WO2004024206A1 - Apparatus and method for delivering compounds to a living organism - Google Patents
Apparatus and method for delivering compounds to a living organism Download PDFInfo
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- WO2004024206A1 WO2004024206A1 PCT/US2003/028828 US0328828W WO2004024206A1 WO 2004024206 A1 WO2004024206 A1 WO 2004024206A1 US 0328828 W US0328828 W US 0328828W WO 2004024206 A1 WO2004024206 A1 WO 2004024206A1
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- inhibitor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
- A61L29/16—Biologically active materials, e.g. therapeutic substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/422—Anti-atherosclerotic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/43—Hormones, e.g. dexamethasone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/432—Inhibitors, antagonists
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures
Definitions
- Vascular diseases include diseases that affect areas of a living organism relating to or containing blood vessels.
- stenosis is a narrowing or constricting of arterial lumen or blood vessels in a living organism (e.g., a human) usually due to atherosclerosis (AS) or coronary heart disease (CHD).
- AS atherosclerosis
- CHD coronary heart disease
- Restenosis is a recurrence of stenosis after a percuteneous intervention such as angioplasty and/or stenting.
- the underlying mechanisms of restenosis comprise a combination of effects from vessel recoil, negative vascular remodeling, thrombus formation and neointimal hyperplasia. It has been shown that restenosis after balloon angioplasty is mainly due to vessel remodeling and neointimal hyperplasia vessel recoil and after stenting is mainly due to neo-intimal hyperplasia.
- Treatment for stenosis and restenosis varies. Stenosis caused by AS or CHD often forces individuals to restrict and limit their activity levels in order to avoid complications, angina, intermittent claudication, rest pain, stroke, heart attack, sudden death and loss of limb or function of a limb stemming from the stenosis.
- the reconstruction of blood vessels, arteries and veins may also be needed to treat individuals suffering from stenosis and restenosis.
- Coronary bypass can also be utilized to revascularize the heart and restore normal blood flow. In other cases, balloon angioplasty may be conducted to increase the orifice size of culprit areas.
- these treatments address the problems associated with stenosis, but they also create a high rate of restenosis that can result in recurrence of cardiac symptoms and mortality. Moreover, these treatments are not preventative in nature, and therefore generally are not utilized until the patient or individual has already developed stenosis.
- Atherosclerosis affects medium and large arteries and is characterized by a patchy, intramural thickening that encroaches on the arterial lumen and, in most severe form, causes obstruction.
- the atherosclerotic plaque comprises an accumulation of intracellular and extracellular lipids, smooth muscle cells and connective tissue.
- the earliest lesion of atherosclerosis is the fatty streak that evolves into a fibrous plaque coating the artery.
- Atherosclerotic vessels have reduced systolic expansion and abnormal wave propagation.
- Treatment of atherosclerosis is usually directed at its complications, for example, angina, myocardial infarction, claudication, arrhythmia, heart failure, kidney failure, stroke, and peripheral arterial occlusion.
- New and improved methods and devices are being sought for treatment and prevention of vascular diseases such as stenosis, restenosis and atherosclerosis.
- the invention provides a method of treating or preventing high-risk plaque.
- the method may include applying to a medical device an effective amount of a composition comprising a sex hormone, anti-hormone, sex-hormone agonist, steroid-hormone inhibitor/antagonist (partial or full), selective estrogen receptor modulator (SERM), or a combination thereof.
- the medical device may be inserted into an area of a living organism that is or has a propensity to be affected by high-risk plaque.
- the invention provides a local-delivery device for treating or preventing high-risk plaque in a living organism.
- the local-delivery device includes a medical device at least partially coated with an effective dose of a composition comprising a sex hormone, anti-hormone, sex-hormone agonist, steroid-hormone inhibitor/antagonist
- the local-delivery device may be suitable for treating or preventing high-risk plaque.
- the invention provides a method of treating high-risk plaque in a living organism.
- the method includes applying an effective dose of a composition comprising estrogen, estradiol or a derivative thereof to a stent by chemical or physical bonding.
- the stent is placed at or near high-risk plaque and estrogen, estradiol or derivative thereof is released
- Figure 1 is a perspective view of a stent embodying the invention.
- Figure 2 is a cross-sectional view taken along line 2—2 in Figure 1.
- Figure 3 is a perspective view of a balloon-injection catheter embodying the invention.
- Figure 4 is cross-sectional view taken along line 4—4 of Figure 3.
- Figure 5 is a cross-sectional view taken along line 5—5 in Figure 5, wherein the catheter is inserted into an affected area of a living organism.
- Figure 6 is a cross-sectional view taken along line 6—6 of Figure 1.
- Figure 7 is a table illustrating photomicrographs of histological section 30 days after delivery of a) control stent b) low dose 17B-estradiol stent, and c) high dose 17B-estradiol stent illustrating intimal proliferation.
- Figure 8 is a table illustrating dosage data for studies performed in Example 2.
- Figure 9 is a table showing averages and standard deviations for the dosage per stent and dosage per unit area.
- Figure 10 shows total dosage per stent for the various stent designs, which was estimated by multiplying the average dosage per unit area by the stent surface areas.
- Figure 11 is a representation of stable plaque.
- Figure 12 is a representation of vulnerable plaque.
- Figure 13 is a representation of a vulnerable plaque, and the consequences of its rupture.
- Factors limiting thrombosis include high flow, fibrinolytic activity, and minor plaque disruption.
- a non-occlusive plaque/thrombus may be silent and result in angina, silent infarction, sudden death or acute coronary syndrome.
- An occlusive thrombus may also result in sudden death.
- Figure 14 is a chart depicting angiographic and JTVUS follow-up results related to Example 3.
- Figure 15 is a chart showing percentage of drug retained on stent versus time.
- the present invention provides apparatuses and methods for delivering a composition to a localized area of a living organism.
- the invention relates to local-delivery devices and methods for treating and preventing proliferative and atherosclerotic vascular diseases in a living organism. More particularly, the invention provides apparatuses and methods for locally delivering a sex hormone (e.g. estrogen), an anti-hormone, a sex-hormone agonist, a steroid-hormone inhibitor/antagonist (partial or full) or a selective estrogen receptor modulator (SERM), or a combination thereof, to a portion of a living organism inflicted by or susceptible to a vascular disease such as stenosis or restenosis.
- the local-delivery device e.g.
- a stent, catheter, injection catheter, balloon or balloon-injection catheter in situ to coat the implanted stent is inserted into an affected area of a living organism to treat or prevent the proliferative and atherosclerotic vascular disease. Balloons have been developed so that drugs can seep out though the wall without being injected.
- Estrogen is known to favorably alter the atherogenic lipid profile and may also have a direct action on blood vessel walls. Estrogen can have both rapid and long-term effects on the vasculature including the local production of coagulation and fibrinolytic factors, antioxidants and the production of other vasoactive molecules, such as nitric oxide and prostaglandins, all of which are known to influence the development of vascular disease.
- estrogen can also act on the endothelium and smooth muscle cells either directly or via estrogen receptors in both men and women. This appears to have an inhibitory effect on many steps in the atherosclerotic process. With respect to the interventional cardiology, estrogen appears to inhibit the response to balloon injury to the vascular wall. Estrogen can repair and accelerate endothelial cell growth in-vitro and in-vivo. Early restoration of endothelial cell integrity may contribute to the attenuation of the response to injury by increasing the availability of nitric oxide. This in turn can directly inhibit the proliferation of smooth muscle cells. In experimental studies, estrogen has been shown to inhibit the proliferation and migration of smooth muscle cells in response to balloon injury. Estrogen has also proved to inhibit adventitial fibroblast migration, the mechanism involved in negative remodeling.
- Sex hormones and sex-hormone agonists may be helpful in preventing and treating certain vascular diseases.
- suitable sex hormones include, but are in no way limited to, estrogens, progesterones, testosterones, dehydroepiandrostrones (DHEAs) and dehydroepiandrosteronesulfates (DHEAs) and derivatives thereof.
- DHEAs dehydroepiandrostrones
- DHEAs dehydroepiandrosteronesulfates
- estrogen has proven to be the most effective in preventing and treating vascular diseases.
- Naturally occurring/plant estrogens or phytoestrogens including isoflavones such as genistein, daidzein and resveratrol are also useful in the treatment of vascular disease.
- Suitable sex- hormone agonists include, but are in no way limited to, estradiol, estrone, ethinyl estradiol, conjugated equine estrogens and
- anti-hormones and steroid-hormone inhibitors/antagonist may be effective in preventing vascular diseases.
- Anti-hormones inhibit or prevent the usual effects of certain other hormones, thereby increasing the relative effectiveness of hormones that are not being inhibited or prevented by these anti-hormones.
- Anti-hormones effective in preventing vascular diseases include, but are not limited to, anti-estrogens (e.g. Faslodex), anti-androgens (e.g. cyproterone acetate) and anti-testosterone (e.g. anti-testosterone wild- type Fab fragment and mutant Fab fragments).
- Examples of steroid-hormone inhibitors/antagonist include, but are not limited to, aminogluthemide, anastrazole and letrozole.
- Selective estrogen receptor modulators including but not limited to raloxifene, tamoxifen, tibolone and idoxifene, may also be effective in treating or preventing vascular diseases such as stenosis and restenosis.
- SERMS Selective estrogen receptor modulators
- these compounds are generally found in a powdered form.
- the powder is generally mixed with a solution of saline or ethanol. This facilitates coating the local-delivery devices or injecting the composition as described below.
- the composition can also be mixed into another solution, gel or substance to control the rate of release from the stent and into the tissue.
- compositions in the exact area of disease or potential disease avoids the negative systemic effects these compounds can produce when administered generally.
- the devices can be inserted into arteries, both coronary and otherwise.
- Oral use of conjugated equine estrogen in combination with a progestin may have effects on the coagulation pathways that attenuate the benefits that may potentially occur to a vascular wall.
- hyperplastic effects of estrogen on the uterus and breast tissue may exist when estrogen is administered systemically.
- general administration may result in potential feminizing effects in males.
- compositions described above are promising alternative to the systemic use of this hormone.
- the basic anti-atherogenic properties of these compositions and their potential to inhibit neointimal proliferation while simultaneously attenuating endothelial repair make them ideal for local administration in the coronary artery to inhibit restenosis.
- Localized delivery of other compositions comprising sex hormones, anti-hormones, sex-hormone agonists, steroid- hormone inhibitors/antagonist (partial or full) or selective estrogen receptor modulators (SERMS), or combinations thereof, to the vasculature may prevent and treat vascular diseases such as stenosis, restenosis and atherosclerosis.
- SERMS selective estrogen receptor modulators
- the local-delivery systems generally comprise a local-delivery device and at least one of the effective compositions described above.
- the compositions can be delivered locally to tissue, tubular organs, blood vessels, the coronary or peripheral of organs as well as to muscles (myocardium, skeletal or smooth muscles).
- the compositions can also be injected directly into the vessel, vessel wall or muscle.
- the local-delivery system is a stent that delivers the above-described compositions to the localized portion of the body of a living organism.
- Figure 1 illustrates a stent 10, which is a hollow member that lies within the lumen of a tubular structure and provides support and assures patency of an intact but contracted lumen.
- Stents may be made from stainless steel or any other suitable material such as biodegradable material (e.g. a Japanese stent). In other words, the stent itself may biodegrade.
- Effective compositions as described above coat or are applied to the stent.
- Figure 2 shows a portion of the stent 10 coated with a composition 12 in cross-section. Because the stent remains in the artery after the angioplasty procedure is performed, it enables the composition 12 to slowly diffuse from the outside of its surface 10 into the adjacent atherosclerotic plaque to which it can affect. The rate of this diffusion varies according to the molecular weight of the compound being administered. Also, the structure of the stent and the type of coating applied thereto also affect the rate of diffusion.
- an effective composition is applied to an injection catheter, and more particularly to a balloon-injection catheter 14.
- a balloon- injection catheter 14 is similar to a balloon angioplasty, except for the added feature of a chamber 16 including injection ports 18 for injecting the compositions described above.
- Figure 5 illustrates a balloon-injection catheter 14 in cross-section after being injected into an affected area 20 of a living organism.
- the hormone can be injected directly into the plaque, vessel wall or tissue 22 via these injection ports 18. If an injection catheter injects the compound into the plaque 22, the composition releases immediately after injection. Accordingly, there is no residual release of the composition once the injection catheter is removed.
- Angiographic, angioplasty, delivery and infusion catheters may also be used to deliver these compounds to affected areas.
- the above-described compositions can be locally delivered to a variety of body structures including grafts, saphenos vein grafts, arterial grafts, synthetic grafts, implants, prostheses or endoprostheses, homo or zeno grafts, cardiac muscle, skeletal or smooth muscle body structure.
- a miniscule amount of composition may provide effective results. For example, at least about l ⁇ g, more particularly, greater than about lO ⁇ g, even more particularly, greater than about 25 ⁇ g, and even more particularly, greater than about 50 ⁇ g may be used. There is no limit as to the maximum amount of composition that can be provided on the device, so long as the device is physically capable of holding the composition. In some examples, however, less than about 3000 ⁇ g of effective composition may be applied to each delivery device. More particularly, less than about 2000 ⁇ g, and even more particularly, less than about lOOO ⁇ g of effective composition may be applied to each delivery device.
- Effective dosages may widely vary; any dosage that restores circulation through a stenosed or restenosed blood vessel and or alleviates the narrowing of the affected area is acceptable for use in the invention. As a result, dosages well in excess of the preferred ranges can be acceptable.
- the manner by which the effective compounds are bonded to the stent can also provide either slow or fast release of the effective compounds. Slow release of the effective compound can take up to ten years. Most preferably, release of the compound takes up to ten weeks, and more particularly, up to four weeks, although any period of time which allows for the effective compound to release from the stent or delivery device such that circulation is restored through the blood vessel and/or the narrowing of the affected area is alleviated is acceptable.
- Application of these effective compositions to a stent or other local-delivery device can be achieved in a number of different ways.
- the compound can be mechanically, electromechanically, biologically, or chemically bonded to the delivery device, e.g. by a covalent bonding process.
- the compounds are directly embedded into a metal or other suitable substance from which the local-delivery system is comprised.
- the effective composition can also be applied using a chemical coating/bonding process, whereby layers of a suitable pharmaceutical agent, vehicle, or carrier entrap the compound.
- a biological or pharmacological coating aheady present on the local-delivery device acts as a platform for coating the compounds described above.
- platforms include, but are not limited to, silicon carbide, carbon, stainless steel, gold, nitinol, polymer absorbable platforms, diamond or diamond-like coating, e.g. polytetrafluoroethylene, hylauronic acid or polyactone.
- Suitable synthetic pharmaceutical agents include, but are not limited to, phosphorylcholine, polyurethane, segmented polyurethane, poly-L-lactic acid, cellulose ester, polyethylene glycol as well as polyphosphate esters.
- Naturally occurring vehicles or carriers include collagens, laminens, heparins, fibrins, genes, DNA, proteins, vectors, viruses, and other naturally occurring substances that absorb to cellulose.
- Using a chemical coating of the stent or other device is particularly advantageous in that it allows the compound or sex hormone to slowly release from the carrier, vehicle, or agent. This extends the time that the affected portion of the body sustains the efficacious effects of the compounds.
- Suitable agents, vehicles, and carriers include polymers, elastomeric encapsulated non-erodable polymers (matrix release), elastomeric encapsulated erodable polymers (matrix release and conjugated release), nanoporous ceramic coatings, erodable polymer inlays, biopolymers, biologic graft materials, fibrin coatings and collagen coatings.
- the compositions may also be directly applied to the delivery devices.
- a solvent, one or more complementary polymers dissolved in the solvent, and at least one of the above-identified effective compositions or agents dispersed in the polymer/solvent mixture may be prepared.
- the solvent may preferably be one in which the polymers form a true solution.
- the effective composition itself may either be soluble in the solvent or form a dispersion throughout the solvent.
- the resultant composition can be applied to the device in any suitable fashion, e.g., it can be applied directly to the surface of the medical device, or alternatively, to the surface of a surface-modified medical device, by dipping, spraying, or any conventional technique.
- the method of applying the coating composition to the device is typically governed by the geometry of the device and other process considerations.
- the coating is subsequently cured by evaporation of the solvent.
- the curing process can be performed at room temperature, reduced or elevated temperature, or with the assistance of vacuum.
- the polymer mixture may be biocompatible, e.g., such that it results in no induction of inflammation or irritation when implanted.
- the polymer combination must be useful under a broad spectrum of both absolute concentrations and relative concentrations of the polymers. This means that the physical characteristics of the coating, such as tenacity, durability, flexibility and expandability, will typically be adequate over a broad range of polymer concentrations.
- the ability of the coating to control the release rates of a variety of the above compositions can preferably be manipulated by varying the absolute and relative concentrations of the polymers.
- a first polymer component may provide an optimal combination of various structural/functional properties, including hydrophobicity, durability, bioactive agent release characteristics, biocompatability, molecular weight, and availability (and cost).
- first polymers examples include poly(alkyl)(meth)acrylates, and in particular, those with alkyl chain lengths from 2 to 8 carbons, and with molecular weights from 50 kilodaltons to 900 kilodaltons.
- a more specific example of a first polymer is poly n- butylmethacrylate.
- Such polymers are available commercially, e.g., from Aldrich, with molecular weights ranging from about 200,000 daltons to about 320,000 daltons, and with varying inherent viscosity, solubility, and form (e.g., as crystals or powder).
- a second polymer component may provide an optimal combination of similar properties, and particularly when used in admixture with the first polymer component.
- suitable second polymers are available commercially and include poly(ethylene- co-vinyl acetate) having vinyl acetate concentrations of between about 10% and about 50%, in the form of beads, pellets, granules, etc. (commercially available are 12%, 14%, 18%, 25%, 33%).
- pEVA co-polymers with lower percent vinyl acetate become increasingly insoluble in typical solvents, whereas those with higher percent vinyl acetate become decreasingly durable.
- a particularly preferred polymer mixture for use in this invention includes mixtures of poly(butylmethacrylate) (pBMA) and poly(ethylene-co- vinyl acetate) co-polymers (pEVA).
- This mixture of polymers has proven useful with absolute polymer concentrations (i.e., the total combined concentrations of both polymers in the coating composition), of between about 0.25 and about 70 percent (by weight). It has furthermore proven effective with individual polymer concentrations in the coating solution of between about 0.05 and about 70 weight percent.
- the polymer mixture includes poly(n- butylmethacrylate) (pBMA) with a molecular weight of from 100 kilodaltons to 900 kilodaltons and a pEVA copolymer with a vinyl acetate content of from 24 to 36 weight percent.
- pBMA poly(n- butylmethacrylate)
- a polymer mixture includes poly(n- butyl ethacrylate) with a molecular weight of from 200 kilodaltons to 400 kilodaltons and a pEVA copolymer with a vinyl acetate content of from 30 to 34 weight percent.
- concentration of the bioactive agent or agents dissolved or suspended in the coating mixture can range from 0.01 to 90 percent, by weight, based on the weight of the final coating composition.
- suitable polymeric agents, vehicles and carriers may include, but are not limited to, at least one of polycarbonate, polyester, polyethylene, polyethylene terephthalate (PET), polyglycolic acid (PGA), polyolefin, poly-(p-phenyleneterephthalamide), polyphosphazene, polypropylene, polytetrafluoroethylene, polyurethane, polyvinyl chloride, polyacrylate (including polymethacrylate), and silicone elastomers, as well as copolymers and combinations thereof.
- PET polyethylene terephthalate
- PGA polyglycolic acid
- polyolefin poly-(p-phenyleneterephthalamide)
- polyphosphazene polypropylene
- polytetrafluoroethylene polyurethane
- polyurethane polyvinyl chloride
- polyacrylate including polymethacrylate
- silicone elastomers as well as copolymers and combinations thereof.
- suitable polymeric agents, vehicles and carriers may include, but are not limited to, at least one of a synthetic polymer or copolymer selected from the group consisting of acrylics, vinyls, nylons, polyurethanes, polyethers, and biodegradable or bioerodable polymers selected from the group consisting of polylactic acid, polyglycolic acid, polydioxanones, polyanhydrides, and polyorthoesters.
- a synthetic polymer or copolymer selected from the group consisting of acrylics, vinyls, nylons, polyurethanes, polyethers, and biodegradable or bioerodable polymers selected from the group consisting of polylactic acid, polyglycolic acid, polydioxanones, polyanhydrides, and polyorthoesters.
- Polymers may be synthetic or naturally occurring.
- synthetic polymers include but are not limited to, oligomers, homopolymers, and copolymers resulting from addition or condensation polymerization.
- Naturally occurring polymers such as polysaccharides and polypeptides, can be used as well.
- Acrylic agents, vehicles and carriers may also be used.
- Such polymers may include hydroxyethyl acrylate, hydroxyethyl methacrylate, glyceryl acrylate, glyceryl methacrylate, acrylic acid, methacrylic acid, acrylamide and methacrylamide; vinyls such as polyvinyl pyrrolidone and polyvinyl alcohol; nylons such as polycaprolactam, polylauryl lactam, polyhexamethylene adipamide and polyhexamethylene dodecanediamide; polyurethanes; polyethers such as polyethylene oxide, polypropylene oxide, and polybutylene oxide; and biodegradable polymers such as polylactic acid, polyglycolic acid, polydioxanone, polyanhydrides, and polyorthoesters.
- the device may be coated with a solution which includes a solvent, a polymer dissolved in the solvent and an effective amount of at least one of the compositions discussed above dispersed in the solvent.
- the solvent may be capable of placing the polymer into solution at the concentration desired in the solution. Examples of some additional suitable combinations of polymer, solvent and therapeutic substance are set forth below.
- the solution is applied to the device and the solvent is allowed to evaporate, thereby leaving on the device surface a coating of the polymer and the effective composition.
- the solution can be applied to the device by either spraying the solution onto the device or immersing the device in the solution. Whether one chooses application by immersion or application by spraying depends principally on the viscosity and surface tension of the solution, however, it has been found that spraying in a fine spray such as that available from an airbrush will provide a coating with the greatest uniformity and will provide the greatest control over the amount of coating material to be applied to the device. In either a coating applied by spraying or by immersion, multiple application steps are generally desirable to provide improved coating uniformity and improved control over the amount of therapeutic substance to be applied to the device.
- the polymer is biocompatible and minimizes irritation to the vessel wall when the device is implanted.
- the polymer may be either a biostable or a bioabsorbable polymer depending on the desired rate of release or the desired degree of polymer stability, but a bioabsorbable polymer is probably more desirable since, unlike a biostable polymer, it will not be present long after implantation to cause any adverse, chronic local response.
- Bioabsorbable polymers that could be used include poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane, ⁇ oly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters) (e.g.
- PEO/PLA polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid.
- biostable polymers with a relatively low chronic tissue response such as polyurethanes, silicones, and polyesters could be used and other polymers could also be used if they can be dissolved and cured or polymerized on the device such as polyolefins, polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics, such as polystyrene, polyvinyl esters,
- the ratio of effective composition to polymer in the solution will depend on the efficacy of the polymer in securing the effective composition onto the device and the rate at which the coating is to release the effective composition to the tissue of the blood vessel. More polymer may be needed if it has relatively poor efficacy in retaining the therapeutic substance on the device and more polymer may be needed in order to provide an elution matrix that limits the elution of a very soluble therapeutic substance. A wide ratio of therapeutic substance to polymer could therefore be appropriate and could range from about 10:1 to about 1:100.
- Estrogen and the other effective compositions described above can also be coated onto or delivered with other drugs or compounds in order to administer synergistic treatment.
- suitable drugs and compounds include antibodies, oligonucleotides (e.g. antisense oligonucleotides), antiproliferatives, anticancer or antimicrotubular agents (e.g. rapamycin, paclitaxel), antiproliferative agents, growth factors, genes, antisense or antithrombotic agents or any other chemical or biological compound that will act synergistically to increase the effectiveness of the primary hormone or compound.
- Additional agents include the following: thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, anti-lipid agents, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, anti metabolites, anticancer chemotherapeutic agents, anti-inflammatory steroid or non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, angiotensin-converting enzyme (ACE) inhibitors, free radical scavengers, chelators, antioxidants, anti polymerases, antiviral agents, photodynamic therapy agents, and gene therapy agents.
- thrombin inhibitors antithrombo
- stent coatings can absorb and release these materials, thus providing an inert depot for controlled drug administration. Loading of the drug can occur for example via diffusion of the drug solution into the coating by hydration/swelling of the polymer matrix.
- bioactive (e.g., pharmaceutical) agents useful in the present invention include virtually any therapeutic substance which possesses desirable therapeutic characteristics for application to the implant site.
- High-risk plaque includes, but is not limited to, vulnerable plaque, atherosclerotic plaque, ruptured plaque, activated plaque, non-critical lesions, as well as plaque that could possibly rupture or become vulnerable or activated
- the invention provides methods of treating a plaque that has been determined to be susceptible to subsequent rupture and/or sudden progression.
- vulnerable plaque is meant to refer to plaque that has the propensity or is prone to rupture or become active and attract platelets, fibrin, thrombin and other coagulation factors to cause thrombosis. Plaque erosions or ruptures can cause acute coronary syndromes.
- Plaques prone to rupture are characterized by a large lipid core and a thin fibrous cap, but plaques with erosion vary in size and composition. Inflammatory activity has been associated with plaque erosion and may have a role in the pathogenesis of endothelial damage. Erosions and subsequent thrombosis can develop in plaques that are relatively rich in proteoglycan matrix and smooth-muscle cells and that lack a superficial lipid core. Plaque rupture may result from intrinsic plaque vulnerability, mechanical stresses, and extrinsic triggers. A plaque with a thin fibrous cap overlaying a large lipid core is a high risk for rupture.
- Vulnerable plaques may have a well-preserved lumen, because plaques grow inwardly initially, as well as the substantial lipid core, and the thin fibrous cap separating the tissue factor.
- the lipid-rich core may be in the central portion of the eccentrically thickened lumina.
- the fibrous cap composed mainly of connective tissue, may be on the luminal side of the lipid core. This fibrous cap may be the only barrier separating the circulation, and its powerful coagulation system designed to generate thrombus, from the lipid core, a highly thrombogenic material rich in tissue factor, one of the most potent procoagulants known.
- SMCs Smooth muscle cells
- stable plaques have relatively thick fibrous caps protecting the lipid core from contact with the blood. Stable plaques are often more detectable but may also be indistinguishable at angiography compared to vulnerable plaques.
- the thickness and integrity of the fibrous cap overlying the lipid-rich core is a principal factor in the stability of the plaque. Plaque stability may be a function of some of the following dynamic factors: VSMC production of the extracellular matrix that is the bulwark of the fibrous cap, interaction of inflammatory cells, inhibition of this process by certain cytokines, and increased degradation of the matrix by matrix metalloproteinases.
- composition and vulnerability of plaque may play one of the primary roles in determining the development of thrombus mediated acute coronary events.
- Rupture at the site of a vulnerable atherosclerotic plaque maybe one of the most frequent causes of acute coronary syndromes.
- such plaque does not cause high-grade stenosis and has a large lipid core and a thin fibrous cap that is often infiltrated by inflammatory cells. Plaque rupture usually leads to various degrees of thrombus formation.
- Vulnerable atherosclerotic plaque may not always cause high-grade stenosis, however, it may result in an acute coronary syndrome, such as unstable angina, myocardial infarction, or in worse cases, sudden death.
- Vulnerable plaque may be identified using a variety of techniques that are well-known in the art. Well-known techniques such as thermagraphy, spectroscopy, radioisotope scinography, use of inflammatory serum markers, intravascular ultrasonography, electron- beam computed tomography, angioscopy, instravascular ultrasound, and magnetic resonance imaging may be used.
- an effective dose of one of the compositions set forth above may be applied to one of the devices discussed above (e.g., a self-expanding or balloon-expandable stent).
- the device is inserted into an area of a living organism affected by the vulnerable plaque in order to treat or prevent the same.
- the device may or may not directly contact the affected area, however, the device allows for the gradual release of the composition therefrom in order to treat or prevent the plaque.
- a stent or other device is at least partially coated with a platform, carrier or agent, which at least partially encompasses an effective dose of a composition comprising estrogen, estradiol, or a derivative thereof.
- the stent is inserted into an area of the body affected by the vulnerable plaque, and the effective dose is allowed to gradually release, thereby treating or preventing the vulnerable plaque.
- the invention may be used to prevent the progression of atherosclerosis.
- powdered or liquid estrogen is mixed with a carrier such as ethanol to form a solution or gel.
- the estrogen gel is then applied to a stainless steel stent using chemical coating methods that are well-known in the art.
- the coated stent is inserted into an arterial lumen of a human being suffering from atherosclerosis.
- the coated stent is inserted into an artery plagued by patchy, intramural plaque.
- the estrogen in the coating slowly diffuses into and penetrates the plaque, thereby providing treatment for this vascular disease.
- low and high dose 17B-estradiol eluting stents were compared with control stents in a randomized fashion in 18 porcine coronary arteries.
- Each artery of six pigs were randomly stented with either a control, low-dose or high-dose 17-estradiol eluting stent. All animals were sacrificed at 30 days for histomorphometric analysis.
- Coronary angiography was performed after intracoronary nitroglycerin (200 ⁇ g) administration and recorded on cine film (Phillips Cardiodiagnost; Shelton, CT). Using high- pressure dilatation (12-14 atm x 30 sec), a single stent of each type was deployed in all 3 coronaries of each animal in a randomized fashion so that the 3 different types of stents were deployed in a different artery for each pig. The operator was blinded to the stent type being deployed. The stent artery ratio was kept between 1:1.3 and 1 : 1.2. All animals tolerated the stenting procedure and survived until 30 days after which they were sacrificed and the hearts were perfusion-fixed.
- the histopathologist was blinded to the stent types in each artery.
- Cross sections of the stented coronary arteries were stained with metachromatic stain (Stat Stain for Frozen Sections, Eng. Scientific, Inc., 82 Industrial Fast, Clifton, New Jersey, 07012), Area measurements were obtained by tracing the external elastic lamina (vessel area, VA, mm ) stent line (stent strut area, mm 2 ) lumen perimeter (luminal area, LA, mm 2 ) and neointimal perimeter (intimal area, IA, mm 2 ).
- the vessel injury score was determined by the method described by Kornowski et al.
- the scoring of endothelialization is based on percent of intimal surface covered by endothelial cells. 1+ equals less than 1/4 of the intimal surface is covered by endothelial cells, 2+ equals over 1/4 and less than 3/4 covered and 3+ equals greater than 3/4 to complete coverage of the intimal surface.
- FIG. 7a) illustrates the histological appearance of the control stented segments at 30 days.
- Figure 7b) illustrates the histological appearance of the low-dose stented segments at 30 days and
- the pathophysiology of restenosis involves neointimal hyperplasia and negative vessel remodeling.
- the low dose 17B-estradiol stents only demonstrated a trend towards a reduction in intimal area
- the high dose 17B-estradiol stents significantly inhibited the neointimal proliferative response by about 40% compared with control stents.
- Coronary stent implantation has been proven superior to conventional balloon angioplasty for the treatment of coronary de-novo lesions.
- coronary stenting procedures are still burdened with an unacceptable high restenosis rate.
- the utilization of antiproliferative agents delivered locally via drug-eluting stents has dramatically reduced these rates.
- concern remains regarding delayed healing of the arterial wall and the long-term effects of cell-cycle inhibitors.
- An alternative approach for the prevention of in-stent restenosis involves the use of a naturally occurring vasculoprotective hormone such as 17/3-Estradiol.
- 17/3-Estradiol has a low molecular weight, is hydrophobic and lipophilic making it pharmacokinetically suitable for loading on a stent delivery system.
- Example 2 suggests that the local delivery of 17/3-Estradiol either via an infusion catheter or impregnated on a stent inhibits neointimal proliferation without affecting endothelial repair and function.
- the BiodivYsio stent delivery system (Biocompatibles Ltd, United Kingdom) is a laser cut, 316L stainless steel balloon-expandable stent coated with phosphorylcholine (PC), a naturally occurring biological substance.
- the biocompatible PC coating constitutes a 50-100 nm thick double layer of synthetic PC coating that is able to adsorb a drug via a "sponge-like" mechanism.
- the method of impregnating the PC coating involves 3 steps: First, immersing the stent into a solution of 17/3-Estradiol (in ethanol) for 5 minutes. After removal of the stent from the solution and allowing it to dry for 1 minute, a second step whereby 10 ⁇ l of the same solution is pipetted onto the stent.
- the PC polymer absorbs the solution like a sponge.
- the stent is then immediately deployed. Laboratory testing has demonstrated a consistent amount of drug (2.52 ⁇ g/mm 2) can be impregnated using this method.
- the mean age of the patients was 61 ⁇ 12 years. A total of 21 patients (70%) were males. Systemic hypertension was the most frequent coronary risk factor, involving 15 patients (49%), followed by smoking in 10 patients (33%) and dislipedemia in 8 (27%) whereas only 3 patients (10%) were diabetics. Eleven patients (37%) had a prior history of myocardial infarction (MI). The procedure was successful in all patients. There were no in- hospital events including no elevation of cardiac enzymes post-procedure. One patient underwent target lesion revascularization at 6-month follow-up due to symptomatic angiographic restenosis. All other patients were asymptomatic at 6-month angiographic follow-up. There was no stent thrombosis or other JMACE (major cardiovascular events including death, MI, stroke or target vessel revascularization) up to 12-month clinical follow- up.
- JMACE major cardiovascular events including death, MI, stroke or target vessel revascularization
- Example 2 Inhibition of neointimal proliferation and accelerated re-endothelialization and function with the injection of 17/3-Estradiol following balloon angioplasty in a pig model is shown in Example 2.
- Estradiol is known to have pleomorphic properties. It has anti-atherogenic, anti-inflammatory and anti-oxidant properties as well as a wide therapeutic window. These features may contribute to its vasculoprotective effect and may also make it a potential agent in the treatment of the vulnerable plaque.
Abstract
Description
Claims
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EP03754558A EP1539268A1 (en) | 2002-09-12 | 2003-09-12 | Apparatus and method for delivering compounds to a living organism |
AU2003272378A AU2003272378A1 (en) | 2002-09-12 | 2003-09-12 | Apparatus and method for delivering compounds to a living organism |
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US41038702P | 2002-09-12 | 2002-09-12 | |
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US8182833B2 (en) | 2003-01-21 | 2012-05-22 | Dimera Incorporated | Method and kit for reducing the symptoms of peripheral vascular disease with topical progesterone |
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US8206035B2 (en) | 2003-08-06 | 2012-06-26 | Nissan Motor Co., Ltd. | Low-friction sliding mechanism, low-friction agent composition and method of friction reduction |
US8575076B2 (en) | 2003-08-08 | 2013-11-05 | Nissan Motor Co., Ltd. | Sliding member and production process thereof |
US7771821B2 (en) | 2003-08-21 | 2010-08-10 | Nissan Motor Co., Ltd. | Low-friction sliding member and low-friction sliding mechanism using same |
US7650976B2 (en) | 2003-08-22 | 2010-01-26 | Nissan Motor Co., Ltd. | Low-friction sliding member in transmission, and transmission oil therefor |
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AU2003272378A1 (en) | 2004-04-30 |
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