FIELD OF THE INVENTION

The present disclosure teaches crosslinked particles (e.g., microparticles or nanoparticles) that are capable of storing and releasing drugs. The particles can release drug by degradation, erosion, diffusion, or a combination of mechanisms.

BACKGROUND OF THE INVENTION

Drug-eluting biodegradable nanoparticles can be used for a variety of biological applications, such as wound healing and arthritis treatment (see e.g., U.S. Pat. No. 7,935,782 and WO 2009/061854, the entire contents of which are hereby incorporated by reference in their entirety). However, it can be difficult to control particle size and morphology to achieve nanoparticles with reproducible results. Additionally, previous attempts to produce crosslinked particles were limited in size and therefore could only be loaded with a limited amount of a given drug. Smaller particles also tended to biodegrade more quickly than larger particles, and were therefore unable to provide sustained release of for a desired duration.

Moreover, current drug delivery particles can suffer from a burst effect, wherein a substantial portion of a drug dispersed therein is released quickly released in a short period followed by a lower release rate. This has the effect of initially over dosing a patient and then later under dosing the patient.

SUMMARY OF THE INVENTION

The present disclosure teaches particles (e.g., microparticles) that are crosslinked and can be used in vivo. The crosslinked particles can include a drug, and can release the drug when used in vivo. In some embodiments, the drug is released as the particle degrades. The microparticles can thus be used to release drugs at the site of wounds, or after surgical procedures to release therapeutic agents and help speed recovery. Additionally, the particles of the current disclosure can be used for the treatment of arthritis. For example, particles comprising arthritis therapeutics can be administered to the site of arthritis pain (e.g., by injection). In some embodiments, the present disclosure provides crosslinked particles such as microparticles that have reproducible size and morphology. In some embodiments, the present disclosure also provides particles that can release a drug for a sustained period of time (e.g., greater than one month) and which do not suffer from a burst effect (e.g., a release of substantial amount of drug soon after immersion in a solvent).

In one aspect, the present disclosure provides a crosslinked degradable particle, comprising:

a plurality of polyester backbones, wherein the plurality of polyester backbones are crosslinked via thioethers, triazoles, or amides; and

a drug dispersed within the crosslinked degradable particle.

In another aspect, the present disclosure provides a crosslinked degradable particle, comprising:

a plurality of polymer backbones obtained from lactone monomer residues, wherein the plurality of polymer backbones are crosslinked via thioethers, triazoles, or amides; and

a drug dispersed within the crosslinked degradable particle, wherein the crosslinked degradable particle has a nominal diameter between 1 μm and 100 μm.

In another aspect, the present disclosure provides a crosslinked degradable particle, comprising:

a plurality of polymer backbones obtained from lactone monomer residues, wherein the plurality of polymer backbones are crosslinked via thioethers, triazoles, or amides; and

a drug dispersed within the crosslinked degradable particle, wherein the crosslinked degradable particle has a nominal diameter between 1 micron and 100 microns.

In another aspect, the present disclosure provides a method of preparing a crosslinked degradable particle, comprising:

combining a polyester containing a plurality of functional groups and a crosslinker to form a mixture; and

reacting the functional groups with crosslinkers to form a crosslinked degradable particle.

In another aspect, the present disclosure provides a method of preparing a crosslinked degradable particle, comprising:

dissolving a polyester containing a plurality of allyl groups, a dithiol, and a photoinitiator in at least one solvent to form a solution;

emulsifying the solution in an aqueous phase to form an emulsion;

irradiating the emulsion with UV light to react the dithiol with two of the allyl groups to form a crosslink; and

evaporating at least a portion of the solvent from the emulsion.

In another aspect, the present disclosure provides a method of preparing a crosslinked degradable particle, comprising:

dissolving a polyester containing a plurality of propargyl groups and a diazide in at least one solvent to form a solution;

emulsifying the solution in an aqueous phase to form an emulsion;

treating the emulsion to react the diazide with two of the propargyl groups to form a crosslink; and

evaporating at least a portion of the solvent from the emulsion.

In another aspect, the present disclosure provides method of preparing a crosslinked degradable particle, comprising:

dissolving a polyester containing a plurality of epoxide groups and a diamine in at least one solvent to form a solution;

emulsifying the solution in an aqueous phase to form an emulsion;

allowing the diamine to react with the epoxide groups to form a crosslink; and

evaporating at least a portion of the solvent from the emulsion.

In another aspect, the present disclosure provides a method of preparing a crosslinked degradable particle, comprising:

dissolving a polyester containing a plurality of carboxylic acid groups and a diamine in at least one solvent to form a solution;

emulsifying the solution in an aqueous phase to form an emulsion;

treating the emulsion to react diamine to react with the carboxylic acid groups to form a crosslink; and

evaporating at least a portion of the solvent from the emulsion.

In another aspect, the present disclosure provides a method of reducing aggregation of a plurality of crosslinked degradable particles, comprising attaching a plurality of polyethylene glycol chains to an exterior of the plurality of crosslinked degradable particles.

In another aspect, the present disclosure provides a method of dispersing a drug within a crosslinked degradable particle, comprising:

swelling the crosslinked degradable particle with a solvent to form a swollen crosslinked degradable particle, wherein the solvent further comprises a drug dispersed therein; and

removing the crosslinked degradable particles from the solvent.

In another aspect, the present disclosure provides a method of preparing a crosslinked degradable implant, comprising:

dissolving a polyester containing a plurality of functional groups and a crosslinker in at least one solvent to form a solution;

treating the solution to react the crosslinker with two of the functional groups to form a crosslink;

wherein the crosslinked degradable implant has a diameter of at least about 1 millimeter.

In another aspect, the present disclosure provides a method of controlling an average size of a distribution of crosslinked degradable particles, comprising:

preparing a plurality of molds of uniform size and shape;

combining a polyester containing a plurality of functional groups and a crosslinker to form a mixture;

dispersing the mixture within the molds; and

treating the mixture to react the crosslinker with two of the functional groups to form a crosslink.

In another aspect, the present disclosure provides a method of controlling an average size of a distribution of crosslinked degradable particles, comprising:

combining a polyester containing a plurality of functional groups and a crosslinker in at least one nonaqueous solvent to form an emulsion wherein the nonaqueous solvent comprises droplets of uniform size,

wherein the polyester and crosslinker, are dissolved in the nonaqueous solvent droplets; and

treating the emulsion to react the crosslinker with two of the functional groups to form a crosslink, wherein the particles are crosslinked while dissolved in the nonaqueous solvent.

In another aspect, the present disclosure provides a crosslinked degradable particle, formed by:

forming a polyester containing a plurality of functional groups and a crosslinker to form a mixture; and

reacting the functional groups with crosslinkers to form a crosslinked degradable particle.

In another aspect, the present disclosure provides a method of treating a disease, comprising:

administering to a subject in need thereof a therapeutically effective amount of the crosslinked degradable particle of the present disclosure containing the drug.

In another aspect, the present disclosure provides use of a crosslinked degradable particle of the present disclosure for the treatment of a disease. In some embodiments, the crosslinked particle contains a drug.

In another aspect, the present disclosure provides the use of a crosslinked degradable particle of the present disclosure in the manufacture of a medicament for the treatment of a disease. In some embodiments, the crosslinked particle contains a drug.

In another aspect, the present disclosure provides a crosslinked degradable particle, comprising:

a polyester backbone of the Formula I:


wherein:
R1is independently, at each occurrence, —H, or —C1-C6alkyl;
R2is independently, at each occurrence, —H, or —C1-C6alkyl;
R3is independently, at each occurrence, —H, or —C1-C6alkyl;
a is 0, 1, or 2;
m is independently, at each occurrence, an integer between 1 and 1000, inclusive;
n is independently, at each occurrence, an integer between 1 and 1000, inclusive;
p is independently, at each occurrence, an integer between 0 and 5, inclusive;
q is independently, at each occurrence, an integer between 0 and 1000, inclusive;
r is independently, at each occurrence, an integer between 0 and 1000, inclusive; and
t is independently, at each occurrence, an integer between 0 and 5, inclusive.

In another aspect, the present disclosure provides a crosslinked degradable particle, comprising:

a polyester backbone of the Formula II:


wherein:
R1is independently, at each occurrence, —H, or —C1-C6alkyl;
R2is independently, at each occurrence, —H, or —C1-C6alkyl;
R3is independently, at each occurrence, —H, or —C1-C6alkyl;
a is 0, 1, or 2;
m is independently, at each occurrence, an integer between 1 and 1000, inclusive;
n is independently, at each occurrence, an integer between 1 and 1000, inclusive;
p is independently, at each occurrence, an integer between 0 and 5, inclusive;
q is independently, at each occurrence, an integer between 0 and 1000, inclusive;
r is independently, at each occurrence, an integer between 0 and 1000, inclusive; and
t is independently, at each occurrence, an integer between 0 and 5, inclusive.

In another aspect, the present disclosure provides a crosslinked degradable particle, comprising:

a polyester backbone of the Formula III:


wherein:
R1is independently, at each occurrence, —H, or —C1-C6alkyl;
R2is independently, at each occurrence, —H, or —C1-C6alkyl;
R3is independently, at each occurrence, —H, or —C1-C6alkyl;
a is 0, 1, or 2;
m is independently, at each occurrence, an integer between 1 and 1000, inclusive;
n is independently, at each occurrence, an integer between 1 and 1000, inclusive;
p is independently, at each occurrence, an integer between 0 and 5, inclusive;
q is independently, at each occurrence, an integer between 0 and 1000, inclusive;
r is independently, at each occurrence, an integer between 0 and 1000, inclusive; and
t is independently, at each occurrence, an integer between 0 and 5, inclusive.

In another aspect, the present disclosure provides a crosslinked degradable particle, comprising:

a polyester backbone of the Formula IV:


wherein:
R1is independently, at each occurrence, —H, or —C1-C6alkyl;
R2is independently, at each occurrence, —H, or —C1-C6alkyl;
R3is independently, at each occurrence, —H, or —C1-C6alkyl;
a is 0, 1, or 2;
m is independently, at each occurrence, an integer between 1 and 1000, inclusive;
n is independently, at each occurrence, an integer between 1 and 1000, inclusive;
p is independently, at each occurrence, an integer between 0 and 5, inclusive;
q is independently, at each occurrence, an integer between 0 and 1000, inclusive;
r is independently, at each occurrence, an integer between 0 and 1000, inclusive; and
t is independently, at each occurrence, an integer between 0 and 5, inclusive.

In another aspect, the present disclosure provides a crosslinked degradable particle, comprising:

a polyester backbone of the Formula V:


wherein:
R1is independently, at each occurrence, —H, or —C1-C6alkyl;
R2is independently, at each occurrence, —H, or —C1-C6alkyl;
R3is independently, at each occurrence, —H, or —C1-C6alkyl;
a is 0, 1, or 2;
m is independently, at each occurrence, an integer between 1 and 1000, inclusive;
n is independently, at each occurrence, an integer between 1 and 1000, inclusive;
p is independently, at each occurrence, an integer between 0 and 5, inclusive;
q is independently, at each occurrence, an integer between 0 and 1000, inclusive;
r is independently, at each occurrence, an integer between 0 and 1000, inclusive; and
t is independently, at each occurrence, an integer between 0 and 5, inclusive.

In another aspect, the present disclosure provides a crosslinked degradable particle, comprising:

a polyester backbone of the Formula VI:


wherein:
R1is independently, at each occurrence, —H, or —C1-C6alkyl;
R2is independently, at each occurrence, —H, or —C1-C6alkyl;
R3is independently, at each occurrence, —H, or —C1-C6alkyl;
a is 0, 1, or 2;
m is independently, at each occurrence, an integer between 1 and 1000, inclusive;
n is independently, at each occurrence, an integer between 1 and 1000, inclusive;
p is independently, at each occurrence, an integer between 0 and 5, inclusive;
q is independently, at each occurrence, an integer between 0 and 1000, inclusive;
r is independently, at each occurrence, an integer between 0 and 1000, inclusive; and
t is independently, at each occurrence, an integer between 0 and 5, inclusive.

In another aspect, the present disclosure provides a crosslinked degradable particle, comprising:

a polyester backbone of the Formula VII:


wherein:
R is independently, at each occurrence, —H, or —C1-C6alkyl
R1is independently, at each occurrence, —H, or —C1-C6alkyl;
R2is independently, at each occurrence, —H, or —C1-C6alkyl;
R3is independently, at each occurrence, —H, or —C1-C6alkyl;
a is 0, 1, or 2;
m is independently, at each occurrence, an integer between 1 and 1000, inclusive;
n is independently, at each occurrence, an integer between 1 and 1000, inclusive;
p is independently, at each occurrence, an integer between 0 and 5, inclusive;
q is independently, at each occurrence, an integer between 0 and 1000, inclusive;
r is independently, at each occurrence, an integer between 0 and 1000, inclusive; and
t is independently, at each occurrence, an integer between 0 and 5, inclusive.

The crosslinked particles (e.g., macroparticles, microparticles or nanoparticles) of the present disclosure can have uniform size and shape along with other characteristics such as stability. This can allow the crosslinked particles of the present disclosure to be used in medical settings with high reproducibility and reliability. Additional features and advantages of the present disclosure will be apparent to one of skill in the art and are set forth in the Detailed Description, below.

