Microspheres containing therapeutic agents and related methods of use
Microspheres, compositions including the microspheres, and methods of using the microspheres are disclosed herein. The microspheres can be substantially spherical and can include a copolymer of a monomer (such as an acrylic monomer) and a cyclodextrin or a derivative thereof. The microspheres can also include a therapeutic agent, such as a platinum-based drug.
1 . A method of embolization, comprising:
administering to a patient microspheres comprising:
a biocompatible, cross-linked polymeric material comprising a copolymer comprising at least one of an acrylic monomer, an acrylamide monomer, or a vinyl monomer, and a cross-linking agent, wherein the polymeric material is dispersed throughout a polymer matrix that forms each of the microspheres;
a biodegradable portion comprising a cyclodextrin;
a non-biodegradable portion that is cross-linked; and
a therapeutic agent,
wherein the microspheres have an average diameter of from about 10 μm to about 2,000 μm;
occluding a blood vessel with the microspheres before the therapeutic agent has been released from the microspheres;
releasing the therapeutic agent into the blood vessel from the microspheres as the biodegradable portion of the microspheres including the cyclodextrin biodegrades in the blood vessel; and
occluding the blood vessel with the microspheres after degradation of the biodegradable portion and release of the therapeutic agent into the blood vessel, the non-biodegradable portion retaining a substantially spherical shape after degradation of the biodegradable portion and decreasing blood flow through the occluded blood vessel by more than 80% after the therapeutic agent has been released and after the biodegradable portion has been degraded.
2 . The method of claim 1 , wherein the cyclodextrin is functionalized to include a moiety that is polymerizable with the at least one acrylic monomer, acrylamide monomer, or vinyl monomer.
3 . The method of claim 1 , wherein the therapeutic agent is released by degradation of the cyclodextrin.
4 . The method of claim 1 , wherein the copolymer comprises an acrylamide monomer.
5 . The method of claim 4 , wherein the acrylamide is selected from at least one of methacrylamide, N-[tris(hydroxymethyl)methyl]acrylamide, or N,N′-methylenebis(acrylamide).
6 . The method of claim 1 , wherein the cyclodextrin is selected from at least one of α (alpha)-cyclodextrin, β (beta)-cyclodextrin, or γ (gamma) cyclodextrin.
7 . The method of claim 1 , wherein the cyclodextrin is incorporated into the backbone of the copolymer.
8 . The method of claim 1 , wherein the microspheres comprise 10 to 100 mg of the therapeutic agent per 50 to 200 mg of dried microspheres.
9 . The method of claim 1 , wherein the microspheres comprise a ratio of the therapeutic agent to dry microspheres that is 0.05:1 to 10:1 by weight.
10 . The method of claim 1 , wherein the microspheres are one or more of hydrophilic, swellable, and water insoluble.
11 . The method of claim 1 , wherein the microspheres have an average diameter of from about 40 μm to about 1,200 μm.
12 . The method of claim 1 , wherein the therapeutic agent comprises a drug selected from one or more of the following: cisplatin, carboplatin, oxaliplatin, oxiplatin, satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, spiroplatin, iproplatin, docetaxel and paclitaxel.
13 . The method of claim 1 , wherein the cyclodextrin is distributed throughout interior regions and outer regions of the microspheres.
14 . The method of claim 1 , wherein the cyclodextrin is disposed only on an outer surface of the microspheres.
15 . The method of claim 1 , further comprising:
loading the therapeutic agent into dry microspheres, wherein the therapeutic agent is loaded into dry microspheres at a ratio of from 0.05:1 to 10:1 by weight.
16 . The method of claim 1 , further comprising:
combining the therapeutic agent and the microspheres at a microspheres:therapeutic agent volumetric ratio of 1:5 or 1:50.
17 . A method of embolization, comprising:
administering to a patient microspheres comprising:
a biocompatible, cross-linked polymeric material comprising a copolymer comprising an acrylamide monomer and an acrylamide cross-linking agent, wherein the polymeric material is dispersed throughout a body of each of the microspheres that includes an inner region and an outer region of a polymer matrix forming each of the microspheres;
a biodegradable portion comprising a cyclodextrin;
a non-biodegradable portion that is cross-linked; and
a therapeutic agent comprising a platinum-based drug, wherein the microspheres comprise 10 to 100 mg of the therapeutic agent per 50 to 200 mg of dried microspheres,
wherein the microspheres have an average diameter of from about 10 μm to about 2,000 μm;
occluding a blood vessel with the microspheres before the therapeutic agent has been released from the microspheres;
releasing the therapeutic agent into the blood vessel from the microspheres as the biodegradable portion of the microspheres including the cyclodextrin biodegrades in the blood vessel; and
occluding the blood vessel with the microspheres after degradation of the biodegradable portion and release of the therapeutic agent into the blood vessel, the non-biodegradable portion retaining a substantially spherical shape after degradation of the biodegradable portion and decreasing blood flow through the occluded blood vessel by more than 80% after the therapeutic agent has been released and after the biodegradable portion has been degraded.
18 . The method of claim 17 , wherein occlusion of the blood vessel with the microspheres after degradation of the biodegradable portion results in less than a 5% change in flux of the blood flow compared to occlusion of the blood vessel with the microspheres before degradation.