Biodegradable shape memory polymers

Description: TECHNICAL FIELD [Detailed description of the invention]

【0001】

(Background of invention) The present application is generally in the field of shape memory polymers, and more specifically with respect to biodegradable shape memory polymers. [0002]

Shape memory is for memorizing its original shape either after mechanical deformation (Fig. 1) (one-way effect) or by cooling and heating (Fig. 2) (bidirectional effect). The ability of the material. This phenomenon is based on a structural phase transition. [0003]

The first material known to have these properties was shape memory alloys (SMAs), including TiNi (Nitinol), CuZnAl, and FeNiAl alloys. The structural phase transition of these materials is known as the martensite transition. These materials have various uses, including vascular stents, medical guide wires, orthodontic wires, vibration dampers, pipe fittings, electrical connectors, thermostats, actuators, eyeglass frames, and brassiere underwires. Proposed. These materials have not yet been widely used, as they are somewhat expensive. [0004]

Shape memory polymers (SMPs) have been developed to replace or enhance the use of SMAs, which are lighter than SMAs, have higher shape recovery potential, and are easier to operate. And because it is somewhat economical. In the literature, SMPs are generally characterized as phase-segmented linear block copolymers with hard and soft segments. Hard segments are typically crystalline (having a defined melting point) and soft segments are typically amorphous (having a defined glass transition temperature). However, in some embodiments, the hard segment is amorphous and has a glass transition temperature rather than a melting point. In another embodiment, the soft segment is crystalline and has a melting point rather than a glass transition temperature. The melting point or glass transition temperature of the soft segment is substantially lower than the melting point or glass transition temperature of the hard segment. [0005]

This material can be shaped if the SMP is heated above the melting point of the hard segment or the glass transition temperature. This (original) shape can be remembered by cooling the SMP below the melting point or glass transition temperature of the hard segment. If the shaped SMP cools below the melting point or glass transition temperature of the soft segment while the shape is deformed, the new (temporary) shape is fixed. The original shape is restored by heating above the melting point or glass transition temperature of the soft segment, but below the melting point or glass transition temperature of the hard segment. Alternatively, the material is deformed at a temperature below the melting point of the soft segment or the glass transition temperature, allowing stress and strain to be absorbed by the soft segment. If this material is heated above the melting point or glass transition temperature of the soft segment, but below the melting point (or glass transition temperature) of the hard segment, this stress and strain will be released and the material will be released. Return to its original form. Restoration of its original shape, which is triggered by an increase in temperature, is called the thermal shape memory effect. The properties that indicate the shape memory ability of a material are the restoration of the original shape and the temporary shape fixing of the shape. [0006]

Some physical properties of SMP other than its ability to memorize shape change significantly in response to external changes in temperature and stress, especially at the melting point or glass transition temperature of soft segments. These properties include modulus of elasticity, hardness, flexibility, gas permeability, damping, refractive index, and permittivity. The modulus of elasticity of an SMP (the ratio of the stress of an object to its corresponding strain) can vary by factors up to 200 when heated above the melting point of the soft segment or the glass transition temperature. Also, the hardness of the material changes dramatically when the soft segment is above its melting point or glass transition temperature. When the material is heated above the melting point of the soft segment or the glass transition temperature, the damping capacity can be up to 5 times higher than conventional rubber products. This material can be easily restored to its original molded shape after many thermal cycles and can be heated above the melting point of the hard segment, reformed, cooled and fixed in its new original form. [0007]

Conventional shape memory polymers are generally segmented polyurethanes and have hard segments containing aromatic moieties. For example, Hayashi et al., US Pat. No. 5,145,935, is a shape memory formed from a polyurethane elastomer (polymerized from a bifunctional diisocyanate, a bifunctional polyol, and a bifunctional chain extender). A polyurethane elastomer molded product is disclosed. [0008]

Examples of polymers used for the preparation of known hard and soft segments of SMP include various polyethers, polyacrylates, polyamides, polysiloxanes, polyurethanes, polyetheramides, polyurethanes / ureas, polyether esters, etc. And urethane / butadiene polymers. For example, Ward et al., US Pat. No. 5,506,300; Hayashi et al., No. 5,145,935; Bitler et al., No. 5,665,822; and Gorden, "Applications of Shape Memory Polyurethanes," Proceedings of the First International Conference on Shape Memory and Superelastic Technologies. , SMST International Committee, pp. 115-19 (1994). [0009]

Although many uses of these polymers have been proposed, their medical use has been limited to devices that are not transplanted or left in the body. It is desirable to have a shape memory polymer that is biodegradable. Many other applications for biodegradable shape memory polymers are obvious, for example in use in the production of diapers or medical drape linings, or in food packaging or other materials with processing problems. is there. It is not clear from commercially available polyurethane materials that biodegradable materials can be incorporated into shape memory polymers and maintain this structure as well as the shape memory polymers and other physical and chemical properties essential for their application. .. Moreover, the components of known polyurethane shape memory polymers contain aromatic groups that are not expected to be biocompatible. [0010]

Therefore, it is an object of the present invention to provide a biodegradable shape memory polymer. [0011]

It is a further object of the present invention to provide a shape memory polymer having physical and chemical properties and a chemical structure that is different from that of conventional shape memory polymers. [0012]

(Gist of the invention) The biodegradable shape memory polymer compositions, their products, and their preparation and use are described. The polymer composition comprises one or more hard segments and one or more soft segments, wherein the composition is biocompatible and at least one segment is biodegradable or Alternatively, at least one segment binds to another segment via a biodegradable bond. [0013]

Hard segment melting point or glass transition temperature (below in the specification, T_tran_s) Is at least 10 ° C, and preferably 20 ° C soft segment T_tra_nsHigher than. Hard segment T_transIs preferably -30 ° C and 270 Between ° C, and more preferably between 30 ° C and 150 ° C. The weight ratio of the hard segment: soft segment is between about 5:95 and 95: 5, preferably between 20:80 and 80:20. These shape memory polymers contain at least one physical crosslink (physical interaction of hard segments) or covalently crosslink in place of the hard segment. These shape memory polymers can also have a cross-penetrating network structure or a semi-interpenetrating network structure. [0014]

In addition to the solid-to-liquid state change (melting point or glass transition temperature), the hard and soft segments can undergo a solid to solid state transition, and the polymer electrolyte segment or high It can then undergo ionic interactions, including supermolecular effects based on organized hydrogen bonds. [0015]

T that is crystalline or amorphous and is within the range specified herein._transAny polymer with can be used to form hard and soft segments. Typical biodegradable polymers include polyhydroxyic acid, polyalkanoate, polyanhydride, polyphosphazene, polyether esters, polyesteramides, polyesters, and polyorthoesters. Examples of biodegradable bonds include ester, amide, anhydride, carbonate, and orthoester bonds. [0016]

Products can be prepared from shape memory polymer compositions, for example, by injection molding, blow molding, extrusion molding, and laser ablation. To prepare an object that remembers its shape, this object is a hard segment of T_transAbove Molded at the temperature of, soft segment T_transCan be cooled to temperatures below To. If this object is formed into a substantially second shape, then this object is a T in a soft segment._transAbove and hard segment T_transIt can be restored to its original shape by heating this object below. [0017]

Thermosetting polymers are macromonomers preformed, for example by extrusion, and the thermosetting polymer T._transAt temperatures above, for example macromonomers It can be prepared by fixing the reactive group to its original form by photocuring. [0018]

(Detailed description of the invention) Describe biodegradable shape memory polymer compositions, their products, and how and how to prepare them. [0019]

(Definition) As used herein, the term "bioresorbable" refers to materials that are bioresorbable and / or decompose and / or disintegrate by mechanical decomposition. Over a period of minutes to 3 years (preferably less than a year), interacting with the physiological environment to break down into metabolizable or excretable components, while maintaining the required structural integrity. To do. As used herein in connection with polymers, the term "degradation" refers to breakage of polymer chains such that the molecular weight remains nearly constant at the oligomeric level and the polymer particles maintain the next degradation. Say. The term "complete degradation" refers to the cleavage of a polymer at the molecular level, which is essentially completely lumpless. The term "decomposition" as used herein includes "complete decomposition" unless otherwise indicated. [0020]

Even if the molded shape of the polymer's original shape is mechanically destroyed at a temperature lower than the shape recovery temperature, the polymer's original shape is at the shape recovery temperature (soft segment T)._transIf recovered by heating above) Alternatively, the polymer is a shape memory polymer if the memorized shape is restored by the application of another stimulus. [0021] [0021]

As used herein, the term "segment" refers to a block or sequence of polymer that forms a portion of a shape memory polymer. [0022]

As used herein, the terms hard and soft segments are T of segments._transRelative term for. Hard segment T (single or plural) is higher than the soft segment (singular or plural) T_transHave. [0023]

A shape memory polymer may contain at least one hard segment and at least one soft segment, or at least one soft segment in which at least one soft segment is crosslinked in the absence of the hard segment. May include. [0024]

The hard segment can be a linear oligomer or polymer, and can be a cyclic compound (eg, crown ether, cyclic di-, tri-, or oligopeptide and cyclic oligo (esteramide)). [0025]

Physical interactions between hard segments can be based on charge transfer complexes, hydrogen bonds, or other interactions, as some segments have melting points above the decomposition temperature. is there. In this case, there is no melting point or glass transition temperature for the segment. A non-thermal mechanism (eg, solvent) is required to alter the segment bond. [0026]

The weight ratio of the hard segment: soft segment is between about 5:95 and 95: 5, preferably between 20:80 and 80:20. [0027]

(Shape memory polymer composition) Thermoplastic shape memory material is a hard segment (s) of T_transShaped / molded into the desired shape above and cooled to a temperature below the shape recovery temperature, where the polymer is subject to mechanical deformation and strain is generated in the polymer. The original shape of the deformed polymers can be restored by heating them to a temperature higher than their shape recovery temperature. Above this temperature, the strain in the polymer is released and the polymer can return to its original form. In contrast, thermosetting shape memory materials are shaped / molded into the desired shape, after which the macromonomers used to form the thermosetting polymer are polymerized. After the shape is fixed, the macromonomer is polymerized. [0028]

The polymer composition can preferably be compressed to at least 1% of its original thickness at temperatures below the shape recovery temperature, or stretched to at least 5%, of heat, light, ultrasonic, magnetic or electric fields. Deformation is fixed by the application of such a stimulus. In some embodiments, the material exhibits a recovery rate of 98% (compared to experimental examples). [0029]

When significant stresses are applied, mechanical deformations performed at temperatures below the shape recovery temperature occur, strain is retained in soft segments or amorphous regions, and bulk shape changes are strained by the elasticity of the polymer. Retained even after partial release of. If the configuration of the molecular chain is hampered by affecting the regulated arrangement of the molecular chain at a temperature below the glass transition temperature, the rearrangement of the molecular chain increases the volume size and decreases the free volume content. Is assumed to be caused by. The original shape is restored by the contraction of the aggregate of hard segments due to the increase in temperature, and the shape of the polymer is restored to the memorized shape, according to the tight control of the conformation of the chain. [0030]

In addition to the state change from solid to liquid state (melting point or glass transition temperature), the hard or soft segments have a supramolecular effect based on ionic interactions or highly organized hydrogen bonds, including polymeric electrolyte segments. I can receive it. SM polymers can also undergo a transition from solid state to solid state (eg, morphological changes). The transition from solid state to solid state is well known to those of skill in the art, for example in poly (styrene-block-butadiene). [0031]

Various changes can occur in the structure of objects formed using shape memory polymers. If the object is a three-dimensional object, the changes in shape can be two-dimensional. If the object is essentially a two-dimensional object (eg, a fiber), the changes in shape can be one-dimensional (eg, along length). The thermal conductivity and conductivity of these materials can also change in response to changes in temperature. [0032]

The water permeability of the composition can vary, especially if the polymer is formed on a thin film (ie, less than about 10 μm). In its original form, some polymer compositions have sufficient permeability for water vapor molecules to permeate the polymer film, but water molecules are not large enough to permeate the polymer film. The resulting material has low moisture permeability below room temperature and high moisture permeability above room temperature. [0033]

Stimuli other than temperature can be used to induce shape changes. As described with reference to the specific embodiments below, shape changes can be induced by photoactivation or exposure to reagents (eg, ions that alter the bonds between polymers). [0034]

(I. Polymer segment) The segment is preferably an oligomer. As used herein, the term "oligomer" refers to a linear molecule having a molecular weight of up to 15,000 daltons. [0035]

The polymer is selected based on the desired glass transition temperature (s) (if at least one segment is amorphous) or melting point (s) (s) (if at least one segment is crystalline). Also considers the environment in which it will be used, based on the desired application. Preferably, the number average molecular weight of this polymer block is greater than 400, preferably in the range between 500 and 15,000. [0036]

The transition temperature at which the polymer rapidly softens and deforms can be controlled by varying the monomer composition and the type of monomer, which allows the shape memory effect to be adjusted at the desired temperature. [0037]

The thermal properties of the polymer can be detected, for example, by electromechanical thermal analysis or differential scanning calorimetry (DSC) studies. In addition, the melting point can be measured using a standard melting point device. [0038]

(1. Thermosetting or thermoplastic polymer) The polymer can be a thermosetting or thermoplastic polymer, but a thermoplastic polymer may be preferred due to its ease of molding. [0039]

Preferably, the degree of crystallinity of the polymer or polymeric block (s) is between 3% and 80%, more preferably between 3% and 60%. If the crystallinity is higher than 80% but all soft segments are amorphous, the resulting polymer composition will have poor shape memory properties. [0040]

T_transThe tensile coefficients of the lower polymers are typically 50 MPa and 2 GP. While it is between a (Gigapascal), T_transHigher polymer tension The coefficient is typically between 1 MPa and 500 MPa. Preferably T_transThe ratio of elastic moduli above and below is 20 or more. The higher this ratio, the better The shape memory of the polymer composition to be obtained is better. [0041]

The polymer segment can be natural or synthetic, but synthetic polymers are preferred. The polymer segment can be biodegradable or non-biodegradable, and the resulting SMP composition is biodegradable, biocompatible polymers are particularly preferred for medical use. Generally, these materials are degraded by hydrolysis, by exposure to water or enzymes under physiological conditions, by surface erosion, bulk erosion, or a combination thereof. Non-biodegradable polymers used in medical applications preferably do not contain aromatic groups other than those found in naturally occurring amino acids. [0042]

Typical natural polymer segments or polymers include proteins (eg, zein, modified zein, casein, gelatin, gluten, serum albumin, and collagen), and polysaccharides (eg, alginate, cellulose, dextran, pullulane), And polyhyaluronic acid), as well as chitin, poly (3-hydroxyalkanoate) (particularly poly (β-hydrokibutyrate), poly (3-hydroxyoctanoate)) and poly (3-hydroxy fatty acid). .. [0043]

Typical natural biodegradable polymer segments or polymers include polysaccharides (eg, alginate, dextran, cellulose, collagen, and their chemical derivatives (eg, substitution, addition, hydroxylation of chemical groups (eg, alkyl, alkylene)). Oxidation, and other modifications commonly made by those skilled in the art)), as well as proteins and copolymers such as albumin, zein and blends thereof, either alone or in combination with synthetic polymers. [0044]

Typical synthetic polymer blocks are polyphosphazene, poly (vinyl alcohol), polyamide, polyesteramide, poly (amino acid), synthetic poly (amino acid), polyanhydride, polycarbonate, polyacrylate, polyalkylene, polyacrylamide, poly. Includes alkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyorthoesters, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidones, polyesters, polylactides, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof. [0045]

Examples of suitable polyacrylates are poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate). , Poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate) and poly (octadecil acrylate). [0046]

Syntheticly modified natural polymers include cellulose derivatives such as alkyl cellulose, hydroxyalkyl cellulose, cellulose ethers, cellulose esters, nitrocellulose, and chitosan. Examples of suitable cellulose derivatives are methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate and cellulose sul. Includes fate sodium salt. These are collectively referred to herein as "cellulose". [0047]

Representative synthetically degradable polymer segments or polymers are polyhydroxyic acids (eg, polylactide, polyglycolide and copolymers thereof; poly (ethylene terephthalate); poly (hydroxybutyrate); poly (hydroxyvaleric acid); poly [lactide- co- (ε-caprolactone)]; poly [glycolide-co- (ε-caprolactone)]); polycarbonate, poly (pseudo-amino acid); poly (amino acid); poly (hydroxyalkanoate); polyanhydrous; polyorthoester Also includes blends and copolymers of these. [0048]

Examples of non-biodegradable polymer segments or polymers include ethylene vinyl acetate, poly (meth) acrylic acid, polyamides, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyvinylphenols, and copolymers and mixtures thereof. [0049]

Rapid bioerodible polymers (eg, poly (lactide-co-glycolide), polyanhydrides, and polyorthoesters) (these are on the outer surface such that the smooth surface of the polymer is eroded. (Having a carboxyl group to be exposed) can also be used. In addition, polymers containing unstable bonds (eg, polyanhydrides and polyesters) are well known for their hydrolysis reactivity. These hydrolysis rates can generally be altered by simple changes in the polymer backbone and its sequence structure. [0050]

Various polymers (eg, polyacetylene and polypyrrole) are conductive polymers. These materials are particularly preferred for use where electrical conductivity is important. Examples of these uses include tissue engineering and any medical application in which cell proliferation is stimulated. These materials can find particular utility in the field of computer science, because they can absorb heat better than SMA without temperature rise. Conductive shape memory polymers are useful in the field of tissue engineering for stimulating cell proliferation (eg, neural tissue). [0051]

(2. Hydrogel) The polymer can be in the form of a hydrogel (typically absorbing up to about 90% by weight of water) and, if desired, can be ionicly crosslinked with a polyvalent ion or polymer. Ionic cross-linking between soft segments can be used to retain the structure, which, when deformed, can be reformed by cutting the ionic cross-links between the soft segments. The polymer can also be in the form of a gel in a solvent other than water or aqueous solution. In these polymers, the temporary shape can be fixed by hydrophilic interactions between the soft segments. [0052]

Hydrogels can be formed from polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylates, poly (ethylene terephthalate), poly (vinyl acetate), and copolymers and blends thereof. Some polymeric segments (eg, acrylic acid) are elastomeric only if the polymer is hydrated to form a hydrogel. Other polymeric segments (eg, methacrylic acid) are crystalline and meltable even when the polymer is not hydrated. Depending on the desired application and conditions of use, any kind of polymeric block can be used. [0053]

For example, shape memory is only observed in the hydrogel state for acrylic acid copolymers. This is because the acrylic acid unit is substantially hydrated and behaves like a soft elastomer with a very low glass transition temperature. The dry polymer is not a shape memory polymer. When dried, the acrylic acid unit behaves as a hard plastic even above the glass transition temperature and does not show abrupt changes in mechanical properties with heating. Conversely, copolymers containing methyl acrylate polymer segments as soft segments exhibit shape memory properties even when dry. [0054]

(3. Polymer that can form a gel at high temperature) Specific polymers (eg poly (ethylene oxide-co-propylene oxide) (PLURONICS)^TM)) Is soluble in water at temperatures below body temperature and becomes hydrogel at temperatures above body temperature. Incorporation of these polymers as segments in shape memory polymers provides shape memory polymers that can respond to changes in temperature in a manner that is the exact opposite of that of typical shape memory polymers. These materials recover their shape when cooled below the shape recovery temperature rather than when heated above the shape recovery temperature. This effect is called the inverted thermal shape memory effect. Shape memory polymer compositions containing these polymer segments are useful in a variety of biomedical applications in which the polymer can be inserted as a liquid in situ and then cooled to restore the intended shape. The reverse heat shape memory effect is T_miscIt is miscible at lower temperatures, but T_miscIt can be obtained by incorporating two different segments into a polymer that is immiscible at higher temperatures. Phase separation at high temperatures stabilizes the temporary shape. [0055]

This polymer is available from commercial sources such as Sigma Chemical Co., St. Louis, MO .; Polysciences, Warrenton, PA; Aldrich Chemical Co., Milwaukee, WI; Fluka, Ronkonkoma, NY; and BioRad, Richmond, CA. Can be obtained from. Alternatively, these polymers can be synthesized using standard techniques from monomers obtained from commercially available sources. [0056]

(II. Polymer segment assembly) Shape memory polymers include one or more hard segments and one or more soft segments, wherein at least one of these segments is biodegradable or of these segments. At least one is bound to another segment via a biodegradable bond. Typical biodegradable bonds include ester-, amide-, anhydride-, carbonate-, or orthoester bonds. [0057]

(1. Polymer structure) The shape memory effect depends on the morphology of the polymer. For thermoplastic elastomers, the initial shape of the object is fixed by physical cross-linking caused by hard segments. For thermosetting polymers, the soft segments are covalently crosslinked instead of having hard segments. The initial shape is determined by the cross-linking process. [0058] [0058]

Contrary to the prior art, segmented polyurethane SMP, the segments of the compositions described herein need not be linear. These segments can be partially grafted or attached to dendritic side chains. [0059]

(A. Thermoplastic and Thermoelastic Polymers) These polymers are in the form of linear diblock, triblock, tetrablock or multiblock copolymers, branched or graft polymers, thermoplastic elastomers (which contain dendritic structures), and blends thereof. possible. Figure 3 illustrates several combinations of suitable classes of thermoplastics that form hard and soft segments. The thermoplastic shape memory polymer composition can also be a blend of one or more homopolymers or copolymers having one or more diblock, triblock, tetrablock or multiblock copolymers, branched or graft polymers. These types of polymers are well known to those of skill in the art. [0060]

As used herein, the term "degradable thermosetting resin" refers to (i) a thermosetting resin SMP containing only one soft segment containing a cleavable bond, and (ii) at least one. A thermosetting resin containing more than one soft segment in which one soft segment is degradable or different soft segments are linked by a cleavable bond. There are four different types of thermosetting polymers with shape memory performance. These include polymer network structures, semi-interpenetrating network structures, mutual penetrating network structures, and mixed interpenetrating network structures. [0061]

(i. Polymer network structure) Polymer network structures are prepared by covalently cross-linking macromonomers (ie, polymers with polymerizable end groups such as carbon-carbon double bonds). The polymerization process can be induced by using a light or heat sensitive initiator or by curing with ultraviolet light (UV light) without an initiator. Shape memory polymer network structures are prepared by cross-linking one or more soft segments that correspond to one or more thermal transitions. [0062]

In a preferred embodiment for biomedical applications, cross-linking is performed using a photo-crosslinking agent and no chemical initiator is required. This photocrosslinker advantageously eliminates the need for initiator molecules that can be toxic. FIG. 4 is a diagram of the reaction sequence of the preferred photocrosslinker synthesis, which produces an overall yield of about 65%. [0063]

(ii. Mutual penetration network structure) A reciprocal intrusion network structure (IPN) is defined as a network structure in which the two components are cross-linked but not cross-linked to each other. The initial shape is determined by the network structure with the highest crosslink density and the highest mechanical strength. This material has at least two Ts corresponding to both soft segments with different network structures._transHave. [0064]

(iii. Mixed type mutual penetration network structure) Mixed IPNs include at least one physically cross-linked polymer network structure (thermoplastic polymer) and at least one covalently cross-linked polymer network structure (thermosetting polymer), which are any physical It cannot be separated by the method. The initial shape is determined by the covalently crosslinked network structure. Temporary shape is T of soft segment_transAnd hard thermoplastic elastomer components Segment T_transCorresponds to. [0065]

A particularly preferred mixed interpenetrating network structure is prepared by polymerizing reactive macromonomers in the presence of thermoplastic polymers, for example by photopolymerization of carbon-carbon double bonds. In this embodiment, the weight ratio of the thermosetting polymer to the thermoplastic polymer is preferably between 5:95 and 95: 5, more preferably between 20:80 and 80:20. .. [0066]

(iv. Semi-interpenetrating network structure) Semi-interpenetrating network structures (semi-IPN) are two independent components, one component being a cross-linked polymer (polymer network structure) and the other component being a non-cross-linked polymer (homopolymer or copolymer). Defined as components, where these components cannot be separated by physical methods. Semi-IPNs have at least one thermal transition corresponding to the soft segment (s) and homopolymer or copolymer components. Preferably, the crosslinked polymer constitutes about 10-90% by weight of the semi-interpenetrating network composition. [0067]

(v. Polymer blend) In a preferred embodiment, the shape memory polymer compositions described herein are formed from a blend of biodegradable polymers. As used herein, a "biodegradable polymer blend" is a blend having at least one biodegradable polymer. [0068]

Shape memory polymers can exist as a physical mixture of thermoplastic polymers. In one embodiment, the shape memory polymer composition can be prepared by interacting or blending two thermoplastic polymers. These polymers can be semi-crystalline homopolymers, semi-crystalline copolymers, thermoplastic elastomers with straight lines, thermoplastic elastomers with side chains or any kind of dendritic element, and branched copolymers. And these can be blended in any combination of these. [0069]

For example, relatively high T_transHard segment with, and relatively low T_transMulti-block copolymers containing soft segments with Low T_transHard segment with and 1st multi-block copoly It can be mixed or blended with a second multi-block copolymer containing the same soft segments as the mer. The soft segments in both multi-block copolymers are identical so that when the soft segments are melted, these polymers are miscible with each other. The resulting blend has three transition temperatures: the transition temperature of the first hard segment, the transition temperature of the second hard segment, and the transition temperature of the soft segment. Therefore, these substances can memorize two different shapes. The mechanical properties of these polymers can be adjusted by varying the weight ratio of the two polymers. [0070]

A blend of at least two multi-block copolymers of other types, where at least one segment is miscible with at least one segment of the other multi-block copolymer, can be prepared. If two different segments are miscible and together form one domain, the thermal transfer of this domain depends on the weight of the two segments. The maximum number of shapes remembered comes from the number of thermal transitions in the blend. [0071]

The shape memory blend may have better shape memory properties than the blend component alone. Shape memory blends are composed of at least one multi-block copolymer and at least one homopolymer or copolymer. In principle, di-, tri- or tetra-block copolymers can be used in place of multi-block copolymers. [0072]

Shape memory blends are very useful for industrial applications, as a wide range of mechanical, thermal and shape memory performance can be obtained simply by blending them from two or three basic polymers in different weight ratios. Is. A twin screw extruder is an example of standard process equipment that can be used to mix ingredients and process their blends. [0073]

(III. How to make SMP) The polymers described above are either commercially available or can be synthesized using conventional chemistry. Those skilled in the art can readily prepare this polymer using known chemistry. Examples 1 and 2 below describe the experimental procedure used to prepare SMP. [0074]

(IV. Molding method of SMP composition) This composition is prepared under suitable conditions (eg, T in a hard segment)._transBeyond At (temperature), the T of the first shape and the soft segment (s)_transCan be cooled to less than. Standard techniques are extrusion and injection molding It is a shape. If desired, the object can be reshaped into a second shape. When heat is applied or other suitable conditions are set, the object returns to its initial shape. [0075]

The thermosetting polymer extrudes a prepolymerized substance (macromonomer) and, for example, photocures the reactive groups of the monomer to allow the T of this thermosetting polymer._transCan be prepared by fixing the initial shape at a higher temperature To. Temporary shape, after deforming the substance, T the substance_transCooling lower Is fixed by. FIG. 5 illustrates the photoinduced shape memory effect. [0076]

Crosslinking can also be performed in a solution of macromonomers. This solvent is removed from the gel formed in subsequent steps. [0077]

These compositions, formed from thermoplastic polymers, can be blown, extruded into sheets, or molded by injection molding to form, for example, fibers. This composition is also produced by other methods known to those skilled in the art for molding solids (eg, laser cutting, micromachining, the use of heat rays, and CAD / CAM (computer-aided design / computer-aided manufacturing) processes. Can be molded. These processes are preferred for molding thermocurable polymers. [0078]

(V. Therapeutic, prophylactic, and diagnostic applications) Any variety of therapeutic, prophylactic and / or diagnostic agents may be incorporated into the polymer composition, which delivers the incorporated agent locally or systemically following administration to the patient. obtain. [0079]

(1. Therapeutic, diagnostic and prophylactic application) Any variety of therapeutic agents can be incorporated into the particles to deliver the incorporated agent locally or systemically following administration to the patient. Examples include synthetic inorganic and organic compounds or molecules, proteins and peptides, polysaccharides and other sugars, lipids, and nucleic acid molecules that have therapeutic, prophylactic or diagnostic activity. Nucleic acid molecules include genes, plasmid DNA, naked DNA, antisense molecules (which bind to complementary DNA and inhibit transcription), ribozymes and ribozyme-inducing sequences. Drugs to be incorporated include various biological activities such as vasoactive agents, neuroactive agents, hormones, growth factors, cytokines, anaesthetics, steroids, anticoagulants, anti-inflammatory agents, immunomodulators, etc. It may have cytotoxic agents, prophylactic agents, antibiotics, antiviral agents, antisenses, antigens and antibodies. In some examples, the protein can be an antibody or antigen, otherwise it must be administered by injection to elicit an appropriate response. A protein is defined to consist of 100 or more amino acid residues; a peptide is less than 100 amino acid residues. Unless otherwise stated, the term protein refers to both proteins and peptides. Polysaccharides such as heparin can also be administered. Compounds with a wide range of molecular weights (eg, 10-500,000 g / mol) can be encapsulated. [0080] [0080]

Contrast media that can be used include proton emission tomography (PET), computed tomography (CAT), monophoton emission tomography, X-ray, X-ray fluoroscopy, magnetic resonance imaging (MRI). And over-the-counter agents used for ultrasound agents. [0081]

(VI. Articles, devices and coatings) SMP compositions can be used to prepare a large number of products for use in biomedical and other applications. [0082]

(1. Goods and devices for biomedical applications) Polymer compositions can be used to prepare products for use in biomedical applications. For example, sutures, orthodontic materials, bone screws, nails, plates, catheters, tubes, films, stents, orthoses, splints, tapes for preparing cast bandages, tissue engineering scaffolds, contact lenses. , Drug delivery devices, implants, and heat indicators can be prepared. [0083]

Preferably, the SMP composition is prepared from a biocompatible polymer, which for most applications is prepared from a biodegradable polymer. Biodegradable polymers decompose at a controlled rate depending on the composition and cross-linking of the polymer. Degradable polymeric implants can be used to eliminate the need to retrieve the implant and at the same time deliver a therapeutic agent. [0084]

These materials can be used in many applications where load-bearing bearing loads and controlled decomposition are required. [0085]

The polymer composition can be formed in the form of a graft that can be implanted in the body to provide mechanical function. Examples of such implants include rods, pins, screws, plates and anatomical shapes. [0086]

A particularly preferred use of this composition is to prepare a suture, which has a composition that is hard enough to provide easy insertion, but softens upon reaching body temperature and still allows healing. , Form a second shape that is more comfortable for the patient. [0087]

Another preferred use is in the field of catheters. The catheter is stiff at body temperature to facilitate insertion, but after warming to body temperature it softens to provide comfort to the patient. [0088]

If required for a particular transplant application, the polymeric composition may be combined with fillers, reinforcing materials, radiocontrast agents, excipients or other materials. Examples of fillers include calcium-sodium metaphosphate described in US Pat. No. 5,108,755. One of ordinary skill in the art can readily determine the amount of these materials suitable for inclusion in the composition. [0089]

As mentioned above, these articles may incorporate a variety of therapeutic and / or diagnostic agents. [0090]

(2. Non-medical application) There are numerous applications of shape memory polymer compositions other than biomedical applications. [0091]

Examples of applications of non-medical types of biodegradable polymers include items for which disposal is a problem (eg, disposable diapers and packaging materials). [0092]

(3. Coating with controlled decomposition) Shape memory polymers can be designed to have varying rates of degradation. For example, in one embodiment, the hydrolytically degradable polymer is coated with a hydrophobic SMP coating that temporarily prevents water from reaching the hydrolyzable cleavable bonds of the bulk polymer. Can be selectively protected by. Thus, the protective feature of the coating is, if desired, by varying the diffusive properties of the coating and applying an external stimulus so that water or other aqueous solution can penetrate the coating and initiate the decomposition process. Can be changed. If the rate of hydrolysis is relatively faster than the rate of diffusion of water, the rate of diffusion of water through the coating determines the rate of decomposition. In another embodiment, a hydrophobic coating consisting of densely crosslinked soft segments can be used as a diffusion barrier for water or aqueous solution. The soft segments should be cross-linked by bonds that can be cleaved by the application of the stimulus, at least in part. The diffusion rate of water can be increased by reducing the crosslink density. [0093]

(VII. How to use) Certain products are designed to retain their intended shape unless acted upon in a manner that contradicts their standard use. For example, a car bumper retains its intended shape until it is impacted. These products can be used in their intended shape, but once damaged, they can be repaired, for example by applying heat. [0094]

Other products are designed and used so that the first shape is intended for initial use and the second shape is intended for subsequent use. Examples of these include biomedical devices, which have a second shape when they reach body temperature or when an external stimulus is applied (which heats the device above body temperature). Can form. [0095]

Yet other products are designed and used to change shape in response to or adapt to temperature changes (eg, temperature detectors for medical devices). [0096]

The present invention is further understood with reference to the following non-limiting examples. [0097]

(Example 1: Copolyester urethane shape memory polymer) A group of biocompatible and biodegradable multi-block copolymers exhibiting thermal shape memory effects was synthesized. These polymers are hard segments that can be crystallized (T)_m) And the heat transition temperature T between room temperature and body temperature_transConsists of soft segments with. In contrast to the prior art, which is segmented polyurethane, the hard segments were oligoesters or oligoether esters and contained no aromatic components. [0098]

Figure 6 shows the mechanism for programming the temporary shape of a multi-block copolymer and for restoring the permanent shape of a multi-block copolymer. The permanent shape of this material melts the polymer and T_transCooling above It was decided by (Fig. 6-top). The polymer then forms a temporary shape (Fig. 6-right), which is T_transFixed by cooling below (Fig. 6-bottom) ). After removing the load, T_transPermanent shape by reheating above Has recovered. [0099]

Synthesis of Telechelics (oligomers with functional groups at both ends). [0100]

Telequilic macrodiol, N₂As a transesterification catalyst in an atmosphere It was synthesized by ring-opening polymerization of cyclic monomers using n-butyl) tin oxide. [0101]

(Hard segment) α, ω-dihydroxy [oligo (ethylene glycol glycolate) ethylene oligo (ethylene glycol glycolate)]-(PDS1200 and PDS1300) was prepared as follows. Prior to use, the oligomer was distilled (thermally depolymerized) to give the monomer p-dioxane-2-one. The monomer (57 g, 0.63 mol), ethylene glycol (0.673 g, 10.9 mmol) and di (n-butyl) tin oxide (0.192 g, 0.773 mmol) were heated to 80 ° C for 24 hours. The termination (equilibrium) of the reaction was determined by GPC. The product was solubilized in heated 1,2-dichloroethane and filtered through a warm Buechner funnel filled with silica gel. The product was obtained by precipitating in hexane and drying under vacuum for 6 hours. [0102]

(Soft segment) (i. Crystal) Different M_nPoly (ε-caprolactone) -diol having is, for example, Al Commercially available from drich and Polysciences. PCL-2000 was used here. [0103]

(ii. Amorphous) α, ω-dihydroxy [oligo (L-lactate-co-glycolate) ethylene oligo (L-lactate-co-glycolate)]-(abbreviated as PLGA2000-15) was prepared as follows. Heat L, L-dilactide (300 g, 2.08 mol), diglycolide (45 g, 0.34 mol) and ethylene glycol (4.94 g, 0.80 mol) in a 1000 ml two-necked round bottom flask at 40 ° C to melt. , Stirred. Di (n-butyl) tin oxide (0.614 g, 2.5 mmol) was added. After 7 hours, GPC determined that the reaction had reached equilibrium. The reaction mixture was dissolved in 1,2-dichloroethane and purified on a silica gel column. The product was obtained by precipitating in hexane and drying under vacuum for 6 hours. [0104]

(Characteristics of Telequilix) As shown in Table 1 below, the molecular weight of macrodiol M_nAnd measure thermal properties did. [0105]

[table 1]

<img file="JP2002503524A_D0001.tif" /> (Synthesis of thermoplastic elastomer (multi-block copolymer)) Two different macrodiols (one hard segment and one soft) as listed in Table 2 below in a 100 ml two-necked round-bottom flask connected to a Soxhlet extractor filled with a molecular sieve of 0.4 nm. Segment) was dissolved in 1,2-dichloroethane (80 ml). The mixture was refluxed and dried by azeotropic extraction of the solvent. Freshly distilled trimethylhexane-1,6-diisocyanate was added via syringe and the reaction mixture was heated to 80 ° C. for at least 10 days. Samples of the mixture were taken at regular intervals and the molecular weight of the polymer was measured by GPC. At the end of the reaction, the polymer was precipitated in hexane to give the product, which was repeatedly dissolved in 1,2-dichloroethane and purified by precipitation in hexane. [0106]

Multi-block copolymers were prepared from two types of polymers: [0107]

(i) A PDC polymer containing poly (ε-caprolactone). Soft segment T_transIs the melting temperature. [0108]

(ii) A PDL polymer containing α, ω-dihydroxy [oligo (L-lactate-co-glycolate) ethylene oligo (L-lactate-co-glycolate)]. Soft segment T_transIs the glass transition point. [0109]

[Table 2]

<img file="JP2002503524A_D0002.tif" /> (Characteristics of thermoplastic elastomer) The physical, mechanical and decomposition properties determined for this composition are provided in Tables 3-9 below. [0110]

The hydrolysis behavior of the new material was tested in a pH 7 buffer at 37 ° C. It has been shown that the polymer is completely degradable and its rate of degradation can be easily adjusted by the concentration of hydrolyzable ester bonds. Relative mass loss value m at 37 ° C_r= m (t₀) / M (t) (%), loss value of relative molecular weight at 37 ° C M_r= M_w( t) / M_w(t₀)(%)。 【0111】

The toxicity of two different multi-block copolymers was investigated using the chicken egg test. It was shown that the blood vessels developed regularly and their condition was unaffected by the polymer sample. [0112]

[Table 3]

<img file="JP2002503524A_D0003.tif" /> 【0113】

[Table 4]

<img file="JP2002503524A_D0004.tif" /> 【0114】

[Table 5]

<img file="JP2002503524A_D0005.tif" /> 【0115】

[Table 6]

<img file="JP2002503524A_D0006.tif" /> 【0116】

[Table 7]

<img file="JP2002503524A_D0007.tif" /> 【0117】

[Table 8]

<img file="JP2002503524A_D0008.tif" /> 【0118】

[Table 9]

<img file="JP2002503524A_D0009.tif" /> (Shape memory characteristics) FIG. 7 shows the results of tensile tests performed on multi-block copolymers as a function of the number of pyrolysis cycles. The dependence of the average shape fixation rate of the thermocyclically treated polymer and the strain recovery rate as a function of the number of cycles is shown in Tables 10 and 11, respectively. The polymer had high shape fixation and reached equilibrium after only 2 cycles. [0119]

[Table 10]

<img file="JP2002503524A_D0010.tif" /> 【0120】

[Table 11]

<img file="JP2002503524A_D0011.tif" /> (Example 2: Degradable shape memory thermosetting resin containing a soft segment that can be crystallized) A range of poly (ε-caprolactone) dimethacrylates and thermosetting resins were evaluated for their mechanical and shape memory properties. [0121]

(Synthesis of macromonomer) Poly (ε-caprolactone) dimethacrylate (PCLDMA) was prepared as follows. Poly (ε-caprolactone) diol (M) in dry THF (200 mL)_n= 2,000gmol^-1, 20.0 g, 10 mmol) and triethyl Methacryloyl chloride (3.7 mL, 38 mmol) was added dropwise to a solution of ruamine (5.3 mL, 38 mmol) at 0 ° C. The solution was stirred at 0 ° C. for 3 days and the precipitated salt was filtered off. After concentrating the mixture at room temperature under reduced pressure, 200 mL of ethyl acetate is added and the solution is filtered again and precipitated in a 10-fold excess mixture of hexane, ethyl ether and methanol (18: 1: 1). I let you. The colorless precipitate was collected, dissolved in 200 mL of dichloroethane, precipitated again and carefully vacuum dried at room temperature. [0122]

(Synthesis of thermosetting resin) Macromonomer (or monomer mixture), its melting temperature (T_m) From 10 It was heated to above ° C and filled into a mold formed of two glass plates (25 mm × 75 mm) and a 0.60 mm thick Teflon spacer. T T this mold for an additional hour to achieve excellent uniformity_mSaved in. T_mIt was photocured for 15 minutes on a plate heated in. The distance between the heating lamp head and the sample was 5.0 cm. After cooling to room temperature, the sample was removed, swollen overnight with 100-fold excess dichloromethane, and washed carefully. Finally, the sample was dried at room temperature under reduced pressure. [0123]

(Characteristics of macromonomer and thermosetting resin) Table 12 below shows the prepared poly (ε-caprolactone) dimethacrylates, each degree of acrylicization (D)._a) (%). 500 units The number following PCLDMA in place is the molecular weight M of the poly (ε-caprolactone) diol used in the synthesis._nAnd this is¹Determined using 1 H-NMR and GPC. [0124]

[Table 12]

<img file="JP2002503524A_D0012.tif" /> Figure 8 shows the melting temperature (T) of thermosetting resins of diols, dimethacrylates and poly (ε-caprolactone)._m) The molar mass weight M of the macromonomer_nShown as a function of. In this graph, macrodiols are represented by-(black squares)-, macromonomers are represented by ... (black circles), and thermosetting resins are represented by-(black triangles)-. [0125]

The tensile properties of the poly (ε-caprolactone) thermosetting resins C1 to C7 at room temperature are shown in Table 13 below, where E is the elastic modulus (Young's modulus) and ε._sIs Shin And σ_sIs the stress at the yield point, σ_maxIs the maximum stress, ε_maxIs σ_maxIs the growth in ε_RIs the elongation at break, σ_RBroke It is the stress of time. Table 14 provided below shows the tensile properties of the same poly (ε-caprolactone) thermosetting resin at 70 ° C. [0126]

[Table 13]

<img file="JP2002503524A_D0013.tif" /> 【0127】

[Table 14]

<img file="JP2002503524A_D0014.tif" /> (Shape memory characteristics) The thermosetting resin was measured to have the thermodynamic properties listed in Table 15. Number average molecular weight (M_n) Is for macromonomers. Lower limit temperature T_lIs 0 ° C and the upper limit temperature T_hIs 70 ° C. Temporary shape elongation is 50%. R_r(2) is the strain recovery rate of the second cycle, R_{r, tot}Is the total strain times after 5 cycles Recovery rate, R_fIs the average strain fixation rate. [0128]

[Table 15]

<img file="JP2002503524A_D0015.tif" />[Simple explanation of drawings]

[Figure 1]

FIG. 1 is an example of a shape memory effect in one direction. [Figure 2]

FIG. 2 is an example of a two-way (thermal) shape memory effect. [Fig. 3]

Figure 3 is an example of the appropriate class combination of thermoplastic materials. [Fig. 4]

FIG. 4 is a diagram of the reaction sequence for the synthesis of a preferred photocrosslinking agent. [Fig. 5]

FIG. 5 is an example of the photoinduced shape memory effect. [Fig. 6]

FIG. 6 illustrates the mechanism of thermal shape memory effect for multi-block copolymers. [Fig. 7]

FIG. 7 is a graph showing stress vs. elongation for shape memory polymers in multi-block copolymers. [Fig. 8]

FIG. 8 is a graph showing the melting points of diols, dimethacrylates, and thermocurable poly (ε-caprolactone) as a function of molar mass weight Mn of macromonomers.