 POLYMER PARTICLES
专利摘要:
Polymer Particles Biodegradable embolic particle of cross-linked polymer is described and methods for its preparation, embolic particles can be used as embolizing agents. 公开号:BR112016005770B1 申请号:R112016005770-8 申请日:2014-09-19 公开日:2021-07-27 发明作者:M. Cruise Gregory；Hincapie Gloria；Harris Clayton 申请人:Terumo Corporation； IPC主号:
专利说明:
Cross-reference to patents and related patent applications [00001] This application claims the benefit of US Provisional Patent Application Number 61/880,036, filed September 19, 2013, the entire disclosure of which is incorporated by reference into this application. DOMAIN OF THE INVENTION [00002] Biodegradable polymer particles are described for the occlusion of vascular sites and cavities within the body, such as the embolization of hypervascularized tumors or arteriovenous malformations. SUMMARY OF THE INVENTION [00003] In this patent application, crosslinked biodegradable polymer particles are generally described. In some embodiments, the particles can be spherical in shape or substantially spherical. Thus, the particles described in this patent application can be referred to as polymer spheres or microspheres. These polymers can be used in/for embolization. The polymer particles can include and/or be formed from one or more monomers and a crosslinking agent susceptible to chemical hydrolysis or enzymatic action. [00004] The biodegradable polymer particles described in this patent application can be used for the occlusion of vascular sites, in the body lumen and in other cavities within the body. In some embodiments, the polymer particles can be used for purposes such as embolizing hypervascularized tumors or arteriovenous malformations. [00005] The polymer particles can comprise: at least one monomer and at least one crosslinking agent. In some embodiments, the polymer particle may be susceptible to degradation through chemical hydrolysis or by enzymatic action. Particles as described in this document can have various sizes, depending on the specific use, but generally can have diameters between about 40 µm and about 1,200 µm or between about 75 µm and about 1,200 µm. [00006] Methods of preparing the polymer particles described in this patent application are also described. Such methods comprise: preparing an aqueous prepolymer solution which includes at least one monomer, at least one crosslinking agent susceptible to degradation by chemical hydrolysis or by enzymatic action, and an initiator; dispersing the prepolymer aqueous solution in mineral oil; and formation of polymer particles through polymerization of monomers. [00007] Other methods for forming polymer particles may include: reacting a solution of prepolymer in an oil to form the polymer particles. The prepolymer solution can include at least one monomer comprising at least one functional group, at least one crosslinking agent susceptible to degradation by chemical hydrolysis or by enzymatic action, and an initiator. [00008] The crosslinking agents used to form the polymer particles can impart biodegradability to the particles. For example, the cross-linking agent can include at least one bond susceptible to degradation through chemical hydrolysis or by enzymatic action. The cross-linking agent can be based on glycidyl, amino glycidyl, thioester or protein. A glycidyl-based crosslinking agent can be amino alcohol bis-glycidyl. A protein-based crosslinking agent can be bifunctionalized methacryloyl-Ala-Pro-Gly-Leu-AEE-methacrylate. BRIEF DESCRIPTION OF THE DRAWINGS [00009] Figure 1 is a graph showing the degradation stages for different polymer particles. [00010] Figure 2 is a graph showing the time to total degradation of different polymer particles. [00011] Figure 3 is another graph that shows the gradation for the degradation of polymer particles. DETAILED DESCRIPTION [00012] Generally speaking, particles made of polymer material are described in this patent application. The polymer material can be a reaction product of one or more monomers and a crosslinking agent. In some embodiments, the polymer particles can be sensitive to hydrolysis or enzymatic action. Particles may be referred to herein as microparticles, microspheres and the like. The particles can have a diameter of between about 40 µm and about 1,200 µM or between about 75 µm and about 1,200 µm. The particles can also be compressible and/or stable for ease of delivery through a medical device such as a needle or catheter. Particles can also be biodegradable once delivered. [00013] Particles can be formed from a mixture such as a prepolymer solution. The prepolymer solution can comprise: (i) one or more monomers that contain a single functional group capable of polymerization and (ii) one or more crosslinking agents. In some embodiments, a polymerization initiator can be used. [00014] In some embodiments, if one of the monomers and/or crosslinking agents is a solid, a solvent can be used in preparing the particles for use as embolics. If liquid monomers and crosslinking agents are used, it may not be necessary to use a solvent. In some embodiments, even when using liquid monomers and crosslinking agents, solvent can be used. Solvents can include any liquid capable of dissolving or substantially dissolving monomer, mixture of monomers, and/or crosslinking agent. Any aqueous or organic solvent, which dissolves the desired monomers, crosslinking agents and/or polymerization initiators, can be used. If an organic solvent is used an aqueous medium may be required for the dispersion. In one embodiment, the solvent can be water. In addition, solutes, eg sodium chloride, can be added to the solvent to increase the rate of polymerization. Solvent concentrations can be about 10% w/w, about 20% w/w, about 30% w/w, about 40% w/w, about 50% w/w , from about 60% w/w, from about 70% w/w, about 80% w/w, from about 90% w/w, between about 20% w/w and about 80% w/ between about 50% w/w and about 80% w/w, or between about 30% w/w and about 60% w/w of the solution. [00015] Any type of crosslinking chemistry can be used to prepare the described polymer particles. In some embodiments, crosslinking chemistries such as, for example, but not limited to, N-hydroxysuccinimide/nucleophile, halide/nucleophile, sulfone/vinyl acrylate or maleimide/acrylate esters can be used. In an exemplary embodiment, free radical polymerization can be used. Therefore, monomers with a single ethylenically unsaturated group, such as acrylate, acrylamide, methacrylate, methacrylamide, and vinyl, can be used when employing free radical polymerization. [00016] Any amount of monomer, which allows for a desired particle, can be used. The concentration of monomer in the solvent can be about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w /w, from about 10% w/w, about 15% w/w, from about 20% w/w, from about 30% w/w, from about 40% w/w, from about 50 % w/w, from about 60% w/w, from about 70% w/w, from about 80% w/w, from about 90% w/w, from about 100% w/w, between about 1% w/w and about 100% w/w, between about 40% w/w and about 60% w/w, between about 50% w/w and about 60% w/w, or between about 40% w/w and about 60% w/w. [00017] Monomers can be selected based on the desired chemical transmission and/or mechanical properties for the polymer particle or embolic particle. If desired, reactive, uncharged moieties can be introduced into the embolic particle. For example, hydroxyl groups can be introduced into the embolic particle by the addition of 2-hydroxyethyl acrylate, 2-hydroxymethacrylate, derivatives thereof, or combinations thereof. Alternatively, relatively unreactive, uncharged portions can be introduced into the embolic particle. For example, acrylamide, methacrylamide, methyl methacrylate, derivatives thereof, or combinations thereof can be added. [00018] In one embodiment, polymer particles can be prepared from monomers that have a single functional group suitable for polymerization. Functional groups can include those suitable for free radical polymerization, such as acrylate, acrylamide, methacrylate and methacrylamide. Other polymerization schemes can include, but are not limited to, N-hydroxysuccinimide/nucleophile, halide/nucleophile, sulfone/vinyl acrylate or maleimide/acrylate esters. The selection of monomers is governed by the desired mechanical properties of the resulting particle and by minimizing the biological effects of the degradation products. [00019] In some embodiments, the monomer may additionally contain an ionizable functional group that is basic (for example, amines, derivatives thereof, or combinations thereof). The amine group can be protonated at pH values lower than the pKa value of the amine, and deprotonated at pH values higher than the pKa value of the amine. In other embodiments, the monomer additionally contains an ionizable functional group that is acidic (e.g., carboxylic acids, sulfonic acids, derivatives thereof, or combinations thereof). The acid group can be deprotonated at pHs higher than the pKa of the acid, and protonated at pHs lower than the pKa of the acid. [00020] If the binding of positively charged drugs is desired, monomers with negatively charged moieties, for example carboxylic acids or other acidic moieties, can be polymerized into the embolic particle. Acidic, ionizable, ethylenically unsaturated monomers can include, but are not limited to, acrylic acid, methacrylic acid, 3-sulfopropyl acrylate, 3-sulfopropyl methacrylate, derivatives thereof, combinations thereof, and salts thereof. On the other hand, if the binding of negatively charged drugs is desired, monomers with positively charged moieties, for example amines, or other basic moieties can be included. Basic, ionizable, ethylenically unsaturated monomers can include, but are not limited to aminoethyl methacrylates, aminopropyl methacrylate, derivatives thereof, combinations thereof, and salts thereof. [00021] Another factor in the selection of the monomer may be the desire that degradation products of the embolic particle produce negligible host response. In other embodiments, there may be a desire for particle degradation products to elicit substantially no host response. [00022] A crosslinking agent can include one or more polymerizable groups, can incorporate monomer chains together, and allow the formation of solid particles. Biodegradation can be transmitted to the embolic particle using a crosslinking agent with bonds susceptible to degradation in a physiological environment. In vivo, over time, bonds can be broken and polymer chains can no longer be linked together. Judicious selection of monomers allows the formation of water-soluble degradation products that diffuse far away and are eliminated by the host. Hydrolysis-susceptible bonds, such as esters, thioesters, carbamates and carbonates or peptides, degraded by enzymes can be used in biodegradable products. [00023] In one embodiment, one or more crosslinking agents may contain at least two functional groups suitable for polymerization and at least one cleavage bond to impart biodegradation to the polymer particle. Bonds susceptible to cleavage in a physiological environment may include, among others, those susceptible to hydrolysis, including esters, thioesters, carbamates and carbonates and those susceptible to enzymatic action, including peptides that are cleaved by matrix metalloproteinases, collagenases, elastases and cathepsins . In some embodiments, multiple cross-linking agents can be used to control the rate of degradation in a way not possible with just one cross-linking agent. In one embodiment, at least one crosslinking agent is susceptible to hydrolysis and at least one crosslinking agent is susceptible to enzymatic degradation. [00024] In some embodiments, the at least one bond is a peptide cleavable by matrix metalloproteinases, a peptide cleavable by matrix collagenases, a peptide cleavable by matrix elastases, a peptide cleavable by matrix cathepsins, or one of combinations thereof. [00025] In other embodiments, the polymers may comprise a second crosslinking agent that includes a second bond selected from an ester, a thioester, a carbonate, a carbamate, a peptide cleavable by matrix metalloproteinases, a peptide cleavable by matrix collagenases, a peptide cleavable by matrix elastases and a peptide cleavable by matrix cathepsins. [00026] In yet other embodiments, the polymers may comprise a third, fourth, fifth or more crosslinking agents, each including the same or a different bond. [00027] Crosslinking agents may include peptide based crosslinking agents, carbonate based crosslinking agents, bis glycidyl amine crosslinking agents, Gly TMP ester crosslinking agents, dithioester crosslinking agents or glycidyl amine crosslinking agents Jeffamine. Preferred concentrations of crosslinking agents in the final product can be about 0.05% w/w, about 0.1% w/w, about 0.5% w/w, about 1, 0% w/w, from about 2.0% w/w, from about 3.0% w/w, about 4.0% w/w, between about 0.1% w/w and about 4.0% w/w, between about 0.5% w/w and about 2% w/w, or between about 1% w/w and about 1.5% w/w. Those skilled in the art understand how to calculate final concentrations based on the amount of solvent already discussed. [00028] In one embodiment, the compounds may be peptide-based crosslinking agents. In one embodiment, a peptide-based crosslinking agent can be or a derivative of it. [00029] In another embodiment, the peptide-based crosslinking agent can be or a derivative of it. [00030] In another embodiment, the peptide-based crosslinking agent may be methacryloyl-Ala-Pro-Gly-Leu-AEE-bifunctionalized methacrylate. [00031] In another embodiment, crosslinking agents may have the structure where the value of n is from 1 to 20; the value of m is from 1 to 20; eX is 0 or S. [00032] In another embodiment, the crosslinking agent may have the structure where the value of n is from 1 to 20; the value of m is from 1 to 20. [00033] In another embodiment, the crosslinking agent may have the structure [00034] A crosslinking agent may also have the structure where the value of o is from 1 to 20; and the p value is from 1 to 20. [00035] In one embodiment, the structure can be [00036] A crosslinking agent may still have the structure where the value of q is from 1 to 20; In one embodiment, q is 1. [00037] A crosslinking agent may still have the structure where the value of r is from 1 to 20; eY and Z are each independently selected from O, S and NH. [00038] In one embodiment, the crosslinking agent may have the structure where the value of r is from 1 to 20. [00039] In addition, in another embodiment, the cross-linking agent may have the structure where G, H, and J are each independently CH2, 0, S, NH, or not present, a, b, and c each independently have the value of 1 to 20; and the value of g is from 1 to 20. [00040] In another embodiment, a, b, and c are each independently 1 to 10. In yet another embodiment, G, H and J are each independently 0 or NH. [00041] In one embodiment, the crosslinking agent has a structure where a, b, and c are each independently 1 to 20. [00042] In addition, in another embodiment, the cross-linking agent may have the structure where L, M and N are each independently CH2, 0, S, NH, or not present, d, e, and f are each independently 1 to 20; and the value of h is from 1 to 20. [00043] In another embodiment, d, e, and f are each independently 1 to 10. In yet another embodiment, L, M and N are each independently 0 or NH. [00044] In one embodiment, the crosslinking agent has the structure where d, e, and f are each independently 1 to 20. [00045] A crosslinking agent may also have the structure where the value of s is from 1 to 20; where the value of t is from 1 to 20; eX1, X2, X3 and X4 are each independently 0 or S. [00046] In one embodiment, the structure can be [00047] A crosslinking agent may also have the structure [00048] In some embodiments, the crosslinking agent may be a tetra-ester, a tetra-thioester or a di-thioester. In other embodiments, the crosslinking agent can be a peptide crosslinking agent or a carbonate crosslinking agent. A glycidyl-based crosslinking agent can be the amino alcohol bis-glycidyl. [00049] The polymerization of the prepolymer solution can be done by reduction-oxidation, radiation, heat, or any other method known in the art. Radiation crosslinking of the prepolymer solution can be achieved with ultraviolet light or visible light with suitable initiators or by ionizing radiation (eg, electron beam or gamma rays) without initiators. Crosslinking can be accomplished by applying heat, either by conventionally heating the solution using a heat source such as a heating well, or by applying infrared light to the monomer solution. Free radical polymerization of the monomer(s) and crosslinking agent(s) is preferred and requires an initiator to start the reaction. In a preferred embodiment, the crosslinking method uses azobisisobutyronitrile (AIBN) or another water-soluble AIBN derivative such as (2,2'-azobis(2-methylpropionamidine)dihydrochloride). Other crosslinking agents can include, but are not limited to, N,N,N',N'-tetramethylethylenediamine, ammonium persulfate, benzoyl peroxides, and combinations thereof, including azobisisobutyronitriles. A preferred initiator can be the combination of N, N, N', N'-tetramethylethylenediamine and ammonium persulfate. [00050] Polymer particles can be produced or formed by methods, comprising: reacting a prepolymer solution that includes at least one monomer which includes at least one functional group, at least one crosslinking agent capable of degradation through chemical hydrolysis or enzymatic action, and an initiator in oil. [00051] The prepolymer solution can be prepared by dissolving the monomer(s), crosslinking agent(s), and optionally initiator(s) in the solvent. Embolic particles can be prepared by emulsion polymerization. A non-solvent for the monomer solution, typically mineral oil, when the monomer solvent is water, is sonicated to remove any trapped oxygen. Mineral oil and a surfactant are added to the reaction vessel. An overhead stirrer is placed in the reaction vessel. The reaction vessel is then sealed, degassed under vacuum, and sparged with an inert gas such as argon. The N,N,N',N'-tetramethylethylenediamine initiator component is added to the reaction vessel and stirring initiated. Ammonium persulfate is added to the polymerization solution and both are then added to the reaction vessel, in which stirring suspends droplets of the prepolymer solution in the mineral oil. [00052] The rate of agitation can affect particle size, with rapid agitation producing smaller particles. Stirring rates can be about 100 rpm, about 200 rpm, about 300 rpm, about 400 rpm, about 500 rpm, about 600 rpm, about 700 rpm, about 800 rpm, about 900 rpm , about 1,000 rpm, about 1,100 rpm, about 1,200 rpm, about 1,300 rpm, between about 200 rpm and about 1,200 rpm, between about 400 rpm and about 1,000 rpm, at least about 100 rpm, at least about 200 rpm, at most about 1300 rpm, or at most about 1200 rpm to produce particles of desired diameters. [00053] The polymer particles described in this patent application can have a generally or substantially spherical shape. Substantially spherical or spherical particles can have diameters of about 10 µm, about 20 µm, about 30 µm, about 40 µm, about 50 µm, about 60 µm, about 75 µm, about 100 µm, about 200 μm, about 300 μm, about 400 μm, about 500 μm, about 600 μm, about 700 μm, about 800 μm, about 900 μm, about 1, 000 μm, about 1,100 µm, about 1,200 µm, about 1,300 µm, about 1,400 µm, about 1,500 µm, about 1,600 µm, between about 50 µm and about 1,500 µm, between about 100 µm and about 1000 µm, between about 75 μm and about 1200 μm, at least about 50 μm, at least about 80 μm, at most about 1,500 μm, or at most about 1,200 μm. In some embodiments, the diameter can be between about 40 µm and about 1,200 µm, between about 40 µm and about 60 µm, or between about 75 µm and about 1,200 µm. [00054] Polymer particles can retain their diameters even after injection through a catheter or other delivery device. In other words, the polymer particles may not fall apart or otherwise fracture during administration. In some embodiments, the polymer particles can retain about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, greater than about 99%, greater than about 98%, greater than about 97%, greater than about 96%, greater than about 95%, greater than about 90%, between about 90% and about 100% of its diameter after delivery. [00055] Polymer particles may also have a characteristic circularity or have a relative shape that is substantially circular. This feature describes or defines the shape of a region, based on its circularity. Polymer particles as described in this patent application can have a round fraction of about 0.8, 0.9, 0.95, 0.96, 0.97, 0.98, 0.99, greater than about 0.8, greater than about 0.9, or greater than about 0.95. In one embodiment, the roundness of the polymer particles is greater than about 0.9. [00056] Polymer particles can retain their circularity even after injection through a catheter or other administration device. In some embodiments, the polymer particles can retain about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, greater than about 99%, greater than about 98%, greater than about 97%, greater than about 96%, greater than about 95%, greater than about 90%, between about 90% and about 100% of its roundness after administration. [00057] The polymerization can be allowed to proceed as long as necessary to produce particles with the desired resilience. Polymerization can continue for about 1 hour, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 18 h, 24 h, 48 h, 72 h, 96 h, between about 1 hour and about 12 h, between about 1 hour and about 6 h, between about 4 h and about 12 h, between about 6 h and about 24 h, between about 1 hour and about 96 hours, between about 12 hours and about 72 hours, or at least about 6 hours. [00058] Polymerization can be carried out at a temperature that produces particles with desired resilience and/or reaction time. The polymerization can be carried out at a temperature of about 10°C, about 20°C, about 30°C, about 40°C, about 50°C, about 60°C, about 70°C , about 80 °C, about 90 °C, about 100 °C, between about 10 °C and about 100 °C, between about 10 °C and about 30 °C, at least about 20 °C, maximum about 100 °C, or about room temperature. In one embodiment, polymerization takes place at room temperature. [00059] After the polymerization is completed, the polymer particles are washed to remove any solute, mineral oil, unreacted monomer(s), and/or unbound oligomers. Any solvent can be used, but care must be taken if aqueous solutions are used to wash particles with bonds susceptible to hydrolysis. Preferred washing solutions can include, but are not limited to acetones, alcohols, water and a surfactant, water, saline, buffered saline, and saline and a surfactant. [00060] Optionally, the washed polymer particles can then be colored to allow visualization prior to injection into a microcatheter. A dye bath can be prepared by dissolving sodium carbonate and the desired dye in water. Embolic particles are added to the dyebath and stirred. After the staining process, any unbound dye is washed away. After staining and washing, the particles can be packaged in vials or syringes, and sterilized. [00061] After preparation of the embolic particles, they can be optionally colored to allow visualization during preparation by the physician. Any of the dyes from the family of reactive dyes that covalently bind to embolic particles can be used. Dyes may include, but are not limited to, reactive blue 21, reactive orange 78, reactive yellow 15, reactive blue No. 19, reactive blue No.4, reactive red 11 CI, reactive yellow 86 CI, reactive blue 163 CI, reactive red 180 CI, reactive black 5 CI, reactive orange 78 CI, reactive yellow 15 CI, reactive blue No. 19 CI, reactive blue 21 CI, or any of the color additives. Some color additives are approved for use by FDA Part 73, Subpart D. In other embodiments, a dye that can irreversibly bind to the embolic particle matrix polymer may be used. [00062] If the polymer particle or microsphere described in this patent application does not properly bind any of the reactive dyes described above, a monomer containing an amine can be added to the monomer solution in an adequate amount to achieve the desired coloration. Even if the polymer particle or microsphere properly binds the reactive dyes described above, a monomer that contains an amine can be added to the monomer solution. Examples of suitable monomer-containing amines include aminopropyl methacrylate, aminoethyl methacrylate, aminopropyl acrylate, aminoethyl acrylate, derivatives thereof, combinations thereof, and salts thereof. Preferred concentrations of the amine containing monomers present in the final product can be less than or equal to about 1% w/w. The particles described in this patent application can be sterilized without substantially degrading the polymer. After sterilization, at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99%, or about 100% of the polymer can remain intact. In one embodiment, the sterilization method can be autoclaving and can be used prior to administration. [00064] The final polymer particle preparation can be administered to the site to be embolized through a catheter, microcatheter, needle, or other similar administration device. A radiopaque contrast agent can be carefully mixed with the particulate preparation in a syringe and injected through a catheter until the blood flow is determined to be occluded from the site using interventional imaging techniques. [00065] In some embodiments, it may be desirable for the particles to degrade over time. In other words, the particles can be degradable and/or biodegradable. In such embodiments, the particles can degrade less than about 40%, about 30%, about 20%, about 10%, about 5%, or about 1% intact after about 2 days, 3 days, 5 days, about 2 weeks, about a month, about 2 months, about 6 months, about 9 months, about a year, about 2 years, about 5 years, or about 10 years. In one embodiment, the particles can be substantially degraded in less than about 1 month. In another embodiment, particles can be substantially degraded in less than about 6 months. [00066] In some embodiments degradability can be accelerated with a suitable and/or appropriate enzyme. In some embodiments, polymer particles can be injected along with an enzyme that can accelerate particle degradation. In other embodiments, an enzyme can be delivered to the site of the implanted particles some time ago and accelerate degradation at that time. [00067] In some embodiments, the greater the percentage of a crosslinking agent in the final polymeric particles, the longer degradation takes. Furthermore, the larger the particle diameter, the longer degradation takes. Thus, the particles with the longest degradation time are those that have the highest concentration of crosslinking agent and the largest diameter. These two properties can be varied to adapt the degradation time as needed. [00068] The polymer particles described in this patent application can be compressible, but stable enough not to break or fragment. Substantially no change in particle circularity or diameter occurs during administration through a microcatheter. In other words, after administration via a microcatheter, the polymer particles described in this patent application remain intact by more than about 60%, about 70%, about 80%, about 90%, about 95% , about 99% or about 100% after administration. [00069] Furthermore, in some embodiments, particles may adhere to the fabric and/or remain in place because of friction with the fabrics. In other embodiments, the particles can act as a plug in a vessel held in place by the blood flow and pressure itself. In still other embodiments, the particles can be cohesive enough to stick together to aid in agglomeration of particles at a particular site of action. [00070] The polymer particles described can be delivered through a microcatheter, or other delivery device, suitable to a remote tissue or can be injected through a needle into local tissues. Polymer particles can be used to occlude vascular sites and cavities within the body. [00071] In some embodiments, polymer particles can be configured for embolization of hypervascularized tumors or arteriovenous malformations. In some embodiments, one can select a patient who has a hypervascularized tumor and/or an arteriovenous malformation. A microcatheter can be navigated to the location of the tumor or malformation. Polymer particles as described in this patent application can be injected into the site to be stabilized and thereby treat the patient's condition. Example 1 Preparation of a glycidyl-based crosslinking agent [00072] An aliquot of 10 g (67.6 mmol) of 2,2'-(ethylenedioxy)bis(ethylamine) was mixed with 10 g (70.4 mmol) of glycidyl methacrylate, and 3 g of glycidyl methacrylate gel. silica (Aldrich 645524, 60 Angstrom, 200-425 mesh). After stirring for 1 hour, a further 9 g (63.4 mmol) of glycidyl methacrylate was added and the suspension stirred for a further 1.5 h. The mixture was diluted with 200 ml of chloroform and filtered through a 600 ml sintered glass Buchner funnel to remove silica gel. LC-MS analysis of the resulting chloroform solution did not show mono-glycidyl amino alcohol and mainly bis-glycidyl amino alcohol of [M + H] + m/z 433.2. The solution was concentrated to about 50 g in vacuo. The resulting slurry was diluted to 100 ml with acetonitrile and stored at -80°C.• Example 2 Preparation of a peptide-based crosslinking agent [00073] A heterobifunctional, tetrapeptide (Acryloyl-Ala-Pro-Gly-Leu-AEE-N-hydroxysuccinimide) was supplied (Bachem, Torrance, CA). The peptide (653 mg, 1 mmol) was dissolved in 5 mL of DMF and N-(3-aminopropyl)methacrylamide hydrochloride (190 mg, 1.1 mmol) and N,N-diispropylethylamine (174 µL, 1 mmol) was added ). After 2 h, 20 mg of butylated hydroxytoluene was added and the reaction mixture was exposed to air. The reaction mixture was precipitated with 200 ml of ethyl ether. Solids were collected using centrifugation. The pellet was redissolved in a 90/5/5 solution of chloroform/methanol/methanol + 5% aqueous ammonia and applied to 50 g of silica gel in a 5x20 cm column (Aldrich, 60 Angstrom, 200-425 mesh). The silica gel column was developed with 500 ml of 90/5/5 chloroform/methanol/methanol+5% aqueous ammonia solution and the peptide containing eluant was concentrated in vacuo to obtain 110 mg of pale yellow oil. The pale yellow oil was dissolved in 10 ml methanol and stored at -80°C. LC-MS analysis of the product showed the desired [M+H]+ at am/q 680 and [M+Na]+ at am/q 702. Example 3 Tetrapeptide crosslinking agent MA-AEEAc-ALAL-AEEac-MA, A LAL [00074] To 841 mg (1 mmol) NHS ester, MA-AEEAc-ALAL-AEEAc-NHS was added 179 mg of 3-aminopropyl-methacrylate-HCl in clean dry 15 ml flask with a dry stir bar and a dry septum, followed by 5 mL of dry dimethylformamide. After stirring, a clear solution resulted and 200 µL (1 mmol) of diisopropylethylamine was added at once. After one hour, the reaction mixture was transferred to a 250 ml pear shaped flask using 3X5 ml methanol and placed in line vacuum (aspirator) overnight. The next day, the reaction mixture was transferred to a scintillation vial with 2 ml methanol to obtain approx. 35% solids, and stored at -80°C. The above crude crosslinking agent gives a single HPLC peak yields [M+H]+ at m/q of 869.9, calculated molecular weight for C41H72N8O12 is 868.5.Example 4 Carbonate crosslinkers [00075] To 33 g (100 mmol) of cesium carbonate suspended in 500 ml of 1:1 acetonitrile:methanol was added 17.2 g (200 mmol) of methacrylic acid over one hour with good stirring. After an additional 2 h of stirring, the solvent was removed from the reaction mixture and the residue was suspended in 500 ml of dry ether and collected by filtration over a 600 ml dry Buchner funnel with a glass frit. After carefully washing the solids in the funnel several times with dry ether, the solids were dried in a vacuum oven overnight to give 45 g of a hygroscopic beige powder (Compound A) which had to be quickly placed in a dry environment. [00076] HEMA-1-chloroethyl carbonate: To 24 ml of HEMA (200 mmol) in 1000 ml of dry ether was added 16.8 ml (213 mmol) of pyridine at 4-10 °C, under argon atmosphere. To that solution was added 21.3 mL (200 mmol) of 1-chloroethyl chlorocarbonate dropwise with stirring over 0.5 h. After stirring 0.5 h at 4-10 °C, the heavy precipitate (Compound B) was removed by filtration and the filtrate was concentrated to an oil under vacuum to give 44 g (100%). [00077] To 4.4 g (20 mmol) of Compound B in 40 mL of anhydrous dimethyl formamide, 0.9 g (4.0 mmol) of Compound A was added at 100 °C, under argon, with good stirring. After 15 minutes, a further 1.2 g (5.4 mmol) of Compound A was added at 100 °C, under argon, with good stirring, followed by a final 0.9 g (4.0 mmol) under them. conditions, for a total of 2.9 g of Compound A (13.4 mmol). The yellow brown reaction mixture was heated at 100 °C for a further 3 h and after cooling to room temperature, the solvent was removed in vacuo, and the residue was left on the vacuum line overnight. The residue was taken up in 50 ml of 1:1 chloroform:hexane, applied to a 750 gram gold column, and eluted with hexane and then 0-20% ethyl acetate in hexane. The following carbonate left after 27 min and the following carbonate came out at 32 min. Example 5 TMP Gly Ester [00078] TMP-chloro-acetamide: To 13.2 g of trimethylolpropane triamino ethoxylate in 250 ml of dry tetrahydrofuran (THF) was added 6.32 g (80 mmol) of pyridine and this solution was added to 6. 44 g of chloroacetyl chloride in 250 ml of THF under good stirring at 4-10 °C under argon (Ar) atmosphere. After stirring for 15 min, the reaction mixture was warmed to room temperature and THF and other volatile materials were removed in vacuo. The resulting solids were dissolved in 200 ml of chloroform which was in turn washed with 100 ml of saturated aqueous sodium bicarbonate, dried over magnesium sulphate and the solvent removed in vacuo. [00079] TMP-NH-Gly-Methacrylate: To approximately 15 g of the above material dissolved in 75 ml of anhydrous dimethylformamide was added 18 g of cesium methacrylate and the resulting suspension was heated at 40-50°C for 2 h. [00080] After precipitation with 500 ml of chloroform, the inorganic salts were collected by filtration and the filtrate was concentrated to an oil in vacuo to give 18 g of a reddish brown oil. This oil could be polymerized with AIBN at 80°C in IPA to a hard pellet. Chromatography on 6 g of this through a buffer of the above silica with 1200 mL of 2-20% methanol in chloroform gave 6 g of a light red colored material. [00081] To 6.6 ml (40 mmol) of 2.2'-(ethylenedioxy)ethanedithiol in 200 ml of tetrahydrofuran (THF) was added 20.9 ml of diisopropylethylamine, and the resulting dry solution was added to 11.5 ml of methacryloyl chloride (120 mmol) in 200 ml of dry THE, at -5°C, with good stirring over 1 h. The reaction mixture was stirred at 0 °C for 1 h and at 20 °C for 1 hour at which time 10 mL of isopropyl alcohol was added and the solvent removed in vacuo. [00082] The residue was applied to a column of 330 g silica (gold) in a minimum volume of chloroform and the column was eluted with 0-5% isopropyl alcohol in methylene chloride at 200 ml/min. The fraction eluting at 13-14 minutes as a single peak was isolated as 1.3 g of yellow oil. The AIBN reaction initiated from 50 mg of this material exhibited a hard pellet. [00083] To 40 ml of dry tetrahydrofuran (THF), at 0°C, containing 0.4 ml (4 mmol) of methacryloyl chloride was added 20 ml of dry THE containing 2.0 g (1.33 mmol) of poly(ethylene glycol)dithiol 1,500 µm and 0.7 ml (4.0 mmol) of diisopropylethylamine, dropwise over 5 min, with rapid stirring. After stirring for 2 h, the reaction mixture was warmed to room temperature and the solvent removed in vacuo. Then 100 ml of chloroform was used to dissolve the reaction mixture and this was removed in vacuo to wash away the methacryloyl chloride. [00084] The reaction mixture was placed on the vacuum line overnight at about 30 microns and a yellow solid formed. Starting the AIBN reaction of 50 mg of this in 50 microliters of isopropyl alcohol resulted in a yellow gel sponge. [00085] To 11 g of Jeffamina (25 mmol) was added 10.5 g of glycidyl methacrylate (75 mmol) followed by 4 g of silica gel and 100 mg of butylated hydroxytoluene. The reaction mixture was stirred at 20 °C. After 2 h, 50 mL of chloroform was added to the thickening reaction mixture and stirring was continued. After a further 18 h, an additional 200 ml of chloroform was added and the reaction mixture was filtered to remove silica gel and most of the solvent was removed in vacuo. The residue was dissolved in 20 ml of isopropyl alcohol to obtain 40 ml of about 50% amine Jeffamine glycidyl. Example 9. Particles prepared with a glycidyl-based crosslinking agent [00086] A prepolymer solution was prepared by dissolving 6.2 g of acrylamide, 14.6 g of potassium salt- 3-sulfopropyl acrylate, and 0.3 g of glycidyl-based crosslinking agent, prepared as in Example 1, in 20.0 g of distilled water. This solution was filtered and then degassed under vacuum for 5 minutes and purged with argon. One liter of mineral oil was sonicated during it, then added to a sealed reaction vessel equipped with an overhead stirring element. The vessel was degassed under vacuum for at least it, then the vacuum replaced by argon. About 3 ml of N,N,N',N'-tetramethylethylenediamine was added to the reaction vessel and upper stirring started at 300 rpm. An initiator solution was made by dissolving 1.0 g of ammonium persulfate in 2.0 g of distilled water. The solution was filtered and approximately 550 ml was added to the prepolymer solution. After mixing, the solution was added to the reaction vessel. After 5 to 10 minutes, a solution of 0.35 ml of SPANS80 in 10 ml of mineral oil was added and the resulting suspension was allowed to polymerize for at least 4 h. Example 10, Particles prepared with a peptide crosslinking agent [00087] A prepolymer solution was prepared by dissolving 3.8 g of acrylamide, 5.4 g of the potassium salt- 3-sulfopropyl acrylate, and 0.05 g of a peptide-based crosslinking agent, prepared as in Example 2, in 10.0 g of distilled water. This solution was filtered and then degassed under vacuum for 5 minutes and purged with argon. Mineral oil (300 mL) was sonicated for 1 h and then added to a sealed reaction vessel equipped with an overhead stirring element. The vessel was degassed under vacuum during it, then the vacuum replaced by argon. N,N,N',N'-tetramethylethylenediamine (2 ml) was added to the reaction vessel and upper stirring was started at 300 rpm. An initiator solution was made by dissolving 10.0 g of ammonium persulfate in 2.0 g of distilled water. The solution was filtered and 300 µL was added to the prepolymer solution. After mixing, the solution was added to the reaction vessel. After 5 to 10 minutes, a solution of 0.5 ml of SPAN®80 in 10 ml of mineral oil was added and the resulting suspension was allowed to polymerize for 5 h. Example 11 Particle purification [00088] After polymerization was complete, the mineral oil was decanted from the reaction vessel and the polymer particles were washed four times with fresh portions of hexane to remove the mineral oil. The particles were then transferred to a separatory funnel with phosphate buffered saline (PBS), and separated from residual mineral oil and hexane. The resulting mixture was washed twice with PBS. [00089] The particles were separated by size using sieving. Sieves were stacked from the largest size (on top) to the smallest size (on the bottom) . A sieve shaker was used to aid the sieving process. The particles were placed on the top sieve together with PBS. Once all the particles were sorted, they were collected and placed in vials according to their sizes. [00090] After sieving, the particles were dehydrated to extend their shelf life. Under agitation, the particles were placed in a graded series of solvent/water mixtures. Both acetone and ethanol have been used successfully to dehydrate the particles. For at least 4 h, the particles were suspended in 75% solvent, 85% solvent, 95% solvent, 97% solvent, and 100% solvent. Subsequently, the particles were lyophilized, packaged and sterilized.Example 12.Determining the administration characteristics of the particles [00091] To assess delivery characteristics, particles prepared similarly to Example 9 were injected through a Headway 17 microcatheter (0.017", 432 μm inner lumen) with a 4.5 x 1 eight-knot, 5 cm. The test sample was prepared by mixing 2 to 3 mL of particles, 3 to 4 mL of saline, and 4 to 5 mL of contrast. The samples were injected through the microcatheter and into a dish using a syringe of 1 mL Pictures were taken of the particles before and after injection through the microcatheter The diameter and circularity of the particles were determined using Axiovision image analysis software The table below summarizes the results. [00092] In some embodiments, the shape factor of a region describes the shape of that region, based on its circularity. A perfect circle is assigned a value of 1. The more elongated the region, the smaller the form factor. The calculation is based on the filled area and Crofton Perimeter parameters. [00093] No change in particle circularity or diameter was observed, indicating that the particles did not separate or fragment during administration through a microcatheter. In other words, the particles remained substantially intact when administered through a catheter.Example 13In vitro determination of hydrolytic degradability [00094] Samples of particles prepared with different amounts of crosslinking agent were placed in PBS and stored at 37 °C to determine the degradation time. Visual analysis included particle color and transparency, ability to see particle outline, and number of visible particles. The grading scale for the samples included (5) no change in particle number, contours, or quantity since the start of the experiment, (3) weak particle contour with good number of particles still visible, (1) very few particles visible, and (0) no particles observed in the sample. The results are illustrated in Figure 1. The results indicate that degradation may be dependent on the concentration of the crosslinking agent. For example, the longest degradation time occurred with the highest concentration of crosslinking agent. [00095] Figure 2 graphically illustrates degradation time at 37 °C as a function of the amount of the crosslinking agent. As illustrated, the higher the percentage of the crosslinking agent, the longer the degradation lasts. Also, the larger the particle diameter (numbers to the right of the graph in micrometers), the longer the degradation lasts. Therefore, the particles with the longest degradation time are those that have the highest concentration of crosslinking agent and the largest diameter. These two properties can be varied to adapt the degradation time as needed.Example 14, Tetra Ester Crosslinking Agent [00096] To a 200 ml pear-shaped flask, 10 g (84.8 mmol) of succinic acid, 40 g (0.689 mol) of allyl alcohol and 30 µL of 98% H2SO4 were added. The reaction mixture was refluxed for 6 h and then quenched by the addition of 25 ml of 1 M sodium carbonate solution. The solvent was removed in vacuo. The crude product was reconstituted in 25 mL of water and the product, diallyl succinate, was extracted with ethyl acetate, 4 x 50 mL. The organic phase was collected and dried over MgSO4 and the solvent was then removed in vacuo to yield 9.26 g of diallyl succinate. [00097] In a 1 L round bottom flask, 5.2 g (26.3 mmol) of diallyl succinate and 20 g (0.116 mol) of meta-chloroperoxybenzoic acid (mCPBA) were dissolved in 400 ml of dichloromethane. The reaction mixture was refluxed at 40 °C overnight. The reaction mixture was then passed through a base-free Amberlyst column to remove the by-product, m-chlorobenzoic acid. The solvent was removed under vacuum to yield the crude product. Chromatography with 5% to 20% ethyl acetate in hexane at 210 nm resulted in pure diglycidyl succinate. [00098] To a 20 mL vial, 1.15 g (5 mmol) of diglycidyl succinate, 950 mg (11 mmol) of methacrylic acid and 1.5 g (7 mmol) of 1-butyl bromide were added. 3-methylimidazolium ([bmim]Br). The reaction mixture was stirred at 75°C. After 1 h, TLC (Thin Layer Chromatography) did not show the presence of the epoxide. The reaction mixture was suspended in 50 ml of 1 M sodium carbonate solution and the product was extracted with ethyl acetate, 3 x 50 ml. The organic layer was collected and dried over MgSO4, then concentrated in vacuo. TLC performed with 50:50 ethyl acetate:dichloromethane showed only one spot. Two grams of the title tetra ester crosslinking agent was collected in 99% yield. Example 15.Tetra Thioester Crosslinking Agent [00099] To a 500 ml flask and 3 round bottom necks under argon, cooled to 0 °C, was added 100 ml of dry THE. Under stirring, 20 g (0.11 mol) of 2,2'-(ethylenedioxy)ethantiol and 16 ml (0.09 mol) of diisopropylethylamine were added. 5 ml (0.045 mol) of succinyl chloride was dissolved in 40 ml of dry THF. Under argon, the solution was added dropwise to the reaction mixture at 0 °C via an addition funnel, with vigorous stirring. After addition, the reaction mixture was stirred for 1 h at 0 °C and then allowed to warm to room temperature for stirring overnight. The reaction mixture was then cooled in ice to precipitate the amine salt. The white precipitate was removed by filtration through a medium glass frit filter and washed with ice-cold THF. The filtrate was collected and concentrated under vacuum. Flash chromatography with ethyl acetate in 0% to 15% DCM at 254 nm gave the intermediate dithiol ester. To a 250 mL flask and 3 round bottom necks under argon, cooled to 0 °C, was added 50 mL of dry THF. Under stirring, 3.17 g (7.1 mmol) of intermediate dithiol ester and 3.6 ml (20 mmol) of diisopropylethylamine were added. 2 ml (20 mmol) of 'methacryloyl chloride were dissolved in 50 ml of dry THF. Under argon, the solution was added dropwise to the reaction mixture at 0 °C via an addition funnel, with vigorous stirring. After addition, the reaction mixture was stirred for 1 h at 0 °C and then allowed to warm to room temperature for stirring overnight. The reaction mixture was then cooled in ice to precipitate the amine salt. The white precipitate was removed by filtration through a medium glass frit filter and washed with ice-cold THF. The filtrate was collected and concentrated in vacuo. Flash chromatography with 0% to 10% ethyl acetate in dichloromethane at 254 nm eluted the desired tetra thiol ester crosslinking agent in 4 min to 12 min. Mass spectrometry analysis resulted in 605.1 which corresponds to [M+Na]+ of the calculated mass of C24H38O8S4. Example 16. Particle Preparation with a Peptide Crosslinking Agent [00101] A prepolymer solution was prepared by dissolving, in 10.0 g distilled water, 3.1 g acrylamide, 7.3 g 3-sulfopropyl acrylate potassium salt, and 0.2 g of a peptide-based crosslinking agent, prepared as in Example 3. This solution was filtered and then degassed under vacuum for 5 minutes and purged with argon. Mineral oil (500 mL) was sonicated during it then added to a sealed reaction vessel equipped with an overhead stirring element. The vessel was degassed under vacuum for at least it, then the vacuum replaced by argon. Approximately 2 ml of N,N,N',N'-tetramethylethylenediamine was added to the reaction vessel and the upper stirring started at 300 rpm. An initiator solution was made by dissolving 1.0 g of ammonium persulfate in 2.0 g of distilled water. The solution was filtered and approximately 250 ml was added to the prepolymer solution. After mixing, the solution was added to the reaction vessel. Subsequently, a solution of 0.35 ml of SPANO80 in 10 ml of mineral oil was added and the resulting suspension was allowed to polymerize for at least 4 h. Example 17, In vitro determination of enzymatic degradability [00102] Particle samples prepared with a peptide cross-linking agent were placed in PBS, without and with an enzyme, and incubated at 37 °C or 55 °C to determine the degradation time. The samples included a high enzyme concentration and a low enzyme concentration. [00103] Visual analysis included color and transparency of particles, ability to see particle outline and number of visible particles. The grading scale for the samples included (5) no change in particle number, contours, or quantity since the start of the experiment, (3) weak particle contour with good number of particles still visible, (1) very few particles visible, and (0) no particles observed in the sample. The results are illustrated in Figure 3. The results illustrate that the particles are slow to hydrolytically degrade, but the rate of degradation can be increased in the presence of a suitable enzyme. For example, the shortest degradation time occurred with the highest concentration of enzyme present in the PBS solution. [00104] The foregoing disclosures are illustrative embodiments. It should be appreciated by those skilled in the art that the devices, methods and techniques disclosed in the present patent application elucidate representative embodiments that function well in the practice of the present disclosure. However, those skilled in the art should, in light of the present disclosure, consider that many changes can be made in the specific embodiments that are disclosed and still obtain an equal or similar result without departing from the spirit and scope of the invention. [00105] Unless otherwise indicated, all numbers expressing amounts of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims, shall be understood to be modified in all cases by the term "about". Therefore, unless otherwise indicated, the numerical parameters set forth in the following specification and appended claims are approximations which may vary depending on the desired properties sought to be achieved by the present invention. At the very least, and not in an attempt to limit the application of the equivalents doctrine to the scope of the claims, each numerical parameter should at least be interpreted in light of the number of significant figures reported and by applying common rounding techniques. Although the numerical ranges and parameters which establish the broad scope of the invention are approximations, the numerical values set forth in the specific examples are presented as accurately as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective test measurements. [00106] The terms "a" and "an" and "the" and similar referents used in the context of describing the invention (especially in the context of the claims that follow) are to be understood to cover both the singular and the plural, unless otherwise indicated to the contrary in this patent application or clearly contradicted by the context. Recitation of ranges of values in this patent application is only intended to serve as an abbreviated method of referring individually to each separate value that falls within the range. Unless otherwise indicated in this application, each individual value is incorporated into the specification as if it were individually recited in this application. All methods described in this patent application may be performed in any suitable order, unless otherwise indicated in this patent application or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (eg, "as") provided in this patent application is for the sole purpose of clarifying the invention and does not constitute a limitation on the scope of the claimed invention. No language in the specification is to be construed as indicating any unclaimed element essential to the practice of the invention. [00107] The use of the term "or" in the claims is made to mean "and/or" unless explicitly stated to refer only to alternatives or the alternatives are mutually exclusive, even though the disclosure supports a definition that refers only to alternatives and "and/or". [00108] The groupings of alternative elements or embodiments of the invention disclosed in this patent application are not to be construed as limitations. Each element of the group may be referred to and claimed individually or in any combination with other members of the group or other elements found in this patent application. It is anticipated that one or more elements of a group may be included in, or eliminated from the group, for reasons of convenience and/or patentability. When such an insertion or deletion occurs, the specification is considered in this patent application to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims. [00109] The preferred embodiments of the present invention are described in this patent application, which includes the best way known to the inventors to carry out the invention. Of course, variations from these preferred embodiments will be apparent to those skilled in the art with ordinary skills in the art upon reading the preceding description. The inventor expects those of ordinary skill in the art to employ such variations, as appropriate, and the inventors intend that the invention be practiced other than as specifically described in this patent application. Thus, the present invention includes all modifications and equivalents to the subject matter cited in the appended claims, as permitted by applicable law. Furthermore, any combination of the above-described elements in all their possible variations is encompassed by the invention, unless otherwise indicated in this patent application or otherwise clearly contradicted by the context. [00110] The specific embodiments described in this patent application may also be limited in the claims by the use of the term formulate consisting of, or consisting essentially of. When used in the claims, whether as filed or added by amendment, the formulaic term "consists of" excludes any element, step or ingredient not specified in the claims. The formulaic term "consisting essentially of" limits the scope of the claim to the materials or steps specified and to those that do not substantially affect the basic feature(s) and the novel(s). Embodiments of the invention thus claimed are inherently or expressly described and enabled in this patent application. [00111] Furthermore, it is to be understood that the embodiments of the invention disclosed in this patent application are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not limitation, alternative embodiments of the present invention may be used in accordance with the teachings set out herein. Consequently, the present invention is not limited to what has been shown and precisely described.
权利要求:
Claims (6) [0001] 1. Polymer particle characterized by comprising: the reaction product of at least one monomer including a functional group; and at least one crosslinker; in which the polymer particle has a diameter, as determined in the experimental section, between 40 μm and 1,200 μm and is susceptible to degradation by hydrolysis or enzymatic action; in which at least one functional group is acrylate, acrylamide, methacrylate or methacrylamide; wherein at least one crosslinker is a thioester crosslinker selected from [0002] 2. Polymer particle according to claim 1, characterized in that at least one monomer is acrylamide. [0003] 3. Polymer particle according to claim 1, characterized in that it includes a second crosslinker including a second bond selected from an ester, a thioester, a carbonate, a peptide cleavable by matrix metalloproteinases, a peptide cleavable by matrix collagenases, a peptide cleavable by matrix elastases, and a peptide cleavable by matrix cathepsins. [0004] 4. Polymer particle according to claim 1, characterized in that at least one monomer includes an ionizable functional group. [0005] 5. Polymeric particle according to claim 4, characterized in that the ionizable functional group is basic. [0006] 6. Polymeric particle according to claim 4, characterized in that the ionizable functional group is acidic.
类似技术:
公开号 | 公开日 | 专利标题 BR112016005770B1|2021-07-27|POLYMER PARTICLES CA3038719C|2020-04-21|Polymer particles BR112016005768B1|2021-09-21|POLYMER FILMS
同族专利:
公开号 | 公开日 BR112016005770A2|2019-01-08| JP2020089742A|2020-06-11| US20190338059A1|2019-11-07| US11135167B2|2021-10-05| US20210401749A1|2021-12-30| CA2923753C|2021-10-12| EP3046952B1|2021-05-12| JP2016538348A|2016-12-08| JP6648224B2|2020-02-14| CN105814120B|2019-07-05| KR20160088284A|2016-07-25| CN110279885A|2019-09-27| US20150079395A1|2015-03-19| JP2019039006A|2019-03-14| US9546236B2|2017-01-17| CN105814120A|2016-07-27| KR102352098B1|2022-01-14| US10144793B2|2018-12-04| US20180186915A1|2018-07-05| US9803043B2|2017-10-31| CA2923753A1|2015-03-26| EP3046952A1|2016-07-27| US10400051B2|2019-09-03| JP6405369B2|2018-10-17| EP3046952A4|2017-05-10| US9938367B2|2018-04-10| US20170283536A1|2017-10-05| US20190062479A1|2019-02-28| AU2014321277A1|2016-03-17| US20170081450A1|2017-03-23| AU2014321277B2|2017-07-20| WO2015042461A1|2015-03-26|
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2019-02-26| B25C| Requirement related to requested transfer of rights|Owner name: MICROVENTION, INC (US) Free format text: A FIM DE ATENDER A TRANSFERENCIA, REQUERIDA ATRAVES DA PETICAO NO 870170084819 DE 03/11/2017, E NECESSARIO APRESENTAR A TRADUCAO JURAMENTADA DO DOCUMENTO, ALEM DA GUIA DE CUMPRIMENTO DE EXIGENCIA. | 2019-06-18| B25A| Requested transfer of rights approved|Owner name: TERUMO CORPORATION (JP) | 2019-12-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]| 2021-01-05| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]| 2021-05-11| B09A| Decision: intention to grant [chapter 9.1 patent gazette]| 2021-07-27| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/09/2014, OBSERVADAS AS CONDICOES LEGAIS. |
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申请号 | 申请日 | 专利标题 US201361880036P| true| 2013-09-19|2013-09-19| US61/880,036|2013-09-19| PCT/US2014/056644|WO2015042461A1|2013-09-19|2014-09-19|Polymer particles| 相关专利
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