CN102459408A

CN102459408A - Bioabsorbable polymeric compositions and medical devices

Info

Publication number: CN102459408A
Application number: CN2010800322217A
Authority: CN
Inventors: R·J·科顿
Original assignee: Orbus Medical Technologies Inc
Current assignee: Orbus Medical Technologies Inc
Priority date: 2009-05-15
Filing date: 2010-05-17
Publication date: 2012-05-16
Also published as: WO2010132899A1; EP2430068A4; EP2430068A1

Abstract

The present invention discloses a stent comprising a blend formed from a polymer. The polymer comprises poly-L-lactide, poly-D-lactide or mixtures thereof and a copolymer moiety comprising poly-L-lactide or poly-D-lactide linked with epsilon-caprolactone or trimethylcarbonate. The poly-L-lactide or poly-D-lactide sequence in the copolymer moiety is random with respect to the distribution of epsilon-caprolactone or trimethylcarbonate and the copolymer moiety molecular weight ranges from about 1.2 IV to about 4.8 IV. The polymere blend may have a wide-angle X-ray scattering (W AXS) 2-theta values of ranging from about 1 to about 35. The properties of the bioabsorbable polymers allow for both crimping and expansion of the stent. The crystal properties of the bioabsorbable polymers may change during crimping and/or expansion allowing for improved mechanical properties such as tensile strength and slower degradation kinetics.

Description

Biological absorbable polymer compsn and medicine equipment

The cross reference of related application

The application is the partial continuous case of following U. S. application: the US application serial No. that on October 13rd, 2009 submitted to: 12/578; 432, the US application serial No. of submitting on October 9th, 2009: 12/576; 965, the US application serial No. of submitting on July 22nd, 2009: the US application serial No. of 12/507,663, submitting on October 20th, 2007: the US application serial No. of 11/875,887, submitting on October 20th, 2007: 11/875; 892, the US application serial No. of submitting on July 20th, 2007: 11/781; The US application serial No. that on July 20th, 234 and 2007 submitted to: 11/781,232, above application is incorporated in full through quoting at this.The right of priority that No. the 61/178th, 878, the U.S. Provisional Application that the application also requires to submit on May 15th, 2009.

Background technology

Though the purposes of biologically absorbable polymer is well-known; But develop the effective biologically absorbable polymer that is used for medicine equipment that bears high pressure (exposing to the open air under pressure) like artery contraction and blood flow; For biomedical family, remain a great challenge.The research and development that the biology that therefore, can keep shape and can in the reasonable time section, not degrade and can not cause the intensive immune response can absorb support are still an outstanding issue.

Biologically absorbable polymer comprises all kinds of various various polymerization things.Most typical biologically absorbable polymer is by the aliphatic polyester that is the basis with the rac-Lactide skeleton; As gather the L-rac-Lactide, gather the D-rac-Lactide, gather D, L-rac-Lactide, Study of Meso-Lactide, NSC 403079, the homopolymer or the heteropolymer that are formed in the multipolymer part with comonomer (like trimethylene carbonate (TMC) or 6-caprolactone (ECL)) constitute.United States Patent(USP) No. 6,706,854; United States Patent(USP) No. 6,607,548; European patent: EP0401844; WO2006/111578 and Jeon et al.Synthesis and Characterization of Poly (L-lactide)-Poly (the Multiblock Copolymers.Macromolecules 2003:36 of ε-caprolactone); 5585-5592. (people's such as Jeon the synthetic and sign of gathering L-rac-Lactide-poly-epsilon-caprolactone segmented copolymer; Macromole; 2003:36,5585-5592).And medicine equipment (like support) stress injure (like restenosis) with uniting of biodegradable material after use helps to overcome relevant with through metal usually wound.

See that from chemical terms people are familiar with (referring to http://vww.puracbiomaterials.com/purac_bio_com for example, October10,2009/ polylactide synthetic very much; Http:// www.boehringer-ingelheim.com/corporate/ic/pharmachern/pr oducts/resomer.asp, on October 10th, 2009).Polymkeric substance is in case form, and can push or moulding with its and other heteropolymer or medicine blend together, makes it stand temperature variation or physical property stress then.These processing have changed final crystalline structure, and mixture that obtains or hybrid material have unique physical property, comprise crystalline structure and mechanical characteristics.

These biological absorbable blends generally include base polymer (self also can be blend) and additional polymer.Additional polymer provides extra molecule free volume to allow the enough molecular motions of polymkeric substance to base polymer, so that under physiological condition, recrystallize can take place.In addition, the molecule free volume of increase also allows the water regain that increases, helps bulk degradation kinetics.This characteristic allowable temperature is responsive, have active pharmaceutical pack includes in the above-mentioned blend.

Because finally causing the inflammation of restenosis is to introduce the subject matter of any " exogenous " medicine equipment (like through metal); Therefore, it is also important that the blend that exploitation can stimulating immune system (degree with the situation of using other medicine equipment can not occur).For example, the hydrophilic increase of some blend polymer can reduce complement system activation (referring to Dong et.al, J.of Biomedical Materials Research; Part A; DOI 10.1002,2006) (people's such as Dong biomedical material research, A part; Digital object sign (DOI): 10.1002,2006).

Therefore, key of problem is the blend that exploitation can produce medicine equipment firm in structure (like support), and wherein said medicine equipment can keep the regular hour in vivo, degrade subsequently, and can be to not producing serious immune response.

Summary of the invention

The present invention provides a kind of support; Said support is made up of blend polymer; Said blend comprises by gathering the L-rac-Lactide, gather the polymkeric substance that D-rac-Lactide or its mixture form, and comprises the multipolymer that gathers the L-rac-Lactide or gather the D-rac-Lactide that is connected with 6-caprolactone or trimethylene carbonate (trimethylcarbonate) and partly constitute.Multipolymer partly comprises gathering the L-rac-Lactide or gathering the D-rac-Lactide of being connected with 6-caprolactone or trimethylene carbonate; Wherein, the order of gathering the L-rac-Lactide or gathering the D-rac-Lactide of said multipolymer part is arbitrarily for the distribution of 6-caprolactone or trimethylene carbonate.The crystalline structure of said blend polymer shows that wide-angle x-ray scattering (WAXS) 2 θ values are about 16.48 and about 18.76.In certain embodiments, multipolymer partly is gathering the L-rac-Lactide or gathering the D-rac-Lactide of being connected with 6-caprolactone.

In one embodiment; Support can make to L-rac-Lactide, about 30% (w/w) to D-rac-Lactide and about 10% (w/w) blend that gathers L-rac-Lactide-TMC multipolymer (in about 60/40 mmole to about 80/20 mmole, embodiment is 70/30 mmole) or gather the L-lactide-epsilon-coprolactone copolymers to about 35% that gathers of about 50% (w/w) that gathers of about 45% (w/w) by containing 20% (w/w) that have an appointment; The content that gathers the L-rac-Lactide or gather the D-rac-Lactide from about 20% to about 95% (w/w); From about 50% (w/w) to about 95% (w/w); From about 60% (w/w) to about 95% (w/w) or from about 70% (w/w) to about 80% (w/w).

In another embodiment; Said support comprises blend; Said blend is partly formed by polymkeric substance and multipolymer; Said polymkeric substance is by gathering the L-rac-Lactide, gather the D-rac-Lactide or its mixture forms, and said multipolymer partly comprises gathering the L-rac-Lactide or gathering the D-rac-Lactide of being connected with 6-caprolactone or trimethylene carbonate.The order of gathering the L-rac-Lactide or gathering the D-rac-Lactide in the multipolymer part is arbitrarily for the distribution of 6-caprolactone or trimethylene carbonate, and contains the amorphous substance at least about 95% (w/w) in the said compsn.In certain embodiments, the per-cent of said amorphous substance is at least about 98% or 99%.In each embodiment, the percent crvstallinity of compsn at about 0% (w/w) to 10%, at about 20% (w/w) to about 70%, about 30% (w/w) to about 60% or at about 30% (w/w) to about 60% (w/w) scope.

Support also can be formed by blend polymer; Said blend comprises by gathering the L-rac-Lactide, gather the polymkeric substance that D-rac-Lactide or its mixture form, and comprises the multipolymer that gathers the L-rac-Lactide or gather the D-rac-Lactide that is connected with 6-caprolactone or trimethylene carbonate and partly constitute.The order of gathering the L-rac-Lactide or gathering the D-rac-Lactide in the multipolymer part is arbitrarily for the distribution of 6-caprolactone or trimethylene carbonate, and wide-angle x-ray scattering (WAXS) 2 θ values are about 16.65 and about 18.96.WAXS 2 θ values can further comprise and are positioned at about 12.00, about 14.80, about 20.67, about 22.35, about 23.92, about 24.92, about 29.16 and the peak of about 31.28 positions.

When utilizing dsc analysis, the blend polymer of support can T occur at about 180 ℃ and about 217 ℃ or about 178 ℃ and about 220 ℃ _mThe peak.

Description of drawings

Specify each embodiment according to accompanying drawing below, each embodiment is property explanation as an example only, and each embodiment under any circumstance, all is not regarded as limitation of the present invention.

Fig. 1 is a computer analoging figure; Be the partial view that biology can absorb medicine equipment, wherein show bracing frame (support) linker parts (strut elements), nested type hoop shape member (nested hoop structures), end ring, locking mechanism (locking mechanism) and connect " H " zone (interconnection " H " regions).

Fig. 2 one comprises that next biology of expanded configuration (expanded configuration) can absorb the computer generation figure of the embodiment of support, wherein shows nested type hoop shape member or annular component, end ring, linker parts (meandering strut element) and locking mechanism wriggle.

Fig. 3 A be one expand (prematurely expanded) in advance biology can absorb the computer analoging figure of support, wherein show alternately ring (alternating ring) or bind round the shape member with sinuous linker parts and locking mechanism.Fig. 3 B illustrates like bracing frame same among Fig. 3 A (support), wherein shows the ring-type fragment (ring segment) that is under the different pressures state.

Fig. 4 A illustrates the plan view of an embodiment, wherein shows biology and can absorb bracing frame (support) structure, it is characterized in that having the repetition linker structure of S shape, and the S shape can be used other design replacement.Fig. 4 A also illustrates nested type hoop shape/annular component.Fig. 4 B is the alternate embodiment under the planar configuration, the characteristic of nested circular shown in the figure, and support linker member can use the design in 8 to substitute.Fig. 4 C is the plane diagram of one embodiment of the invention, and wherein structural style constitutes spirane structure.Fig. 4 D illustrates the local supporting structure with hoop shape or ring texture parts and bracing frame (support) parts of manufacturing.The demi-inflation structure of the supporting structure of Fig. 4 D shown in Fig. 4 E.The expanded configuration of the supporting structure of Fig. 4 D shown in Fig. 4 F.

The biology that Fig. 5 illustrates a kind of sinuous linker parts of showing with sinusoidal wave pattern can absorb the oblique drawing of support embodiment.

Expansible hoop or ring that the partial top view of Fig. 6 A shows a support embodiment can absorb the linker parts with sinuous or sinusoidal wave shape (6B) biology.Fig. 6 C illustrates a kind of biology can absorb hoop shape or endless member, wherein shows radial/lateral load power (radial/transverse load) and how in annular component, to distribute.As shown in the figure, this member provides the distribution character of better power, makes support be in open state in the stressed maintenance down that possibly cause deformation of timbering.Fig. 6 D illustrates the hoop of radial swelling just gradually.The radial swelling gradually of Fig. 6 E diagram little ring of support (or ringlet).Fig. 6 F illustrates the phenomenon that is called " necking down ", and the xsect that wherein shows little ring dwindles at the specific part of the linker parts that wriggle, and crystallization is along little ring transverse dispersion.

Fig. 7 A-7C illustrates the arrangement situation of the polymer fiber among the embodiment that biology can absorb medicine equipment, and these arrange how generation plastic deformation under pressure.Fig. 7 A illustrates the non-crystalline state state of the polymer compsn that is used to make said medicine equipment.The polymer fiber that Fig. 7 B illustrates under the demi-inflation structure is arranged; Fig. 7 C illustrates the crystalline state that a biology can absorb fiber when expanding among the support embodiment.

Fig. 8 A illustrates the plat that a biology can absorb bracing frame (support) embodiment, and this biology can absorb bracing frame (support) and comprise structure wriggle linker parts (structural meandering strut elements), nested type hoop shape/endless member and be provided with end ring at the support tube opening part.Fig. 8 B illustrates the partial plan view of the bracing frame (support) of Fig. 8 A, wherein shows the structure that forms bracing frame (support) sinuous linker parts, nested type hoop shape/endless member and transom.The state of bracing frame (support) when making illustrates, and nested type annular component and structure various structures under also is shown simultaneously wriggles and have the junctor that " H " alphabetical shape is constructed between parts and the hoop shape parts.Fig. 8 C illustrates the demi-inflation structure of Fig. 8 B medium-height trestle structure.Fig. 8 D, 8E, 8F are the plats that biology can absorb bracing frame (support) wall, wherein show the embodiment of the alternative design of the interconnecting piece that can between sinuous linker parts, replace.Fig. 8 G is the plan view that biology can absorb bracing frame (support) wall; Wherein show the embodiment of the linker parts and the alternative design of hoop shape/ring texture pattern; And shown the alternative interconnecting piece and how to change design, to change the snappiness of bracing frame (support).The state of Fig. 8 H diagram bracing frame (support) manufacturing wherein shows the nested type hoop shape/annular component between the nested sinuous linker parts.Fig. 8 I is the demi-inflation structural map of Fig. 8 H, and Fig. 8 J and Fig. 8 H, 8K are identical, and Fig. 8 H is its expanded configuration figure, and Fig. 8 K is its expansion structural map.

Fig. 9 A is the plan view that biology can absorb bracing frame (support), wherein shows various assemblies, nested type hoop shape/ring texture parts, the improvement transom that wriggle/sinusoidal linker assembly, end ring parts and parts junction has O shape ring.Fig. 9 B is the oblique drawing of the expanded configuration of the bracing frame shown in Fig. 9 A (support).

Figure 10 A is the interconnecting piece that the biology shown in Fig. 9 A can absorb bracing frame (support), the state when wherein showing the junctor manufacturing; Shown in Figure 10 B and Figure 10 C is the demi-inflation state, and shown in Figure 10 D is the expansion state.

Figure 11 A is the plan view that the biology of unexpanded alternative can absorb bracing frame (support) design, wherein shows the alternative arrangements pattern of junctor between the linker parts, and biology can absorb bracing frame (support) and comprises the end ring member.Shown in Figure 11 B is the expanded configuration of Figure 11 A.Figure 11 C is that the biology of Figure 11 A can absorb supporting structure, and this biology can absorb supporting structure and under its expanded configuration, be fixed on the foley's tube.

Figure 12 A shows the plan view that biology can absorb the alternative embodiment of bracing frame (support) structure, wherein shows the alternative design of the linker parts under the expanded configuration, and shows hoop shape/endless member.Figure 12 B is that the biology of Figure 12 A can absorb supporting structure, and this biology can absorb supporting structure and under its expanded configuration, be installed on the foley's tube.

Figure 13 A illustrates the embodiment that a biology can absorb bracing frame (support), and this biology can absorb bracing frame (support) and comprise the radiopaque tag structure body (radio-opaque marker structures) that places end ring and the interconnecting piece between the linker fragment.Figure 13 B illustrates a kind of embodiment, and wherein the radiopaque material is placed with diagonal way, so that behind implantation instrument, discern through the ray contrast art.

Figure 14 A-14D is the xsect of the alternative embodiment of the biology single marking thing tag member that can absorb bracing frame (support).

Figure 15 A and Figure 15 B further illustrate biology can absorb the position that label radiopaque affinity tag is placed among bracing frame (support) embodiment; Figure 15 C is the ray contrast figure that biology can absorb the radiopaque affinity tag label among the support linker embodiment.

Figure 16 A illustrates a kind of end ring parts that comprise, the plan view under the expanded configuration of the support embodiment end of the sinuous parts of locking mechanism and support linker.Figure 16 B is the bracing frame shown in Figure 16 A (support) embodiment, and the bracing frame that illustrates (support) is under its shrinkage structure (crimped configuration).Figure 16 C illustrates an expansible bracing frame (support), wherein shows the distribution situation of stress.Figure 16 D illustrates a biology can absorb the segmental embodiment of bracing frame (support), wherein shows nested type hoop shape/annular component, the sinuous fragment of support and locking mechanism and maybe can use alternative design to engage the maintenance structure (retention features) of (or engagement).

Figure 17 A and Figure 17 B illustrate the expansion plan view of bracing frame (support) alternative embodiment, locking mechanism of throwing off shown in the figure and terminal end ring member thereof.

Figure 18 A-Figure 18 F illustrates the alternative embodiment that a biology can absorb bracing frame (support), wherein shows the plan view and the oblique drawing of the locking mechanism of apparatus end ring position, and throws off (disengage) and the position of engagement.Figure 18 G illustrates a kind of embodiment, and wherein bracing frame (support) is installed on the foley's tube, and the locking mechanism engagement makes support remain on the conduit with structure consistent in the rack body plane.Figure 18 H is the front view of the bracing frame shown in Figure 18 G (support), the circumference of conduit shown in it, end ring and sacculus.

Figure 19 A describes the plan view of a kind of bracing frame (support) embodiment, wherein shows a kind of alternative embodiment of the terminal locking mechanism of support of manufacturing.Figure 19 B is the shrinkage state of support shown in Figure 19 A, wherein shows a kind of locking mechanism of engagement.Figure 19 C illustrates the amplification plan view (19D) of locking mechanism of amplification plan view, the demi-inflation structure of the locking mechanism of shrinkage state; The oblique drawing of the end ring that locking mechanism partly meshes (19E); Shrinkage structure view (19F) is installed in the view (Figure 19 G) on the foley's tube.

The biology that Figure 20 A shows expanded configuration can absorb the plan view of support embodiment locking mechanism alternative design, the plan view (20B) of shrinkage structure.Figure 20 C is the plan view of terminal portions, and terminal (the snap-fit locked end) plan view of shrinkage of snap lock and the plan view of expanded configuration (20D) of shrinkage structure is shown.The oblique drawing of the expanded configuration of the bracing frame (support) shown in Figure 20 E and Figure 20 F pictorial image 20A-Figure 20 F and shrinkage structure.Figure 20 G diagram is installed in the bracing frame (support) on the foley's tube.

Figure 21 one is in the plan view of the terminal portions of bracing frame (support) embodiment under relaxed state and the demi-inflation state, and this terminal portions comprises locking mechanism and the support linker of end ring parts, a series of disengagements parts that wriggle.

Figure 22 further illustrates the functional details and the constructional details of the locking mechanism shown in Figure 21.

Figure 23 shows the plan view that fastens locking steps A to the progressively engagement process of E.

Figure 24 illustrates support and keeps structure, and wherein figure (A) illustrates the closure device (locking means) of disengagement; Figure B illustrates the closure device of engagement; Figure (C) illustrate shrinkage conduit is installed and closure device mesh the support of (locking) fully.

Figure 25 A and Figure 25 B illustrate a kind of radiopaque particle and are contained in the cavity 108 of lock uint plug and susceptor bound fraction by bag; Figure 25 C and Figure 25 D are this CT scan visual images that comprises the closure device of the radiopaque particle that cuts from spun gold.

Figure 26 illustrates the planar stent area, has wherein discerned the details of the lock uint in the stent area.

Figure 27 is the DSC collection of illustrative plates of (former) material P11228 of being untreated

Figure 28 is 120 ℃ of DSC collection of illustrative plates of 15 minutes P11228 of annealing down

Figure 29 is the DSC collection of illustrative plates of 120 ℃ of following annealing 15 minutes and the P11228 after the application of force (stressed)

Figure 30 is the DSC collection of illustrative plates of untreated P11369

Figure 31 is 80 ℃ of DSC collection of illustrative plates of 15 minutes P11369 of annealing down

Figure 32 is the DSC collection of illustrative plates of 80 ℃ of following annealing 15 minutes and the sample P after the application of force 11369

Figure 33 is the DSC collection of illustrative plates of untreated P11371

Figure 34 is 80 ℃ of DSC collection of illustrative plates of 15 minutes P11371 of annealing down

Figure 35 is the DSC collection of illustrative plates of 80 ℃ of following annealing 15 minutes and the sample P after the application of force 11371

Figure 36 is the WAXS collection of illustrative plates of untreated samples P11228

Figure 37 a is 120 ℃ of WAXS collection of illustrative plates of 15 minutes sample P 11228 of annealing down

Figure 37 b is 120 ℃ of peak analyses of the WAXS collection of illustrative plates of 15 minutes sample P 11228 of annealing down

Figure 38 a is the WAXS collection of illustrative plates of 120 ℃ of following annealing 15 minutes and the sample P after the application of force 11228

Figure 38 b is the peak analysis of the WAXS collection of illustrative plates of 120 ℃ of following annealing 15 minutes and the sample P after the application of force 11228

Figure 39 is the WAXS collection of illustrative plates of untreated samples P11369

Figure 40 a is 80 ℃ of WAXS collection of illustrative plates of 15 minutes sample P 11369 of annealing down

Figure 40 b is 80 ℃ of peak analyses of the WAXS collection of illustrative plates of 15 minutes sample P 11369 of annealing down

Figure 41 a is the WAXS collection of illustrative plates of 80 ℃ of following annealing 15 minutes and the sample P after the application of force 11369

Figure 41 b is the peak analysis of the WAXS collection of illustrative plates of 80 ℃ of following annealing 15 minutes and the sample P after the application of force 11369

Figure 42 is the WAXS collection of illustrative plates of untreated samples P11371

Figure 43 a is the WAXS collection of illustrative plates of 15 minutes sample P 11371 of 80 ℃ of annealing

Figure 43 b is 80 ℃ of peak analyses of the WAXS collection of illustrative plates of 15 minutes sample P 11371 of annealing down

Figure 44 a is the WAXS collection of illustrative plates of 80 ℃ of following annealing 15 minutes and the sample P after the application of force 11371

Figure 44 b is the peak analysis of the WAXS collection of illustrative plates of 80 ℃ of following annealing 15 minutes and the sample P after the application of force 11371

Figure 45 a is the elongation of sample P 11369

Figure 45 b is the elongation of sample P 11371

Figure 46 a is the tensile strength of sample P 11369

Figure 46 b is the tensile strength of sample P 11371

Embodiment

Medicine equipment of the present invention comprises a plurality of sinuous linker parts or member, forms consistent pattern (consistent pattern), the ring texture of for example arranging along the circumference of apparatus with the form of repeat pattern.The linker structure of wriggling can be placed adjacent to each other and/or oppositely, and they can radially and equably be expanded on the whole length of expandable bracing frame (support) along the longitudinal axis of apparatus.In one embodiment, expandable bracing frame (support) can comprise the specific structure pattern, like optional crystalline network (lattice structure) with even bracing frame of lateral branching, double-spiral structure.

Supporting structure generally includes a large amount of serpentine structure patterns." wriggle ", promptly mean and advance with non-directional route.Because the doctor need embed unexpanded support in the vascular system, serpentine structure is generally sinusoidal form naturally, promptly has multiple crest and trough order.Usually, these sinusoidal configuration are by normalization method (normalized), so crest or therefrom line computation of trough, are generally equally spaced." non-sinusoidal " promptly means a kind of crest or trough that does not have repetitive sequence, and do not have a series of structural styles with the identical sunk part of the identical bump of middle line computation spacing or spacing.The characteristic of support can be to have 3 not isostructures: unswollen state (when making), shrinkage state (with respect to a kind of compressed state of unswollen state) and swelling state (state when discharging as implants in vivo).

In one embodiment, sinuous linker can replace each other.Through the various difform special connectors of having of the point of crossing between adjacent linker, one-level (primary) wriggle that linker wriggles with secondary (secondary) or little ring linker parts all can be in shrinkage structure and expanded configuration or the structure when implanting under its relative position shrinkage of maintenance.Can use such cross-connect (crossing connector) of each or selected quantity with the multiple mode.These interconnecting pieces can make the sinuous linker of bracing frame (support) embodiment keep the position between homogeneous phase.The purpose of these junctors is to bear in original tube columnar structure to transmitting sacculus (delivery bulb) or inserting the change that the tight shrinkage state on the device is constructed to spreading.The stretching, extension of this bracing frame (support) is exerted pressure to assembly linker and hoop/ring, and makes its crystallization, and becoming is the wreath (circularity) of cylindric or taper on the whole.

Linker interconnecting piece or junctor can be arranged by repetitive mode, to stablize and to be connected adjacent sinuous linker parts.This purpose of design is to keep the sinuous linker of plasticity flexible to be fixed in tubular support frame (support) structure.

In another embodiment; The present invention includes a kind of refrigerating unit or state (cooling means or condition); Be used for fixing with the stable carrier system on plasticity bracing frame (support), make it keep shrinkage and locked configuration, to increase the safety of delivery system.And in another embodiment, this medicine equipment comprises that the stress that can produce when expanding (like inflation) is orientated and/or crystalline polymer support frame (support) structure, to improve the mechanical property of medicine equipment.These mechanical propertys include, but is not limited to resistance to compression, retraction ability (recoiling) and elasticity.

Medicine equipment comprises the polymkeric substance with slow decomposition kinetics performance, to avoid in implant site generation tissue overload (tissue overload) or other inflammatory response.Typical medicine equipment can structurally design, make its have the ability that changes, with implant the ability that the zone adapts and make the normal restorative ability of local organization.For example, medicine equipment can make with for example using through metal (like stainless steel stent) and compare from the solid polymer state-transition to " rubbery state ", and surgical operation becomes and is more prone to.Deformation is big more, and the power that the apparatus structure parts are bestowed is just big more.Polyreaction is preferably carried out (discussing hereinafter) through the D type of polymkeric substance and the block copolymerization reaction of L type isomer; To obtain the polymkeric substance raceme, this polymkeric substance raceme can impel polymer moieties to reset from the crystallization that general amorphous structure is transformed into stretching, extension relevant with expansion or strain inducing.Mechanical characteristics is accompanied by the flexible hoop stretching, extension inflexible that fades to of shrinkage and changes, when especially a kind of variation in back (hoop stretching, extension) appears at the nested of the sinuous linker of secondary and holds position ring or hoop to expand.In one embodiment, pharmaceutical composition can be incorporated polymkeric substance into, as before extruding medicine equipment with pharmaceutical composition and mixed with polymers, or pharmaceutical composition is grafted on the polymer active position, or pharmaceutical composition is coated on the medicine equipment.This medicine equipment can comprise any polymeric medical device that is used to implant, and comprises support, transplant, structural transplantation sheet, synthetic vascular transplant, splitter and conduit etc.A typical medicine equipment can be a support, wriggles/the sinusoidal shape component configuration with first on its structure, and comprises ring texture parts nest formula second parts when having a large amount of expansion.

The expansible implant should have mechanical property, as to a certain degree rigidity be attended by flexible, to prevent dislocation or creep.The embodiment of various biologically absorbable polymer supports and/or support has different structures.For example, support is the tubular structure that comprises a bracing frame (support), and wherein the linker parts of this bracing frame (support) are designed to make the structure of the open space of blood flow between parts.Particularly wriggling has certain space between the linker, so that most of adjacent tissue surface keeps and the contacting of blood.The characteristics of the support Design of this uniqueness comprise depend on support to be discharged size different radially with vertical parameter.The structure of support can be diversified, like bifurcation structure or be configured and make the blood vessel far-end that can further be applied to initial implantation point.Support can comprise that side props up improved have homogeneity and flexible bracing frame (support) structure.After the original position support is put first, can insert second support through the internal chamber wall of first support.In one embodiment, can transform, to add radiopaque or radioparent material, after dispensing, to detect the effect of its position or definite its life-time service (6 months or 2 years) medicine equipment.Possible remodeling method has multiple different type, like the disperse or the some distribution mark of bracing frame (support).Correspondingly, the radiopaque material can directly wrap with the form of mixture or covalent conjunct agent and include in the initial plastic composition.In addition, the radiopaque material can place a plurality of being evenly distributed in the surperficial or inner specific site susceptor (receptacles) of bracing frame (support).Perhaps, radiopaque material or transmissive wire material can be coated on bracing frame (support) surface as shallow layer.Therefore, utilizing electron dense or refraction of X-ray affinity tag, is very favorable for the contrast enhancing detection (contrast detection enhancement) of anatomic implants.This type of affinity tag can find in being full of the biodegradable spot storehouse (spot depots) of radiopaque compsn, and this radiopaque compsn is processed with visible material in photographs by the refrangible X ray.These suitable materials include but not limited to: radiopaque compound of 10%-90% or particulate; These compounds or particulate can be embedded in the biodegradable part; Especially be the paste composition form, this paste composition is stored in a plurality of cup-shaped susceptors that are arranged in preformed polymer support frame (support) linker parts.The radiopaque compound can be selected from X ray densification or refractive compound, like metallic particles or salt.Suitable affinity tag metal can comprise pure substance or its organic cpds of iron, gold, colloid silver, zinc, magnesium.Other radiopaque material comprises tantalum, tungsten, platinum/iridium or platinum.The radiopaque affinity tag can constitute with above-mentioned one or more biodegradable polymers of mentioning (like PLLA, PDLA, PLGA, PEG etc.) wedding agent.For obtaining suitable marker material mixture, solution system comprises among acetone, toluene, methylbenzene, the DMSO etc. two kinds or more kinds of.In addition, the affinity tag storehouse can be used as anti-inflammatory drug, as is selected from the group that PPAR agonist, steroidal, mTOR suppressor factor, calcineurin suppressor factor etc. are formed.In a kind of embodiment that comprises the radiopaque affinity tag; Iron containing compounds or the particle and the PLA polymeric matrix that are packaged with iron carry out crosslinked; Form a kind of pasty substance, this slurry like material can be injected or be stored in the hollow susceptor suitable in the polymkeric substance linker parts.The size of this cup-shaped susceptor is in the width range of bracing frame (support) linker parts.Heavy metal and heavy soil element (heavy earth elements) are to all cpds, and be very useful like ferrous salt, organic iodide, bismuth salt or barium salt etc.Other embodiment can use the iron particle (like ferritin) of natural coating, and it can be further crosslinked with linking agent.In addition, the ferritin gel can constitute through the glutaraldehyde cross-linking with lower concentration (0.1-2%).The radio opaque markers thing can use and link with polymkeric substance in many ways.For example, the liquid of affinity tag or pasty mixture can be contained in the syringe and be injected into lentamente in the Biodegradable scaffold linker in preformed cavity or the cupping through needle point.The solvent that comprises in the liquid mixture can be attached to marker material on the cavity wall.The support that contains radiopaque mark object point can heated drying or vacuum-drying.After the implantation, biodegradable adhesive can resolve into the simple molecules that can be absorbed by the body or discharge.Therefore, the radiopaque material will be scattered near the zone the implantation position first.

The mechanical property of bracing frame (support) can be by real-time detection, to detect any retraction conservation rate and whether to have the restenosis tissue.Similarly, degraded of bracing frame (support) polymer biological and metabolic condition can be through assessing echogenicity and the quantitative change measurement that tissue is formed.The local mechanical performance can be assessed (6 months by palpography; 2 years).The minimizing of quality can be assessed (6 months by OTC in the polymer degradation certain hour; 2 years).Restenosis rate can be carried out quantitative measurment (18 months) by MSCT.Experimental evidence has been explained biodegradable and can have been absorbed bracing frame (support) and be used in the advantage in the support for example.It has been found that, bracing frame (support) send rapidly with consistency on, its behavior is similar to metal bracket for eluting medicament (DES).But, have been found that the bracing frame of being placed (support) is absorbed and all metabolism naturally.Therefore, (support (can be the tubular bracket form) can be by metabolism up hill and dale, not residual permanent implant and stay the natural blood vessel or the tissue of healing for biological absorbable bracing frame.Bracing frame of the present invention (support) can carry out the CT radiography.

Among a bracing frame (support) embodiment, bracing frame (support) comprises the polymer support of a shrinkage therein, and this support can be through being used for the sacculus transfer system insertion that blood vessel is implanted.Yet the pliable and tough plasticity of bracing frame (support) can cause being used for support shrinkage structure lax on the carrier system that blood vessel inserts or transmit.As a result, the bracing frame of shrunk (support) possibly have the trend of " creep ", promptly leaves the predetermined position of sacculus carrier or become to relax fully.Therefore, in one embodiment, polymkeric substance apparatus (like support) is equipped with safety mechanism, with prevent with its fixing or when being applied to the target location in the pipe when being loaded into delivery system and with the shrunk apparatus accident open.Safety mechanism can be designed, and makes adjacent to the far-end of periphery and proximal loop linker (secondary wriggle linker parts).In some certain embodiments, bracing frame (support) is equipped with closure device and is in the position of firm grip to keep the shrinkage structure, prevents that it from deformation (buckling) taking place, and is beneficial to the safety dispensing of apparatus.In addition, closure device can prevent that plastic support frame (support) shrinkage is configured in when handling and gets loose from carrier system.This sealed machinery receives dysplasia design and/or the influence of the additional friction that possibly caused by mutual pressure (mutual pressure engagement).According to the description among the embodiment, the nature of friction of locking mechanism possibly receive the influence of the plasticity composition of selectivity transformation, and ion wherein or nonionic additive may help keeping the shrinkage structure of bracing frame (support).

In certain embodiments, bracing frame (support) uses various designs, comprises being positioned at far-end and near-end or near the fastening structure it, so that bracing frame (support) is locked in the transfer system carrier part with the shrinkage state.In present embodiment or other embodiment, can design one or more fastening components, be located at the end of the sinuous linker parts of bracing frame (support), perhaps be positioned at some repeatable position place of bracing frame (support).As desired in the shrinkage structure, locking mechanism can increase the confining force of support.Adjacent fastening lock construction is designed to the successive secondary and wriggles or ring-type/hoop shape member; Be connected to that secondary wriggles or ring-type/hoop shape member on or the part of or ring-type/hoop shape member sinuous as secondary; And it is effectively designed, make it with shrinkage state and the terminal engagement of bracing frame (support) and pin, enough confining forces are provided; Thereby make bracing frame (support) remain on the home position, and keep identical diameter along the longitudinal axes of apparatus.In certain embodiments, when apparatus expanded, terminal sinuous parts may form the ring that stretches fully, for for example support increases tightening force.

As stated, apparatus possibly be equipped with the structure closure device of " lock-key " structural form, is similar to the interlocker (interlocking means) of the ball and socket joint type (ball-socket joint type) of fastening.In one embodiment, the sinuous member of one or more nested units is provided, has been used to form hoop shape or ring texture pattern in the expanded configuration.

The present invention also comprises the method for making this medicine equipment.Made the suitable polymer compsn that contains one or more medicines or do not contain medicine.Polymkeric substance is moulded or is pushed then, constitutes the medicine equipment that supplies to implant usefulness.For support, it is made tubular structure, under laser is auxiliary, cut then, make needed various structural style.In one embodiment, the method that is used to make this medicine equipment comprises preparation biodegradable polymer structure; Said polymer structure is designed, make it to implant in patient's body; With laser said paradigmatic structure body is cut into various structural styles, make medicine equipment can pass through opening (otch) and make medicine equipment can form the shrinkage shape.Formed structure can comprise the closure device that is used for stablizing the shrunk apparatus, so that it is firmly held on carrier or the implant system.In another kind of embodiment; To being used for the auxiliary closing device that forms the shrinkage state or load bracing frame (support) in the closure device, can be through in bracing frame (support) or bracing frame (support) composition, adding biocompatible nonionic or ion reagent or carrying out chemically modified or reinforcement with range upon range of or grafting mode.These can homogeneous or intersperse on interlocking surfaces subtly through negatively charged ion, positively charged ion or the nonionic layer modified.The consumption of positively charged ion or reagents for anion (also can be tensio-active agent) can for about 0.01wt% to about 10wt% (in mass).

These ion reagent preferably are used in the support outside, and after so support expanded in position, it can be removed through dissolving at an easy rate.Low consumption ground uses non-ion reagent to be applicable to increases friction interaction, the especially friction between each locking mechanism.Preferably through the non-ion reagent of FDA approval, the consumption level is 0.05%-2.5%.In embodiment of frictional force of increase bracing frame (support), especially an interactive surfaces, decorative layer has been carried out the nonionic doping.Suitable non-ion reagent can be selected from chemical such as ethoxy fatty amine, fatty ester and direactive glyceride and double glyceride.

Biologically absorbable polymer of the present invention and compsn can be made balloon expandable stent.This support can form corrugated in the balloon delivery catheter system, so that in sending intravasation.Alternatively, biology can absorb support and can be the self-expanding formula.The inflation medicine equipment comprises a hot-bulb or a non-hot-bulb.Foley's tube upper bracket gauffer and expansion can take place and do not crack in the character of biologically absorbable polymer.The crystallographic property of biologically absorbable polymer takes place can change in gauffer and/or the expansion process at it, and its mechanical property such as tensile strength, creep properties and slower degradation kinetics are improved.

Compare with being seen biologically absorbable polymer in other prior art, biologically absorbable polymer of the present invention shows lower immunogenicity in decomposition course, as reducing the generation of IL-2 or other cytokine.Under physiological condition, preserve after 1 month (as 37 ℃ phosphate buffered saline), the external degradation kinetics of biologically absorbable polymer of the present invention has and is less than about total rate of decomposition of 5%.In other embodiments, under physiological condition, preserved 1 month, 2 months, 3 months or after 6 months, its total rate of decomposition is lower than about 10%, 20%, 30% or 40% respectively.So the place is stated, and total rate of decomposition has comprised the change of molecular property, like the reduction of crystallographic property, decrease in molecular weight or mechanical property.After biologically absorbable polymer of the present invention is made the support implant into body, can keep enough physical strengths, to keep opening of blood vessel, the time was at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years or 3 years.Support of the present invention can be made the structure that adapts with any vascular shape.

Fig. 1 is a computer analoging figure, and the partial view that a kind of unexpanded biology can absorb medicine equipment embodiment is shown.Contrast 10 is bracing frame or support.The linker parts 17 that wriggle are described with end ring 16 with nested hoop shape structure 14, and the two all comprises the not structure in same plane, the locking mechanism 18 that links to each other with other locking mechanism (not shown) and interconnected " H " zone 15 (can contain ring-type expansion through hole 11 at nested hoop shape member 14 places).

Fig. 2 one comprises the computer generation figure that biology under the expanded configuration can absorb the embodiment of support, wherein show nested type hoop shape member 14 (or annular components), usually be in end ring 16 in the same plane, wriggle linker parts 17 and, and the isolating locking mechanism 18 of other locking mechanism.Shown expansion through hole 11 has extended to this near in slotted eye of expanded configuration.

Fig. 3 be one in advance the expansible biology can absorb the computer analoging figure of bracing frame (support), wherein show alternately ring-type or hoop shape member with sinuous linker parts 17 and locking mechanism 18.Fig. 3 B is and identical bracing frame (support) shown in Figure 3, wherein shows the ring-type fragment that is under the different pressures state.Under arbitrary situation, the member that comprises each ring or hoop is usually located in the same plane.

Fig. 4 A illustrates the plan view of an embodiment, wherein shows bracing frame (support) structural style 13, and this structural style can be biological absorbable, is shaped as S shape (19), can use other design form replacement shown in 6.Fig. 4 A also illustrates nested type hoop shape/annular component 14.Fig. 4 B is the alternative embodiment under the planar configuration, the characteristic of nested circular shown in the figure 14, and its medium-height trestle linker member can use the design in 8 to substitute.Fig. 4 C is the plane diagram of one embodiment of the invention, and wherein the linker parts 17 of sinusoidal configuration form the member 9 (in plan view, illustrating with diagonal lines) of volution pattern in one-piece construction.The part with hoop shape or ring texture parts 14 and bracing frame (support) parts that Fig. 4 D illustrates manufacturing is the expanding stent structure not.The demi-inflation structure of the supporting structure of Fig. 4 D shown in Fig. 4 E.The expanded configuration of the supporting structure of Fig. 4 D shown in Fig. 4 F, each ring is the cylindrical shape that is in substantially in the same plane.

Fig. 5 illustrates the oblique drawing that a kind of unexpanded biology can absorb support embodiment, shows the sinuous linker parts 22 and end ring 23 of sinusoidal wave pattern.

Fig. 6 A shows the partial top view of expansible hoop or ring, and situation when this hoop of Fig. 6 B diagram or ring do not expand is shown biology by the sinuous sinusoidal shape (6B) of support embodiment in the drawings and can absorbs the linker parts and constitute.Fig. 6 C illustrates a kind of biology can absorb hoop shape or endless member, wherein shows radial/lateral load power and how in annular component, to distribute.As shown in the figure, this member provides the distribution of better power, makes this support under the pressure that possibly cause deformation of timbering, stay open state.Fig. 6 D diagram one is the hoop of radial swelling just gradually.Fig. 6 E illustrates the little ring of support and experiences radial swelling process gradually.Sinuous parts stretch, and deformation takes place then.It is about 250 that tensile modulus can be, and 000PSI is to about 550,000PSI.Deformation comprises reducing of wriggle linker parts one segmental cross-sectional dimension (width and thickness).Deformation may take place in linker parts (fragment) of little ring, brings reducing of change and/or cross-sectional area on the crystallographic property subsequently, demonstrates specific wide-angle x-ray scattering (WAXS) 2 θ values after the stretching, and about 1 to about 35, as 1,2, and 3,4,5,6; 7,8,9,10,11,12,13,14,15,16; 17,28,19,20,21,22,23,24,25,26; 27,28,29,30,31,32,33,34,35.At a kind of embodiment, cross-sectional area reduces, but does not have the change on any crystalline structure subsequently.In radial swelling, take place that this crystal changes and the number of fragments of the sinuous parts that cross-sectional area reduces is 1,2,3 to n, this variation takes place until whole sinuous parts or the little ring of support (hoop).When the little ring xsect that is positioned at the parts specific part that wriggles reduces, crystallization is during around little ring lateral expansion, and this phenomenon also can be called " necking down ".Necking is known by people in the polymkeric substance among Fig. 6 F; And usually occur in axial force S and stretch ratio λ and be not on the homogeneous phase solid polymer bar of single relation (S/ λ is not a single value) (film or filament), and this uniform polymeric solid bar is done under the situation of unilateral stretching.At this moment, polymkeric substance strip thing can not deform equably.Yet two cross sections much at one appear in this sample: one almost equates with initial thickness, and another cross-sectional dimension is considerably thin.Consult Leonov; A.I.; A Theory of Necking in Semi-Crystalline Polymers, Int ' l J.of Solids and structures, 39 (2002) 5913-5916 (Leonov; A.I., the necking down in the semi-crystalline polymer is theoretical. international solid and structure magazine .39 (2002) 5913-5916); Other sees also http://www.eng.uc.edu/-gbeaucag/Classes/Characterization/Stress Strainhtml/StressStrain.html (on May 6th, 2010); Other sees also http://materials.npl.co.uk/NewIOP/Polymer.html (on May 6th, 2010).

Except that WAXS, double refraction method or dsc also can be measured sample.Also can use Instron (Instron) universal testing machine the sample mechanical drawing to be carried out the assessment of tensile properties.See et al.Acta Materialia:56:5083-5090 (2008) (people such as Wong. material journal: 56:5083-5090 (2008).Drawing can be in the drawing temperature T _dUnder carry out T wherein _dCan with the second-order transition temperature T of polymkeric substance _gIdentical or different.For example, drawing temperature can be about 65 ℃ to about 120 ℃.

Fig. 7 A-7C illustrates arrangement situation and these that biology can absorb polymer fiber among the medicine equipment embodiment and arranges how generation elastic deformation under pressure.Fig. 7 A illustrates the non-crystalline state state of the polymer compsn that is used to make said medicine equipment.The ordered state of the polymer fiber of Fig. 7 B diagram demi-inflation structure; The crystalline state of fiber when the biology that Fig. 7 C diagram is made up of racemization or three-dimensional composite polymeric compositions can absorb support embodiment and expands.

Fig. 8 A illustrates one and comprises the plan view that structure is wriggled linker parts 17, nested type hoop shape/endless member 14 and can be absorbed bracing frame (support) at the unexpanded biology that the support tube opening part is provided with end ring 16.Fig. 8 B is the plan view that the bracing frame shown in Fig. 8 A (support) part is shown, and wherein shows the transom that structure is wriggled linker parts 17, nested type hoop shape/endless member 28,30 and constituted bracing frame (support).The state of bracing frame (support) when making illustrates, and also shows the nested type annular component 28,30 of various structures simultaneously.As focusing on sight the transom between sinuous parts of structure and the hoop shape parts, may find the alphabetical H shape that stylizes.Fig. 8 C illustrates the segmental expanded configuration of Fig. 8 B.Fig. 8 D, Fig. 8 E and Fig. 8 F are the plan view that biology can absorb bracing frame (support), wherein show the embodiment A-G of the alternative design of the tie point between the linker parts 17 that wriggles.A ' among Fig. 8 E-G ' is the corresponding plan view of structural style A-G among Fig. 8 D.In Fig. 8 F, the support frame structure pattern 13 of S shape (19) can be used other design replacement shown in 2.Fig. 8 F also shows nested type hoop shape member/annular component 14.Fig. 8 G is the plan view that biology can absorb bracing frame (support) wall, and it shows the alternative design embodiment of linker and hoop shape/ring-type pattern and the interconnecting piece 3 how this design is selected else is transformed, to change bracing frame (support) flexibility.The bracing frame (support) of Fig. 8 H diagram manufacturing wherein shows and is embedded in the nested type hoop shape member/annular component that wriggles between the linker parts.Fig. 8 I is the demi-inflation structural map of Fig. 8 H, and Fig. 8 J and Fig. 8 H, 8K are identical, and Fig. 8 H is its expanded configuration figure, and Fig. 8 K is its expansion structural map.

Fig. 9 A shows the plan view that biology can absorb bracing frame (support); Wherein show various assemblies, nested type hoop shape/ring texture parts 28, wriggle/sinusoidal linker assembly 38, transformation transom 9 that end ring parts 16 and parts junction have O shape ring.The oblique drawing of the expanded configuration of the bracing frame (support) shown in Fig. 9 B pictorial image 9A.

Figure 10 A is the transom that the biology shown in Fig. 9 A can absorb bracing frame (support), the state when wherein showing the junctor manufacturing.Shown in Figure 10 B and Figure 10 C is the demi-inflation state, and shown in Figure 10 D is the expansion Status view.As shown in the figure, hollow shape changes along with the expansion of bracing frame (support).

Figure 11 A is the plan view that the biology of unexpanded alternative can absorb bracing frame (support) alternative design, wherein shows the alternative arrangements pattern of junctor 55 between the linker.Shown in Figure 11 B is the expanded configuration figure of Figure 11 A.Figure 11 C is similarly expanded configuration, and it discharges on the expansible foley's tube.

Figure 12 A shows the plan view that biology can absorb the alternative embodiment of bracing frame (support) structure, wherein shows the alternative design of the linker parts under the expanded configuration, and shows hoop shape/endless member 14,16.Figure 12 B can be that the biological expanded configuration that can absorb supporting structure and its are installed on the foley's tube among Figure 12 A.

Another biology of Figure 13 A diagram can absorb bracing frame (support) embodiment and (see also U.S. Patent number 7682384 and 7329277 in addition; U.S. Patent Publication: 20090024207,20090024198,20080319537,20080294244,20080294243,20080294241,20080288053,20080288052,20080288051,20080288050,20080281407 and u.s. patent application serial number 12/727; 567 content; To obtain the more explanation of this embodiment), it comprises the radiopaque affinity tag member 65 that places end ring position and the interconnecting piece between the linker fragment.Figure 13 B illustrates a kind of embodiment, and wherein the radiopaque material is placed so that after implantation, discern through the ray contrast art with diagonal way 65 '.

Figure 14 A-14D diagram biology can absorb the xsect of alternative embodiment of the single marking thing tag member of bracing frame (support).As shown in the figure, the single marking thing can be placed on the support (14D) or place (14B) or various through hole (14A and 14C) in the groove.

Figure 15 A and Figure 15 B further illustrate biology can absorb the position that label radiopaque affinity tag 65 is placed among bracing frame (support) embodiment.Figure 15 C is the low coverage ray diagram that biology can absorb the radiopaque affinity tag label among the support linker embodiment.May use and various support is fixed on supravasal locking mechanism.In a bracing frame (support) embodiment, bracing frame (support) comprises a polymer support that can become shrunk, and this support can be inserted into through the balloon-expandable delivery system and be used for the blood vessel implantation.Yet the variable plasticity-of bracing frame (support) can cause being used for support shrinkage structure lax on the carrier system that blood vessel inserts or send.Especially, its plasticity-patient temperature of being received treatment increases.As a result, the bracing frame of shrunk (support) possibly have the trend of " creep ", promptly leaves the predetermined position of sacculus carrier or become to relax fully.Therefore, in a preferred embodiment, polymkeric substance apparatus (like support) is equipped with safety mechanism, with prevent with its fixing or when being applied to the predetermined position in the pipe when being loaded into delivery system and with the shrunk apparatus accident open.Disclosed herein multiple can with the common safety mechanism that uses of medicine equipment.Figure 16-26 discloses and can be used to guarantee that plasticity bracing frame (support) is fixed on the exemplary embodiments of the safety mechanism on the delivery system.

The sealed effectiveness that fastens polymer support frame (support) catches through the hook-like assembly unit of acceptor portion that inductive strain crystallization obtains increasing in the arrow embedded part process.But because the stress point of these locks is yielded to radial swelling power, bracing frame (support) expansion stages, in precipitation process, the composition of polymkeric substance can cause trailing or the distortion of linker or locking mechanism.This locking member remarkable advantages is to obtain through the special strain crystallization characteristic of the polymer compsn that is used to make bracing frame or support.Safety mechanism can be designed; Make adjacent to periphery far-end and near-end end ring linker (secondary wriggle linker parts); And any position that is positioned at stent design, with the creep of restriction shrinkage support embodiment or limit so-called plastic construction relaxation (plastic structural relaxation).Alleged creep may cause the support on the sacculus carrier to be moved or reset.In some certain embodiments, bracing frame (support) is equipped with closure device, is in the position of firm grip to keep the shrinkage structure, prevents deformation and is beneficial to discharging safely of apparatus.In addition, closure device can limit or prevent that plastic support frame (support) shrinkage is configured in when operation and gets loose from carrier system.This operation possibly need a kind of method support to be embedded and guides it in the cranky path of arterial vascular system.Especially, the shrunk support entity of pinning must bear at patient's lesion vessels hostile environment.The pathological change of thrombus artery that contains patch has the calcification of thorn-like appears or thorn, may sting the support that the sacculus carrier dwindles it or can hook the sacculus carrier or link to each other with conduit.Therefore, the quantity of lock (no matter which kind of design) can be 1,2,3 to being installed in as much as possible around the shrunk circumference.Lock possible quantity and be the size of employed lock.Lock is preferably installed along the support circumference equally spacedly so that make between each lock of two locks with 180 degree angle distribution, between three each locks of lock with between each lock of angle distribution or four lock of 120 degree with the angle distribution of 60 degree.This locking mechanism receives dysplasia design and/or the influence of the additional friction factor that possibly caused by mutual pressure.According to the description among the embodiment, the friction factor of locking mechanism possibly receive the influence of the plasticity composition of selectivity transformation, and wherein, ion or nonionic additive may help keep the shrinkage structure of bracing frame (support).

In concrete embodiment, bracing frame (support) uses various designs, comprises being positioned at far-end and near-end or near the fastening structure it, so that bracing frame (support) is locked in the shrinkage of delivery system carrier part with the shrinkage state.In this embodiment or other embodiment, can design one or more fastening components, be located at the end of the sinuous linker parts of bracing frame (support), perhaps be positioned at some repeatable position place of bracing frame (support).As desired in the shrinkage structure, locking mechanism can increase the confining force of support.Adjacent fastening lock construction is designed to the successive secondary and wriggles or ring-type/hoop shape member; Be connected to that secondary wriggles or ring-type/hoop shape member on or as secondary wriggle or ring-type/hoop shape member a part of; And it is effectively designed, make it with shrinkage state and the terminal engagement of bracing frame (support) and pin, so that enough confining forces to be provided; Thereby make bracing frame (support) remain on the home position, and keep identical diameter along the longitudinal axes of apparatus.In certain embodiments, when apparatus expanded, terminal sinuous parts may form the ring that stretches fully, for for example support increases tightening force.

As stated, apparatus is equipped with the closure device of lock-key structure (key-in-lock configuration) form, and its design class is similar to the interlocker of the ball and socket joint type of fastening.In one embodiment, the sinuous member of one or more nested units is provided, has been used to form hoop shape or ring texture pattern in the expanded configuration.

Bracing frame (support) embodiment can make various structures in many ways.For example, we possibly use the latched position with the end cyclic formula that fastens form, wherein when being locked in the support shrinkage when textural, the suspended wall shape or finger-like linker parts shrinkage meeting closely cooperate in the linker surface of adjacent counterpressure.In another embodiment, closure device comprises finger-like suspended wall expandable part, slides with manner engagement ground, by way of slyness (commensurately) curvature portion of plasticity bracing frame (support) linker parts.In this embodiment, termination device or friction device serve as in safety mechanism, produce enough frictional force, are in the shrunk attitude to keep bracing frame (support) end.A kind of closure device of alternative illustrates with the locking form of the fastening closure device (snap-fit locking means) of globe joint.

Another embodiment that fastens closure device is shown among Figure 19 or Figure 20, is divided into locked configuration and non-locking structure, and wherein, suspended wall embodiment uses and is positioned at a groove shape susceptor on the adjacent linker parts, in order to accept the tip portion of suspended wall.

In one embodiment, the structure closure device of medicine equipment can be designed to lock-structure of key or ball and socket joint, wherein, the suspended wall hook-type interlocker that is positioned at opposite location is in the state of locking and non-locking.

Figure 16 A illustrates the plan view of the end of the support embodiment under the expanded configuration, and this support embodiment comprises end ring parts 16, locking mechanism 75 and the support linker parts 17 that wriggle.Shown in Figure 16 B is the bracing frame (support) under the shrinkage structure shown in Figure 16 A, and it has 75 shrinkages of interlocking locking mechanism.Shown in Figure 16 C is an expansible support, wherein shows the situation of stress distribution, and shows the support situation that locking mechanism 75 is threaded off in expanded configuration.Figure 16 D illustrates the fragment that a biology can absorb bracing frame (support) embodiment, shows wherein that nested type hoop shape member/annular component 14, support wriggle linker parts 17 and locking mechanism 75 or the maintenance structure of the alternative design that can be used for meshing.

Figure 17 A and Figure 17 B illustrate the expansion plan view of bracing frame (support) alternative embodiment, locking mechanism 75 of throwing off shown in the figure and terminal end ring member 16 thereof.Figure 17 A and Figure 17 B also show the interconnecting piece 42 between the linker parts.As shown in the figure, locking mechanism 75 is fastened and connected through public female part.

Figure 18 A to Figure 18 F illustrates the alternative embodiment that a biology can absorb bracing frame (support), wherein shows the plan view and the oblique drawing of the locking mechanism 75 that is positioned at the apparatus end ring position, and the disengagement and the position of engagement.Locking mechanism 75 in the present embodiment comprises a fastening ball and socket joint structure.Figure 18 A, 18D, 18E illustrate isolating locking mechanism 75; Figure 18 B, 18C, 18F illustrate the locking mechanism 75 of lock-out state.Figure 18 G illustrates an embodiment, and wherein bracing frame (support) is installed on the foley's tube 60, and locking mechanism and its engagement make support remain on the conduit with structure consistent in the rack body plane.Figure 18 H is the front view of the bracing frame shown in Figure 18 G (support) 16, wherein shows circular conduit 60, end ring 16 and sacculus 70.

Figure 19 A is the plan view of a kind of bracing frame (support) embodiment, wherein shows a kind of alternative embodiment of the terminal locking mechanism of support of manufacturing.Figure 19 B is the shrinkage state of support shown in Figure 19 A, wherein shows a kind of locking mechanism of engagement.Figure 19 C illustrate the locking mechanism of shrinkage state amplification plan view, demi-inflation structure locking mechanism amplification plan view (19D), end ring that locking mechanism partly meshes oblique drawing (19E), shrunk structure view (19F), be installed in the view (Figure 19 G) on the foley's tube.

The biology that Figure 20 A shows under the expanded configuration can absorb the plan view of support embodiment locking mechanism alternative design, the plan view (20B) of shrinkage structure.Figure 20 C is the plan view of terminal portions, wherein shows plan view and the plan view (20D) of expanded configuration of the terminal shrinkage of snap lock of shrinkage structure.Figure 20 E and Figure 20 F are respectively the oblique drawings of bracing frame (support) expanded configuration shown in Figure 20 A-Figure 20 F and shrinkage structure.Figure 20 G diagram is installed in the bracing frame (support) on the foley's tube.

Figure 21 one is in the plan view of bracing frame (support) embodiment 120 terminal portionss under relaxed state and the demi-inflation state, and this terminal portions comprises locking mechanism and the support linker of end ring parts 121, a series of disengagement parts 122 that wriggle.Lock uint 99 combines and combines with cavity or pocketed thing 106 with susceptor 107, embedding assembly 100 uniquely, to store the radiopaque material.

Figure 22 further illustrates the alternative embodiment of the locking mechanism of tubular apparatus.Figure 22 illustrates the functional details and the constructional details of the locking mechanism 99 shown in Figure 21.Therefore, the special shape that embeds assembly 100 can embed the susceptor 107 of relative position, makes arrow shaped embed the stop member 105 that most advanced and sophisticated 101 conflicts cause compressing.The conflict of the stop member 105 in arrow 101 and the susceptor parts 107 is connected the distortion that can further cause stop member 105, is positioned at the susceptor hook-like assembly unit 102 of susceptor parts 107 both sides with formation.Susceptor hook-like assembly unit 102 has intilted tuck at the stop member place of adjacent fulcrum 104.Thus, hook-like assembly unit 102 and interference surface (interference surface) 103 engagements are to advance susceptor part 107 with arrow parts 100 locks.The pressure that is in contact with one another of hook-like assembly unit 102 and 103 in arrow 101 maintenance faces (retention surface) produces a tension force that acts on polymer materials, makes surface in contact generation crystallization, hardening, the locking action/effect of the lock uint of steady closure thus.Referring to Figure 23.

Figure 23 is the plan view of embodiment shown in Figure 22, wherein shows to fasten the progressively engagement process of locking steps A to E.Steps A illustrates carries out susceptor part 107 engagements that orientation makes itself and near-end to embedded part 100; Step B illustrates arrow tip ramp 101 and contacts with the initial of surface of in opposite directions susceptor 107 hook-like assembly units 102; Step C further illustrates the displacement and the plastic deformation of the hook-like assembly unit 102 at susceptor fulcrum 104 places; Step D illustrates the situation that arrow 101 contacts with the initial embedding of dog catch 105 at the impact point place, and wherein, the hook-like assembly unit 102 that displacement takes place does not return back to the position 107 (steps A) of original susceptor; Step e illustrates latched position, and wherein, hook-like assembly unit 102 has been replied the position 107 of original susceptor, contacts so form engagement with arrow interference surface 103.In the operating process of shrinkageization, strain crystallization takes place because embedded part is locked the fulcrum district that impact force that susceptor into partly produces causes, make the state of hook-like assembly unit become very stable.

Figure 24 divides three width of cloth figure to describe embodiment shown in Figure 22, a kind of support is shown keeps structure, and wherein figure (A) illustrates and is arranged in the closure device 160 that lax stent design is thrown off; Figure B illustrates the closure device that meshes in the shrinkage state support; Figure (C) illustrate one conduit is installed support 200, support 200 curls and is pressed on the conduit of a sacculus shape, and the closure device 99 of support 200 through engagement (locking) fully is by firm.The embodiment of Figure 25 A and Figure 25 B diagram Figure 22 wherein shows radiopaque particle 108, and this particle is advanced in the supporting structure shown in Figure 25 A by Bao Na, and for example the goldc grains bag is contained in the cavity 108 of the closure device 160 between fastening the lock plug part and accepting partly.Figure 25 C and Figure 25 D illustrate this CT scan visual image that comprises the closed closure device 160 of radiopaque gold grain, like this, just can original position confirm the position of support in blood vessel.

Figure 26 describes the two dimensional structure of Figure 22 medium-height trestle embodiment, comprises the lock uint 250 of non-locking, and in this device, pocketed thing 108 can wrap particularly receives radiopaque material.The details of this lock uint is explained in Figure 21.In addition, the firm Bao Na of goldc grains is shown in the image among Figure 25 in the specific pocketed thing of the lock uint of locking.This phenomenon has also been explained the feasibility that this affinity tag is arranged, helps the visual of implant.Polymeric implant embodiment may owing to lack mass density or do not have signal and almost detect less than.Therefore, these embodiment can wrap and receive the radio opaque markers thing, these radiopaque point such as Fig. 1 to Fig. 9, and Figure 24 is to shown in Figure 26.These points can be coated in the radiopaque material of pulpous state in the depression or susceptor of rivet-like on bracing frame (support) parts the insides or surface, or from radiopaque material, as cutting in the gold thread.As shown in the figure, bracing frame (support) is gone up usual manner or the particular form (as placing in lock uint pocketed thing or the cavity) that radiopaque point stores thing, can help ray detection is carried out in this implant position.

Biologically absorbable polymer comprises all kinds of various various polymerization things.Typically; Biologically absorbable polymer comprises the aliphatic polyester that is the basis with the rac-Lactide skeleton; As gather the L-rac-Lactide, gather the D-rac-Lactide, gather D; L-rac-Lactide, Study of Meso-Lactide, NSC 403079, lactone, it can be homopolymer or multipolymer, and forms the multipolymer part with comonomer (like trimethylene carbonate (TMC) or 6-caprolactone (ECL)).USP 6,706,854; USP 6,607,548; EP0401844; With Jeon et al.Synthesis and Characterization of Poly (L-lactide)-Poly (.Multiblock Copolymers.Macromolecules 2003:36 of ε-caprolactone); 5585-5592. (people's such as Jeon the synthetic and sign of gathering L-rac-Lactide-poly-epsilon-caprolactone segmented copolymer; Macromole; 2003:36,5585-5592).Multipolymer comprises unit such as L-rac-Lactide or the D-rac-Lactide part with sufficient length; So that multipolymer can crystallization, and do not receive the steric restriction of NSC 403079, polyoxyethylene glycol (PEG), 6-caprolactone, trimethylene carbonate, the end capped PEG of mono methoxy (PEG-MME).For example, in certain embodiments, can be arranged in the polymkeric substance in order greater than 7,8,9,10,50,75,100,150,250 L or D-rac-Lactide.Fukushima et al.Sterocomplexed polylactides (Neo-PLA) as high-performance bio-based polymers:their formation; Properties and application.Polymer International 55:626-642 (2006). (people's such as Fukushima three-dimensional compound polylactide (Neo-PLA) is as high performance biotype polymkeric substance: their synthetic, character and application; International polymkeric substance, 55:626-642 (2006)).These L or D-rac-Lactide block can help cross section crystallization (cross moiety crystallization), even in blend composition, add anti-impact modifier.Through making one or two T _g(second-order transition temperature), this blend can be used to polymer compsn or the blend of design special in medicine equipment.The cross section crystallization of compsn and multipolymer is generally has the multipolymer that illustrates as follows and the blend of the monomeric mol ratio of copolymerization: about 50: 50 to about 60: 40,99: 1,95: 5,90: 10,88: 12,70: 30,80: 20.

Biologically absorbable polymer of the present invention has comprised mixture of a great variety, that concentration is different.For example, the amount of lactide polymer, as gather the L-rac-Lactide, gather the D-rac-Lactide or gather D, the amount of any bonded mixture of L-rac-Lactide or aforementioned polymer can be that about 20% (w/w) is to about 95% (w/w).The mass percent of polymkeric substance is from about 50% (w/w) to about 95% (w/w), from about 60% (w/w) to about 95% (w/w), from about 70% (w/w) to about 95% (w/w), from about 70% (w/w) to about 80% (w/w).In one embodiment; What compsn can comprise about 70% (w/w) gathers the L-rac-Lactide; Limiting viscosity (IV) is about 2.0 to about 4.4 or about 2.5 to about 3.8; ((70/30 moles/mole), limiting viscosity (IV) are about 1.2 to about 1.8 or about 1.4 to about 1.6 as gathering L-rac-Lactide-co-front three subunit carbonic ether (TMC) with the multipolymer part.In another kind of embodiment; Polymer formulators comprises a blend, and its three blocks with about 70% (w/w) gather L-rac-Lactide-co-polyoxyethylene glycol (PEG) (99/01 moles/mole) blend, and limiting viscosity (IV) is about 2.0 to about 4.8; About 1.2 to about 4.8; Or about 2.5 to about 3.8, its with gather L-rac-Lactide-co-TMC (70/30 moles/mole) and mix, limiting viscosity (IV) is about 1.2 to about 1.8 or about 1.4 to about 1.6.In another embodiment; Polymer compsn comprises a blend; Its diblock with about 70% (w/w) gathers L-rac-Lactide-co-and gathers ethanol; Limiting viscosity (IV) is about 2.0 to about 4.4 or about 2.5 to about 3.8, and ((70/30 moles/mole), limiting viscosity (IV) are about 1.2 to about 1.8 or about 1.4 to about 1.6 as gathering L-rac-Lactide-co-TMC with multipolymer.

Polymer compsn can also comprise a blend; It has about 70% (w/w) diblock polymer, gather L-rac-Lactide-co-PEG-MME (monomethyl ether) (95/5 moles/mole); Limiting viscosity (IV) is about 2.0 to about 4.4, about 2.5 to about 3.8; When mixing, limiting viscosity (IV) is about 1.2 to about 1.8 or about 1.4 to about 1.6 as gathering L-rac-Lactide-co-TMC (about 60/40 moles/mole to about 80/20 moles/mole, one of them embodiment is about 70/30 moles/mole) for itself and multipolymer.As the 6-caprolactone in the multipolymer is replaced with TMC, the IV of multipolymer is 1.2 to 2.6.(annotating: also be applicable to any situation) with 6-caprolactone replacement TMC

In another embodiment; Polymer compsn comprises blend; This blend contains gathering L-rac-Lactide, about 35% (w/w) gathering D-rac-Lactide and about 10% (w/w) gathering L-rac-Lactide-co-TMC (about 60/40 to about 80/20 moles/mole, and one of them embodiment is about 70/30 moles/mole) or gathering the L-lactide-epsilon-coprolactone to about 35% (w/w) to about 50% (w/w) of the 20%-45% that has an appointment (w/w).

Each composition that can contain 33% (w/w) that have an appointment, 47% (w/w) and about 20% (w/w) or about 40% (w/w), 40% (w/w) and about 20% (w/w) during another is implemented respectively; Be respectively and gather the L-rac-Lactide, gather the D-rac-Lactide; Gather L-rac-Lactide-co-TMC (about 60/40 to about 80/20 moles/mole, is about 70/30 moles/mole among the embodiment) or gather the L-lactide-epsilon-coprolactone.

The limiting viscosity (IV) that contains the multipolymer of the blend that gathers L-rac-Lactide-co-TMC or gather the L-lactide-epsilon-coprolactone can be about 0.8-2.6,1.2-2.6,1.2-1.8 or 1.4-1.6 (if TMC replaces with 6-caprolactone, then the limiting viscosity of multipolymer (IV) can be about 0.8 to 6.0,1.2-2.4,1.4-1.6,2.0-2.4).

Blend polymer can also comprise the copolymer mixture that gathers the L-lactide-epsilon-coprolactone and gather L-rac-Lactide-co-TMC, and its ratio from 10: 1 (w/w) to 1: 10 (w/w) does not wait TMC to replace with 6-caprolactone, then multipolymer.

The generation of rac-Lactide raceme or three-dimensional composite crystalline structure between polymer compsn of the present invention and blend permission L and the D part; In certain embodiments, three-dimensional composite crystalline structure can form between active pharmaceutical ingredient, small molecules, peptide, protein or vehicle.Such crystal further improves the mechanical property of support or medicine equipment.The formation of raceme (three-dimensional compound) crystalline structure is by containing

There is the partition of following ingredients to cause: to gather the L-rac-Lactide and gather the D-rac-Lactide and gather L-rac-Lactide-co-TMC; Gather the D-rac-Lactide and gather L-rac-Lactide-co-TMC; Gather the L-rac-Lactide and gather D-rac-Lactide-co-TMC; Gather the L-rac-Lactide and gather the D-rac-Lactide and gather D-rac-Lactide-co-TMC; Gather L-rac-Lactide-co-PEG and gather D-rac-Lactide-co-TMC; And, gather D-rac-Lactide-co-PEG and gather L-rac-Lactide-co-TMC; Diblock gathers the D-co-L-rac-Lactide and gathers L (or D)-rac-Lactide-co-TMC and diblock and gather the D-co-L-rac-Lactide and gather L (or D)-rac-Lactide-co-TMC (above-mentioned every kind of polymkeric substance, can with the alternative front three methyl carbonic of 6-caprolactone).

When crystallization from melts or solution, the homogeneous phase solution that gathers the L-rac-Lactide or gather the D-rac-Lactide can form left-handed respectively or dextrorotation 10 ₃Helical conformation generates the R crystal formation through in structure cell, arranging in pairs.Beta crystal exists only in the solution spun fiber that high temperature pulls out, and characteristics are to have six 3 at orthorhombic unit cell ₁Spirochete, and can be arranged in more stable R crystal formation.When crystallization from melts or solution, gather the L-rac-Lactide and gather D-rac-Lactide blend and can form the three-dimensional mixture of racemization.The fusing point of this solid mixture (230 ℃) is higher 50 ℃ than the fusing point of the straight polymer enantiomorph of R crystal formation.Brochuet al.Sterocomplexation and Morphology of Polylactides.Macromolecules:5230-5239 (1995) .Polymers blends may also form an amorphous mixture. (the three-dimensional compound and morphology of people's such as Brochuet polylactide, macromole: 5230-5239 (1995)).Blend polymer also can form amorphous mixture).See United States Patent(USP) No. 6,794,485.Its percent crvstallinity can be measured through differential scanning calorimeter method (DSC).Sarasua; Et al.Crystallinity and mechanical properties of optically pure polylactides and their blends.Polymer Engineering and Science:745-753 (2005). (people's such as Sarasua optical purity polylactide and blend percent crystallinity and mechanical property, Polym Eng Sci: 745-753 (2005)).

Polylactide raceme compsn can have the ability of " cold formation " or " cold bend(ing) ", does not need heating.If the blend polymer bag is received the medicament (pharmaceutical agent) of easy generation modification (denaturation), this just possibly seem very important.Cold blend bracing frame of the present invention (support) need not make it have enough snappinesies through heating and insert in the carrier apparatus or so that adapt to organ in irregular shape space so that can curl.Cold formation comprises physiological temp and envrionment temperature, and scope is from about 15 ℃ to about 37.5 ℃ in implanting the organ space time, as the intravascular space of beating, and the bracing frame of cold bend(ing) (support) can produce enough snappinesies of formation expansion bracing frame (support).For example, with regard to support, in certain embodiments, it is desirable using polymer compsn, and these polymer compsns have quite a large amount of amorphous copolymer parts after manufacturing; And, to send sacculus or inflation and be used for implanting and stretch when receiving stress when bracing frame (support) is installed to through shrinkage, these polymkeric substance can form crystallization.This cold bend(ing) polymer support frame (support) embodiment need not carry out preheating before the running surface space that implants makes it become pliable and tough state.Cold bend(ing) property also makes these blends can shrinkage and expansion under physiology and normal temperature, and does not produce be full of cracks.Martins et al.Control the Strain-Induced Crystallization of Polyethylene Terephthalate by Temporally Varying Deformation Rates:A Mechano-optical Study.Polymer.2007:48; 2109-2123 (people's such as Martins the of short duration conversion deformation rate of passing through is controlled the polyethylene terephthalate strain-crystallization: machinery-optical research. polymkeric substance .2007:48,2109-2123.)

Other examples of the biologically absorbable polymer that can use with method of the present invention comprise aliphatic polyester; Biological glass fiber is plain; The chitin collagen protein multipolymer of NSC 403079; Lactide copolymer; Elastin; Tropoelastin; Scleroproein; NSC 403079 L-lactide copolymer (PGA/PLLA); NSC 403079/trimethylene carbonate multipolymer (PGA/TMC); Hydrogel rac-Lactide/tetramethyl glycolide multipolymer; Rac-Lactide/trimethylene carbonate multipolymer; Rac-Lactide/epsilon-caprolactone copolymer; Rac-Lactide-σ-valerolactone multipolymer; L-rac-Lactide/DL-lactide copolymer; TEB 3K-N-vinyl is than pyrrolidone multipolymer; Modified protein; Nylon-2PHBA/ γ-hydroxyl pentanoate copolymer (PHBA/HVA); The PLA/ polyethylene oxide copolymer; PLA-polyethylene oxide (PELA); Gather (amino acid); Gather (trimethylene carbonate); Polyhydroxyalkanoatecopolymers copolymers (PHA); Gather (oxalic acid alkylene ester); Gather (diethyl alkyd Aden ester); Gather (butyric ester) (PHB); Gather (the n-vinyl is than pyrrolidone); Gather (ortho ester); Gather alkyl-2-cyanoacrylate; Gather acid anhydrides; Polybutylcyanoacrylate; Gather (alpha hydroxy acid/a-amino acid) (polydepsipeptides); Gathering the dihydro ratio mutters; Gather-DL-rac-Lactide (PDLLA); Polyesteramide; The polyester of oxalic acid; Gather NSC 403079 (PGA); Gather iminocarbonic ester; Polylactide (PLA); Poe; Gather dioxanone (PDO); Polypeptide; Polyphosphonitrile; Polysaccharide; Urethane (PU); Z 150PH (PVA); Gather ethylene lactic acid ester (PHPA); Gather beta-hydroxy-butanoic acid ester (PBA); Gather σ-valerolactone; Gather the beta chain alkanoic acid; Gather-beta-malic acid (PMLA); Gather-6-caprolactone (PCL); Puppet is gathered (amino acid); Starch; Trimethylene carbonate (TMC) and tyrosine base polymer.Referring to USP the 7th, 378, No. 144.

Pharmaceutical composition can maybe can be coated on the blend polymer through spraying, dipping or coating method with polymer blending.Disclose the 2006/0172983rd A1,2006/0173065 A1,2006/188547 A1,2007/129787 A1 number referring to the U.S..Perhaps, pharmaceutical composition can be packed in the microcapsule, then with polymer blending.Referring to USP the 6th, 020, No. 385.May they be connected on monomer or the polymkeric substance (referring to http://www.piercenet.com/products/browse.cfm through different or identical bifunctional crosslinking agent if pharmaceutical composition and blend polymer are covalently bound? FldID=020306).Be appreciated that the blend polymer with pharmaceutical composition blend, coating or connection does not need the over-drastic experiment to prepare.

Pharmaceutical composition can comprise (i) medicine (pharmacological agents), like (a) antithrombotic, like heparin, heparin derivatives, urokinase and PPack (D-phenylalanyl prolyl arginyl chloromethane ketone); (b) antiphlogiston, like DEXAMETHASONE BP98, prednisone, Kendall compound, budesonide, oestrogenic hormon, Salazosulfamide than pyridine and mesalazine; (c) antitumour drug/antiproliferative agents/anti-miotic; As taxol, 5-fluor-uracil, cis-platinum, vincaleucoblastine, vincristine(VCR), esperamicin, endostatin, angiostatin, angiopeptin, the outgrowth monoclonal antibody that can block smooth muscle cell, thymidine kinase suppressor factor, rapamycin, 40-0-(2-hydroxyethyl) rapamycin (SDZ-RAD), 40-0-benzyl rapamycin, 40-0-(4 '-(methylol) benzyl rapamycin, 40-0-[4 '-(1; The 2-dihydroxy ethyl)] benzyl rapamycin, 40-allyl group rapamycin, 40-0-[3 '-(2; 2-dimethyl--1; 3-dioxolane-4 (S)-2 '-the third-1 '-thiazolinyl]-20 rapamycins, (2 ': E; 4 ' S)-40-0-(4 '; 5 '-dihydroxyl-2 '-penta-1 '-thiazolinyl) rapamycin, 40-0-(2-hydroxyl) ethoxy carbonyl methyl-rapamycin, 40-0-(3-hydroxypropyl) rapamycin, 40-0-(hydroxyl hexyl) rapamycin, 40-0-[(2-(2-hydroxyl) oxyethyl group) ethyl] rapamycin, 40-0-are [(3S)-2; 2-dimethyl--dioxolane-3-yl] methyl rapamycin, 40-0-are [(2S)-2; 3-two hydroxypropyls-1-yl] rapamycin, 40-0-(2-acetoxyl group) ethyl rapamycin, 40-0-(nicotinylsalicylic oxygen) ethyl rapamycin, 40-0-[2-(N-25-morpholinyl) acetoxyl group ethyl] rapamycin, 40-0-(2-N-imidazolyl) acetoxyl group) ethyl rapamycin, 40-0-[2-(N-methyl-N '-piperazinyl) acetoxyl group] ethyl rapamycin, 39-0-demethyl-3.9; 40-0; 0 ethylene-rapamycin, (26R)-26-dihydro-40-0-(2-hydroxyethyl) rapamycin, 28-O-methyl rapamycin, 40-0-(2-aminoethyl) rapamycin, 40-0-(2-acetamido ethyl) rapamycin, 40-0 (2-vitamin PP ethyl) rapamycin, 40-0-(2-(N-Methylimidazole-2 '-Ji-(the carbonyl oxyethyl group is amino) ethyl)-30 rapamycins, 40-0-(2-ethoxycarbonyl aminoethyl)-rapamycin, 40-0-(2-toluol sulfonamide ethyl)-rapamycin, 40-0-[2-(4 '; 5 '-diethoxy formyl-1 '; 2 '; 3 '-triazole-1 '-yl) ethyl] rapamycin, 42-table-tetrazyl rapamycin (tacrolimus), 42-[3-hydroxyl-2-(methylol)-2 Methylpropionic acid ester] rapamycin (fit, temsirolimus) (WO2008/086369) by special cancer; (d) anaesthetic is like lignocaine, bupivacaine and ropivacaine; (e) antithrombotics is like D-D-phenylalanyl-prolyl-arginine chloromethyl ketone (D-Phe-Pro-Arg), the compound that contains the RGD peptide, heparin, r-hirudin, antithrombin compound, platelet receptor antagonist, antithrombin antibody, antiplatelet receptor antibody, Frosst), prostaglandin inhibitor, platelet suppressant drug and tick antiplatelet peptide; (f) growth stimulant of vascular cell, like growth factor, activating transcription factor, and translational enhancer; (g) vascular cell growth suppressor factor is like growth factor receptor inhibitors, growth factor receptor antagonist, the bifunctional molecule of transcribing inhibition system, TI, replication inhibitors, inhibition antibody, the bifunctional molecule of forming to the antibody of growth factor, by growth factor and cytotoxin, being made up of antibody and cytotoxin; (h) protein kinase and tyrosine kinase inhibitor (for example tyrosine protein kinase inhibitor, genistein, quinoxaline); (i) prostacyclin; (j) anticholesteremic agent; (k) angiogenin; (l) antiseptic-germicide such as triclosan, cephalosporins, aminoglycoside and Norwich); (m) cell toxicity medicament, cytostatics and inhibition of cell proliferation; (n) vasodilator; (o) disturb the machine-processed medicine of endogenous vasoactive; (ii) gene therapeutic agents; Comprise antisense DNA and RNA and the DNA of following (a)-(e) gene of encoding: (a) sense-rna; (b) be that tRNA or rRNA coding is to be substituted with DNA (c) angiogenesis factor of defective or lacking of endogenous molecule; Comprise acidity and Prostatropin, VEGF, Urogastron, transforming growth factor a and P, platelet-derived ECGF, platelet-derived growth factor, tumour necrosis factor a, pHGF and rhIGF-1; (d) cell cycle inhibitor comprises CD suppressor factor and (e) thymidine kinase (" TK ") and other effective medicines of interference cell proliferations.

Can be incorporated into polymer blends other agents (pharmaceutical? Agents) include acarbose, antigens, β-blockers, non-steroidal anti-inflammatory drug (NSAID), cardiac glycosides, acetyl salicylic acid, virus inhibitors, aclarubicin, acyclovir, cisplatin, actinomycin, α-and β-sympathomimetic drugs (α-and? β-sympatomimetic), omeprazole (dmeprazole) , allopurinol, alprostadil, prostaglandin, amantadine, ambroxol, amlodipine, methotrexate, S-amino salicylic acid, amitriptyline, amoxicillin, anastrozole, atenolol , azathioprine, balsalazide, beclomethasone, betahistine, bezafibrate, bicalutamide, diazepam and diazepam derivatives, budesonide, bufexamac, buprenorphine Philippines, methadone, calcium, potassium, magnesium, candesartan, carbamazepine, captopril, cephalosporins, cetirizine, chenodeoxycholic acid, ursodeoxycholic acid, tea alkali and theophylline derivatives, trypsin, cimetidine, clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidine, sulfamethoxazole (cotrimoxazole), codeine, coffee result, vitamin D and vitamin D derivative, cholestyramine, cromoglycate, coumarin and coumarin derivatives, cysteine, cytarabine, cyclophosphamide, cyclosporin, cyproterone acetate ( cyproterone), cytabarine, of prazosin, desogestrel, budesonide, hydralazine, diltiazem, ergot alkaloids, dimenhydrinate, dimethyl sulfoxide, dimethyl silicone oil, domperidone and domperidone derivative substance, dopamine, doxazosin, doxorubicin, doxylamine, reaching prazosin, benzodiazepine drugs, diclofenac, aminoglycoside antibiotics, desipramine, econazole, ACE inhibitors, enalapril Plymouth, ephedrine, epinephrine, erythropoietin and erythropoietin derivatives, do furans, calcium antagonists, irinotecan, modafinil, orlistat, peptide antibiotics, phenytoin, Lee Lu azole, risedronate, sildenafil, Toby esters, macrolide antibiotics, estrogen and estrogen derivatives, progesterone and progesterone derivatives, derivatives of testosterone and testosterone, androgen and androgen hormone derivatives, ethenzamide, Etofenamate, according Tuobei Te, fcnofibrate (fenofibrate), according Tuofen Ni, etoposide, famciclovir, famotidine, felodipine, fenoftbrate (fenofibrate ), fentanyl, fenticonazole, helicase inhibitors, fluconazole, fludarabine, flunarizine, fluorouracil, fluoxetine, flurbiprofen, ibuprofen, flutamide, fluvastatin, follicle-stimulating hormone, formoterol, fosfomycin, furosemide, fusidic acid, Gallo verapamil, ganciclovir, gemfibrozil, gentamicin, ginkgo, St. John grass, glibenclamide, oral anti-diabetic drugs urea derivatives, glucagon, glucosamine and glucosamine derivatives, glutathione, glycerol and glycerol derivatives, hypothalamic hormones, goserelin, helicase enzyme inhibition agents, guanethidine, Halofantrine, haloperidol, heparin and heparin derivatives, hyaluronic acid, hydralazine, hydrochlorothiazide and hydrochlorothiazide derivatives, salicylates, hydroxyzine, go methoxy soft red mold Su, ifosfamide, imipramine, indomethacin, indole Lamin, insulin, interferons, iodine and iodine derivatives, Isoconazole, isoproterenol, sorbitol, sorbitol derivatives, Ito itraconazole, ketoconazole, ketoprofen, ketotifen, Lacidipine, lansoprazole, levodopa, L-methadone, thyroid hormones, lipoic acid and lipoic acid derivatives, lisinopril, ergot B urea, Los non Paming, lomustine, loperamide, loratadine, maprotiline, mebendazole, mebeverine, America Crowe triazine, mefenamic acid, mefloquine, Merlot meloxicam, methyl indole lol, meprobamate, meropenem, mesalazine, A Hu amines, dipyrone, metformin, methotrexate, Ritalin, methylprednisolone, Mepiquat thiophene tons, A Oxygen metoclopramide, metoprolol, metronidazole, mianserin, miconazole, minocycline, minoxidil, misoprostol, mitomycin, Mizolastine, Moxi Pu Lee, morphine and morphine derivatives, evening primrose, nalbuphine, naloxone, tilidine, naproxen, noscapine, natamycin, neostigmine, nicergoline, Nikethamide , nifedipine, niflumic acid, nimodipine, Niemoller azole, Nimustine, nisoldipine, epinephrine and epinephrine derivatives, norfloxacin sulfone (novamine? sulfone), Connaught Secretary Card products, nystatin, ofloxacin, olanzapine, olsalazine, omeprazole, Ao Mokang azole, ondansetron, Osage Ciro, oxacillin, Oxiconazole, hydroxymethyl oxazoline, pantoprazole, acetaminophen, paroxetine, penciclovir, oral penicillin, pentazocine, spray for theophylline, pentoxifylline, perphenazine, pethidine, plant extracts , antipyrine, non Nila Min, barbituric acid derivatives, phenylbutazone, phenytoin, pimozide, pindolol, piperazine, Bilaxitan, pirenzepine, compared to shellfish uniform than piroxicam, pramipexole, pravastatin, prazosin, procaine, Puma triazine, propiverine, propranolol, isopropyl antipyrine, prostaglandins, propylthiouracil Isonicotinic amines, hydroxypropyl theophylline, quetiapine, quinapril, quinoline enalaprilat, ramipril, ranitidine, Rip Castro, reserpine, ribavirin, rifampicin, Lee risperidone, ritonavir, ropinirole, Roxatidine, roxithromycin, saponins, rutin and rutin derivatives, Sabah grass, salbutamol, salmeterol, scopolamine, selegiline, Ertaczo, sertindole, sertraline, silicates, sildenafil, simvastatin, sitosterol, sotalol, Division glutamic acid, sparfloxacin, spectinomycin, spiral mold Su, Spirapril, spironolactone, stavudine, streptomycin, sucralfate, sufentanil, sulbactam, sulfonamides, sulfasalazine than pyridine, sulpiride, sultamicillin, Sutai Ming (sultiam) , sumatriptan, succinylcholine chloride, tacrine, tacrolimus, talinolol, tamoxifen, taurocholate Luoding, tazarotene, temazepam, teniposide, for Lornoxicam, terazosin, terbinafine, terbutaline, terfenadine, terlipressin, special sotalol, tetracyclines, Tetrahydrozoline, theobromine, theophylline, cloth for triazine (butizine), methimazole, phenothiazines, thiotepa, tiagabine, tiapride, propionic acid derivatives, ticlopidine, timolol, tinidazole, tioconazole, sulfur birds purine, thiophene Pramipexole ketones, benzene amine amide Gui, tizanidine, Torah oxazoline, tolbutamide, tolcapone, tolnaftate, Tolperisone, topotecan, torasemide, anti- estrogen drugs, tramadol, tramazoline, trandolapril, anti-amphetamine, trapidil, trazodone, triamcinolone acetonide, triamcinolone acetonide derivatives, triamterene, three haloperidol , trifluoroacetic uridine, trimethoprim, trimipramine, curved than Namin, triprolidine, three phosphonamide, Qu amantadine, tromethamine, Trotskyist flat (tropalpin), troxerutin , duly Botero, tyramine, tyrothricin, urapidil, ursodeoxycholic acid, chenodeoxycholic acid, valacyclovir, valproic acid, vancomycin, vecuronium chloride, Viagra , venlafaxine, verapamil, vidarabine, vigabatrin, Vera triazine (viloazine), vinblastine, Changchun amines, vincristine, vindesine, vinorelbine, vinpocetine , Victoria quinoline to Seoul, warfarin, Xanthinol nicotinate, Xipa amines, zafirlukast, zalcitabine, zidovudine, zolmitriptan, azole than tanks, zopiclone, Zuo for equality.Referring to USP the 6th, 897, No. the 6th, 497,729, No. the 6th, 838,528, No. 205, USP and USP.

Medicine equipment can comprise any medicine equipment that is used to implant, and comprises support, electrode sleeve, conduit, lead, implanted pacemaker, conversion device or defibrillator shell, endocranium closure or suture line, spinal fusion cage (spine cage), joint, screw, rod, ophthalmology implant, femur pin, hip replacement thing (hip replacement), Steel Plate For Fixation Of Fracture, graft such as bone graft fixture (bone graft containment device), transplanting fixer, previous anastomotic equipment, blood vessel periphery strip of paper used for sealing, suture line, staple, hydrocephalus splitter, dialysis graft, colostomy bag accessory device, drainage tube, pacemaker and implantation conversion device and defibrillator lead, intervertebral disk, nail, stitching riveting, hemostatic material (hemostatic barrier), anchor clamps, screw, plate, clip, blood vessel implant, tissue adhesive and sealing agent, organizes (intraluminal) equipment, blood vessel supporting rack etc. in bracing frame (support), all kinds of dressing (like wound dressings), bone substitute, the chamber.

In one embodiment, medicine equipment comprises and expands in position when structurally being configured in artery or vein to arrange and adapt to vessel lumen, with the support of the blood flow of dredging the affected part again.This support can be constructed with a lot of different modes of arranging so that before layout, can be in the shrinkage state, in case and cloth postpone can under physiological condition, expand.Medicine equipment of the present invention comprises the biologically absorbable polymer support of various embodiments and/or has heteroid cradle wall.USP the 6th, 117,165,7,108,714 and 7,329, the instance of showing several kinds of this supports No. 277.This support can be the tubular structure that comprises pillar (strut), and this pillar is designed for and makes blood cross its wall, and when this zone, the tissue that is adjacent is soaked into or is in contact with it with convenient blood flow.The support Design of this uniqueness depends on support size radially and longitudinally.

The present invention also provides the method for making the biologically absorbable polymer implant; Comprise: will comprise the crystallizable polymer compsn of the base polymer that gathers the L-rac-Lactide and/or gather the D-rac-Lactide and comprise that the modification that gathers L (or D) rac-Lactide-co-TMC or gather L (or D)-rac-Lactide-co-6-caprolactone is copolymer blended; This modification multipolymer exists with the segmented copolymer form or as the block random copolymer form; Rac-Lactide chain sufficiently long wherein, make can be under various concentration with gather-cross section crystallization (cross-moiety crystallization) takes place in L-rac-Lactide or gather-D-lactide polymer; Moulding, extruding or casting polymer compsn are to construct implant from structure, like support; And the cutting implant is to form the pattern of expectation.In some embodiments, L or the D-rac-Lactide greater than 7,8,9,10,50,75,100,150 or 250 molecules is arranged in the polymkeric substance in order.Fukushima et al.; Sterocomplexed polylactides (Neo-PLA) as high-performance bio-based polymers:their formation; Properties and application.Polymer International 55:626-642 (2006) (people such as Fukushima; Three-dimensional coordinate polylactide (Neo-PLA) is as high performance biotype polymkeric substance: their formation, character and application, Polymer International 55:626-642 (2006)).

Polyreaction is known for polymkeric substance synthetic technician.Its principle, application and technology, like the initiation and the molecular weight control of polyreaction, can be referring to George Odian, Principles of Polymerization, 4 ^ThEd

2004 Wiley-Interscience (" the polymerization principle " that George Odian writes the 4th edition, Wiley-Interscience, 2004).Polymer poly-L-rac-Lactide with gather-the D-rac-Lactide can prepare through corresponding monomeric polymerization.The most frequently used catalyzer is a stannous octoate, but also can use other catalyzer, like dibutyl tin (IV) and tin protochloride (II).Polyreaction also can be caused by initiator, like terepthaloyl moietie or long-chain alcohol.Reaction can be carried out with melt polymerization (fusion polymerization), mass polymerization or any other polymerization technique well known to those skilled in the art.Synthesizing of polymkeric substance at USP the 6th; 706,854,6,607; 548, EP 0401844, WO 2003/057756 and No. 2006/111578, WO, Jeon et al.; Synthesis and Characterization of Poly (L-lactide)-Poly (the Multiblock Copolymers.Macromolecules 2003:36 of ε-caprolactone), (people such as Jeon gathers (L-rac-Lactide)-gathers the synthetic of (6-caprolactone) segmented copolymer and characterizes 5585-5592; Macromolecules 2003:36, open in 5585-5592).Gather-L-rac-Lactide-co-6-caprolactone synthetic also at Macromolecules 2003:36, open among the 5585-5592.In addition, polymkeric substance is commercially available.Supplier comprises http://www.purac.com, http://www.boehringer-ingelheim.com/corporate/home/home.asp,, www.lakeshorebio.com and http://www.absorbables.com/.The IV scope of polymkeric substance comprises about 1.2 to about 4.4, about 1.2 to about 1.8, about 2.0 to about 4.4 and about 2.5 to about 3.8.In some embodiments, can use IV to be lower than about 2.0 and greater than about 4.5 polymkeric substance.

For example, the gathering of target molecular weight-L-rac-Lactide is synthetic through the ring-opening polymerization of lactide monomer.With L-rac-Lactide (1mo1), stannous octoate [5mmol, monomer/catalyst is 200 than (M/C)] and 1,6-pinakon (25mmol) is weighed to one and is equipped with in the churned mechanically round-bottomed bottle.Product is dissolved in the chloroform, and the pore membrane strainer through 0.45 μ m carries out micro-filtration.Separate out polymkeric substance through polymers soln is poured in the excessive methyl alcohol, filter, and vacuum-drying.As technology known in the art, reaction conditions like M/C, temperature of reaction and reaction times, can be adjusted with control and gather-molecular weight of L-rac-Lactide.Though preferred catalyzer is a stannous octoate, also can use like other catalyzer of tin protochloride (II) or like the initiator of terepthaloyl moietie.Gather-the typical scope of Tm of L-lactide polymer is about 160 ℃ to about 194 ℃, and the IV scope be about 2.0 to about 4.4 (referring to, for example USP the 6th; 706; 854,6,607,548, No. 2006/111578, EP 0401844, WO 2003/057756 and WO).

It is synthetic through ring-opening polymerization by lactide monomer to have the gathering of target molecular weight-D-rac-Lactide.With D-rac-Lactide (1mol), stannous octoate [5mmol, monomer/catalyst is 200 than (M/C)] and 1,6-pinakon (25mmol) is weighed to one to be furnished with in the churned mechanically round-bottomed bottle.Round-bottomed bottle is with the exsiccant nitrogen purging, and immerses in 130 ℃ the oil bath 5 hours.The product of gained is dissolved in the chloroform, and carries out micro-filtration through the pore membrane strainer of 0.45 μ m.Separate out polymkeric substance through polymers soln is poured in the excessive methyl alcohol, filter, and vacuum-drying.As technology known in the art, reaction conditions like M/C, temperature of reaction and reaction times, can be adjusted with control and gather-molecular weight of D-rac-Lactide.Though preferred catalyzer is a stannous octoate, also can use like other catalyzer of tin protochloride (II) or like the initiator of terepthaloyl moietie.Gather-T of D-lactide polymer _mTypical scope is about 160 ℃ to about 194 ℃, and the IV scope is about 2.0 to about 4.4.

Random copolymers part is synthesized through ring-opening polymerization with the 6-caprolactone monomer by D-rac-Lactide or L-rac-Lactide.USP the 6th, 197,320,6,462,169,6,794, No. 485.With caprolactone (100mmol), D-rac-Lactide or L-rac-Lactide (100mmol), stannous octoate (1mmol) and 1,6-pinakon (0.5mmol) is weighed in the glass ampoule bottles of being furnished with magnetic stirring bar.With ampoule be 90 ℃ with behind the nitrogen purging three times at the vacuum lower seal, heating and stirring 24 hours in 150 ℃ of oil baths then.After the reaction, smash ampoule; Polymkeric substance is dissolved in the chloroform, and the pore membrane strainer through 0.45 μ m carries out micro-filtration.Separate out through polymers soln is poured in the excessive methyl alcohol, filter, and vacuum-drying.Through the control reaction conditions, like the ratio of rac-Lactide/6-caprolactone, ratio, temperature of reaction and the reaction times of monomer/catalyst, the molecular weight of multipolymer part can be controlled.Preferred catalyzer is a stannous octoate; But also can use other catalyzer or initiator or terepthaloyl moietie like tin protochloride (II).Mol ratio through control D-rac-Lactide or L-rac-Lactide, the number that is arranged in order the L-rac-Lactide in the random copolymers part can be controlled, and this number range is 10-20,20-30,30-40,40-50,100-150 or 150-200.(referring to, for example EP 1468035 B1, No. the 6th, 706,854, USP, WO 2006/111578 A1 and WO 03057756 A1).TMC can replace the 6-caprolactone in the above-mentioned building-up process.

In each embodiment, can use contain gather-the L-rac-Lactide with gather-Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock of D-rac-Lactide.The Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock of use L-rac-Lactide and D-rac-Lactide can increase the formation of raceme crystalline structure in polymeric blends blend process, and this raceme crystalline structure has D-rac-Lactide and L-rac-Lactide simultaneously when homotype enantiomorph (homo-enantiomer) cocrystallization.

In the building-up process of lactide polymer, can be through impelling reaction " completion " and/or using abstraction technique, like SX or supercritical CO ₂Extraction extracts monomer from reaction.USP the 5th, 670, No. 614.

Being used for polymkeric substance that medicine controlled releasing sends must have biocompatibility and be degraded to no mutagenicity, no cytotoxicity, nothing without exception and cause struvite nontoxic molecule.The polymkeric substance and the multipolymer that the example of useful polyanhydride of the preparation of blend polymer of the present invention and polyester are comprised following material: lactic acid, oxyacetic acid, hydroxybutyric acid, racemic melic acid, caprolactone, sebacic acid, 1; Two (to the carboxyl phenoxy) propane (CPP) of 3-, two (to the carboxyl phenoxy) methane, dodecandioic acid (DD), m-phthalic acid (ISO), terephthalic acid, hexanodioic acid, fumaric acid, nonane diacid, pimelic acid, suberic acid, methylene-succinic acid, biphenyl-4; 4 '-dioctyl phthalate and benzophenone-4,4 '-dioctyl phthalate.Polymkeric substance can be aromatic, aliphatic, hydrophilic or hydrophobic.

Blend polymer uses known method to form, like solvent or melting mixing.In the solvent process, in the suitable organic solvent of aequum or mixed solvent, the mixing of target weight in order to every kind of polymkeric substance of blend, and polymers soln is mixed.Then organic solvent is removed, for example, obtained the blend polymer resistates through evaporation.Through remove desolvate before with pharmaceutically active agents or additive dissolving or be dispersed in the blend solution, can pharmaceutically active agents or additive be introduced in the blend polymer.This method is particularly useful for making to add has the blend polymer to the pharmaceutically active agents of high temp. sensitive.

In the melting mixing process, polymer melt or is heated to each polymkeric substance fusing point separately respectively together, then both is mixed one definite period, for example about two minutes to about 30 minutes (5,10,15,20 and 25 minutes).Then blend is cooled to room temperature.Can through before the blend with pharmaceutically active agents or additive dissolving be dispersed in the blend solution or separately melt solution in introduce them.USP discloses No. 2006/0172983.

Second-order transition temperature (T _g), Tc (T _c) to go into temperature of fusion (T _m) be the key characteristic parameter of blend polymer.The mutual solubility of polymer blend is by the single second-order transition temperature (T of blend _g) indication (squint or broaden with respect to the blend composition).Have two or more T _gBlend show the degree of not dissolving each other of polymkeric substance.Blend polymer can not have temperature of fusion (T yet _m), the expression blend polymer is the non-crystalline state blend, or has one or more temperature of fusion.Have a plurality of temperature of fusion and show crystalline polymer, wherein crystallization is single or a plurality of homotype enantiomorphs or part (co-moiety) crystal altogether, for example gathers-L-rac-Lactide and gathering-three-dimensional compound or racemization crystalline structure between the D-rac-Lactide.The present invention includes a kind of polymorphic polymer system, have the difference degree (with the farmland size that causes thus) of dissolving each other, can influence mechanical property and degradation kinetics.

The molecular weight of blend polymer or viscosity typically are the molecular weight of composition polymkeric substance and the MV of viscosity.Polymkeric substance can be through using melt kneading, like two roller mills, Banbury milling device, single screw rod or twin screw extruder, mesh in the same way screw extrusion press and multiple screw extruder blend together.Chris Rauwendaal.Mixing in Polymer Processing.Wiley, 1993 (the mixing .Wiley in the Chris Rauwendaal. polymer processing, 1993); Http:// www.rauwendaal.com/; Www.radcastle.com.Blend polymer also can be extruded through thin plate, abnormal shape is extruded, inflation film is extruded, blowing, rotoforming, thermoforming processing, compressed moulding, transfer mould or injection moulding are processed.www.me.gatech.edu/jonathan.colton/me4210/polymer.pdf。

In one embodiment, gather-the L-rac-Lactide, gather-the D-rac-Lactide with gather-L-rac-Lactide-co-TMC (or 6-caprolactone) is in the same place through do mixing blend.After the material composition drying, material composition is done mixed in multiaxis Turbula type blender under nitrogen.To do mixed thing then sends in extrusion machine or the injection moulding machine.In addition, the exsiccant composition can be individually by being metered in extrusion machine or the shaper.After the extruding, blend polymer is its T in TR _g(second-order transition temperature) is extremely greater than raceme T _mTemperature under process.

In forcing machine or shaper mixing process, component of polymer deliquescing and/or fusing flow in the unit of plasticating of forcing machine or shaper then.They can be used as independent melt region and visible, up to the action of plasticizing screw through shearing and the expansion mobile is used to facilitate closely and mixed.This formation that allows the racemization crystalline structure by the tightness between the rac-Lactide enantiomorph of external force.Because its molecular weight is big, the racemization colloid can be greater than enantiomorph T _m(promptly 180 ℃) but less than raceme T _mThe temperature of (230 ℃) forms in this molten mass.The raceme crystallization needs to surpass raceme T in about 195 ℃ of beginnings _mHigher temperature of fusion, and/or extra mixing and melt extruding.The T of of the present invention gathering-L-rac-Lactide/gather-D-rac-Lactide raceme _mTypical range is about 195 ℃ to about 235 ℃.Brochu et al.Sterocomplexation and Morphology of Polylactides.Macromolecules 1995 28:5230 (people such as Brochu; The three-dimensional compound and morphology of polylactide, Macromolecules 1995 28:5230).

Blend polymer also can fusion-cast or is transferred in the pressing mold (transfer mold).Can carry out moulding or extruding to polymkeric substance, form final device.Perhaps, blend polymer can be solution or gel forming.In solution or gel forming, when removing solvent phase, in the blend polymer crystallization can appear.Remove speed, i.e. crystallization between controllable portion through the control solvent.Solution shaping membrane or moulding pipe can stand the thermal treatment of further isothermal recrystallization.In melting process, through introducing high mixed in molten mass or through this temperature is increased to enantiomorph T _mMore than, promote the formation of the three-dimensional mixture of polylactide crystalline of high Mw.Brochu et al.Sterocomplexation and Morphology of Polylactides.Macromolecules 1995 28:5230 (people such as Brochu; The three-dimensional compound and morphology of polylactide, Macromolecules 1995 28:5230).Device finished product or work in-process or component can stand the thermal treatment of further isothermal recrystallization.

Polymer compsn can be used commercially available particulate material and copolymer additives preparation.In one embodiment, dry ingredient is weighed in the container according to the weight ratio of expection, rotated 30 minutes or, can then carry out further drying then up to obtaining uniform mixture, as under vacuum in 60 ℃ of dry 8-12 hours or spend the night.Can carry out melt blending and be injected in a pair of matching diaphragm through thorough blended component.Compsn can utilize length-to-diameter ratio under 185 ℃-250 ℃ of temperature of fusion be that 16/1 to 32/1 or 24/1 to 26/1 screw rod is extruded under 2-100rpm.Blend polymer can be extruded formation for example pipe, plate or fiber.Pipe can be cut into support or small pieces.In addition, fibre plate can be cut into or process support.

Support shape frame (support) can be used for angioplasty.Support is placed in the narrow vessel lumen with the support blood vessels wall.Can prevent the elastical retraction and the closure of artery at ill artery fragment placing rack.Support can prevent that also artery from partly cut-away taking place along the artery middle level.Support can be in any physiologic spaces or the inner use of potential spatial lumen, like artery, vein, bile duct, urinary tract, digestive tube, tracheobronchial tree, cerebral aqueduct or urogenital system.Support also can be placed on human and non-human animal's tube chamber inside.Two kinds of supports are generally arranged: self-expanding formula and inflation formula.Balloon expandable stent is inserted the blood vessel infected area through the support with shrunk and is placed in the vascular lesion position.Support expands through inserting sacculus at internal stent.Make inflation then and support is expanded.Artery plaque is reinvented in expansion, and support is fixed in the lesion vessels.

On the contrary, self-expanding stent can expand through self.Self-expanding stent has a lot of different designs, comprises tortuous shape (volution), annular, cylindrical, roll forming, reducing tubulose, high-order coiled type, cage type or mesh-like.USP the 6th, 013, No. 854.Self-expanding stent inserts affected part through the support that will receive the pencil attitude, like narrow zone, is positioned in the blood vessel.In case remove the beam tube sheath, support will freely be expanded to predefined diameter.Support can utilize to have external diameter and compresses than the little pipe of the internal diameter of affected part area vasculosa.When support in pipe when constrained state discharges, support is able to expansion, recovers its original shape, and is relying on vessel wall firmly to be fixed in the blood vessel.

The hollow tube of support from processing by biologically absorbable polymer.In pipe, process groove or hole, constitute the parts of support.Groove and hole can utilize laser, form like " ultraviolet quasi-molecule (Eximer) laser " or " femtosecond (Femtosecond) laser ".Can utilize the high-repetition-rate from the emission of titanium sapphire (Ti:sapphire) vibrator, the near infrared femto-second laser pulse of low pulse energy, the local indexes of refraction structure of polymkeric substance inside is carried out little processing.The formation that is used to prepare groove and the hole of said support is considered to those of ordinary skills' general knowledge.Blend polymer also can be injection molded into finished product or work in-process shape.Yoklavich et al.Vessel Healing Response to Bioaborbable Implant.Fifth World Biomaterials Congress.May 29-June 2; 1996, Toronto, Canada (people such as Yoklavich; Can absorb the blood vessel callus reaction of implant to biology; The 5th world's biomaterial meeting, Toronto, 29 days-June 2 May in 1996).

For ease of placing rack in patient's body, can before blend, electron dense or refraction of X-ray affinity tag be mixed with polymeric materials.Radiopaque compound can be selected from X ray densification or refractive compound, like metallics or salt.Suitable affinity tag metal can comprise iron, gold, colloid silver, zinc, magnesium, pure form or organic cpds all can, tantalum, tungsten, platinum/iridium, platinum or radiopaque pottery, like zirconium white.For obtaining suitable marker material blend, solvent system can comprise among acetone, toluene, methylbenzene, the DMSO two kinds or more kinds of.

The physical property of polymeric blends can utilize various method to characterize.Following not exhaustive, can also use other method.The molecular weight of polymkeric substance can be measured through GPC (GPC) or size exclusion chromatography, (SEC) (like Waters HPLC system 410 differential refractometers, three PLGel posts (HR2, HR4 and HR5E), 515 pumps) with distributing.Molecular-weight average (Mw), number-average molecular weight (Mn) and MWD can be measured through GPC." MWD " is to draw Mw divided by Mn.People also can use the dilute solution viscosity instrumentation amount limiting viscosity relevant with polymericular weight.(referring to, www.boehringer-ingelheim.com/.../ic/.../N02-06_IV_vs_SEC .pdf for example, on October 10th, 2009).

Dsc (DSC) can be used for studying thermodynamic property, the percent crystallinity and three-dimensional compound of this compsn.In one embodiment, the result of the dsc measurement of use DSC is expressed as the relation curve of heat flux and temperature.The instance of the characteristic of polymkeric substance can utilize DSC to obtain, and comprises glass transition temperature (T _g), Tc (T _c) and temperature of fusion (T _m).DSC also can be used for detecting the purity and the composition of polymkeric substance.The percent crystallinity scope of this polymer compsn can be for about 0% to about 10%, about 10% to about 20%, about 20% to about 70%, about 20% to about 40%, about 30% to about 60% or about 40% to about 50% (all values all be weight ratio (w/w)).

Can wide-angle x-ray scattering (WAXS) or small angle x-ray scattering (SAXS) (SAXS) be used to measure crystalline structure, percent crystallinity and three-dimensional compound (the http://www.panalytical.com/index.cfm of polymkeric substance? Pid=43).In one embodiment, sample scans in the wide-angle x-ray goniometer, and with the function construction of scattering strength as 2 θ angles.Tsuji; Poly (lactide) Sterocomplexes, Formation, Structure; Properties; Degradation and Applications.Macro.Mol.Bio.Sci.5:569-597 (2005) (Tsuji, the three-dimensional mixture of polylactide, formation, structure, character, degraded and application, Macro.Mol.Bio.Sci.5:569-597 (2005)).

The form of this polymkeric substance can be studied through sem (SEM) or transmission electron microscope (TEM).In one embodiment, be fixed on polymer sample on the microscope before, use sputter coating appearance sputter-coated gold layer.For the external degradation test, hole, crackle, groove or other similar structure occur and possibly show the corrosion that polymkeric substance is taking place.

The form of this polymkeric substance can also be measured through polarized light microscopy, atomic power microscopy (AFM) or energy dispersion x-ray spectrometry (EDS).In one embodiment, use the polarization optics microscope of being furnished with heating unit.Sample places on the sheet glass, is heated to its temperature of fusion (Tm), is cooled to 120 ℃ with 10 ℃/min then.

The chemical constitution of this polymkeric substance can be identified through infrared (IR) or Raman spectroscopy.The chemical constitution of this polymkeric substance, multipolymer and blend ratio and end group can be studied through nuclear magnetic resonance spectrometry (NMR).In one embodiment, the H of polymkeric substance ¹-NMR spectrum is at CDCl ₃Middle record.In another embodiment, record polymkeric substance ¹³The C-NMR spectrum.The limiting viscosity of polymkeric substance and molecular weight can advance to measure through viscometry.

The molecular weight of this polymkeric substance can also be measured through static light scattering method (SLS).The thermostability of this polymkeric substance can be measured through thermogravimetric analysis (TGA), and the surface chemistry of this polymkeric substance is formed and can be studied through x-ray photoelectron microscopy (XPS).Melt viscosity of this polymkeric substance and stress relaxation can be measured through rheology.

Also can assess the mechanical property of polymkeric substance.For example, tension test can use the Instron trier to carry out, and with its sample that stretches, record makes the required power of breakage.Obtain stress-strain(ed) curve thus, therefrom can measure mechanical properties (modulus, intensity, force-at-yield and extension at break amount).Compression tests also can use the Instron trier to carry out, and it places sample under the crushing load and the record distortion.Pliability test can use Instron trier or dynamic state material analysis to carry out, and sample is placed the three-point bending test set, the hardness of recording materials.In this test, record bending strength and modulus in flexure.Dynamic mechanical analysis (DMA) is used to measure heat deflection performance and the mechanical property that is changed the polymkeric substance that causes by the temperature that acts on sample, time, frequency, external force and tensile.Density also can be measured through gas balloon.httt://www.polymathiclabs.com/mechanical_physical.php。

Also will detect strain-crystallization.Single shaft and twin shaft deformation and after annealing stage can influence the development of structure and performance.The crystalline structure of polymer compsn and physical parameter were measured in each stage that deformation takes place.X-ray diffraction technology, online spectrum birefringence technique, real-time FTIR, Raman (RAMAN) spectrography and PET can be used to monitor percent crystallinity.People such as Martins, Polymer 48:2109-2123 (2007).

Many polymkeric substance show another kind of local yielding behavior, cause the polymkeric substance in the largest deformation district to bleach.At microscopically, the regional area of these surrenders shows through forming the fine fisssure by polymkeric substance O-fiber bridge joint, and volume increases (expansion).Tiny crack and stress whitening are typical deformation mechanisms.Because tiny crack is mechanism of intumescence, can be expected at zone and occurs, like the lateral edges in the hole that cuts out in thick sample interior or the sample with high expansion stress.I.M.Ward, " Mechanical Properties of Solid Polymers, 2 ' nd Ed. " Wiley, NY, 1983. (I.M.Ward, " mechanical property of solid polymer ", (second edition), Wiley, NY, nineteen eighty-threes).

Also will measure the degraded of extruding or moulding rear copolymer blend.USP the 6th, 794, No. 485.For example, the sample of moulding such as the support polymkeric substance that can directly be used for biological degradation test or blend can be cut into cubes after extruding.The shape of any expection or volume can be used for test, and scope is about 0.5mm ³To about 1mm ³, 10mm ³To about 100mm ³, about 20mm ³To about 80mm ³, or about 40mm ³To about 60mm ³Then polymer samples is placed solution, to study its degraded.In one embodiment, under 37 ℃ with sample place phosphate buffer solution (PBS, pH=7.4).Can carry out the research of about 1 month, 2 months, 3 months, 4 months, about 6 months or 1 year to the physical property of polymer samples.The external degradation kinetics of this biologically absorbable polymer shows that after (like 3 ℃ phosphate buffered saline (PBS)) stored 1 month under physiological condition, its total rate of decomposition was lower than about 5%; In other embodiment, under physiological condition, store 1 month, 2 months, 3 months or after 6 months, total rate of decomposition is lower than about 10%, 20%, 30% or 40%.The solution of testing that is used to degrade also can be Tris BS (TBS), 4-(2-hydroxyethyl)-1-piperazine ethyl sulfonic acid (HEPES) damping fluid, 3-(N-morpholino) propanesulfonic acid (MOPS) damping fluid, piperazine-N, and N '-two (2-ethanesulfonic acid) is damping fluid or any other required buffer system (PIPES).The pH scope of damping fluid can be about 6 to about 8.5, about 6.8 to about 8 or about 7.2 to about 7.6.Degraded test can be at 20 ℃ to about 50 ℃, about 25 ℃ to about 45 ℃, about 47 ℃ or under about 37 ℃, carry out.The pH of buffer system, composition and volume can extremely finish to keep identical or change from the test beginning.Degrading the temperature of testing can be from testing beginning to finishing the identical or change of maintenance.Before polymer samples is characterized, can be with distilled water wash and dry under vacuum.The physics and the mechanical characteristics of polymkeric substance are examined and determine by the above.In one embodiment, the molecular weight of polymkeric substance passes through gpc measurement.Degradation rate can be through mass loss (%) and decrease in molecular weight (%) estimation.Blend polymer also can pass through sem (SEM) and detect.

The degraded of polymkeric substance also can use the TOF-SIMS spectrography to detect.USP the 6th, 864,090 and 6,670, No. 190.Through adjusting biodegradable polymer of the present invention, it is degraded with particular rate, the wash-out of medicine can accurately be controlled, and along with polymkeric substance is degraded fully and stopped.

In addition; Through of the influence of titration degraded product to and the following; Detect its immunological characteristic: (i) leucocyte migration, (ii) adhesion, (iii) adhesion, (iv) T cell proliferation, (v) B cell proliferation, (vi) T cell activation, (the vii) active calibrating of the COX, (activation of viii) cytokine activation, (ix) arachidonic acid cascade (cascade), (x) matrix metalloproteinase, (xi) signal transduction pathway of mediated by integrin of endotheliocyte; For example EGF, (xii) transcription factor; For example, NF κ B and (xiii) growth factor, for example TGF.

That the following example is considered to indefiniteness and only represent selected embodiment.

Embodiment 1

Three batches of blend polymers have been prepared.The composition of each batch is shown in down Table I.

Table I: the composition of each batch of polymkeric substance as expressed in weight percent

1. gather-the L-rac-Lactide

2. gather-the D-rac-Lactide

3. gather-L-rac-Lactide-co-6-caprolactone

4. gather-L-rac-Lactide-co-TMC

5. mol ratio L-rac-Lactide/6-caprolactone: notice that these mol ratios only represent the nominal ratio, promptly standard error is ± 5%

6. nominal mol ratio is gathered L-rac-Lactide/TMC

7. nominal mol ratio is gathered L-rac-Lactide/TMC

To hot method of each sample undergo differential scanning calorimetry (DSC) and wide-angle scattered x-ray diffraction (" WAXS ").

Blend polymer is squeezed into the long hollow tube with different wall.In some cases, pipe is cut into the ringlet that width is the 1-2 millimeter.Before the analysis; Pipe or ringlet are placed on external diameter to be equal to or less than on the annealing mandrel of internal diameter of pipe; And the temperature between the temperature of fusion of glass transition temperature of polymer and blend polymer, about 5 minutes to 18 hours time of annealing in air, under inert atmosphere or the vacuum.In various embodiments, the annealed time from about 5 minutes to about 2 hours, about 10 minutes to about 1 hour, about 15 minutes to about 30 minutes or about 15 minutes.The annealed TR from about 60 ℃ to about 150 ℃, from about 70 ℃ to about 140 ℃, from 80 ℃ to about 120 ℃.In the present embodiment, P-11371 and P-11369 were 80 ℃ of annealing 15 minutes, and P-11228 annealed 15 minutes down at 120 ℃.

In some cases, after the annealing through managing or ringlet slides on the external diameter conic mandrel bar bigger than pipe or the internal diameter of ringlet, to pipe or ringlet stress application.The extension degree scope is extremely about 50% (d1/d2) of about 10% (d1/d2), and wherein d1 representes beginning or initial diameter, the diameter after d2 representes to stretch.

The DSC thermogram of each batch (P11228, P11369 and P11371) is shown in Figure 27 to Figure 35.The DSC thermogram uses TA instrument Q10 DSC to produce.Every kind of about 3mg of material is placed aluminium dish and sealing.Sample disc is put into the DSC instrument, does its reference with the aluminium dish of sky.Use climbing program (ramp program) from-50 to 250 ℃ material to be heated with 20 ℃/min.Use TA computed in software T then _g, T _cAnd T _mApproximation, the words that occur like their.

Table II: dsc analysis general introduction

1.T _mValue is represented approximate peak, and smaller value is first or homotype enantiomorph crystal value of fusing, and higher value is the approximate peak of the fused of three-dimensional mixture.

2. the value of mark is an approximation.

3. the value of mark is an approximation.

Figure 27, P11228 is untreated, shows single strong T _gAt about 64 ℃, the crystallization exotherm is at about 115 ℃, H _cBe about 26.6J/g.Two tangible T are arranged _m, a peak is located at about 179 ℃, and expression gathers-the homotype enantiomorph crystal of L-rac-Lactide or gather-D-rac-Lactide, another peak is located at about 217 ℃, the three-dimensional mixture of expression L and D.115 ℃ of H that locate _cDo not offset total H _m, there is the crystallization of some feed states or the state that is untreated in expression.But corresponding WAXS (Figure 37) shows that untreated sample is mainly amorphous.The heat of crystallization of three-dimensional mixture seems to drop in the same TR with the part of homotype enantiomorph melting curve, covers exotherm or makes the exotherm skew.

Figure 28, the P11228 annealed shows about 61 ℃ and 128 ℃ two glass transitions locating.128 ℃ of T that locate _gAppearance explanation have the significant farmland difference between the compound glass transformation relevant and three-dimensional mixture and the homotype enantiomorph crystal with three-dimensional mixture.Locate not have in the crystallization exotherm explanation DSC test process to pine for not taking place crystallization adding at about 115 ℃, and explain that 180 ℃ form in annealing process with 217 ℃ of two kinds of relevant crystalline structure of locating.

Figure 29, P11228 through annealing with stress, independent T that demonstration is only had an appointment 59 ℃ and located _gAnd two different T _m, one is positioned at about 179 ℃ and locates (expression polylactide homotype enantiomorph crystal), and another is positioned at about 217 ℃ and locates (representing three-dimensional compound crystal).Do not exist and be positioned at 128 ℃ of the 2nd T that locate _g(seeing Figure 28) explains that strain inducing is rearranged into crystal habit.

Through annealed sample corresponding WAXS figure See Figure 37a and Figure 37 b; Confirmed to exist simultaneously to gather-L-rac-Lactide or gather-the triclinic(crystalline)system crystal of the false rhombic system structure of D-rac-Lactide homotype enantiomorph crystalline and polylactide solid mixture, shown in DSC (Figure 28).Behind the stress application, See Figure 38a and 38b continue to show to have L and/or D homotype enantiomorph crystal habit and three-dimensional mixture simultaneously.Peak width representes that percent crystallinity increases along with the introducing of sample stress.

Figure 30, the DSC of the untreated P11369 of sample shows about 55 ℃ of single T that locate _g, the strong crystallization heat release of about 100 ℃ of about 23.7J/g that locate is located two different fusion endothermic processes, bonded H with about 224 ℃ for about 179 ℃ _mBe about 38.5J/g.These two melting peaks with gather-the polycrystal form of the three-dimensional mixture of L-and/or D-rac-Lactide homotype enantiomorph and polylactide conforms to.About 100 ℃ of H that locate _cAs if be 23.7J/g, all do not occupy the crystalline structure fusion in the endothermic curve of two back, there is certain percent crystallinity in this explanation untreated samples or has not inclusive crystallization heat releases in 195 ℃ of zones.The WAXS diffractogram (Figure 39) of the correspondence of this sample confirms that untreated sample is mainly amorphous.

Figure 31 shows the DSC of annealed P11369, shows about 64 ℃ of independent strong T that locate _gAnd about 179 ℃ located respectively with 225 ℃ and gather-L-rac-Lactide and/or gather-D-rac-Lactide homotype enantiomorph crystal and corresponding 2 the different crystallization fusions heat absorptions of the three-dimensional compound crystal structure of polylactide.Among Figure 31, locate not have the crystallization heat release, explain crystallization takes place in annealing process at about 100 ℃.Corresponding WAXS analyzes referring to figure below 40a and 40b, shows that the dominant crystalline structure that exists is D and/or L polylactide homotype enantiomorph.Have three-dimensional mixture although this has disclosed in this sample of DSC demonstration, as if being formed under this annealing conditions of three-dimensional mixture is suppressed, and the formation in the DSC heating cycle is occupied an leading position.

Figure 32 is the DSC of the P11369 of the annealed and the application of force, shows about 63 ℃ of independent T that locate _gAnd about 178 ℃ and 223 ℃ strong crystallization fusion heat absorptions of locating, representative gathers the L-rac-Lactide and/or gathers D-rac-Lactide homotype enantiomorph and polylactide stereoscopic composite crystal habit.Corresponding WAXS analyzes referring to figure below 41a and 41b, shows wideer peak, shows because the increase of the percent crystallinity that stress application causes.Further, the stress induced crystal habit of the sample of the application of force does not seem to remain unchanged.

Figure 33 illustrates the DSC of undressed P11371.This DSC is presented at about 59 ℃ of strong T that locate _g, and 0 ℃ of weak transformation of locating shows slight not mutual solubility.The tangible crystallization heat release of 25J/g appears at about 106 ℃ and locates.Gather the three-dimensional compound crystal structure of L and/or D rac-Lactide homotype enantiomorph and polylactide, total H about 179 ℃ and 220 ℃ two crystallization fusion heat absorption expressions locating _mBe about 35.7J/g, have certain percent crystallinity in the surperficial undressed sample or do not calculate crystallization heat release at about 190 ℃ of three-dimensional mixtures of locating.The WAXS diffractogram that this sample is corresponding (referring to following Figure 42) confirms that untreated sample is mainly amorphous.

Figure 34 illustrates the DSC through annealed P11371.This DSC demonstration is positioned at about 60 ℃ of single T that locate _g, about 105 ℃ of about 5.6J/g that locate hang down the crystallization heat release, are positioned at about 108 ℃ of crystallization fusions heat absorptions different with about 220 ℃ locate two, and the Hm of combination is about 41.98J/g.The existence of crystallization heat release shows that this annealing conditions of this pattern makes polymkeric substance crystallizable come out in the heat of DSC is climbed circulation, promptly keeps further crystallization.Corresponding WAXS data are referring to figure below 43a and 43b, and the WAXS of annealed P11371 shows that dominant is the crystal habit that gathers L and/or D polylactide homotype enantiomorph.As if having three-dimensional mixture although this has just disclosed in this sample of DSC demonstration, the formation of three-dimensional mixture is suppressed under this annealing conditions, and the formation in the DSC heating cycle is occupied an leading position.

Figure 35 shows the DSC through the P-11371 of the annealing and the application of force.This DSC demonstration is positioned at about 58 ℃ of T that locate _g, the brilliant heat release of the brief summary of about 103 ℃ of about 4.1J/g that locate, be positioned at about 177 ℃ with about 220 ℃ two different crystallization fusions heat absorptions locating, representative gathers L and/or D rac-Lactide homotype enantiomorph crystal and polylactide solid mixture.A little bit smaller a little with respect to the heat of crystallization among Figure 34 among this DSC, this shows that existence is by the stress induced crystallization that acts on sample.

Sample is analyzed with X-ray diffraction.(v.4.1.20) common detector system, GADDS collect the XRPD collection of illustrative plates to utilize Bruker D-8 Discover diffractometer and Bruker ' s General Detector System.Use the fine focusing pipe (40kV, 40mA),

mirror and the alpha-emitting incident microbeam of 0.5mm double needle hole collimator generation Cu K.Incident X-rays optics is actually " collimated beam ".Owing to used surface detection system, between sample and detector, do not had secondary x rays optics.Before sample test, analyze silicon standard substance (NIST SRM 640c) to confirm the peak position of Si 111.

The sample of sample uses kapillary to support, and is fixed on the mobile platform.Utilize pick up camera and laser that test zone is located, so that the incident X-rays light beam intersects in reflection geometry.Allow like sample geometry, vibrating example is orientated statistic data to optimize a little in collecting data procedures.Settle the bundle door screen reducing to minimum nearby from the air scattering of incoming beam.

Utilization is positioned at apart from the Hi-Star surface detector of sample 15cm collects diffraction pattern, and uses GADDS to handle.Detector and incident X-rays light beam are mobile during carrying out the current data collection, and surface detector returns the two-dimentional powdery diffractometry image that is produced by sample.The intensity of the GADDS image of diffraction pattern is used the scope integrates of the step-length of 0.04 ° of 2 θ at 2.0 to 37.6 ° of 2 θ.The pattern of integration shows that the intensity of diffraction is the function of 2 θ.The adz of 2 θ (X-axle) is ± 0.2 degree, and relative error (difference at peak and peak) is about ± 0.02.The error of peak intensity is about 5% (referring to H.P.Klug and L.E.Alexander:X-ray Diffraction Procedures For Polycrystalline and Amorphous Materials:Wiley-Interscience Publication; 1974 (second edition) (H.P.Klug and L.E.Alexander: the X-ray diffraction detection method of polycrystalline state and amorphous material; Wiley-Interscience Publication, second edition in 1974)).Table III is listed the WAXS data.

Table III: WAXS analyzes general introduction

Figure 42 illustrates the X-ray powder diffraction pattern that from the harmless pipe of raw material or undressed material (P11371), obtains.Sample appears as non-crystalline state, does not promptly observe the crystallinity of this sample.The sensitivity of WAXS instrument can detect in the sample 1% or more crystalline material.Amorphous substance shows that total percent crystallinity is less than about 95% (w/w), less than about 98% (w/w) or less than about 99% (w/w).

Figure 43 a and 43b (diffraction peak of identification) illustrate the X-ray powder diffraction pattern that obtains from through the harmless tube material (P11371) of annealed.Observe and the corresponding big crystallization reaction on amorphous dizzy (amorphous halo) of about 23.4% percent crystallinity.The peak width at primary crystallization peak (pseudo Voight peak) is about 0.352 degree.

Figure 44 a and 44b (diffraction peak of identification) illustrate the X-ray powder diffraction pattern that obtains from through the harmless little loop material (P11371) of the annealing and the application of force.Stress causes through material is slided on conic mandrel bar, and is similar with finding in the DSC data.Observe with the corresponding amorphous of about 36.5% percent crystallinity the big crystallization reaction on dizzy.The peak width at primary crystallization peak (pseudo Voight) is about 0.418 degree.

Figure 39 illustrates the X-ray powder diffraction pattern that from the harmless pipe of raw material or undressed material (P11369), obtains.It mainly is non-crystalline state that the X-ray powder diffraction pattern shows, observes the little peak crystallization at 16.5 2 θ places, the percent crystallinity corresponding to about 1.0%.Figure 40 a and 40b (diffraction peak of identification) illustrate the X-ray powder diffraction pattern that obtains from through the harmless tube material (P11369) of annealed.Observe and the corresponding big crystallization reaction on amorphous is dizzy of about 29.5% percent crystallinity.The peak width at primary crystallization peak (pseudo Voight) is about 0.367 degree.The peak width at primary crystallization peak (pseudo Voight) is about 0.352 degree.

Figure 41 a and 41b (diffraction peak of identification) illustrate the X-ray powder diffraction pattern that obtains from through the harmless little loop material (P11369) of the annealing and the application of force.Observe and the corresponding big crystallization reaction on amorphous is dizzy of about 35.7% percent crystallinity.The peak width at primary crystallization peak (pseudo Voight) is about 0.388 degree.

Figure 36, Figure 37 a and 37b (diffraction peak of identification) and Figure 38 a and 38b (diffraction peak of identification) illustrate the WAXS pattern of the following batch of P11228 of condition shown in each figure.WAXS shows all that with corresponding DSC pattern the triclinic(crystalline)system crystalline that gathers L-rac-Lactide or false rhombic system crystal of D-rac-Lactide homotype enantiomorph crystalline and the three-dimensional mixture of rac-Lactide exists.

Table IV has been summed up two batches, the percent crvstallinity of each special state among P11369 and the P11371.

Table IV-percent crvstallinity

Table IV illustrates the peak width of various samples under several different conditions.The crystalline diffraction peak width is the good measure of the kinetics integrity (kinetic perfection) of crystalline material, can be used for characterizing from the angle of the size of complete crystal region and the microstrain between the crystal region microstructure of material.Lanford et al., Powder Diffraction, Rep.Prog.Phys.59:131-234 (1996) (people such as Lanford, powdery diffractometry, Rep.Prog.Phys.59:131-234 (1996)).

Table V-peak width

Tensile strength and the ductility of batch P11369 and P11371 have also been tested.Tensile strength is a maximum stress on engineering stress-strain curve, and the observed value of the plastic deformation degree of being kept when ductility is fracture can be used the elongation quantificational expression: %EL=(l _f-10/10) * 100.

Test is carried out according to the following steps.Combination Elongation test anchor clamps (United Pull Test Fixture), model #SSTM-1.Use combination 51b pressure transmitter (United 51b Load Cell), model #5LB T.Sample is cut into the segment of 1-2mm, then it is loaded on the U-shaped test wire, and segment is fixed between upper grip and the lower chuck.Sample is reduced in the water-bath under the physiological temp, and "/min lifts repeatedly with about 4.7 then.After lifting, sample is removed from chuck, on the Micro-Vu of calibration, measured.Figure 45 a and 45b illustrate the result that elongation is analyzed, and Figure 46 a and 46b are tensile strength or tensile strength.The average elongation per-cent of undressed P11369 is 186% ± 49%, and the average elongation per-cent of 15 minutes P11369 of annealing is 93% ± 67% under 80 ℃; The average elongation per-cent of undressed P11371 is 163% ± 46%, and is 23% ± 16% at the average elongation per-cent of 80 ℃ of following P11371 of 15 minutes.The average tensile strength of undressed P11369 is 43.81 ± 8.6 (unit is megapascal (MPa) " Mpa "), and the average tensile strength of 15 minutes P11369 of annealing is 54.88 ± 10.97MPa under 80 ℃; The average tensile strength of undressed P11371 is 37.89 ± 5.44MPa, and is 44.88 ± 1.62MPa in the average tensile strength of 80 ℃ of following P11371 of 15 minutes.

The best approach of the present invention that the embodiment of explanation and discussion only is used to instruct those skilled in the art to make and uses the contriver to know in this specification sheets.Any content all should not be regarded as the restriction to protection scope of the present invention in this specification sheets.Can make above-mentioned embodiment of the present invention and improving or distortion, but not deviate from the present invention, can understand according to above-mentioned instruction like those skilled in the art.Therefore, should be appreciated that except that specifying, in the scope of claim and equivalents thereof, this patent can be implemented.

All patents that this paper quoted, patented claim, open, testing method, document and other material are all introduced the application for your guidance.

Claims

1. support; It comprises blend; Said blend is by gathering the L-rac-Lactide, gathering D-rac-Lactide or its mixture and multipolymer and partly constitute; Said multipolymer partly comprises gathering the L-rac-Lactide or gathering the D-rac-Lactide of being connected with 6-caprolactone or trimethylammonium carbonic ether; Wherein, the order of gathering the L-rac-Lactide or gathering the D-rac-Lactide in the said multipolymer part is arbitrarily for the distribution of 6-caprolactone or trimethylene carbonate, and the wide-angle x-ray scattering of said blend (WASX) 2 θ values are about 16.48 and about 18.76.

2. support according to claim 1, wherein, said multipolymer partly comprises and gathers the L-rac-Lactide or gather the D-rac-Lactide, and the said L-of gathering rac-Lactide or gather the D-rac-Lactide and be connected with 6-caprolactone.

3. support according to claim 2, wherein, said polymer moieties comprises and gathers the L-rac-Lactide.

4. support according to claim 2, wherein, said polymer moieties comprises and gathers the D-rac-Lactide.

5. support according to claim 1, wherein, said multipolymer partly is gathering the L-rac-Lactide or gathering the D-rac-Lactide of being connected with TMC, the molecular weight of said multipolymer at about 1.2IV to about 2.6IV scope.

6. support according to claim 2, wherein, the molecular weight of said multipolymer about 0.8 to about 6.0 scopes.

7. support according to claim 1, wherein, said WAXS 2 θ values also comprise and are positioned at about 11.92, about 20.66, about 22.24 and the peak at about 28.84 places.

8. support according to claim 1; Wherein, said blend contains gathering L-rac-Lactide, about 35% (w/w) gathering D-rac-Lactide and about 10% (w/w) gathering L-rac-Lactide-copolymerization-TMC or gathering the L-lactide-epsilon-coprolactone to about 35% (w/w) to about 50% (w/w) of the 20%-45% that has an appointment (w/w).

9. support according to claim 1, wherein, the said L-of gathering rac-Lactide or the content that gathers the D-rac-Lactide are that about 20% (w/w) is to about 95% (w/w).

10. support according to claim 9, wherein, the said L-of gathering rac-Lactide or the content that gathers the D-rac-Lactide are that about 50% (w/w) is to about 95% (w/w).

11. support according to claim 10, wherein, the content of the said L-of gathering rac-Lactide is that about 60% (w/w) is to about 95% (w/w).

12. support according to claim 11, wherein, the content of the said L-of gathering rac-Lactide is that about 70% (w/w) is to about 80% (w/w).

13. support according to claim 1 wherein, is being arranged in said multipolymer part more than 7 L-rac-Lactides or D-rac-Lactide in an orderly manner.

14. support; It comprises blend; Said blend is by gathering the L-rac-Lactide, gathering D-rac-Lactide or its mixture and multipolymer and partly constitute; Said multipolymer partly comprises gathering the L-rac-Lactide or gathering the D-rac-Lactide of being connected with 6-caprolactone or trimethylammonium carbonic ether; Wherein, the order of gathering the L-rac-Lactide or gathering the D-rac-Lactide in the said multipolymer part is arbitrarily for the distribution of 6-caprolactone or trimethylene carbonate, and said support contains the amorphous substance at least about 95% (w/w).

15. support according to claim 14, wherein, said support contains the amorphous substance at least about 98% (w/w).

16. support according to claim 15, wherein, said support contains the amorphous substance at least about 99% (w/w).

17. support according to claim 1, wherein, the percent crvstallinity of said support at about 0% (w/w) to about 10% (w/w) scope.

18. support according to claim 1, wherein, the percent crvstallinity of said support at about 20% (w/w) to about 70% (w/w) scope.

19. support according to claim 18, wherein, the percent crvstallinity of said support at about 30% (w/w) to about 60% (w/w) scope.

20. support according to claim 19, wherein, the percent crvstallinity of said support at about 30% (w/w) to about 60% (w/w) scope.

21. support; It comprises blend; Said blend is by gathering the L-rac-Lactide, gathering D-rac-Lactide or its mixture and multipolymer and partly constitute; Said multipolymer partly comprises gathering the L-rac-Lactide or gathering the D-rac-Lactide of being connected with 6-caprolactone or trimethylammonium carbonic ether, and wherein, the order of gathering the L-rac-Lactide or gathering the D-rac-Lactide in the said multipolymer part is arbitrarily for the distribution of 6-caprolactone or trimethylene carbonate; The wide-angle x-ray scattering of said blend (WASX) 2 θ values are about 16.65 and about 18.96.

22. support according to claim 21, wherein, said wide-angle x-ray scattering 2 θ values further comprise about 12.00, about 14.80, about 20.67, about 22.35, about 23.92, about 24.92, about 29.16 and about 31.28.

23. support according to claim 1, wherein, the T of said support _mThe peak appears at about 180 ℃ and about 217 ℃.

24. support according to claim 21, wherein, the T of said support _mThe peak appears at about 178 ℃ and about 220 ℃.

25. support according to claim 21, wherein, the T of said support _gBe about 61 ℃ and about 128 ℃.