JP2009535104A - Insertable hydrophilic shape memory medical products - Google Patents

Abstract

  An insertable shape memory medical product with a body formed from a crosslinked hydrophilic polymer is described.

Description

Cross-reference to related applications This non-provisional patent application is based on 35 USC §119 (e) and is a United States provisional application filed on April 25, 2006 under the name "Insert hydrophilic shape memory medical product". Patent application serial number 60 / 795,019 and patent application Bruce M. Jelle and Stephen J. Chudzik with the name of “insertable hydrophilic shape memory medical product” on April 19, 2007 Claims priority to a US provisional patent application with SRM0082 / P2. These provisional patent applications are incorporated in this specification for reference.

  The present invention relates to an insertable medical product formed from a hydrophilic polymer and having shape memory properties.

  In implantable medical devices (eg, stents), shape memory alloys (SMA) have often been utilized to construct them. In general, after deforming the device from its original shape, simply applying heat (one-way effect) during no load or bringing the surroundings to a higher temperature returns itself to its original shape (pseudoelasticity or superelasticity) . These properties are due to the temperature dependent martensitic phase transformation from low symmetry to high symmetry crystal structure. These crystal structures are known as martensite (any crystal structure formed by substitutional transformation and not by much slower diffusion transformations) and austenite.

  Shape memory alloys (SMA) form a group of metals with interesting thermal and mechanical properties. After an SMA material such as Nitinol is deformed when it is in the martensite state (small yield strength condition), when it is heated to the transition temperature to the austenite state, the SMA material returns to its original (undeformed) shape. I will. The speed at which it returns to its original shape depends on the amount and speed of thermal energy applied to the material. Cooling the SMA material will return to the state and shape of the martensite.

  Nickel-titanium (NiTi) is a shape memory alloy commonly used to manufacture shape memory devices (eg, vascular prostheses for treating vascular stenosis). When the prosthesis is placed in a blood vessel in the body and then heated to the transition temperature, the prosthesis spreads and is firmly fixed to the inner wall of the blood vessel in the body. After the prosthesis has expanded, the lumen diameter of the prosthesis is approximately equal to the diameter of the body vessel passage. The prosthesis can also be used in other passages in the body.

  Shape memory alloys clearly provide excellent mechanical strength, but other properties are not ideal for use in the body. One drawback is that metals (including Nitinol) do not provide an ideal biocompatible surface. As a result of previous studies of tissue response when a metal stent is placed in a blood vessel or heart, it is generally understood. Tissue responses include stages of clotting factor attachment, inflammation, cell recruitment, proliferation, and late stages associated with the presence of endothelial cells (EC) and smooth muscle cells (SMC) on the surface of the device (eg, Edelman , ER and Rogers, C., 1998, Am. J. Cardiol. 81: 4E-6E). However, the surface of metallic stents is generally associated with hyperplasia and restenosis due to SMC overgrowth at a later stage.

  Further, after a desired treatment period, an implantable metal device made of an alloy such as nitinol is left in the body or a surgical operation is performed to remove the device.

  Biodegradable synthetic polymers (eg, polyglycolide type molecules) have been used as metal substitutes. For example, US Pat. No. 6,991,647 describes a self-expanding biodegradable stent made from a mixture of poly-L-lactide (PLLA) and poly-ε-caprolactone (PLC).

  For example, as an alternative to non-biodegradable systems, biodegradable synthetic polymers (eg, polyglycolide type molecules) have been used to construct implantable devices to deliver bioactive agents. Such polyglycolide type molecules can be decomposed into acid products, which can cause undesirable side effects in the body due to the presence or concentration of the acid product in the body. cause. These undesirable side effects include the occurrence of an immune reaction, the accumulation of degradation products in the body as poisons, and other undesirable effects on cells or tissues in the body.

  The present invention provides an insertable medical product having shape memory properties. The insertable medical product includes a body that includes a matrix of a hydrophilic polymer that has sufficient internal strength to return from the second state to the first state. Internal strength can be achieved by making a body consisting of a matrix containing a crosslinked low molecular weight hydrophilic polymer. By using a low molecular weight hydrophilic polymer, a tightly crosslinked network can be formed, and a main body having high elasticity can be obtained. In addition to having this elasticity, the product becomes extremely obedient to external forces and is therefore resistant to harm and breakage. Otherwise, the product body could be damaged or broken as a result of moving from one state to another. Since the main body has the internal strength, it can return from the second state to the first state.

  In some aspects, according to the present invention, an insertable medical product comprising a body comprising a cross-linked matrix composed of a hydrophilic polymer having a molecular weight of 100,000 Da or less when the body is inserted, An insertable medical product is provided that is capable of shape memory transition from a second state to a first state at a target site in a subject's body.

  The present invention also provides a method of manufacturing an insertable medical product with a body having shape memory properties. This method of manufacturing a product comprises: (a) providing a first state composition comprising a hydrophilic polymer having a molecular weight of 100,000 Da or less and a reactive group; and (b) reacting the reactive group. Forming a matrix of a hydrophilic polymer to produce a body in a first state. By this method, a body with sufficient internal strength to return from the second state to the first state is formed.

  In some cases, the hydrophilic polymer comprises a protruding polymerizable group as a reactive group, and the polymerizable group is activated to polymerize the hydrophilic polymer and form a matrix.

  In some cases, the hydrophilic polymer includes a first reactive group protruding from the hydrophilic polymer as a reactive group. The matrix further includes a hydrophilic second component that includes a second reactive group. When the first group and the second group are mixed, they react specifically to form a matrix of a crosslinked hydrophilic polymer. Therefore, the main body in the first state is manufactured.

  In some aspects, the present invention provides an insertable medical product with a body consisting of a hydrophilic matrix that includes a first polymer network (“interpenetrating network”) that penetrates a second polymer network. . This product includes a first component that is a hydrophilic polymer that includes a first reactive group, a second component that is a hydrophilic polymer that includes a second reactive group, and a hydrophilic that includes protruding polymerizable groups. And a third component that is a polymer. The first reactive group and the second reactive group react specifically, and these groups combine to form a first polymer network. The third component forms a second polymer network that penetrates the first polymer network by polymerization. A body in a first state is provided by forming a first polymer network and a second polymer network. The main body can return from the second state to the first state.

  In some features, the body can be in a straight second state. The body can take a non-linear state before returning to the first state. Non-linear conditions include curvilinear conditions (eg, coil conditions) that may be useful for treatment at the target site for the subject. The target site can be any site selected from within the body. For example, a position in a blood vessel or a part of an eye can be mentioned.

  The body can be in any form desired. This form can take two or more states (eg, a first state and a second state). For example, the body can be in the form of a filament, sheet, or cylinder. For example, the first state of the filament can be a coil and the second state can be linear. The cylinder can be expanded in the first state and collapsed in the second state.

  In some features, the second state is maintained by physically restraining the body. For example, it can be restrained by limiting the body to the inside of the insertion tool. When the product is released from the inserter at the target location, the body can return to the first state.

  In this aspect, according to the present invention, an insertable medical product comprising a body comprising a matrix of a hydrophilic polymer, the body has an internal strength and the shape memory transition from the second state to the first state An insertable medical product is provided.

  The body in the second state can be easily delivered to a target location in the body. For example, the body can be delivered to the target site through the vasculature or through a portion of the eye. In some features, the second state of the body can be sized or shaped to be retained in the insert. This is used to deliver the shape memory product to the target site where it is released and returns to the first state. The second state of the body can be sized or shaped to pass through a part of the body. Otherwise, the product in the first state will not pass.

  In some aspects, the present invention provides a method in which a body in a first state exerts a force on a target tissue to treat a target site in a subject. The method includes (a) obtaining an insertable medical product comprising a body comprising a matrix of a hydrophilic polymer, the body being capable of shape memory transition from a second state to a first state; b) delivering the product in a second state to a target site in the body and allowing the body to return from the second state to the first state at the target site; The body in state exerts a force on the tissue at the target site.

  In another feature, the body is maintained in the second state in a dehydrated state. By this dewatering state, the main body can be maintained in the second state without being physically restricted (to the second state). The main body returns to the first state when it returns to the water-containing state. Such insertable products are referred to herein as having a “moisture-based shape memory” property, as the body changes state due to the hydrated state. In this aspect, the present invention provides a body in a second state comprising a matrix of hydrophilic polymer material. The main body in the second state has the second water-containing state, and can make a shape memory transition to the first state. The shape memory transition to the first state can occur when the body enters the first water content state as the water content increases.

  In some aspects, according to the present invention, an insertable medical product comprising a body comprising a cross-linked matrix composed of a hydrophilic polymer having a molecular weight of 100,000 Da or less, wherein the body has a second moisture content. There is an insertable medical product that can be transferred to the first state when this product is inserted into the target site of interest and the water content of the main body is increased to the first water content state. Provided.

  In some aspects, the present invention provides a method of manufacturing an insertable medical product with a body having shape memory properties based on moisture content. In this aspect, the method comprises (a) providing a composition comprising a hydrophilic polymer having a molecular weight of 100,000 Da or less, a reactive group, and a liquid; and (b) hydrophilizing by reacting the reactive group. Forming a matrix of a functional polymer to produce a body in a first state; (c) changing the state of the body from a first state to a second state; (d) a liquid Removing at least a portion to stabilize the body in the second state.

  The removing step includes an operation of removing about 50% or more of liquid (for example, water) from the main body. The main body is temporarily fixed in this second state (for example, dehydrated form) and cannot return to the first state until it returns to the water-containing state.

  In some aspects, the present invention provides a method in which a body in a first state exerts a force on a target tissue to treat a target site within a subject. The method comprises the steps of: (a) obtaining an insertable medical product comprising a body comprising a hydrophilic polymer matrix and having a shape memory property based on water content; and (b) placing the product in a second state. Delivering to a target site within the subject; and (c) hydrating the body of the product to promote a change to the first state.

  The novel product of the present invention is advantageous for use as a shape memory prosthesis device in the body. Many prosthetic devices (eg, stents) are designed to be placed in a vessel lumen and exert a force on the lumen wall. Since the main body of the shape memory product of the present invention is made of a hydrophilic polymer material, biocompatibility can be improved compared to other prosthetic devices made of metal or other non-hydrophilic polymer materials. Improved biocompatibility reduces the undesirable tissue response in the target area and reduces the occurrence of restenosis. Therefore, the operating life of the prosthesis device can be extended.

  The hydrophilic polymer used to form the body is biostable or biodegradable. In some aspects, the body of the implantable product is made from a biodegradable hydrophilic polymer material. Implantable biodegradable medical products (eg, stents) can be manufactured to have a desired operational life in vivo. An implantable product having a predetermined operating life in a living body can be disassembled after being placed at a target site and performing its function for a predetermined period of time. In this way, it is not necessary to remove the product from the body after the desired period of use. For example, in some features, the implantable product is manufactured to have an in vivo operating life of up to about 6 months, or in the range of about 2 to about 6 months.

  In some aspects of the invention, the product comprises a biodegradable body that includes a matrix of natural biodegradable polysaccharides. This biodegradable body can have improved degradation quality, in addition to the body's elastic properties and the ability to obey the external force significantly. Biodegradable shape memory products made with biodegradable polysaccharides can have the advantage of degrading by surface erosion rather than bulk erosion common to other biodegradable polymers.

  This can be advantageous in many ways. For example, in some features, shape memory products based on natural biodegradable polysaccharides degrade and gradually lose mechanical strength. As a result, stress is transmitted more slowly to the surrounding tissue. This can greatly benefit treatment of certain medical conditions. In addition, since the product degrades due to surface erosion, the risk of the degraded particles moving to another location and acting as an embolus is eliminated. In these features, biodegradable polysaccharides also have the advantage of breaking down into inactive degradation products (eg glucose). Natural mono- or disaccharides are common serum components with little or no risk of immune response or poison to humans.

  The shape memory product can also include a bioactive agent. In the case of a biodegradable matrix, the bioactive agent can be released when one or more portions of the body are degraded. In this regard, the body may exert a force on the target tissue, but it does not have to be.

  In some features, the bioactive agent is selected from the group consisting of polypeptides, polynucleotides, polysaccharides. In some aspects, the insertable medical product includes a bioactive agent having a molecular weight of 10,000 or greater.

  In another aspect, the body includes microparticles, which microparticles include a low molecular weight bioactive agent. The use of microparticles can be one way to control the low molecular weight bioactive agent released from the body of the shape memory product.

  In some features, the insertable medical product includes an antithrombotic agent. The insertable medical product can include, for example, heparin. Heparin can be used in shape memory products such as stents to prevent thrombus formation near the stent.

  In some features, the insertable medical product includes a thrombus promoter, and the insertable medical product can include, for example, collagen. Collagen can be used in shape memory products such as occlusive devices to promote a thrombus generation response in the vicinity of the shape memory product.

  The present invention also provides a method of delivering a bioactive agent to a subject. The method obtains an insertable medical product comprising (a) a body comprising a matrix of a hydrophilic polymer and a bioactive agent, the body being capable of shape memory transition from a second state to a first state. (B) delivering the product in a second state to a target site within the subject; (c) returning the body from the second state to the first state at the target site; (d) Release of the bioactive agent from the body at the target site can be included.

  In some aspects, a method of delivering a bioactive agent to a subject using a dehydrated form of the product is provided. The method comprises the steps of: (a) obtaining an insertable medical product having a shape memory property based on water content and comprising a body comprising a matrix of hydrophilic polymer and a bioactive agent; Delivering to the target site in the body in the state of 2; (c) facilitating returning the body to the first state by hydration; (d) releasing the bioactive agent from the body at the target site; Steps may be included.

  The present invention also provides a system for delivering an insertable medical product with a body having shape memory properties to a body part. The system includes an insertable medical product with a body that includes a cross-linked matrix of hydrophilic polymer, the body from a second state when the product is inserted into a target site of interest. Shape memory transition to the first state is possible. The system also includes an insert that can hold the product in the second state. The system can be provided with the shape memory product attached to a portion of the inserter in the second state.

  The embodiments of the invention described in this specification are not intended to be exhaustive or to limit the invention to the precise form disclosed in the following detailed description. Rather, the embodiments have been selected and described so that others skilled in the art can understand the principles and practices of the invention.

  All publications and patents mentioned in this specification are herein incorporated by reference. The publications and patents disclosed in this specification are cited solely to indicate that the contents are disclosed. Nothing in this specification acknowledges that the inventor cannot be preceded by any publication and / or patent (including any publications and / or patents cited therein) Do not assume that.

  The present invention provides an insertable medical product having a body made of a low molecular weight hydrophilic polymer and having shape memory properties. The body is formed in the first state and can be released from the second state (different from the first state) and returned to the first state.

  A change in “state” means a fundamental change in the shape of the product. An example is a change from a linear state to a non-linear state or vice versa. This change is not simply a spread of a particular state, as seen when the hydrogel expands in contact with water and the size of the first state increases. Rather, the insertable medical product can be described as having a first end and a second end, and in the first state, the first end and the second end. A path in between (for example, a linear path or a non-linear path) defines one shape of the product. In the second state, the path between the first end and the second end is different from the first state.

  In some cases, when the insertable medical product changes from the second state to the first state, the body may be able to increase in size. This expansion along with the change of state can occur when the body in the second state is in a dehydrated state and the water content increases in the first state.

  According to the present invention, the body of the shape memory product is prepared from a hydrophilic polymer that can be of low molecular weight. Using a low molecular weight polymer makes it possible to produce a body having a matrix with high polymer density and excellent internal strength. In general, the molecular weight of this hydrophilic polymer is 100,000 Da or less. The molecular weight is preferably 50,000 Da or less, 25,000 Da or less, or 10,000 Da or less. A particularly preferred size range for the hydrophilic polymer is from about 1000 Da to about 10,000 Da. Another preferred size range for the hydrophilic polymer is from about 1000 Da to about 5,000 Da.

  In some preparations, the hydrophilic polymer is degradable. The preparation can be used to form a shape memory product that decomposes in whole or in part. Some preferred hydrophilic polymers that are degradable are natural biodegradable polysaccharides. As used herein, a “natural biodegradable polysaccharide” means a non-synthetic polysaccharide that can be enzymatically degraded but is generally stable to hydrolysis without the use of enzymes. Natural biodegradable polysaccharides include polysaccharides and / or polysaccharide derivatives obtained from natural sources (eg, plants and animals). Natural biodegradable polysaccharides include any polysaccharide that has been treated or modified from a natural biodegradable polysaccharide (eg, maltodextrin is a natural biodegradable polysaccharide that has been starch-treated).

  When a natural biodegradable polysaccharide is used to form the body of a shape memory product, the polysaccharide is preferably a low molecular weight polymer. Examples of natural biodegradable polysaccharides include amylose, maltodextrin, cyclodextrin, polyalditol, hyaluronic acid, starch, dextran, heparin, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, dextran sulfate, polysulfate pentosan, There are low molecular weight preparations such as chitosan. Natural biodegradable polysaccharides are substantially unbranched or completely unbranched poly (glucopyranose) polymers.

As used herein, “amylose” or “amylose polymer” means a linear polymer in which a plurality of glucopyranose repeating units are linked by α-1,4 bonds. Some amylose polymers can contain very little branching (less than about 0.5% of the linkages) through α-1,6 linkages, but such amylose polymers are still linear. It exhibits the same physical properties as an (unbranched) amylose polymer. In general, amylose polymers derived from plant sources have a molecular weight of about 1 × 10 ⁶ Da or less. In contrast, amylopectin is a branched polymer in which straight portions where a plurality of glucopyranose repeating units are linked by α-1,4 linkages are linked to each other by α-1,6 linkages. The number of branch point bonds is generally greater than 1% of all bonds, typical values being 4% to 5% of all bonds. In general, amylopectin derived from plant sources has a molecular weight of 1 × 10 ⁷ Da or higher.

  Amylose is available from a variety of sources. Alternatively, amylose is present in various sources. In general, amylose is obtained from non-animal sources (eg, plant sources). In some aspects, a purified preparation of amylose is used as a starting material to prepare an amylose polymer having a coupling group. This amylose polymer can be used to form the body of a shape memory product. In another aspect, amylose as a starting material can be used in a mixture containing other polysaccharides.

  Maltodextrins generally use heat-stable α-amylase, hydrolyze the starch slurry at 85-90 ° C. until the desired level of hydrolysis, and then heat-treat α-amylase by a second heat treatment. Obtained by inactivation. Maltodextrin is purified by filtration and then spray dried to the final product. Maltodextrins are generally characterized by a dextrose equivalent (DE) value. This value is related to the degree of hydrolysis defined as DE = (molecular weight of dextrose / number average molecular weight of starch hydrolyzate) × 100.

  A starch preparation that is fully hydrolyzed to dextrose (glucose) has a DE of 100, whereas starch has a DE of nearly zero. A DE greater than 0 and less than 100 is characteristic of the average molecular weight of the starch hydrolyzate, and maltodextrins are believed to have a DE of less than 20. Maltodextrins of various molecular weights (eg, about 500-5000 Da) are commercially available (eg, Carbomer, San Diego, Calif.).

  Another possible class of natural biodegradable polysaccharides are natural biodegradable non-reducing polysaccharides. An example of a non-reducing polysaccharide is polyalditol having a non-reducing end (devoid of aldehyde groups) and is available from GPC (Muscatine, Iowa). Non-reducing polysaccharides can provide an inert matrix, thus improving the stability of sensitive bioactive agents such as proteins and enzymes (when included in the body of the shape memory product). Non-reducing polysaccharides include non-reducing disaccharides (two monosaccharides linked through the anomeric center, trehalose (α-D-glucopyranosyl α-D-glucopyranoside) and sucrose (β-D-fructofuranosyl α). -D-glucopyranoside)) and the like. In another aspect, the polysaccharide is a glucopyranosyl polymer (eg, a polymer comprising (1 → 3) O-β-D-glucopyranosyl repeating units).

  In some preferred features of the invention, the body of the shape memory product comprises a biodegradable polysaccharide selected from among maltodextrin, amylose, polyalditol, cyclodextrin. For example, the main body is a biodegradable polysaccharide containing protruding polymerizable groups and having a molecular weight of 10,000 Da or less, which is selected from maltodextrin, amylose, polyalditol, and cyclodextrin It can be formed of objects. As another example, the main body is a biodegradable polysaccharide containing a protruding first reactive group of a reaction pair and having a molecular weight of 10,000 Da or less, and is among maltodextrin, amylose, polyalditol, and cyclodextrin. It can be formed with a composition comprising one selected from:

  In some features, the body of the shape memory product includes a degradable hydrophilic synthetic polymer. A degradable synthetic polymer can be made entirely biodegradable or partially degradable. For example, a synthetic polymer that is partially biodegradable can include a biodegradable compartment and a non-biodegradable compartment.

  Some examples of degradable hydrophilic synthetic polymers containing hydrophilic monomers are described in US Pat. No. 5,410,016. Such polymers include hydrophilic poly (ethylene glycol) oligomers comprising biodegradable poly (α-hydroxy acid) extensions and acrylate type monomers or oligomers that serve as end caps.

  Dextran-based copolymers (eg, dextran modified with methacrylate) can also be used to make the body. Examples of polymers based on dextran are described in US Pat. Nos. 6,303,148 and 6,805,879.

  Other degradable hydrophilic synthetic polymers include polyanhydride homopolymers. It is prepared, for example, from an aromatic diacid that has been acetylated and modified with an ethylene glycol compartment (Biomaterials, 2005, 26, 721-728).

  In some aspects of the invention, the body includes a non-biodegradable hydrophilic polymer. Examples of non-biodegradable polymers include poly (ethylene oxide) (PEO), polyvinyl alcohol (PVA), poly (vinyl pyrrolidone) (PVP), poly (ethylene glycol), polyacrylamide, poly (hydroxyalkyl methacrylate), poly ( Hydroxyethyl methacrylate), hydrophilic polyurethane, HYPAN, oriented HYPAN, poly (hydroxyethyl acrylate), poly (ethyloxazoline), poly (propylene oxide) (PPO) and the like.

  In some features, the body is formed from a composition comprising a non-biodegradable hydrophilic polymer containing protruding polymerizable groups and having a molecular weight of 10,000 Da or less.

  Another hydrophilic component can be used to form the body of the shape memory product. For example, the matrix of the main body can be formed using a hydrophilic second component having a protruding reactive group and a hydrophilic second component. The second component includes a reactive group (which can be a polymerizable group) or one member of a reactive pair (eg, a member that will react with the first reactive group protruding from the hydrophilic polymer) Can do. The second component can be a hydrophilic polymer. When a hydrophilic polymer is used as the second component, it can be degradable or non-degradable. Other hydrophilic components (eg, low molecular weight non-polymeric hydrophilic components) can be used to form the body.

  Thus, the body can also be formed from a mixture of two or more hydrophilic polymers that contain protruding coupling groups that can form the body of the shape memory product of the present invention by crosslinking the coupling groups. The mixture may comprise a mixture of polymers having different molecular weights or a mixture of different types of polymers.

  Compositions containing hydrophilic polymers (eg, natural biodegradable polysaccharides) and used to form the body can be prepared at particularly high concentrations (eg, about 250 mg / ml or more, or 300 mg / ml or more). it can. Thus, the body prepared from this composition has a high internal strength.

  A body including a matrix made of a hydrophilic polymer can be formed using a composition including a hydrophilic polymer having a protruding coupling group. The coupling group can be activated when the composition is in the desired first state. By activating the coupling group, the crosslinking of the polymer is promoted, and the main body in the first state can be formed. The body has an internal strength based on the formed matrix in the first state and can return to the first state when released from the second state.

  A variety of synthetic procedures can be utilized to provide coupling groups that protrude from the hydrophilic polymer (eg, groups that react to allow crosslinking between the hydrophilic polymers). This procedure can provide the desired number of coupling groups protruding from a hydrophilic polymer (eg, a natural biodegradable polysaccharide backbone). For example, a hydroxyl group on the polymer can be reacted with a coupling group-containing compound, or a hydroxyl group on the polymer can be modified to react with a coupling group-containing compound. The number and / or density of coupling groups (eg acrylate groups) can be controlled with the method of the invention. For example, the relative concentration of the reactive group with respect to the hydroxyl group content may be controlled.

  In preferred features, the matrix is formed using a coupling group capable of crosslinking the hydrophilic polymer. However, the crosslinking includes a covalent bond.

  “Binding group” includes (1) a chemical group capable of forming a reactive species that reacts with the same or similar chemical group to form a bond that can bind hydrophilic polymers to each other ( For example, the formation of reactive species can be facilitated by an initiator), or (2) two different types that can react specifically to form a bond that can bind hydrophilic polymers together. A chemical group pair is included. The coupling group can be attached to any suitable hydrophilic polymer (eg, a biodegradable polymer or a non-biodegradable polymer).

  Possible reactive pairs include reactive group A and corresponding reactive group B as shown in Table 1 below. To prepare the composition that forms the body, a reactive group is selected from group A to protrude from the first hydrophilic polymer group, and a corresponding reactive group B is selected to select a second hydrophilic component group (e.g., hydrophilic Projecting from the conductive polymer). The reactive group A and the reactive group B can represent a first coupling group and a second coupling group, respectively. At least one, preferably two or more reactive groups protrude from the individual hydrophilic polymer or hydrophilic component. The body of the shape memory product by combining the first hydrophilic polymer group or the second hydrophilic component group and, if necessary, reacting, for example, thermochemically, to promote the coupling of the hydrophilic polymer / component. Can be formed.

table 1
Reactive group A Reactive group B
Amine, hydroxyl, sulfhydryl N-oxysuccinimide (“NOS”)
Amine Aldehydeamine Isothiocyanate amine, sulfhydryl bromoacetylamine, sulfhydryl chloroacetylamine, sulfhydryl iodoacetylamine, hydroxyl anhydride amine, hydroxyl carbamic acid imidazole hydrazide amine, hydroxyl, carboxylic acid isocyanate amine, sulfhydryl maleimide sulfhydryl vinyl sulfone

Amines also include hydrazide (R-NH-NH ₂ ).

  A suitable coupling pair would be, for example, a hydrophilic polymer having an electrophilic group and a hydrophilic polymer having a nucleophilic group. An example of a suitable electrophilic-nucleophilic pair is the N-hydroxysuccinimide-amine pair. Another suitable pair would be an oxirane-amine pair.

  Thus, in some preparations, the hydrophilic matrix comprises at least a hydrophilic polymer having two or more first reactive groups (referred to herein as “Component A”), and two or more second And a hydrophilic component having a reactive group (referred to as “component B” in this specification). When the first reactive group and the second reactive group are mixed, they react specifically to bond the hydrophilic polymer with the hydrophilic component to form a crosslinked hydrophilic matrix.

  Various combinations of A and B components can be used. For example, the component A can be a degradable or non-degradable hydrophilic polymer. In some cases, the B component is the same as the A component except that the second reactive group is different from the first reactive group. For example, both A component and B component can be natural degradable polysaccharides. The matrix can be formed mainly of the A-decomposable component and the B-decomposable component, or can be formed of only the A-decomposable component and the B-degradable component.

  In some preferred methods of manufacturing the body, the matrix is formed from a degradable A component and a non-degradable B component. For example, the B component can be a non-degradable hydrophilic polymer or a non-degradable hydrophilic non-polymer compound. Using these components results in a crosslinked matrix consisting of biodegradable and non-biodegradable components. The shape memory product is decomposed when the A component is decomposed in vivo by, for example, enzymatic decomposition. When natural biodegradable polysaccharides are used as the A component, the embedded product can be degraded in vivo by surface erosion, resulting in loss of matrix components from the product surface. After the A component is fully degraded, the non-degradable B component is lost from the matrix and can leave the body.

  In one preparation method, the A component is a hydrophilic polymer that is a natural degradable polysaccharide (eg, maltodextrin, polyalditol, amylose). To prepare the component A, as an example, a part of the hydroxyl group of a natural degradable polysaccharide is derivatized with a first reactive group (amine group) to form an aminated polysaccharide. Using various reaction schemes known in the prior art, natural degradable polysaccharides with protruding amine groups can be obtained. In one method, a two-step reaction scheme is applied to the polysaccharide to obtain protruding amine reactive groups. In the first step, a polysaccharide is reacted with a hydroxyl reactive compound to obtain a binding group, and an amine-containing compound is reacted with the binding group to obtain an amine group protruding from the polysaccharide. This amine group becomes the first reactive group. In the first step, the hydroxyl reactive compound is used at a predetermined concentration to obtain the desired degree of substitution on the polysaccharide.

  In some aspects, non-reducing polysaccharides are used to form the A component. The non-reducing polysaccharide is, for example, a polyalditol having a non-reducing end (for example, the polysaccharide does not have an aldehyde group at the end).

  Non-reducing polysaccharides are preferred when amine groups are introduced into the A or B component, or when amine groups are present in the A or B component. This is because non-reducing polysaccharides do not contain protruding aldehyde groups. The protruding aldehyde group may react with the protruding amine group on the amine functional polysaccharide, reducing the reactivity of the amine functional polysaccharide and / or shortening the product lifetime.

  One example of a hydroxyl reactive compound that provides a linking group for this type of synthesis is 1,1′-carbonyldiimidazole (CDI). CDI is a useful linking group because it reacts with hydroxyl groups present in natural biodegradable polysaccharides to form carbamates. When CDI reacts with a hydroxyl group on a natural biodegradable polysaccharide to form a carbamate, the reactivity when the projected carbamate imidazole group reacts with a second hydroxyl group is significantly reduced. This is an advantage. This is because the protruding imidazole carbamate group remains as a non-reactive group protruding from the polysaccharide and can be used to form a covalent bond with another molecule (generally more reactive active hydrogen compounds such as amines). .

  After the reaction, the polysaccharide is provided with a protruding reactive carbamic acid imidazole group, which further reacts with the compound to become a protruding amine group. In many embodiments of the invention, the projected carbamic acid imidazole group is reacted with an amine-containing compound to form a polysaccharide having a projected amine group. For example, an imidazolyl carbamate group is reacted with a compound having at least two amine groups (eg, diamine). In the case of diamine, one of the amine groups reacts with the carbamic acid imidazole binding group, and after the reaction, the other amine group protrudes from the polysaccharide to become the first reactive group.

An amine-containing compound containing two or more primary amine groups separated by a linking group can be reacted with a polysaccharide intermediate. In some embodiments, the amine-containing compound has the general formula H ₂ NR—NH _{2, where} R is a linear or branched alkyl group. Representative examples of polyfunctional amine compounds include 1,6-diaminohexane, 1,4-diaminobutane, 1,3-diaminopropane, and the like.

  In general, the imidazole functional polysaccharide is reacted with an excess of diamine compound so that one amine has little or no reaction with two imidazole linking groups. For example, in many embodiments, the imidazole functional polysaccharide is slowly added to the solution containing the amine-containing compound, resulting in a reaction condition in which the amine-containing compound is significantly in excess compared to the imidazole functional polysaccharide.

  The reaction scheme described above can be modified to produce aminated polysaccharides with different degrees of substitution (DS). In this specification, the term “degree of substitution” generally means the average number of derivatized hydroxyl groups per glycopyranose monomer residue (polysaccharides such as maltodextrins are one monomer residue). Maltodextrins with a DS of 1 have about one hydroxyl group per substituted monomer residue). In some embodiments, the degree of substitution (DS) of the polysaccharide ranges from about 0.1 to about 1.0. In a more preferred embodiment, the degree of substitution is from about 0.2 to about 0.3, although other values of substitution may be desirable. In one embodiment, the polyalditol is reacted with CDI and then with 1,6-diaminohexane to produce an aminated polyalditol having a degree of substitution ranging from about 0.2 to about 0.3.

  FIG. 8 shows the reaction between polyalditol and CDI followed by reaction with 1,6-diaminohexane, which is an amine-containing compound.

  After reaction with the excess amine-containing compound, the resulting aminated polysaccharide is generally purified to remove any unreacted amine. Examples of the purification method include recrystallization (for example, using THF) and other precipitation methods and / or dialysis methods.

  In some aspects of the invention, the body of the shape memory product is formed by the reaction of at least one component A that contains an aminated natural biodegradable polysaccharide and component B that contains an amine-reactive hydrophilic compound. The

  As an example, Component B can be any suitable hydrophilic biocompatible compound having two or more amine reactive groups (ie, second reactive groups) for use with an aminated polysaccharide. It is.

  In one preparation method, Component B is a hydroxyl-containing compound that has been chemically modified to introduce an amine reactive group. Component B using a hydroxyl-containing compound with at least two protruding (typically 2 to 4) hydroxyl groups, biocompatible, fairly water soluble, and a molecular weight of about 10,000 Da or less It is desirable to synthesize.

In many embodiments, the hydroxyl group is present as a protruding group from a hydrophilic compound having a hydrophilic organic skeleton containing carbon, hydrogen, and oxygen atoms. In some embodiments, the organic backbone is an alkoxyalkane backbone. Representative examples of this type of hydrophilic compound include polyalkoxyalkanes such as poly (ethylene glycol), tetraethylene glycol, triethylene glycol, trimethylolpropane ethoxylate, and pentaerythritol ethoxylate. In some aspects, the hydrophilic compound is a liquid at about room temperature (about 25 ° C.). In many embodiments, preferred hydroxyl-containing compounds are ethylene glycol polymers or oligomers having the structure HO— (CH ₂ —CH ₂ —O) _n —H. Generally, the value of n is about 3 to about 150, and the number average molecular weight (Mn) of poly (ethylene glycol) is in the range of about 100 Da to about 5000 Da (more commonly in the range of about 200 Da to about 3500 Da). .

  Various synthetic schemes can be used to obtain hydrophilic compounds having amine reactive groups. In one embodiment, the hydroxy functional compound is reacted with 1,1′-carbonyldiimidazole (CDI) to form an amine reaction compound. 1,1'-carbonyldiimidazole reacts with the hydroxyl group of the hydrophilic compound to form a protruding carbamate imidazole group. That is the second reactive group. The reaction of poly (ethylene glycol) with CDI produces the amine reaction compound shown in FIG.

  The protruding imidazole carbamate group reacts with an amine group (eg, an amine group present in the aminated polysaccharide described above).

  Another method for preparing component B having a second reactive group is to first react an succinic anhydride with a polyol (eg, diol, triol, tetrol) to form a polyfunctional carboxylic acid to form an amine reactive compound. To prepare. Succinic anhydride reacts with the hydroxyl groups of the polyol to form ester bonds and terminal carboxylic acid groups. Next, the polyfunctional carboxylic acid is reacted with N-hydroxysuccinimide (NHS). NHS then reacts with the terminal carboxylic acid group to form an amine-reactive NOS group. In one embodiment, polyethylene glycol is reacted with succinic anhydride to form a dicarboxylic acid compound (see FIG. 10, product 1). The dicarboxylic acid compound is then reacted with N-hydroxysuccinimide (NHS) to form an amine-reactive compound having two terminal NOS groups (see FIG. 10, product 2).

  Given that the first component and the second component react spontaneously, these components are generally held in separate containers until it is desirable to form a matrix that forms the body of the shape memory product. . When it is desired to form a matrix, component A and component B are mixed together in the desired ratio to initiate matrix formation. For this purpose, for example, an amine-containing polysaccharide is reacted with an amine-reactive alkoxyalkane. When the first component and the second component are reacted with each other, a matrix is formed that is degraded by the enzyme. This matrix forms the body of the shape memory product. For example, the reaction of the product of FIG. 8 with the product of FIG. 9 is shown in FIG.

  Generally, component A and component B are reacted with each other in the desired stoichiometric ratio to form a matrix. One way to describe the amounts of Component A and Component B used to form the matrix is to determine the stoichiometry of the number of moles of amine groups in the amine functional polysaccharide to the number of moles of amine reactive groups in the amine functional compound. A specific value of the target ratio is used. For example, the stoichiometric ratio of amine groups to amine reactive groups can range from about 1: 5 to about 5: 1.

  After initiating formation of the matrix material by reacting component A with component B, these components are generally cured in a period of about 1 minute to several hours to form the matrix. More generally, these components are cured for a period of about 1 to about 60 minutes to form a matrix material.

  By adjusting the cure time of a matrix material of a given composition, a particular body can be made or adapted to the particular method utilized to form the body. For example, the body can be formed from a specific mold or by a specific method that would be facilitated by using a relatively slow cure composition (mixture of component A and component B). One way to adjust the reaction rate is to control the pH of the composition comprising the mixture of component A and component B. In general, in chemical reactions using amine groups and amine reactive groups as the first and second groups, the higher the pH, the greater the reaction rate between the first and second components. In contrast, a lower pH will result in a lower reaction rate between the first and second components. In most embodiments, the pH is controlled between a lower limit of about 7.5 and an upper limit of about 9.5, although other pH values may be suitable for some applications. The pH of the matrix material is determined by buffering the first component and / or the second component with a conventional buffer material (eg, phosphate buffer, borate buffer, bicarbonate buffer). Can be controlled.

  The cure time of the composition can also be adjusted by changing the molecular weight of component B (eg, the amine reaction component). In general, amine reactive components formed from low molecular weight polyol components are highly reactive (ie, have a shorter cure time). This can be achieved, for example, by controlling the molecular weight of the hydroxyl functional material used to form the amine reaction component.

  The molecular weight and reactivity of Component B (eg, the amine reactive component) can also affect the physical properties of the matrix formed when cured. Therefore, by selecting component B, a body having specific physical characteristics can be obtained. The present invention shows that a component B having a smaller molecular weight can result in a matrix having an increase in one or more of density and hardness. Conversely, as the molecular weight of component B increases, the matrix material becomes softer and more flexible.

  The same is observed for reactivity. As the reactivity of component B increases, one or more of the density and hardness of the matrix increases.

  By changing the physical properties, the desired properties for a given end use can be achieved. For example, a shape memory prosthesis can be made from a mixture of component A and component B. This mixture provides a combination of hardness and flexibility so that the product can exert a force on the tissue at the target site in the first state.

  In some aspects, the coupling group of the hydrophilic polymer is a polymerizable group. In a free radical polymerization reaction, polymerizable groups can bond a plurality of hydrophilic polymers in the composition, thereby forming a hydrophilic polymer matrix that forms the body.

  One preferred polymerizable group is an ethylenically unsaturated group. Suitable ethylenically unsaturated groups include vinyl groups, acrylate groups, methacrylate groups, ethacrylate groups, 2-phenyl acrylate groups, acrylamide groups, methacrylamide groups, itaconate groups, styrene groups, and the like. There can be various combinations of unsaturated groups of the ethylene type in the hydrophilic polymer.

  Hydrophilic polymers can be successfully derivatized in a suitable solvent system to obtain macromers. In general, a solvent system is used that can dissolve the polymer and that can control the derivatization using a polymerizable group. One solvent that is particularly useful for polymer derivatization is formamide. Other solvents or combinations of solvents can also be used.

  The preparation of the macromer (addition of a polymerizable group to the polymer) can be carried out using any suitable method. A polymerizable group (eg, glycidyl acrylate) can be added to a hydrophilic polymer (eg, polysaccharide) by a simple synthetic method.

  For example, a polysaccharide can be reacted with a compound containing a polymerizable group (for example, glycidyl acrylate) in the presence of formamide (and TEA for pH control) to obtain an acrylate-derivatized polysaccharide. The number and / or density of acrylate groups can be controlled utilizing the method of the present invention. For example, the relative concentration of the reactive group with respect to the sugar group content may be controlled.

  In some embodiments, the hydrophilic polymer has a protruding coupling group amount of about 0.7 micromolar or less per mg of hydrophilic polymer. In one preferred feature, the amount of coupling group per mg of hydrophilic polymer ranges from about 0.2 micromolar to about 0.7 micromolar. For example, a hydrophilic polymer (for example, amylose or maltodextrin) is reacted with an acrylate group-containing compound, and the acrylate group content level is in the range of about 0.3 micromol / mg to about 0.7 micromol / mg. You can get a macromer.

  In some features, the body includes a matrix consisting of an interpenetrating network (“IPN”) that includes a hydrophilic polymer component. An IPN is a matrix consisting of at least two polymer networks that penetrate each other but are not crosslinked. The two polymer networks may partially interpenetrate or may completely interpenetrate.

  For purposes of illustration, one feature of the present invention is described for a body formed from an IPN comprised of an “A” polymer network and a “B” polymer network. If desired, one or more additional polymer networks (such as “C”) can be formed.

  In general, when forming an IPN, each polymer network is formed using a different chemical bonding mechanism (for example, the mechanism described in this specification, in which the polymerization process is included) The polymer network does not become bonded to each other. For example, an A polymer network can be formed using a polymerizable free radical component, and a B polymer network can be formed using a component in which a first reactive group and a second reactive group are bonded through a nucleophilic reaction be able to. Alternatively, the body can be formed by ionically crosslinking a hydrophilic polymer (eg, cationic polymerization or anionic polymerization). As another option, complex coordination polymerization can be utilized.

  In some features, the body is formed from an IPN that includes an A polymer network composed of a first hydrophilic polymer and a B polymer network composed of a second hydrophilic polymer that is the same as or different from the first hydrophilic polymer. The In a preferred embodiment, both A and B polymer networks are formed from hydrophilic biodegradable polymers (eg, natural biodegradable polysaccharides). For example, the A polymer network and the B polymer network can be formed from a polysaccharide selected from the group consisting of amylose, maltodextrin, and polyalditol. If desired, other hydrophilic components can be used to form the polymer network.

As an example of forming a biodegradable body of a shape memory product, a biodegradable polysaccharide (eg, aminated polyalditol) having a _first reactive group “component A ₁ ” and a second reactive group “component A ₂ ” A polymer network is formed from a hydrophilic component (eg, amine-reacted polyethylene glycol) having The B polymer network is formed from a biodegradable polysaccharide having a polymerizable group “component B” (eg acrylated maltodextrin or acrylated polyalditol).

First composition comprising combination generally do not react with one another component A ₁ with component B when by preparing may be prepared one composition. The composition can also include components that aid in free radical polymerization (eg, initiator) and one or more auxiliaries (eg, initiator, and / or reducing agent, and / or polymerization accelerator). The second component may include a component A _2. If desired, other components can be included in the second composition (eg, components that would promote free radical polymerization of component B).

The first composition and the second composition can be mixed and immediately put into a first state (eg, in a mold). After mixing, the first polymer network A _1-2 is formed by reaction protrusion reaction groups of component A ₁ with component A _2, it can be a composition in the shape of the first state. The first polymer network in this state can provide some properties (eg, flexibility) that are desirable to accompany the shape memory product. The mixture is then treated to promote polymerization of component B to form a second polymer network that can penetrate the first polymer network. For example, a photoinitiator can be included in the mixture and the mixture can be treated to promote free radical polymerization of component B. By forming the second polymer network, the characteristics of the matrix can be changed compared to when only the first polymer network is formed. For example, by forming the second polymer network, characteristics such as strength can be added to the shape memory product.

In some special features, component A ₁ includes a polyalditol having a protruding first reactive group (eg, a protruding amine group), and component A ₂ is about about having a protruding amine reactive group. It contains up to 10,000 Da hydrophilic alkoxyalkanes and component B contains natural biodegradable polysaccharides (eg maltodextrin, polyalditol, amylose) and protruding polymerizable groups. The polysaccharide components (A ₁ and B) preferably have a molecular weight of about 100,000 Da or less, or about 50,000 Da or less, and more preferably about 25,000 Da or less.

  In preparing a composition for forming a shape memory product, the hydrophilic polymer is dissolved in a suitable liquid. In general, hydrophilic polymers are soluble in water. In some cases, the hydrophilic polymer is dissolved in an aqueous solution comprising a mixture of water and an organic liquid that is miscible with water. In some features, an alcohol (eg, ethanol) may be included in a composition that includes a hydrophilic polymer.

  The hydrophilic polymer is dissolved in the composition at a concentration sufficient to form a hydrophilic shape memory product. Depending on what the desired use of the implantable product is, a composition with a predetermined concentration of hydrophilic polymer is prepared so that the body of the product has the appropriate internal strength.

  In some features, a composition with a relatively high concentration of hydrophilic polymer is used, has sufficient internal strength to return from the second state to the first state, and in the second state it is physically internal in the body. An insertable medical product that can perform its function can be made. For example, a product in a second state can exert a therapeutic effect on a subject because it can exert a force on tissue in the body. In some features, the product in the second state is an implantable prosthetic device (eg, a stent). In this case, the main body not only returns from the second state to the first state, but also has an internal strength that exerts a force on the tissue in the first state. For example, in the first state, the body can exert a force on the inner wall of the blood vessel. In the second state, the stent can be delivered to the target site through the vasculature.

  In the composition, the hydrophilic component is present at a concentration that forms a body and provides a product having shape memory properties. The composition used to form the body has a matrix-forming material concentration of at least 50 mg / ml. In some methods of manufacturing shape memory products, a composition is prepared in which the concentration of one or more matrix-forming components (eg, hydrophilic polymer) is about 250 mg / ml (20% by weight solids) or higher. More commonly used to form a body. The concentration of the matrix-forming component in the composition should be 300 mg / ml (23 wt% solids) or higher, or 500 mg / ml (33 wt% solids) or higher, or even 750 mg / ml (43 wt% solids). You can even do more. Using natural biodegradable polysaccharides (eg selected from among amylose, maltodextrin, cyclodextrin, polyalditol, hydrophilic polymers (eg PEG)) to form compositions with very high solids content be able to. Accordingly, such products can be made to have high internal strength using these compositions.

  The main body contains a matrix-forming material (for example, one or more kinds of hydrophilic polymers) and water in a certain ratio in a water-containing state after formation. Generally, the body includes about 15% or more of the matrix forming material (eg, the matrix forming material in the range of about 15% to about 75%). The body preferably includes from about 30% to about 50% matrix forming material. In some cases, the body has a total solids content of the matrix forming component of about 40%. When the main body is dehydrated, the ratio of the matrix forming material to the total weight of the main body increases.

  In another aspect, an insertable medical product having shape memory properties can be produced using a composition having a low concentration of hydrophilic polymer. With these features, the body can have sufficient internal strength to return from the second state to the first state. However, the body need not exert a force on the tissue at the target site to provide the function of the prosthesis. In these features, for example, the body can return to a first state that is particularly suitable for staying at the target site to provide one or more other non-prosthetic functions.

  For example, the target site can be a region within the back of the eye. The shape memory product can return from the second state to the first state when inserted into the eyeball. Since the body is not linear in the first state, it is an improved product for delivering bioactive agents to the eye. Since the first state is not linear, the central field of view does not interfere.

  The target site may be an aneurysm. A shape memory product is delivered to the aneurysm, where it can return to the first state to substantially fill the aneurysm.

  The body can be manufactured from a composition containing a predetermined amount of liquid (eg, water). In some features, the composition includes up to about 50% by weight liquid. In some features, the composition includes up to about 15% by weight liquid. Once the body is formed, the amount of liquid can be retained in the body or the amount can be changed (eg, by removing the liquid from the body).

  Other ingredients can be added to the composition. In some features, other ingredients are added to the composition as compounds that can promote the formation of the body when the composition is processed.

  For example, a biocompatible hydrophilic crosslinking component containing an unsaturated group may also be included in the composition. The composition can include, for example, a cross-linking agent. Cross-linking agents include diallyl itaconate, diallyl maleate, diallyl fumarate, dimethallyl fumarate, dimethallyl maleate, diallyl diglycolate, diethylene glycol bis (allyl carbonate), diallyl oxalate, diallyl adipate, diallyl succinate, azelain Examples include diallyl acid, divinylbenzene, divinyl adipate, and divinyl ether.

  In some features, the composition includes an initiator. As used herein, “initiator” means one compound or two or more compounds that can promote the formation of reactive species from a polymerizable group. For example, the initiator can promote free radical polymerization of hydrophilic polymers having protruding polymerizable groups. In one embodiment, the initiator is a compound that includes a photoreactive group (photoinitiator). For example, the photoreactive group can include an aryl ketone photogroup selected from among acetophenone, benzophenone, anthraquinone, anthrone, anthrone-like heterocycles, and derivatives thereof.

  In some aspects, the photoinitiator includes one or more charged groups. The presence of charged groups can increase the solubility of photoinitiators (which can include photoreactive groups such as aryl ketones) in aqueous systems. Suitable charged groups include, for example, organic acid salts (sulfates, phosphates, carboxylates, etc.) and onium groups (quaternary ammonium, sulfonium, phosphonium, protonated amines, etc.). According to this embodiment, suitable photoinitiators include one or more aryl ketone photogroups selected from, for example, acetophenone, benzophenone, anthraquinone, anthrone, anthrone-like heterocycles, and derivatives thereof, and one type. These charged groups can be included. Examples of such types of water soluble photoinitiators are described in US Pat. No. 6,077,698.

  Polymerization of a hydrophilic polymer having a projecting polymerizable group can also be promoted using a thermally reactive initiator. Examples of thermally reactive initiators are 4,4'-azobis (4-cyanopentanoic acid), 2,2-azobis [2- (2-imidazolin-2-yl) propane] dihydrochloride, similar to benzoyl peroxide There is a body. Polymerization of a hydrophilic polymer having a projecting polymerizable group can be promoted using a redox initiator. In general, a group for polymerization is generated using a combination of an organic or inorganic oxidizing agent and an organic or inorganic reducing agent. An explanation of the initiation by redox can be found in “The Principle of Polymerization”, 2nd edition, Odian, G., John Wiley & Sons, pages 201-204, 1981.

  A polymerization initiator may also be present on the surface of the hydrophilic polymer containing the initiating group (referred to herein as “initiating polymer”). The polymer portion of the starting polymer may be the same as or different from the one or more hydrophilic polymers used to form the body.

  A composition comprising a hydrophilic polymer having protruding polymerizable groups and a polymerization initiator can also contain one or more other auxiliaries that help promote the formation of the body. Examples of such auxiliaries include polymerization co-initiators, reducing agents, and polymerization accelerators known in the prior art. These auxiliaries can be included in the composition at any useful concentration.

Examples of coinitiators include organic peroxides (eg, derivatives of hydrogen peroxide (H ₂ O ₂ ) where one or both hydrogens are replaced with organic groups). Organic peroxides contain —OO— bonds in their molecular structure, and the chemical properties of the peroxides are derived from these bonds. In some aspects of the present invention, the peroxide polymerization co-initiator is a stable organic peroxide (eg, alkyl hydroperoxide). Examples of alkyl hydroperoxides include t-butyl hydroperoxide, p-diisopropylbenzene peroxide, cumene hydroperoxide, acetyl peroxide, t-amyl hydrogen peroxide, cumyl hydrogen peroxide and the like.

  Other polymerization co-initiators include azo compounds such as 2-azobis (isobutyro-nitrile), ammonium persulfate, and potassium persulfate.

  In some aspects of the invention, the composition used to form the body can include a reducing agent (eg, a tertiary amine). In many cases, reducing agents (eg, tertiary amines) can improve the generation of free radicals. Examples of amine compounds include primary amines (such as n-butylamine), secondary amines (such as diphenylamine), aliphatic tertiary amines (such as triethylamine), and aromatic tertiary amines (p-dimethylaminobenzoic acid). and so on.

  In another aspect of the invention, the composition used to form the body can include one or more polymerization accelerators in addition to these components. As a polymerization accelerator, n-vinylpyrrolidone or the like can be used. In some features, a polymerization accelerator having a biocompatible functional group (eg, a biocompatible polymerization accelerator) is included in the composition of the present invention. The biocompatible polymerization accelerator can also contain N-vinyl groups (eg, N-vinylamide groups). Biocompatible polymerization accelerators are described in United States Patent Application Publication 2005/0112086 assigned to the assignee.

  In some features of the invention, the product provides certain mechanical features to the target portion of the body when the body is in the first state. The body in the first state can exert a force on the tissue at the target site. In this case, this mechanical feature can avoid the need for one or more other forms of treatment (eg, treatment with a drug) at the target location.

  In some features, a bioactive agent can be associated with the body of the hydrophilic shape memory product. In some features, hydrophilic shape memory products are primarily used to deliver bioactive agents to a subject (eg, a target location). In this case, the hydrophilic shape memory product can function primarily as a drug delivery device and can provide pharmacological activity locally at the target location.

  In another aspect, the bioactive agent is associated with a hydrophilic shape memory product that provides mechanical characteristics to the target location when in the first state. The bioactive agent can be selected to provide a therapeutic effect that can supplement the mechanical characteristics provided by the product.

  If a bioactive agent is associated with the body, it can be associated with the body in any suitable manner. For example, the bioactive agent can be released from the product, or the bioactive agent can be stably associated with the surface of the product.

  In some aspects of the invention, the bioactive agent can be included in the body of the shape memory product. For example, the bioactive agent can be present in a body formed from a hydrophilic biodegradable polymer and can be released from the body as it degrades. The body can thus function as a medium for slow or controlled release of the bioactive agent.

  The bioactive agent can also be present in a coating formed on the surface of the body. The coating can be a biodegradable coating or a biostable coating. In some features, the bioactive agent is present in a biostable body or biodegradable body having a biodegradable coating. Biodegradable coatings can be formed using the natural biodegradable polysaccharides described in this specification.

  The bioactive agent may be contained in the fine particles attached to the main body or may be contained as fine particles attached to the main body. For example, the body can include microparticles having a bioactive agent that can be released from the body. In some features, the body includes microparticles that include a low molecular weight bioactive agent. The use of microparticles is one way to control the release of low molecular weight bioactive agents from the body of the shape memory product. An example of a particulate system that is useful for delivering low molecular weight bioactive agents is described in Applicant's US Provisional Application No. 60 / 759,241, filed Jan. 13, 2006.

  The term “bioactive agent” is a synthetic or natural inorganic or organic molecule that causes a biological effect when administered into the body of an animal (eg, birds, mammals (including humans), etc.). Means things.

  In some aspects, shape memory products made in accordance with the present invention can be used to release bioactive agents that fall into one or more of the following classes. In other words, ACE inhibitors, actin inhibitors, analgesics, anesthetics, antihypertensive agents, antipolymerase agents, antisecretory agents, anti-AIDS agents, antibiotics, anticancer agents, anticholinergic agents, anticoagulants as classes Agents, anticonvulsants, antidepressants, antiemetics, antifungals, antiglaucoma solutes, antihistamines, anti-inflammatory agents (eg NSAIDs), antimetabolites, antimitotics, antioxidants, antiparasitics and / or anti Parkinson's substance, antiproliferative agent (including anti-angiogenic agent), protozoan solute, antipsychotic substance, antipyretic agent, antiseptic agent, anticonvulsant, antiviral agent, calcium channel blocker, cell response modifier , Chelator, chemotherapeutic agent, dopamine agonist, extracellular matrix component, fibrinolytic agent, free radical scavenger, growth hormone antagonist, hypnotic, immunosuppressant, immunotoxin, surface sugar Protein receptor inhibitors, microtubule inhibitors, miotics, muscle contractors, muscle relaxants, neurotoxins, neurotransmitters, polynucleotides and their derivatives, opioids, photodynamic therapies, prostaglandins, ligands Examples include, but are not limited to, modeling inhibitors, statins, steroids, thrombolytic agents, tranquilizers, vasodilators, vasospasm inhibitors.

  In another aspect, the shape memory product can include a high molecular weight bioactive agent. In addition, the body of the present invention is particularly useful for the delivery of high molecular weight bioactive agents such as polypeptides (including proteins and peptides), nucleic acids (including DNA and RNA), polysaccharides (such as heparin). . The bioactive agent can be mixed directly with the composition used to form the body of the product. Alternatively, the high molecular weight bioactive agent can be placed in or used as a microparticle. In some cases, the bioactive agent has a molecular weight of 10,000 or greater.

  In some cases, the high molecular weight bioactive agent is a therapeutic antibody or fragment thereof. Examples of such bioactive agents include trastuzumab (Herceptin®), humanized anti-HER2 monoclonal antibody (moAb); alemtuzumab (Campus®), humanized anti-CD52 moAb; gemtuzumab (Milotarg®) )), Humanized anti-CD33 moAb; rituximab (Rituxan (registered trademark)), chimeric anti-CD20 moAb; ibritumomab (zevalin (registered trademark)), mouse moAb conjugated with β-ray emitting radioisotope; tositumomab (Bexar (registered trademark)) )), Mouse anti-CD20 moAb; edrecolomab (Panolex (registered trademark)), mouse anti-epithelial cell adhesion molecule moAb; cetuximab (erbitux (registered trademark)), chimeric anti-EGFR moAb; bevacizumab (Avastin (registered trademark)), human And anti-VEGF moAb.

  In some aspects, a bioactive agent can be selected to improve the surface compatibility (eg, compatibility with blood and / or surrounding tissue) of the shape memory product. Such agents, referred to herein as “biocompatible agents”, when combined with a shape memory product, can make blood components difficult to adhere to the medical product, so that thrombus or embolism (released downstream) The formation of moving thrombus is reduced.

  Representative examples of bioactive agents having antithrombotic effects include heparin, heparin derivatives, sodium heparin, low molecular weight heparin, hirudin, lysine, prostaglandins, argatroban, forskolin, bapiprost, prostacyclin analogs, D- Phenylalanyl-L-prolyl-L-arginyl-chloromethyl ketone (synthetic antithrombin), dipridamole, glycoprotein IIb / IIIa platelet membrane receptor antibody, coprotein IIb / IIIa platelet membrane receptor antibody, recombinant hirudin, thrombin inhibition Agents (such as those commercially available from Biogen), chondroitin sulfate, modified dextran, albumin, streptokinase, tissue plasminogen activator (TPA), urokinase, nitric oxide inhibitors and the like.

  Bioactive agents can also provide anti-restenosis effects (eg, anti-proliferative effects, anti-platelet effects, anti-thrombotic effects). In some embodiments, bioactive agents can include anti-inflammatory agents, immunosuppressive agents, cell adhesion factors, receptors, ligands, growth factors, antibiotics, enzymes, nucleic acids, and the like. Examples of compounds having an antiproliferative effect include actinomycin D, rapamycin, analogs of rapamycin, angiopeptin, c-myc antisense, paclitaxel, taxane, 13-cis retinoic acid, retinoic acid derivative, 5-fluorouracil, etc. is there.

  In some aspects, the bioactive agent is an anti-inflammatory agent, such as hydrocortisone, hydrocortisone acetate, 21-dexamethasone phosphate, fluocinolone, medorizone, methylprednisolone, 21-prednisolone phosphate, prednisolone acetate, fluorometallone, betamethasone, triamcinolone And triamcinolone acetonide. In some aspects, the bioactive agent is an angiogenesis inhibitor, such as an annecortab acetate and a receptor tyrosine kinase antagonist.

  In some aspects, the bioactive agent can include a polymerizable group, and the bioactive agent can be incorporated into the body of the shape memory product. For example, a polymer bioactive agent having a polymerizable group (eg, polysaccharide, polypeptide, polynucleotide) can be included in the composition and polymerized with the hydrophilic polymer. The bioactive agent can be incorporated into the body in a stable or releasable state.

  For example, the body is formed from a hydrophilic biodegradable polymer (eg, a natural biodegradable polysaccharide having a protruding polymerizable group, or a bioactive polymer having a protruding polymerizable group or an active portion thereof). be able to. This can provide a biodegradable body that can release a bioactive polymer or an active portion thereof when degraded.

  In some cases, the body can include a bioactive agent in the form of a fiber growth promoting macromer (eg, collagen macromer). A body formed of a fibroproliferative macromer is particularly useful for making an occlusive device (eg, a device useful for treating an aneurysm). For example, an aneurysm can be filled using a shape memory aneurysm device having a biodegradable body that can assume a coiled first state. As the body breaks down, collagen is released to promote a thrombus response in the vicinity of the body, thus providing an improved system for closing an aneurysm. A fiber growth promoting macromer can also be used to provide a polymer network to the IPN used to form the body.

  By reacting an amine containing a lysine residue with acryloyl chloride, a polymerizable group can be added to collagen or an active portion thereof. Collagen can be dissolved in formamide with acryloyl chloride (and TEA for pH control) to form acrylate-derivatized collagen molecules.

  In some cases, the body can include a bioactive agent in the form of an antithrombotic macromer (eg, heparin macromer). A body formed of an antithrombotic macromer is particularly useful for the manufacture of stents. For example, a shape memory stent having a body that can assume an expanded first state can be used at an intravascular target site. The stent provides a useful mechanical function for a predetermined period of time (ie, in vivo life based on the degradation rate of the stent) at the target site and releases an antithrombotic agent (eg, heparin) in the vicinity of the stent. Prevents thrombus formation. Heparin macromers can be prepared in a variety of ways (eg, by reacting with glycidyl acrylate as described herein). Antithrombotic macromers can also be used to provide a polymer network for the IPN used to form the body.

  A radiopaque agent may also be included in the composition used to form the body. Radiopaque agents can improve imaging of shape memory products inserted into the body. This facilitates detection of the shape memory product when and / or after insertion of the shape memory product at the desired position in the body.

  In some special features, the radiopaque agent includes iodine. Iodine can be used in combination with a biodegradable shape memory body formed from natural biodegradable polysaccharides. Natural biodegradable polysaccharides are known to be complexed with iodine and are a useful way to improve product imaging in the body. It is harmless if iodine is released when the body formed from the polysaccharide is degraded or after degradation.

  The radiopaque agent can be iodine or a second compound (eg, a commercially available iodine-containing radiopaque agent).

The radiopaque agent may be a radioisotope (eg, I ¹²⁵ ). Radioisotopes can also have a second function. For example, radiation treatment of tissue in contact with the body of the shape memory product.

  In some cases, shape memory products are temporarily or permanently introduced into mammals for the prevention or treatment of medical diseases. Shape memory products can be introduced subcutaneously, transdermally, or surgically introduced into an organ, tissue, organ lumen (eg, artery, vein, ventricle, atrium).

  Examples of medical products include vascular implants, vascular grafts, stents, surgical devices; synthetic prostheses; vascular prostheses (eg, endovascular prostheses, stent-graft combinations, endovascular prosthesis-stent combinations); small diameter grafts, abdominal aorta Aneurysm graft; anastomosis device and anastomosis closure device; aneurysm exclusion device; shunt such as cerebrospinal fluid (CSF) shunt, glaucoma drainage shunt; dental device and dental implant; ear device (eg ear drainage tube), Tympanostomy opening tube; ophthalmic device; device cuff and cuff (eg drainage tube cuff, implanted drug infusion tube cuff, catheter cuff, seam cuff); spinal column device and nervous system device; orthopedic device (Eg orthopedic joint implants, bone repair / increase devices, cartilage repair devices); urogenital and urethral devices (eg urine) Use implants, bladder system, kidney apparatus, hemodialysis apparatus), and the like.

  In some special features, shape memory products are used as prostheses in the cardiovascular or genitourinary system.

  The product placed in the inner part of the eye can remain in any area desired by the eye. In some aspects, the shape memory product is an ophthalmic product that is placed in an intraocular region (eg, the vitreous). This shape memory product can take a first state. The devices underlying this first state are US Pat. No. 6,719,750 B2 (“Devices for Intraocular Drug Delivery”, Varner et al.), No. 5,466,233 (“Fasteners for Intraocular Drug Delivery” And Weiner et al.), US Patent Application Publication 2005/0019371 A1 (“Controlled Release Bioactive Agent Delivery Device”, Anderson et al.), 2004/0133155 A1 (“Ocular Device for Internal Drug Delivery ", Varner et al.), 2005/0059956 A1 (" Device for Intraocular Drug Delivery ", Varner et al.), US Patent Application No. 11 / 204,195 (August 15, 2005) Application, Anderson et al., 11 / 204,271 (filed 15 August 2005, Anderson et al.), 11 / 203,981 (filed 15 August 2005, Anderson et al.), 11 / 203,879 (2005) Filed August 15, Anderson et al.), 11 / 203,931 (filed August 15, 2005, Anderson et al.) Which is incorporated herein by reference.

  The implantable shape memory product of the present invention can be simple or complex. A simple shape is a medical product, for example in the form of a filament (eg a thread, string, bar, etc.). The filament can assume the first state. The product is formed in this first state, which is the “memory” state. In the case of a filament, the first state can be non-linear. For example, the filament has a curved state, a coiled state, a curved state, and the like. The second state can be any state different from the first state. For example, if the first state is a coil state having a specific size and shape (eg, outer diameter, inner diameter, coil spacing, curvature, etc.), the second state is different from that specific size in the first state Can be in any state.

  Simple geometric shape memory products can be made in a variety of ways. One method of making a simple geometric shape memory product (eg, a filament) can include forming a body in a first state in a mold. In one embodiment, a composition comprising a hydrophilic polymer having protruding polymerizable groups and a polymerization initiator is placed in a mold. This mold can be, for example, a flexible tube fixed in a predetermined state corresponding to the first state of the main body. For example, as shown in FIG. 1, the mold is formed by winding a flexible tube 10 around a mandrel 11 in a coiled state. Here, the tube is fixed and its state is stable. Alternatively, the mold can be inflexible.

  A composition 12 containing a matrix-forming component can be injected into the tube to fill the tube. The composition can be treated to activate the polymerization initiator (eg, polymerization is initiated by light or heat). Polymerization promotes cross-linking of the hydrophilic polymer and establishes a polymer matrix in a first state. Since the polymer matrix provides internal strength to the body, the body remembers this first state. That is, when the main body is in the second state (an arbitrary state different from the first state is possible), the main body can return from the second state to the first state due to the internal strength of the main body.

  In some preparation methods, the body is formed using a composition that includes a reactive hydrophilic polymer that includes a first reactive group and a second component that is hydrophilic and includes a second reactive group. In general, it is desirable to immediately mix the mixture and place it in the mold because it reacts when the polymer and the second component are mixed. Alternatively, the polymer and the second component are independently supplied to the mold, and both are mixed therein.

  In one embodiment, the first component and the second component are held in separate rooms of a mixing device (eg, a double injector mixing device). When it is desirable to cure the matrix, hand pressure is applied simultaneously to the plungers of both syringes in the device, and both the first and second components are removed from each syringe by a stationary mixing device (eg, Into a “separated flow” type mixer). In the fixed mixing device, the first component and the second component are mixed with each other at a predetermined ratio. After mixing, the matrix-forming composition exits the device through a single outlet hole and enters the mold in the first state. A useful double-injector mixing device is commercially available from Mixpack Systems (Rothkreuz, Switzerland) under the trade name "MIXPAC".

  In order to promote efficient mixing, it is generally desirable that the first component and the second component have similar viscosity. In many embodiments, the first component and the second component have a viscosity of up to about 500 cps.

  In some features, the first body can be formed and then removed from the mold. The body can be forcibly removed from the mold using hydrostatic pressure, or can be removed by breaking the mold. As shown in FIG. 2, the body emerges from the mold in a first state 20.

  Referring to FIG. 2 again, the main body in the first state 20 (coiled state) has a certain size. The main body in the first state 20 has a length 21, an outer diameter 22, an inner diameter 23, and a gap 24. The main body in the first state has a first end 25 and a second end 26.

  FIG. 3 is a cross-sectional view of the filament 30 formed by the mold and shows the cross-sectional shape. The cross section is circular here. This circular cross section has a diameter of 31. The filament is shown having a circular cross section, but can have any cross section that depends on the shape of the mold. For example, the cross-section of the filament can be any curved cross-sectional shape (eg, a circular cross section or an elliptical cross section). The cross-sectional shape may include a straight portion. Examples include arbitrary polygons, such as triangles, squares, rectangles, hexagons, octagons, and the like.

The cross section of the product can also be defined by the cross sectional area. The cross-sectional area can be very small in many cases. For example, in some cases, making the cross-sectional area of the product to about 1.5 mm ² or less than about 1.0 mm ² or less, contrary may even be about 0.5 mm ² or less. The small cross-sectional area allows the product to be easily delivered to a target site in the body.

  The body of the shape memory product is put into the second state before being implanted in the body. The second state can be any state different from the first state. In some features, the body in the first state is brought into the second state and maintained in the second state by the insert used to deliver the shape memory product to the target location in the body. The body is maintained in the second state, for example by a needle or catheter. In this aspect, the body can be maintained in a hydrated state, or in some cases (although not necessarily) maintained in a dehydrated state. When the main body is in a water-containing state, the insertion tool prevents the main body from returning from the second state to the first state.

  As already mentioned, the body can be in any suitable second state. For example, the coiled main body shown in FIG. 2 is brought into the linear second state 40 shown in FIG. 4a. The second state 40 is a state where the coil is unfolded. The main body in the second state has a first end 41 and a second end 42. The distance between the first end 41 and the second end 42 of the main body in the second state is generally the first end 25 of the main body in the first state along the path of the coil. Will be the same as the distance between the second ends 26. However, the length of the body in the second state will be greater than the length 21 of the body in the first state.

  Another example of the second state is a coil state different from the coil in the first state. For example, as shown in FIG. 4b, the second state 43 is a coil wound more tightly than the coil shown in FIG. In the second state 43, the outer diameter 44 and the inner diameter 45 are smaller than the outer diameter 22 and the inner diameter 23 of the coil in the first state 20, respectively. Conversely, the length 46 of the main body in the second state may be longer than the length 21 of the main body in the first state. Alternatively, the gap between the filaments in the second state can be narrower than the gap 24 between the filaments in the first state (not shown).

  In another feature of the present invention, the main body is dehydrated and stabilized in the second state after being changed from the first state to the second state. In the dehydrated state, the body needs to be stabilized by a second device (eg, a needle or catheter). When returning to the water-containing state, the main body returns from the second state to the first state (referred to as shape memory based on the water-containing state in this specification).

  In order to stabilize the second state of the dehydrated product, after the step of forming the main body, the main body is brought into the second state, and the main body is dehydrated while maintaining the state. In some embodiments, if a flexible mold is used, the mold can be in a second state and the body can be dehydrated in the mold. After dehydrating the body, it can be removed from the mold. To do so, for example, the mold may be separated from the main body.

  Dehydration can be performed by any suitable method. For example, the main body is heated or placed in an environment with reduced humidity. The body is dehydrated for a sufficient period of time to remove a predetermined amount of water from the body so that the body is maintained in the second state. The amount of water removed from the body during the dehydration process depends on the amount of water contained in the product prior to the dehydration process. For example, in some features, the first body is about 30% water by weight. The body is put into the second state and about 50% or more of the water is removed from the body. This leaves a body containing water that does not exceed 15% by weight. In some cases, about 50% to about 75% of the liquid present in the composition is removed. The amount of water removed from the body during dehydration can depend on one or more factors. The factors include, for example, the amount of water contained in the main body in the first state, the type of hydrophilic polymer used to form the main body, and the degree of crosslinking of the matrix contained in the main body.

  The cross-sectional shape of the dehydrated body will generally be the same shape as the hydrous form. That is, referring to FIG. 3, the filament will have the same circular cross-sectional shape in both the hydrated and dehydrated states. However, the diameter of the dehydrated filament will be somewhat smaller than the hydrous diameter. In general, this decrease in diameter in the dehydrated state will not be greater than about 10% or 15% of the diameter in the hydrous state using a product formed from a composition containing a high concentration of hydrophilic polymer.

  In another aspect, referring to FIG. 5, the shape memory product has a first state in the shape of a cylindrical body 50. The cylinder 50 can be sized to be used in a blood vessel in the body. For example, in the first state, the outer diameter 51 of the cylindrical body can be about 4 mm or less. In some features, a cylinder 50 is made for use as a stent. In the first state, the outer surface of the main body can exert a force on the inner wall of the blood vessel.

  In some cases, referring again to FIG. 5, a cylinder including one or more windows 53 can be formed. The window 53 can improve the function of this cylinder in the body, for example by allowing fluids and cells to move through the window. The window can also provide improved structural features to the cylinder. The window may be formed as a slit or hole of the desired size or shape in the cylindrical wall.

  The cylindrical body 50 can be formed by placing the composition in a mold and processing the composition to form a body in a first state. This method can be the same method used for forming the filament. A mold useful for forming a shape memory cylinder can be formed using the “tube in tube” method in which a smaller diameter tube is placed within the inner diameter of a larger tube. Spacers can be used to separate the outer diameter of the smaller tube from the inner diameter of the larger tube. This gap is generally uniform at the periphery. By assembling a set of tubes with appropriate spacers, a gapped mold can be obtained that helps form a shape memory cylinder with walls of the desired thickness. For example, using this method, products having a wall thickness of about 2.5 mm or less, or about 2.25 mm or less, or about 2.0 mm or less can be formed. In some cases, the product wall thickness ranges from about 0.5 mm to about 2.0 mm, or from about 1.0 mm to about 2.0 mm.

  Alternatively, the cylindrical body 50 can be formed by placing a composition on the surface of a mandrel and then processing the placed composition to form a body. This method can be used to form a cylinder with a very thin wall. For example, after a composition comprising a hydrophilic macromer and a polymerization initiator is coated on the surface of the mandrel by dip coating or spray coating, the coating can be treated to crosslink the macromer. After processing, a cylinder 50 having a wall 52 with a certain thickness is obtained. The thickness of the wall 52 can be increased by repeating the placement and processing steps. For example, a suitable wall thickness can range from about 50 μm to about 150 μm.

  The cylindrical body is brought into the second state before being implanted in the body. Referring to FIG. 6a, a cross section of a cylindrical body 60 in the first (fully expanded) state and having an outer diameter 61 is shown. A force (F) (indicated by arrow F in FIG. 6b) can be applied to one (or more) positions along the outer wall of the cylinder to collapse the cylinder. The cylinder is then forced into a “C” shape, as shown in FIG. 6c. The crushed cylinder is further processed, and a force is applied to bring the points 62 and 63 closer together, thereby reducing the outer diameter. Then, the collapsed cylindrical body shown in FIG. 6d is obtained. The outer diameter 64 of the cylindrical body in this collapsed state is significantly smaller than the outer diameter 61 in the first state. This is advantageous when delivering at least the cylinder to the target site.

  In some cases, the cylinder in the second state is dewatered to stabilize the second state. In another case, the cylinder is hydrated and the second state is maintained by holding the cylinder in an inserter (eg, a catheter).

  The collapsed cylinder (eg, shown in FIG. 6b) can pass through the blood vessel to reach the target site, or can be placed in a catheter and delivered to the target site. Once delivered to the target site, the cylinder returns from the second (collapsed) state to the first (expanded) state. The cylindrical body in the first state can exert a therapeutic effect on the subject by exerting a force on the inner wall of the blood vessel.

  In another aspect, referring to FIG. 7a, it can be seen that the cylinder 70 can be in a first state to include a slit 71 extending from the first end 72 to the second end 73. FIG. The cylindrical body 70 has an outer diameter 74 in the first state. In this case, the main body takes the form of a rolled sheet in the first state, and can exert a force on the inner wall of the blood vessel. The cylindrical body can be in a second state with a rounded shape as shown in FIG. The rolled cylinder (eg, as shown in FIG. 7b) can be placed through the blood vessel to reach the target site or to be delivered into the catheter for delivery to the target site. The cylinder returns from the second (rolled) state to the first (expanded) state when delivered to the target site.

  The shape memory product can also be provided as a system for introducing the product into a subject. This system (eg, an implant delivery kit) includes at least a shape memory product and an insert that easily introduces the shape memory product into a portion of the body. In this system (eg, a system delivered to a user such as a physician), the shape memory product can be mounted on a portion of the insert (eg, in the needle of the insert) or provided separately.

  When the product is mounted on a part of the insertion tool, it can be mounted in the second state. In some configurations, the inserter can constrain the product and maintain it in the second state. For example, a product in a first state can be generally straight, and the insert can include a product holder (eg, a needle or catheter) that maintains the product in a second state. Alternatively, the product can be attached to a part of the insertion tool in the second state in a dehydrated form. In this case, the inserter helps deliver the product to the target site, but does not need to constrain the product to the second state.

  When using the product, once the distal end of the inserter is positioned at a target location on the body, the product can be forced out of the product holder of the inserter. The product can be forced out using the mechanical characteristics of the insert, or by pneumatic or liquid pressure, or a combination of these. The shape memory product returns to the first state while exiting or after exiting the insert.

  A simple form of the system can include a needle and plunger or a needle and syringe as an inserter. In that case, the shape memory product is attached to the needle. The insert may be a catheter for delivering a shape memory product as an endovascular prosthesis.

  The invention will also be described below with reference to exemplary embodiments.

Preparation of maltodextrin methacrylate macromer (methacrylic acid MD) The following procedure was carried out to obtain acrylic acid MD. Maltodextrin (MD; Aldrich; 100 g; 3.67 mmol; DE: 4.0-7.0) was dissolved in 1,000 ml of dimethyl sulfoxide (DMSO) with stirring. The size of maltodextrin was found to be in the range of 2,000 Da to 4,000 Da by calculation. After the reaction was completed, 1-methylimidazole (Aldrich; 2.0 g; 1.9 ml) was added with stirring, and then methacrylic anhydride (Aldrich; 38.5 g) was added. The reaction mixture was stirred at room temperature for 1 hour. At that time, the reaction mixture was quenched with water and dialyzed against deionized water using a 1,000 MWCO dialysis tube. Separation of methacrylic acid MD by lyophilization gave 63.283 g (yield 63%). The calculated charge of this methacrylate to macromer was 0.33 micromole per mg of polymer.

Synthesis of Aminated Polyalditol Polyalditol PD60 (10.00 g) dried in a vacuum oven was dissolved in anhydrous dimethyl sulfoxide (DMSO) (50 ml) in a 120 ml brown vial. In a separate 30 ml vial, 1,1′-carbonyldiimidazole (CDI) (3.00 g) was dissolved in dry DMSO (25 ml). The CDI solution was poured into a maltodextrin solution, purged with nitrogen gas, and then capped. The reaction solution was placed on a rotary shaker for 20 minutes. In a separate 120 ml brown vial, 1,6-diaminohexane (10.80 g) was warmed to 45 ° C., dissolved in dry DMSO (10 ml), and then added to a stir plate made of Teflon (registered trademark). Placed on top. The maltodextrin / CDI solution was slowly poured into the stirred diamine solution for 20 minutes. When the addition was complete, the reaction vial was transferred to a 55 ° C. oven and stirred overnight. The next day, the reaction solution was poured into 1 liter of tetrahydrofuran (THF) and a white precipitate formed. After the mixture was stirred for 1 hour, the solvent was decanted. Fresh THF (1 liter) was poured into a 2 liter Erlenmeyer beaker and the white precipitate was stirred for 1 hour. This step was repeated twice. The final mixture was filtered using a water aspirator, Buchner funnel, Whatman filter paper and a white precipitate was collected (13.14 g). The precipitate was then dried overnight at 40 ° C. under vacuum. In a 7 ml vial, a small material sample (50 mg) was dissolved in 5 ml deionized water. To this sample was added 1 ml ninhydrin solution (3.6 mg / ml in IPA). The sample was capped and heated to 70 ° C. for several minutes in a water bath. Thereafter, the solution turned dark purple. This indicates the presence of primary amine.

Poly (ethylene glycol) ₃₃₅₀ -di (imidazolyl carbamate)
Poly (ethylene glycol) dried in a vacuum oven (MW about 3350) (6.70 g) was dissolved in anhydrous tetrahydrofuran (THF) (20 ml) in a slightly heated (40 ° C.) 60 ml brown vial . In another 60 ml brown vial 1,1′-carbonyldiimidazole (CDI) (0.811 g) was dissolved in 10 ml dry THF. A Teflon (R) stir bar was placed in the CDI solution and placed on the stir plate. The PEG solution was pipetted into the CDI solution stirred at room temperature. When the addition was complete, the reaction vial was purged with nitrogen gas. The reaction was stirred at room temperature for 2 hours. After 2 hours, the reaction solution was precipitated in 1 liter of cold anhydrous diethyl ether with stirring. The ether solution was decanted and the precipitate was rinsed three more times (3 × 1 liter) with stirring fresh anhydrous ether. The precipitate was collected by vacuum filtration using a water aspirator, Buchner funnel, Whatman filter paper. The collected white precipitate (6.84 g) was dried in a vacuum oven (30 ° C.) overnight.

Poly (ethylene glycol) ₂₀₀₀ -di (imidazolyl carbamate)
Poly (ethylene glycol) (MW 2000) (20.00 g) dried in a vacuum oven was dissolved in anhydrous tetrahydrofuran (THF) (200 ml) in a 500 ml brown vial heated slightly (40 ° C.). In a separate 500 ml brown vial 1,1′-carbonyldiimidazole (CDI) (4.10 g) was dissolved in 50 ml dry THF. A Teflon (R) stir bar was placed in the CDI solution and placed on the stir plate. The PEG solution was pipetted into the CDI solution stirred at room temperature. When the addition was complete, the reaction vial was purged with nitrogen gas. The reaction was stirred at room temperature for 2 hours. After 2 hours, the reaction solution was precipitated in 2 liters of cold anhydrous diethyl ether with stirring. The ether solution was decanted and the precipitate was rinsed three more times (3 × 1 liter) with stirring fresh anhydrous ether. The precipitate was collected by vacuum filtration using a water aspirator, Buchner funnel, Whatman filter paper. The collected white precipitate (19.41 g) was dried in a vacuum oven (30 ° C.) overnight.

Poly (ethylene glycol) ₁₅₀₀ -di (imidazolyl carbamate)
Poly (ethylene glycol) (MW 1500) (15.00 g) dried in a vacuum oven was dissolved in anhydrous tetrahydrofuran (THF) (150 ml) in a 500 ml brown vial slightly heated (40 ° C.). In a separate 500 ml brown vial 1,1′-carbonyldiimidazole (CDI) (4.10 g) was dissolved in 50 ml dry THF. A Teflon (R) stir bar was placed in the CDI solution and placed on the stir plate. The PEG solution was pipetted into the CDI solution stirred at room temperature. When the addition was complete, the reaction vial was purged with nitrogen gas. The reaction was stirred at room temperature for 2 hours. After 2 hours, the reaction solution was precipitated in 2 liters of cold anhydrous diethyl ether with stirring. The ether solution was decanted and the precipitate was rinsed three more times (3 × 1 liter) with stirring fresh anhydrous ether. The precipitate was collected by vacuum filtration using a water aspirator, Buchner funnel, Whatman filter paper. The collected white precipitate (14.68 g) was dried in a vacuum oven (30 ° C.) overnight.

Poly (ethylene glycol) ₁₀₀₀ -di (imidazolyl carbamate)
Poly (ethylene glycol) (MW 1000) (20.59 g) was dissolved in anhydrous tetrahydrofuran (THF) (200 ml) in a 500 ml brown vial. In a separate 500 ml brown vial 1,1′-carbonyldiimidazole (CDI) (8.40 g) was dissolved in 50 ml dry THF. A Teflon (R) stir bar was placed in the CDI solution and placed on the stir plate. The PEG solution was pipetted into the CDI solution stirred at room temperature. When the addition was complete, the reaction vial was purged with nitrogen gas. The reaction was stirred at room temperature for 2 hours. After 2 hours, the reaction solution was precipitated in 2 liters of cold anhydrous diethyl ether with stirring. The ether solution was decanted and the precipitate was rinsed three more times (3 × 1 liter) with stirring fresh anhydrous ether. The precipitate was collected by vacuum filtration using a water aspirator, Buchner funnel, Whatman filter paper. The waxy precipitate (17.59 g) was dried in a vacuum oven (22 ° C.) overnight.

Poly (ethylene glycol) ₆₀₀ -di (imidazolyl carbamate)
Poly (ethylene glycol) (MW = 600) (30.15 g) was transferred to a 150 ml round bottom flask and dissolved in 50 ml dichloromethane (DCM). The solvent was removed using a rotary evaporator and a hot water bath. This step was repeated two more times. 1,1′-carbonyldiimidazole (CDI) (22.90 g) was dissolved in 250 ml DCM in a 500 ml round bottom flask. Under a nitrogen atmosphere, a stir bar made of Teflon was placed in the CDI solution and placed on the stir plate. PEG ₆₀₀ was dissolved in 50 ml DCM and added slowly to the stirring CDI solution and stirred for 2 hours at room temperature under nitrogen atmosphere. The reaction solution was transferred to a 1 liter separatory funnel and washed twice with 1 mM HCl and then twice with brine solution. The organic solution was collected and dried using magnesium sulfate. The dried solution was filtered through Whatman filter paper into a clean 500 ml round bottom flask and the DCM was evaporated on a rotary evaporator with slight heating (30 ° C.). A clear, slightly yellowish oil was recovered (37.02 g).

Tetraethylene glycol-di (imidazolyl carbamate)
Tetraethylene glycol (TEG) (MW 194.23) (21.80 g) was transferred to a 500 ml round bottom flask and dissolved in 100 ml dichloromethane (DCM). The solvent was removed using a rotary evaporator and a hot water bath. This removal step was repeated twice. 1,1′-carbonyldiimidazole (CDI) (40.05 g) was dissolved in 380 ml DCM in a 1000 ml round bottom flask. Under a nitrogen atmosphere, a stir bar made of Teflon was placed in the CDI solution and placed on the stir plate. TEG was dissolved in 200 ml DCM and added slowly to stirring CDI and the resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction solution was transferred to a 1 liter separatory funnel and washed twice with 1 mM HCl and then twice with brine solution. The organic solution was collected and dried using magnesium sulfate. The dried solution was filtered through Whatman filter paper into a clean 500 ml round bottom flask and the DCM was evaporated on a rotary evaporator with slight heating (30 ° C.). A clear oil was recovered (39.46 g).

Triethylene glycol-di (imidazolyl carbamate)
Triethylene glycol (TrEG) (MW 150.17) (3.01 g) was transferred to a 50 ml round bottom flask and dissolved in dichloromethane (DCM) (30 ml). The solvent was removed using a rotary evaporator and a hot water bath. This removal step was repeated twice. 1,1′-carbonyldiimidazole (CDI) (7.14 g) was dissolved in 100 ml DCM in a 250 ml round bottom flask. Under a nitrogen atmosphere, a stir bar made of Teflon was placed in the CDI solution and placed on the stir plate. TrEG was dissolved in 50 ml DCM and added slowly to the stirring CDI solution. The resulting mixture was then stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction solution was transferred to a 250 ml separatory funnel and washed twice with 1 mM HCl and then twice with brine solution. The organic solution was collected and dried using magnesium sulfate. The dried solution was filtered through Whatman filter paper into a clean 250 ml round bottom flask and the DCM was evaporated on a rotary evaporator with slight heating (30 ° C.). A clear oil was recovered (5.93g).

Trimethylolpropane ethoxylate (20 EO) -tri (imidazolyl carbamate)
Trimethylpropane ethoxylate (20/3 EO / OH) (MW 1014) (10.14 g) was transferred to a 150 ml round bottom flask and dissolved in 50 ml dichloromethane (DCM). The solvent was removed using a rotary evaporator and a hot water bath. This removal step was repeated twice. 1,1′-carbonyldiimidazole (CDI) (6.49 g) was dissolved in 250 ml DCM in a 1000 ml round bottom flask. Under a nitrogen atmosphere, a stir bar made of Teflon was placed in the CDI solution and placed on the stir plate. Trimethylolpropane ethoxylate was dissolved in 100 ml DCM and added slowly to the stirring CDI solution and the resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction solution was transferred to a 500 ml separatory funnel and washed twice with 1 mM HCl and then twice with brine solution. The organic solution was collected and dried using magnesium sulfate. The dried solution was filtered through Whatman filter paper into a clean 500 ml round bottom flask and the DCM was evaporated on a rotary evaporator with slight heating (30 ° C.). A clear oil was recovered (12.07 g).

Pentaerythritol ethoxylate (15 EO) -tetra (imidazolyl carbamate)
Pentaerythritol ethoxylate (15/4 EO / OH) (MW 797) (11.96 g) was transferred to a 500 ml round bottom flask and dissolved in 100 ml dichloromethane (DCM). The solvent was removed using a rotary evaporator and a hot water bath. This removal step was repeated twice. 1,1′-carbonyldiimidazole (CDI) (16.22 g) was dissolved in 200 ml DCM in a 1000 ml round bottom flask. Under a nitrogen atmosphere, a stir bar made of Teflon was placed in the CDI solution and placed on the stir plate. Pentaerythritol ethoxylate was dissolved in 100 ml DCM and added slowly to the stirring CDI solution and the resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction solution was transferred to a 500 ml separatory funnel and washed twice with 1 mM HCl and then twice with brine solution. The organic solution was collected and dried using magnesium sulfate. The dried solution was filtered through Whatman filter paper into a clean 500 ml round bottom flask and the DCM was evaporated on a rotary evaporator with slight heating (30 ° C.). A clear oil was recovered (15.89 g).

Manufacture of shape memory coil made of methacrylic acid MD Straight silicone tube (inner diameter (ID) 0.029 inch, outer diameter (OD) 0.071 inch, Helix Medical, Carpinteria, CA) A solution of methacrylic acid MD having a concentration of 800 mg / ml (prepared as in Example 1) and a photoinitiator 4,5 having a concentration of 10 mg / ml prepared as described in US Pat. No. 6,278,018. A solution of -bis (4-benzoylphenyl-methyleneoxy) benzene-1,3-disulfonic acid (Example 1) in deionized water was loaded by infusion using a syringe. The end of the tube was pinched closed with a clip, and the tube loaded with the solution was wrapped around a silicone tube with a larger OD of 2.5 mm, but without stretching. In order to keep the silicone tube straight, a steel rod was inserted into the ID. Next, the coiled tube loaded with the solution was fixed to both ends of the rod to prevent the coil from unwinding. The coiled tube loaded with the solution was then placed in a UV light chamber. The tube was placed in an irradiation system (Daimax 400 watt power supply with 365 nm lamp; Daimax Corp.) and cured for 3 minutes while rotating. When the tube hardened, it was removed. The unwound silicone tube is almost straight. The cured polymer matrix formed in the silicone tube was forcibly removed by injecting a stream of water at one end using a syringe. The cured polymer matrix jumped out of the other end in the same coil shape as the tube wrapped in size and shape.

Preparation of Coiled Silicone Mold A 0.014 inch stainless steel wire coated with Teflon was tightly wound around a 0.035 inch stainless steel mandrel to form a coil. When this coil was fully extended, the gap became a coil with equal intervals. The coil was then inserted into a silicone tube that was larger than the OD of the coil and the tube was filled with curable RTV-silicone. This tube was slowly filled with RTV-silicone so that the coil was centered in the tube without any bubbles. During this process, a steel coil coated with Teflon was embedded in RTV-silicone. The silicone was cured at room temperature for 3 days. After curing, the Teflon (registered trademark) coil was removed from the cured silicone by turning the screw to leave a gap in the shape of the coil. Both ends of the mold were cut so that both ends of the coiled gap were open.

Production of Shape Memory Coil Made of Methacrylic Acid MD from Mold Acrylic acid MD / photoinitiator prepared as in Example 12 was filled into a mold made as in Example 13. The mold was placed in the UV chamber described in Example 12 along with the solution and irradiated for 2 minutes while rotating to cure the solution and form a polymer matrix. The mold was removed from the UV chamber and the formed polymer coil was forcibly removed from the mold by a water stream. Polymer coils emerged from the coil mold as coils of the same size and shape. The formed coil was rinsed in a bath of deionized water.

Shape Modification and Dehydration of Shape Memory Coil Made of Methacrylic Acid MD The water-containing coil produced in Example 14 was placed on a flat Teflon (registered trademark) surface. After the coil is dried from the moisture state to a moisture content of about 50-75%, the coil is spread using a pair of Teflon rods (both rods starting from the same gap in the coil). , Move them in opposite directions). When the coil is straight, the rod is kept in contact with the coil and the coil remains straight until the coil is sufficiently dry to remain straight without any external pressure.

Intraocular delivery of straightened shape memory coil made of methacrylic acid MD, return to water content, shape change The straight coil formed in Example 15 was inserted into a 19 gauge needle. The needle was inserted into the eye removed from the pig, a metal mandrel was used as the plunger, and a dry straight coil was pushed through the needle into the vitreous. The needle was withdrawn from the eye and the dried straight coil was hydrated in the vitreous. Within 2.5 minutes, the coil became wet and returned to its original shape.

Intraocular delivery and shape change of a straight shape memory coil made of methacrylic acid MD that has returned to a water-containing state After inserting the straight coil described in Example 15 into a 19 gauge needle in a dehydrated and straight state, the needle It was returned to a water-containing state using deionized water. This needle was inserted into the eyeball taken out from the pig, and the water-containing coil was pushed into the vitreous body of the eyeball using a metal plunger. The coil that was kept straight by the needle jumped out of the end of the needle and immediately took the shape of the coil (ie the coil jumped out of the end of the needle like a corkscrew). The polymer coil became suspended in the vitreous and did not move or sink from the delivered location.

Production of biodegradable shape memory coil from mold Prepare acrylic MD / photoinitiator composition as prepared in Example 12 and prepare bovine serum albumin (BSA) in a concentration range of about 30-40%. Added.

  The resulting solution was poured into a coiled silicone mold and UV cured. When the cured polymer / protein matrix was forcibly removed from the mold, the shape of the coil was maintained. The coil was rinsed with deionized water and then removed and allowed to air dry in a petri dish.

Manufacture of biostable shape memory coils
A solution prepared by dissolving 33% PEG macromer of triacrylate (described in US Patent Application Publication No. 2004 / 0202774-A1) and 6.6 mg / ml photoinitiator described in Example 12 in deionized water Were injected into a 35-37 cm long silicone tube (0.029 inch ID) and then sealed at both ends with a mouth clip. The tube was then tightly wrapped around a 2.5 mm diameter silicone tube (with a steel mandrel inserted for support). Both ends of the tube containing the solution were secured to a silicone / steel tube to maintain the coil. The system was then placed in a UV light chamber (with rotation) and irradiated for 2 minutes to cure the polymer matrix. When the tube with the hardened solution / matrix was unwound, it was slightly wavy but mostly straight. When the UV cured polymer matrix was removed by forcing water into one end of the tube, it emerged from the other end of the tube as a coil of the same size and shape as the outer silicone tube.

Production of tapered biostable shape memory coil A solution of PEG macromer triacrylate and photoinitiator described in Example 19 in a 35-37 cm long silicone tube (0.029 inch ID) from Helix Medical Then, both ends were sealed with mouth clips. The tube was then tightly wrapped around the distal end of a plastic pipette (tapered from straight). Both ends of the tube containing the solution were fixed to this plastic pipette to maintain the coil shape. The system was then placed in a UV light chamber (with rotation) and irradiated for 2 minutes to cure the polymer matrix. When the tube containing the cured solution / matrix was unwound, it was slightly wavy but mostly straight. When the UV cured polymer matrix is removed by forcing water into one end of the tube, it emerges from the other end of the tube as a coil (tapered coil) of the same size and shape as the outer silicone tube. It was.

Manufacture of “8-shape” biostable shape memory product A solution of PEG macromer triacrylate and photoinitiator described in Example 19 was prepared from a 35-37 cm long silicone tube (0.029) from Helix Medical. Inch ID) and then sealed at both ends with mouth clips. The tube was then wrapped relatively loosely around a 0.035 inch steel mandrel bent into a “U” shape and having a gap of about 1.3 cm (forming a series of eight figures). Both ends of this “U” made of steel were inserted into a silicone plug to keep it from collapsing. Both ends of the tube containing the solution were fixed to a steel mandrel and maintained in a wound state. The whole was then placed in a UV light chamber (with rotation) and irradiated for 2 minutes to cure the polymer matrix. When the tube containing the cured solution / matrix was unwound, it was slightly wavy but mostly straight. When water was forced into one end of the tube to remove the UV-cured polymer matrix, it emerged from the other end of the tube as a series of eight figures that basically overlapped one another.

Production of knotted biostable shape memory product A solution of PEG macromer triacrylate and photoinitiator as described in Example 19 is a 35-37 cm long silicone tube (0.029 inch ID) from Helix Medical. Then, both ends were sealed with mouth clips. The tube was then tied to form 8 loose knots. Each knot was about 1 cm in diameter. This knotted tube was hung vertically (about 10 cm long) and irradiated in a UV chamber (with rotation) for 2 minutes to cure the polymer matrix. When water is forced into one end of the tube without unwinding it, the UV-cured polymer matrix pops out of the other end of the tube and immediately becomes similar in size and shape to the knotted silicone tube. However, the knot did not actually become a loop like a real knot (all the bends were in exactly the same position as present in the knotted silicone).

Manufacture of cylindrical body made of methacrylic acid MD Using a solution of methacrylic acid MD and a photoinitiator prepared as described in Example 12, a Teflon (registered trademark) rod having a cross-sectional diameter of 1 mm was dip coated. . A 3.1 cm portion of this rod was immersed in the solution at a speed of 0.5 cm / second, left for 15 seconds, and then pulled out at 0.1 cm / second. The coated rod was immediately placed in a UV chamber (rotating) and allowed to cure for 45 seconds. This process was repeated two more times to coat the matrix a total of three times. The cured rod / coating was then immersed in deionized water for 10 minutes. After soaking, the cured polymer matrix containing water was pulled from the Teflon rod by applying moderate pressure with the fingers to break the physical adhesion to the rod. The polymer matrix left the bar as a tube. After air drying, the polymer tube uniformly contracted by about 14%.

Change in shape and dehydration of methacrylic acid MD cylindrical body The hydrous cylindrical body from Example 23 was placed in a silicone half-pipe prepared by cutting a 2 mm diameter silicone tube in the length direction. Lateral pressure was applied throughout the length of the hydrous cylinder using a 0.2 mm diameter wire. The cylinder collapsed slowly without breaking. The wire was removed and the collapsed cylinder was completely dehydrated. The diameter of the collapsed cylinder was almost half that of the non-collapsed cylinder. When this cylinder was again hydrated, it slowly (after about 2 minutes) turned into the original unbroken cylinder shape.

Mold for manufacturing shape memory cylinder A mold ("tube in tube" design) for manufacturing a shape memory cylinder was prepared. Smaller diameter silicone tubing (Dow Corning Q7-4750; ID = 3.35mm; OD = 4.65mm; Helix Medical (Carpinteria, CA), catalog number 60-011-11) Placed in a large silicone tube (Dow Corning Q7-4750; ID = 6.35 mm; OD = 11.11 mm, catalog number 60-011-25). Use a section cut from the ribbed tip of the 200 μl pipette tip as a spacer between the tubes at both ends (the small tube fits snugly inside the pipette tip section and the outer tube is the pipette tip It fits snugly over the compartments) to allow for uniform gaps or voids between the tubes. One end (upper end) has a hole between the spacer and the tube (caused by the pipette's tip section rib) to allow air to escape. The opposite end (bottom end) was sealed by covering this end of the tube and the tip section of the pipette with Parafilm®. The outer silicone tube wall had a small hole just above the bottom spacer / ring.

Production of Shape Memory Cylinder Using a mold produced according to Example 25, a biodegradable shape memory cylinder was made from reagents that form an interpenetrating network (IPN) of biodegradable polymer material. The IPN was formed by combining polymer components that react with each other (PEG-diimidazolyl carbonate and aminated polyalditol) and a UV-induced free radical reaction polymer component (maltodextrin methacrylate).

  A first solution (solution A) containing a biodegradable macromer component capable of free radical polymerization and a monomer component was prepared. Solution A was placed in an 8 ml clear glass vial in a 650 mg methacrylic acid MD (see Example 1) and 325 mg diacetone acrylamide (DAAM) (Lot # B5176B; Alpha Ether, Ward Hill, Mass. And 5 mg / ml 4,5-bis (4-benzoylphenylmethyleneoxy) benzene-1,3-disulfonic acid solution 1.3 prepared as described in US Pat. No. 6,278,018 (Example 1). Prepared by adding a solution of ml in deionized water. The solution was stirred for 5 minutes and then sonicated for 20 seconds to remove air bubbles.

A second solution (Solution B) was prepared by adding 556 mg of PEG ₁₀₀₀ -di (imidazole carbamate) (see Example 6) along with 560 μl of Solution A to the second vial. The solution was stirred for 10 minutes and then sonicated for 60 seconds to remove air bubbles.

A third solution (Solution C) consisting of about 950 mg / ml (pH adjusted to 7) PD60-NH ₂ (see Example 2) was prepared.

  About 950 μl of viscous solution C was added to the vial containing solution B, and the resulting mixture was stirred for 2 minutes and then sonicated for 2 minutes to remove most of the foam. This solution was then drawn up into a 1 ml syringe. A 200 μl pipette was cut near the tip and tightly fitted to the end of the syringe. The curable solution was then injected into the mold prepared in Example 25 with a syringe by inserting the true tip of a 200 μl pipette into the hole near the bottom of the mold. The mold was positioned so that the solution filled the mold without bubbles as air escaped from the top as the solution entered the mold.

  The mold filled with the solution was placed upright in a sealed container and allowed to cure overnight at room temperature. The next day, remove the mold from the sealed container and place it in a UV light box (1 dimax lamp-400 watt power supply-face down toward the sample on a flat surface) for a total of 2 Irradiated for minutes. The mold was rotated 1/4 turn every 30 seconds, and the solution was poured into a mold made of a silicone tube.

  The spacers were removed from both ends of the mold and the smaller inner silicone tube was pulled out of the mold so that the formed matrix was not damaged. The mold was then opened at room temperature and the matrix was air dried and shrunk. The matrix was pulled from the silicone wall as the matrix contracted, but was easily extruded when dried. The dried cured matrix tube was relatively uniform and could be folded. This tube uniformly shrunk by about 20% in size.

Shape memory coil with therapeutic microparticles Biodegradable shape memory coils containing microparticles loaded with antiproliferative agents were made.

  Microparticles were prepared using poly (L-lactide-co-caprolactone-co-glycolide) (pLLCG) lot 08723kA (Sigma) and rapamycin lot ASW-106 (sirolimus, Wyeth). A pLLCG solution containing 500 mg of pLLCG in 10 ml of dichloromethane was prepared. 25 mg of rapamycin was added to 2 ml of pLLCG solution to form a 25% w / w polymer solution. This polymer solution was thoroughly mixed with 10 ml of 0.2% w / w polyvinyl alcohol (PVA) solution. The mixture was poured onto ice and further dispersed by pulsing (2 second pulse and 0.5 second rest) sonication (probe). The dispersion was poured into 100 ml of 0.2% PVA solution, mixed by hand for 1.5 minutes and stirred at room temperature for 3 hours. Microparticles were separated by centrifugation (10k RPM over 5 minutes). The sample was then frozen and dried. Yield was 58.4 mg (47%).

  For the body, polyaldiacrylate acrylate as in Example 18 of 1000 mg PD60-A (US Patent Application Publication 2007/0065484 (Chudzik et al .; Application Serial No. 11 / 525,006; publication date March 22, 2007)). Was added to an 8 ml clear glass vial and 5 mg / ml 4,5-bis (4-benzoylphenylmethyleneoxy) benzene-1,3-disulfonic acid was dissolved in deionized water 2.5 ml of solution was added in 0.5-1.0 ml portions. The solution / vial was agitated between one and the next addition. The solution was then mixed on an orbital shaker for 4 hours, at which time 500 mg of DAA was added to the mixture and the resulting solution was stirred again to break up the solid. This solution was then mixed overnight on an orbital shaker. The final volume of the prepared solution was estimated to be 4.5 ml ± 0.1 ml.

  Next, to this solution / vial was added 33.2 mg of pLLCG particles loaded with 25% of the targeted drug. The solution was stirred and sonicated intermittently for 40 minutes to disperse the microparticles and remove bubbles.

  Next, this solution containing the suspended fine particles was injected into a 44 cm long silicone tube (inner diameter 1.2 mm, outer diameter 2.45 mm) with a syringe. Next, after plugging both ends of the tube filled with the solution, the tube was tightly wound around a cylindrical shaft having an outer diameter of 7 mm to fix both ends. The tube, filled with the solution, was then irradiated while rotating UV for 2 minutes between two dimax lamps (400 watt power supply) facing each other.

  After UV curing, the parafilm layer was wrapped around the middle section of the coil, leaving both ends exposed. The plug at each end was removed and a water stream was injected into one end of the silicone tube using a syringe, forcing the cured matrix out of the other end of the silicone tube. The matrix was in the form of a coil formed when it exited the tube.

  One end of the formed coiled matrix is hung, a light weight is attached to the other end, and the coil is straightened to straighten the coil. The coil whose state has changed is dried in a straight line. When dry, this coil whose state has changed remains straight if no force is applied to the coil. When the coil whose state has changed is brought into a water-containing state again, it returns to the shape of the original coil.

FIG. 3 is a view of a mold for forming a shape memory coil, the mold comprising a flexible tube covering the periphery of a mandrel. FIG. 3 is a diagram of a shape memory coil in a first state. It is a figure of the circular cross section of a shape memory coil. FIG. 6 is a diagram of a shape memory coil in a second (straight) state. FIG. 3 is a diagram of a shape memory coil in a second (tightly wound) state. FIG. 3 is a diagram showing a shape memory cylinder (stent) having a plurality of windows in a first (expanded) state. FIG. 3 is a cross-sectional view of a shape memory cylinder (stent) in a first (expanded) state. FIG. 3 is a cross-sectional view of a shape memory cylinder (stent) in a second (collapsed) state. FIG. 3 is a cross-sectional view of a shape memory cylinder (stent) in a second (collapsed) state. FIG. 3 is a cross-sectional view of a shape memory cylinder (stent) in a second (collapsed) state. FIG. 3 is a diagram showing a shape memory cylinder (stent) having a slit in a first (expanded) state. FIG. 3 is a diagram showing a shape memory cylinder (stent) having a slit in a second (rolled) state. FIG. 4 is a reaction scheme showing the preparation of an amine functional polysaccharide. 2 is a reaction scheme showing the preparation of an amine reaction compound. 2 is a reaction scheme showing the preparation of an amine reaction compound. 4 is a reaction scheme showing that a matrix material is formed by reaction of an amine functional polysaccharide with an amine reactive compound.

Claims (42)

  An insertable medical product comprising a body comprising a cross-linked matrix composed of a hydrophilic polymer having a molecular weight of 100,000 Da or less, wherein the body is a second at a target site in the subject's body when the product is inserted. An insertable medical product capable of shape memory transition from state to first state.   The insertable medical product according to claim 1, wherein the molecular weight of the hydrophilic polymer is 50,000 Da or less.   The insertable medical product according to claim 2, wherein the molecular weight of the hydrophilic polymer is 25,000 Da or less.   4. The insertable medical product according to claim 3, wherein the molecular weight of the hydrophilic polymer is in the range of 1,000 to 10,000 Da.   The insertable medical product according to claim 1, wherein the matrix comprises a hydrophilic polymer crosslinked through polymerized groups.   The matrix includes a hydrophilic polymer and a hydrophilic component cross-linked through a first reactive group and a second reactive group, and the first reactive group protrudes from the hydrophilic polymer, and the second reactive group The insertable medical product according to claim 1, wherein a reactive group protrudes from the hydrophilic component.   7. The insertable medical product of claim 6, wherein the first reactive group is present on the surface of the polysaccharide in an amount that results in a degree of substitution of 1.0 or less.   8. The insertable medical product of claim 7, wherein the first reactive group is present on the surface of the polysaccharide in an amount that results in a degree of substitution ranging from 0.2 to 0.3.   7. The insertable medical product according to claim 6, wherein the first reactive group and the second reactive group are amine groups.   The insertable medical product according to claim 6, wherein the second component is non-biodegradable.   7. The insertable medical product according to claim 6, wherein the molecular weight of the second component is 10,000 Da or less.   The insertable medical product according to claim 6, wherein the molecular weight of the second component is 3,500 Da or less.   7. The insertable medical product according to claim 6, wherein the hydrophilic component comprises an alkoxyalkane.   The alkoxyalkane is selected from the group consisting of tri (ethylene glycol), tetra (ethylene glycol), poly (ethylene oxide) (PEO), poly (ethylene glycol), poly (propylene oxide) (PPO). 9. An insertable medical product according to claim 8.   7. The insertable medical product according to claim 6, wherein the hydrophilic component is a liquid at 25 ° C.   2. The insertable medical product according to claim 1, wherein the hydrophilic polymer is a natural biodegradable polymer.   13. The insertable medical product according to claim 12, wherein the selection of the natural biodegradable polymer is made from the group consisting of maltodextrin, amylose, polyalditol, cyclodextrin.   The insertable medical product according to claim 1, wherein the body comprises 15 wt% or more of a hydrophilic polymer.   2. The insertable medical product according to claim 1, wherein the second state is linear.   The insertable medical product according to claim 1, wherein the first state includes a state of a coil.   2. The insertable medical product according to claim 1, wherein the body is cylindrical.   2. The insertable medical product of claim 1, comprising a body for use in the vasculature.   The insertable medical product according to claim 1, wherein the body in the first state can exert pressure on the tissue at the target site.   24. The insertable medical product of claim 23, comprising a stent.   2. The insertable medical product of claim 1, comprising a body for use in the eye.   2. The insertable medical product of claim 1 comprising a bioactive agent.   27. The insertable medical product of claim 26, comprising a bioactive agent selected from the group consisting of polypeptides, polynucleotides, polysaccharides.   27. The insertable medical product of claim 26, comprising a bioactive agent having a molecular weight of 10,000 Da or higher.   The main body in the second state has a second water content state, and when inserted into the target site of interest, the water content of the main body increases to become the first water content state to the first state. 2. The insertable medical product of claim 1 capable of shape memory transition.   30. The insertable medical product according to claim 29, wherein the body has a water content of 35% or less in the second water content state. A method of manufacturing an insertable medical product comprising a body with shape memory characteristics,
Providing a composition in a first state comprising a hydrophilic polymer having a molecular weight of 100,000 Da or less and a reactive group;
Forming a matrix of a hydrophilic polymer by reacting the reactive groups to produce a body in a first state,
A method by which the body can return from a second state to the first state when inserted into a target site of interest or after insertion.   32. The method of claim 31, wherein in the step of providing a composition, the composition comprises a hydrophilic polymer at a concentration of 250 mg / ml or greater.   32. The method of claim 31, wherein in the step of providing a composition, the composition comprises 50 wt% or less of water.   34. The method of claim 33, comprising removing at least a portion of water from the body to bring the body into the stable second state.   35. The method of claim 34, wherein the removing step removes at least 50% water present in the body.   In the step of preparing the composition in the first state, the sub-step of mixing the hydrophilic polymer having a molecular weight of 100,000 Da or less and containing the first reactive group with the second component containing the second reactive group And when mixed, the first reactive group and the second reactive group cause a specific reaction to form a matrix composed of a crosslinked hydrophilic polymer. 35. The method of claim 34, wherein the method is manufactured.   38. The method of claim 36, wherein the hydrophilic polymer and the second component react to form a first polymer network, and the composition comprises a second hydrophilic that includes protruding polymerizable groups. The polymer further comprising polymerizing the second hydrophilic polymer to form a second polymer network, and penetrating the second polymer network into the first polymer network. The method further comprising forming the body. A method of treating a target site in a subject's body,
Obtaining an insertable medical product comprising a body comprising a cross-linked matrix of hydrophilic polymer, the body being capable of shape memory transition from a second state to a first state;
Delivering the product in a second state to a target site in the body, allowing the body to return from the second state to the first state at the target site;
A method of treating a target site by causing the body in a first state to exert a force on tissue at the target site.   40. The method of claim 38, wherein in the step of returning the body to the first state, the change to the first state is facilitated by the body becoming wet. A method of delivering a bioactive agent to a subject comprising:
Insertable with a cross-linked matrix made of a hydrophilic polymer with a molecular weight of 100,000 Da or less and a body containing a bioactive agent that can undergo a shape memory transition from the second state to the first state Obtaining a new medical product;
Delivering the product in a second state to a target site in the body;
Returning the body from the second state to the first state at the target site;
Releasing the bioactive agent from the body at the target site.   A body formed from a hydrophilic matrix including a first polymer network that penetrates a second polymer network, the body being capable of shape memory transition from the second state to the first state Insertable medical product.   A system for delivering an insertable medical product comprising a body having shape memory properties to a body part comprising: (a) a body comprising a cross-linked matrix of hydrophilic polymer, when inserted An insertable medical product whose body is capable of shape memory transfer from the second state to the first state at the target site in the body of the subject; and (b) the body holding the product in the second state And an inserter that can be delivered to a portion of the system.

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