiphilic polymer may be the same as the first amphiphilic polymer.
A composition to be applied to an implantable component is prepared by conventional methods wherein all composition components are combined and blended. For example, a predetermined amount of a polymer is added to a predetermined amount of a solvent. The term polymer is intended to include a product of a polymerization reaction inclusive of homopolymers, copolymers, terpolymers, etc., whether natural or synthetic, including random, alternating, block, graft, crosslinked, hydrogels, blends, compositions of blends and variations thereof. The solvent can be any single solvent or a combination of solvents capable of dissolving the polymer. The particular solvent or combination of solvents selected is dependent on factors such as the material from which implantable device is made and the particular polymer selected. Representative examples of suitable solvents include, but are not limited to, aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, ketones, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dihydrofuran (DHF), dimethylacetamide (DMAC), acetates and combinations thereof.
Sufficient amounts of a MMP inhibitor or a combination thereof are then dispersed in the blended composition of the polymer and the solvent. The MMP inhibitor may be in true solution or saturated in the composition. If the MMP inhibitor is not completely soluble in the composition, operations such as gentle heating, mixing, stirring, and/or agitation can be employed to effect homogeneity of the residues. However, care should be taken to ensure that the use of heat to effect dissolution does not also cause denaturation of a heat-sensitive anti-apoptotic drug substance.
Alternatively, the MMP inhibitor substance may be encapsulated in a sustained delivery vehicle such as, but not limited to, a liposome or an absorbable polymeric particle. The preparation and use of such sustained delivery vehicles are well known to those of ordinary skill in the art. The sustained delivery vehicle containing the MMP inhibitor is then suspended in the composition.
Inclusion of the MMP inhibitor in the composition should not adversely alter the composition or characteristic of the MMP inhibitor. Accordingly, the particular MMP inhibitor is selected for mutual compatibility with the other components of the composition.
Details of methods of coating or impregnating metallic and/or polymeric components with drugs are described in the following patents: U.S. Pat. No. 6,287,628, titled “Porous Prosthesis and a Method of Depositing Substances into the Pores;” U.S. Pat. No. 6,506,437, titled “Methods of Coating an Implantable Device Having Depots Formed in a Surface Thereof;” U.S. Pat. No. 6,544,582, titled “Method and Apparatus for Coating an Implantable Device;” U.S. Pat. No. 6,555,157, titled “Method for Coating an Implantable Device and System for Performing the Method;” U.S. Pat. No. 6,585,765, titled “Implantable Device Having Substances Impregnated Therein and a Method of Impregnating the Same” and U.S. Pat. No. 6,616,765, titled “Apparatus and Method for Depositing a Coating onto a Surface of a Prosthesis.”
In one embodiment, the device is a stent made of a nonbiodegradable, biocompatible material such as shape memory metal, or may be elastically self-expanding, for instance, be a braided stent or a balloon expandable stent. In one embodiment of the invention, in which a topcoat is provided, the topcoat may be part of a coherent coating formed over both a stent and a stent delivery device, for instance, a balloon of a balloon catheter from which a balloon expandable stent is delivered. In this case, the balloon may additionally be provided with a coating having the MMP inhibitor, for instance, adsorbed onto parts of its exterior surface between stent struts. Such a device may be produced by loading the stent with the MMP inhibitor after the stent has been mounted onto the delivery catheter.
In one embodiment, contact of the polymer coated stent with a liquid MMP inhibitor composition may be by dipping the stent into a body of the stent, and/or by flowing, spraying or dripping a liquid composition onto the stent with immediate evaporation of solvent from the wet stent. Such steps allow good control of drug loading onto the stent, and are particularly useful for forming the crystals of drug at the surface of polymer.
While the stent may be provided with drug coating prior to being mounted onto its delivery device, the stent to be premounted onto its delivery device prior to coating the stent. In this embodiment, it is primarily the outer wall of the stent (as opposed to the inner wall of the stent) which becomes coated with the MMP inhibitor. This method generally results in the MMP inhibitor being coated onto the stent delivery section of the delivery catheter. The outer surface of the delivery catheter with a coating of a MMP inhibitor, is a source to deliver the inhibitor adjacent tissue upon placement of the stent. Generally the delivery catheter is in contact with such tissue for a short period, whereby contact is not maintained for a prolonged period, and limited level of transfer of drug from the balloon takes place.
In another embodiment of the invention, local delivery of the MMP inhibitor is achieved using a microparticle, polymeric matrix delivery system which releases the drug into surrounding tissue. Both non-biodegradable and biodegradable matrices can be used for delivery of the drug, although biodegradable matrices are preferred. These may be natural or synthetic polymers. The polymer is selected based on the period over which drug release is desired. The microparticles can be microspheres, where the drug is dispersed within a solid polymeric matrix, or microcapsules, where the core is of a different material than the polymeric shell, and the drug is dispersed or suspended in the core, which may be liquid or solid in nature.
Bioerodible microspheres can be prepared using any of the methods developed for making microspheres for drug delivery, for example, as described by Mathiowitz and Langer, J. Controlled Release, 5:13 (1987); Mathiowitz et al., Reactive Polymers, 6:275 (1987); and Mathiowitz et al., J. Appl. Polymer Sci., 35:755 (1988), the teachings of which are hereby incorporated by reference. The selection of the method depends on the polymer selection, the size, external morphology, and crystallinity that is desired, as described, for example, by Mathiowitz et al., Scanning Microscopy, 4:329 (1990); Mathiowitz et al., J. Appl. Polymer Sci., 45:125 (1992); and Benita et al., J. Pharm. Sci., 73:1721 (1984), the teachings of which are incorporated herein.
Delivery of the microspheres is facilitated by a catheter or lead placed in or near the treatment site. The tip of the catheter or lead is placed upstream from the target treatment site such that when the microspheres are released through the catheter tip, they disperse and lodge themselves in the treatment area.
Any one or more catheters may be used to deliver the one or more MMP inhibitors to the infarct region area. Several catheters have been designed in order to precisely deliver agents to a damaged region within the heart for example an infarct region. Several of these catheters have been described (U.S. Pat. Nos. 6,102,926, 6,120,520, 6,251,104, 6,309,370; 6,432,119; 6,485,481). The delivery device may include an apparatus for intracardiac drug administration, including a sensor for positioning within the heart, a delivery device to administer the desired agent and amount at the site of the position sensor. The apparatus may include, for example, a catheter body capable of traversing a blood vessel and a dilatable balloon assembly coupled to the catheter body comprising a balloon having a proximal wall. A needle may be disposed within the catheter body and includes a lumen having dimensions suitable for a needle to be advanced there through. The needle body includes an end coupled to the proximal wall of the balloon. The apparatus also includes an imaging body disposed within the catheter body and including a lumen having a dimension suitable for a portion of an imaging device to be advanced there through. The apparatus may further include a portion of an imaging device disposed within the imaging body adapted to generate imaging signal of the infarct region within the ventricle. The apparatus may be suitable for accurately introducing a treatment agent at a desired treatment site.
In another embodiment a needle catheter used to deliver the agent to the ventricle for example, the infarct region, may be configured to include a feedback sensor for mapping the penetration depth and location of the needle insertion. The use of a feedback sensor provides the advantage of accurately targeting the injection location. Depending on the type of agent administered, the target location for delivering the agent may vary. For example, one agent may require multiple small injections within an infarct region where no two injections penetrate the same site.
In other embodiments, the catheter assembly may include a maneuverable instrument. This catheter assembly includes a flexible assembly. The catheter assembly, may be deflectable and includes a first catheter, a second catheter, and a third catheter. The second catheter fits coaxially within the first catheter. At least one of the first catheter and the second catheter include a deflectable portion to allow deflection of that catheter from a first position to a second position, and the other of the first catheter and second catheter includes a portion which is preshaped (e.g., an angled portion formed by two segments of the angled portion). The third catheter has a sheath and a medical instrument positioned within the sheath. The third catheter fits coaxially within the second catheter. In another embodiment, a stabilizer, such as a donut shaped balloon, is coupled to a distal portion of the third catheter. Each catheter is free to move longitudinally and radially relative to the other catheters. The catheter assembly uses coaxially telescoping catheters at least one or more being deflectable, to position a medical instrument at different target locations within a body organ such as the left ventricle. The catheter assembly may be flexible enough to bend according to the contours of the body organ. The catheter assembly may be flexible in that the catheter assembly may achieve a set angle according to what the medical procedure requires. The catheter assembly will not only allow some flexibility in angle changes, the catheter assembly moves in a three coordinate system allowing an operator greater control over the catheter assembly's movement portion of the second catheter, allowing for the distal tip of the third catheter to be selectively and controllably placed at a multitude of positions. It will be appreciated that the deflectable portion may alternatively be on the second catheter and the preshaped portion may be on the first catheter.
In a further embodiment, an apparatus is disclosed. In one embodiment, the apparatus includes a first annular member having a first lumen disposed about a length of the first annular member, and a second annular member coupled to the first annular member having a second lumen disposed about a length of the second annular member, wherein collectively the first annular member and the second annular member have a diameter suitable for placement at a treatment site within a mammalian body. Representatively, distal ends of the first annular member and the second annular member are positioned with respect to one another to allow a combining of treatment agents introduced through each of the first annular member and the second annular member to allow a combining of treatment agents at the treatment site. Such an apparatus is particularly suitable for delivering a multi-component gel material (e.g., individual components through respective annular members that forms a bioerodable gel within an infarct region of a ventricle).
In the embodiments described herein, a substance delivery device and a method for delivering a substance are disclosed. The delivery device and method described are particularly suitable, but not limited to, local drug delivery in which a treatment agent composition (possibly including multiple-treatment agents and/or a sustained-release composition) is introduced via needle delivery to a treatment site within a mammalian host. A kit of a treatment agent composition is also described. One suitable application for a delivery device is that of a catheter device, including a needle delivery system. Suitable therapies include, but are not limited to, delivery of drugs for the treatment of arterial restenosis, therapeutic angiogenesis, or cancer treatment drugs/agents.
In various embodiments, an MMP inhibitor is locally delivered using an implantable or percutaneous device. Examples of such devices include leads, stents, and catheters, as discussed below with reference to
With reference to
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The elongate body 32 forms an insulating sheath covering around the conductor 34. The conductor 34 is coupled to a ring or ring-like electrode 36 at or near the distal end portion 18 of the elongate body 32. The conductor 34 is coupled to a connector 38 at or near the proximal end 16 of the elongate body 32. The device 14 includes a receptacle for receiving the connector 38, thereby obtaining electrical continuity between the electrode 36 and the device 14.
The electrode 36, or at least a portion thereof, is not covered by the insulating sheath of the elongate body 32. The electrode 36 provides an exposed electrically conductive surface around all, or at least part of, the circumference of the lead 10. In one example, the electrode 36 is a coiled wire electrode that is wound around the circumferential outer surface of the lead 10. The lead 10 also includes other configurations, shapes, and structures of the electrode 36.
As illustrated in
In one embodiment, the coating 40 includes substantially soluble particles dispersed in a substantially insoluble medium, such as biocompatible silicone rubber medical adhesive, other polymer, or other suitable biocompatible adhesive substance. The soluble particles are at least partially dissolvable when exposed to an aqueous substance such as blood or bodily fluids. In accordance with the present invention, the soluble particles include the MMP inhibitor. The particles may also include a drug enhancer. When the coating 40 is exposed to an aqueous environment, the substantially soluble MMP inhibitor particles dissolve, providing sustained release of the MMP inhibitor into the surrounding tissue. During manufacture of the lead, one or more portions of the lead are coated with the coating. The coating cures such that it adheres to the lead. Details relating to the coating formation are described in U.S. Pat. No. 6,584,363, titled “Implantable Lead With Dissolvable Coating for Improved Fixation and Extraction,” assigned to Cardiac Pacemakers, Inc., the disclosure of which is hereby incorporated by reference.
With reference to
With reference to
With reference to
To facilitate the elution of the MMP inhibitor, the collar 50 is constructed of a carrier material and the MMP inhibitor. The carrier material is typically a silicone rubber or a polymeric matrix, such as polyurethane. Generally, the carrier material is selected and formulated for an ability to incorporate the MMP inhibitor during manufacture and release the MMP inhibitor within the patient after implantation. The amount of the MMP inhibitor incorporated into collar 50 is determined by the effect desired, the potency of the MMP inhibitor, the rate at which the MMP inhibitor is released from the carrier material, as well as other factors that will be recognized by those skilled in the art.
The collar 50 in accordance with the present invention may be made by mixing (or dissolving, or melting). The MMP inhibitor will typically be mixed with uncured silicone rubber that includes, but is not necessarily limited to, two part liquid silicone rubbers, gum stock silicone rubbers, or medical adhesives used for creating or bonding silicone rubber components. The MMP inhibitor is added to the uncured silicone rubber in various quantities and following the mixing, the silicone rubber is cured and formed into the collar component for the delivery of the MMP inhibitor. Care should be taken that the method selected does not heat the mixture including the MMP inhibitor beyond a point that would destroy the MMP inhibitor. The collar 50 can be formed by any suitable process, including molding, extruding or other suitable processes recognized by those skilled in the art.
In another embodiment, the collar 50 of
In other embodiments, any exposed metallic or polymer component of the lead 10, such as the elongate body 32 (
In another method, a plurality of pores, called “depots,” are formed in the outer surface of the component. The depots are sized and shaped to contain the composition to ensure that a measured dosage of the composition is delivered with the device to the specific treatment site. Depots formed on the components of the implantable device have a particular volume intended to be filled with the composition to increase the amount of the composition that can be delivered from the implantable device to the target treatment site.
The component can be made of a metallic material or an alloy such as, but not limited to, stainless steel, Nitinol, tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof. The component may also be made from bioabsorbable or biostable polymers. A polymeric component should be chemically compatible with any substance to be loaded onto the component.
Depots, which may also be referred to as pores or cavities, can be formed in virtually any component structure at any preselected location. The location of depots within a component varies according to intended usage and application. Depots may be formed on the component by exposing the outer surface to an energy discharge from a laser, such as, but not limited to, an excimer laser. Alternative methods of forming such depots include but are not limited to, physical and chemical etching techniques. Such techniques are well known to one of ordinary skill in the art.
While the various embodiments of the lead configuration described thus far have been passive delivery devices, active delivery embodiments are contemplated. For example, with reference to
In another active delivery embodiment, electrophoresis is used to control delivery of the MMP inhibitor. With reference to
With reference to
The catheter assembly 62 as illustrated in
In
In an exemplary procedure to implant the stent 60, the guide wire 72 is advanced through the patient's vascular system by well known methods so that the distal end of the guide wire is advanced past the plaque or diseased area 78. Prior to implanting the stent, the cardiologist may wish to perform an angioplasty procedure or other procedure, i.e., atherectomy, in order to open the vessel and remodel the diseased area. Thereafter, the stent delivery catheter assembly 62 is advanced over the guide wire 72 so that the stent 60 is positioned in the target area. The expandable member or balloon 74 is inflated so that it expands radially outwardly and in turn expands the stent 60 radially outwardly until the stent 60 is apposed to the vessel wall. The expandable member 74 is then deflated and the catheter withdrawn from the patient's vascular system. The guide wire 72 is left in the lumen for post-dilatation procedures, if any, and subsequently is withdrawn from the patient's vascular system. As illustrated in
The stent 60 serves to hold open the artery after the catheter is withdrawn, as illustrated by
In one embodiment, the entire surface of the stent 60 is coated to carry and deliver the MMP inhibitor. In another embodiment, portions of the surfaces of the stent 60, e.g., the tissue contacting portions, are coated to carry the MMP inhibitor. The stent 60 may be formed of either a metal or a polymer material and thus the methods available for medicating the stent 60 are the same as those described above with respect to the metallic and polymeric components of the lead configuration.
With reference to
As illustrated in
As illustrated in
The coating 104 extends circumferentially completely (or at least partially) around the exterior surface of the catheter 94 at the distal end portion 96. When the distal end portion 96 is inserted into the body, the coating 104 dissolves and the MMP inhibitor is released. The time duration of the release of the MMP inhibitor is determined based on the length of time during which the distal end portion 96 is placed in the intravascular or intracardiac region during a catheterization procedure. The speed at which the coating 104 dissolves, and thus the MMP inhibitor is released, may be controlled based on the selection of the coating material and the concentration of the MMP inhibitor.
In one embodiment, the coating 104 includes substantially soluble particles dispersed in a substantially insoluble medium, such as biocompatible silicone rubber medical adhesive, other polymer, or other suitable biocompatible adhesive substance. The soluble particles are at least partially dissolvable when exposed to an aqueous substance such as blood or bodily fluids. The soluble particles include a MMP inhibitor and may also include a drug enhancer. When the coating 104 is exposed to an aqueous environment, the substantially soluble MMP inhibitor particles dissolve, providing sustained release of the MMP inhibitor into the surrounding tissue. The coating 104 is coated onto the distal end portion 96 during the manufacturing of the catheter 94. The coating 104 cures to adhere to the surface of the distal end portion 96 of catheter 94. Details relating to the coating formation are described in U.S. Pat. No. 6,584,363.
As illustrated in
To facilitate the elution of the MMP inhibitor, the collar 118 is constructed of a carrier material and the MMP inhibitor. Examples of the carrier material include a silicone rubber or a polymeric matrix, such as polyurethane. Generally, the carrier material is selected and formulated for an ability to incorporate the MMP inhibitor during manufacture and release the MMP inhibitor when the distal end portion 110 is within the patient. The amount of the MMP inhibitor incorporated into collar 118 is determined by the effect desired, the potency of the MMP inhibitor, the rate at which the MMP inhibitor is released from the carrier material, as well as other factors that will be recognized by those skilled in the art.
In various embodiments, the collar 118 is made by mixing (or dissolving, or melting). The MMP inhibitor is mixed with uncured silicone rubber. In one embodiment, two part liquid silicone rubbers, gum stock silicone rubbers, or medical adhesives are used for creating or bonding silicone rubber components. The MMP inhibitor is added to the uncured silicone rubber in various quantities and following the mixing, the silicone rubber is cured and formed into the collar component for the delivery of the MMP inhibitor. Care should be taken that the method selected does not heat the mixture including the MMP inhibitor beyond a point that would destroy the MMP inhibitor. The collar 118 can be formed by any suitable process, including molding, extruding or other suitable processes recognized by those skilled in the art. In another embodiment, the collar 118 is a microporous collar, such as described in U.S. Pat. No. 6,361,780.
With reference to
As illustrated in
A lumen 132 extends within the elongate body 128 between the distal end portion 122 and the proximal end portion 124. The lumen 132 allows injection of the MMP inhibitor to the vascular location where the distal end portion 122 is placed.
As illustrated in
As illustrated in
For illustrative but not restrictive purposes, catheters shown in
In one embodiment, the entire surface of heart patch 160 is coated to carry and deliver the MMP inhibitor. In another embodiment, portions of the surfaces of heart patch 160, e.g., the portions configured to contact the epicardial surface, are coated to carry the MMP inhibitor. Heart patch 160 may be formed of either a metal or a polymer material and thus the methods available for medicating the heart patch are the same as those described above with respect to the metallic and polymeric components of the lead configuration. In one embodiment, heart patch 160 is made of a biodegradable material that is absorbed by the body after providing support to heart 12 for a certain period of time and the MMP inhibitor has been eluted.
The MMP inhibitors of the invention may be employed in conjunction with other therapies, e.g., therapies for ischemia or arrhythmias. The amount of MMP inhibitor and/or other drugs which are exogenously administered will vary depending on various factors
Administration of the agents in accordance with the present invention may be continuous or intermittent, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners. The administration of the agents of the invention may be essentially continuous over a preselected period of time or may be in a series of spaced doses.
The formulations may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods well known to pharmacy. Such methods may include the step of bringing into association the agent with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combinations thereof, and then, if necessary, introducing or shaping the product into the desired delivery system.
Pharmaceutical formulations containing the agents of the invention can be prepared by procedures known in the art using well known and readily available ingredients. For example, the agent can be formulated with common excipients, diluents, or carriers. Examples of excipients, diluents, and carriers that are suitable for such formulations include the following fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose, HPMC and other cellulose derivatives, alginates, gelatin, and polyvinyl-pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols. The formulations can include buffering agents such as calcium carbonate, magnesium oxide and magnesium carbonate, as well as, inactive ingredients such as cellulose, pregelatinized starch, silicon dioxide, hydroxy propyl methyl cellulose, magnesium stearate, microcrystalline cellulose, starch, talc, titanium dioxide, benzoic acid, citric acid, corn starch, mineral oil, polypropylene glycol, sodium phosphate, zinc stearate, and gelatin, microcrystalline cellulose, or sodium lauryl sulfate, or liquid vehicles such as polyethylene glycols (PEGs) and vegetable oil.
The pharmaceutical formulations of the agents of the invention can also take the form of an aqueous or anhydrous solution or dispersion, or alternatively the form of an emulsion or suspension.
The compositions according to the invention can also contain thickening agents such as cellulose and/or cellulose derivatives. They can also contain gums such as xanthan, guar or carbo gum or gum arabic, or alternatively polyethylene glycols, bentones and montmorillonites, and the like.
It is possible to add, if necessary, an adjuvant chosen from antioxidants, surfactants, other preservatives, film-forming, keratolytic or comedolytic agents, perfumes and colorings. Also, other active ingredients may be added, whether for the conditions described or some other condition.
Additionally, the agents are well suited to formulation as sustained release dosage forms and the like. The coatings, envelopes, and protective matrices may be made, for example, from polymeric substances, such as polylactide-glycolates, liposomes, microemulsions, microparticles, nanoparticles, or waxes. These coatings, envelopes, and protective matrices are useful to coat indwelling devices, e.g., a stent, epicardial patch, lead, and the like.
The formulations and compositions described herein may also contain other ingredients such as antimicrobial agents, or preservatives. Furthermore, as described herein the active ingredients may also be used in combination with other therapeutic agents or therapies.
All publications, patents and patent applications are incorporated herein by reference. While in the foregoing specification, this invention has been described in relation to certain preferred embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details herein may be varied considerably without departing from the basic principles of the invention.
