CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority to U.S. Provisional Application No. 62/337,033, filed on May 16, 2016, the entire contents of which are

incorporated herein by reference.

TECHNICAL FIELD

[0002] Provided herein are methods for treating incisional pain or wound pain in a subject.

BACKGROUND

[0003] Clinical management of surgical incisional pain or wound pain predominantly comprises administration of opioids (e.g. morphine), local anesthetics (e.g. bupivacaine), non- opioid analgesics (e.g. Tylenol) and/or non-steroidal anti-inflammatory drugs (e.g. ibuprofen). Traditional methods of acute pain management often necessitate longer hospitalization or clinical care. Long-term, systemic use of opioids has well-established side effects, including addiction. Some clinical studies of opioid use for acute (or sub-acute) pain also indicate a risk for addiction. Thus, alternatives to their use in the management of acute and/or post-operative pain is clinically desired. Extended, local delivery of anesthetics (e.g. bupivacaine) is effective, however the longevity of this approach is greatly restricted because of inherent toxicity concerns. Even therapeutic regiments of non-opioid analgesics and non-steroidal antiinflammatory drugs can exhibit undesired health effects when taken long-term for the management of pain indications.

[0004] Anticonvulsants have been shown to be useful in the treatment and management of many pain indications, as this class of drugs is known to exert important biochemical effects on nerve cells. Such effects reduce the tendency for nerves to transmit signals, and hence, drugs that have an antiepileptic effect are known to reduce the tendency for nerves to send pain signals to the brain. Most drugs belonging to these classes, however, have short circulation half-lives and considerable side effects including, but not limited to, sedation, vertigo, diplopia, skin rash, nausea, vomiting, chronic diarrhea, aplastic anemia,

thrombocytopenia, jaundice, oliguria, hypertension, cardiac dysrhythmias, chronic suppression of white blood cell counts, and hyponatremia. These side effects limit the potential systemic therapeutic use of anticonvulsants for the management of pain. Consequently, physicians cannot always dose enough drug to have the desired anti-pain effect without causing problematic, pleiotropic systemic side effects. Local delivery of anticonvulsants would abrogate these pleiotropic, systemic side effects and enable their therapeutic intervention for the management of pain. For example, a localized injection of a depot formulation of an anticonvulsant agent would permit the use of a lower initial dose than would be required for systemic or oral administration of the agent because the depot would establish therapeutically efficacious concentrations of the agent specifically at the desired site of action.

[0005] There remains an outstanding need for formulations comprising, consisting of, or consisting essentially of anticonvulsant agents that can provide desirable release profiles, limit systemic levels in order to avoid side effects, and that possess physical characteristics that are consistent with clinical translation as an injectable or topical solution.

SUMMARY

[0006] Provided herein are methods of administering disclosed compositions to treat surgical incisional pain or wound pain comprising administering to a subject having the pain a composition comprising, consisting of, or consisting essentially of an anticonvulsant agent and a biodegradable carrier.

[0007] Further provided are kits for producing disclosed compositions for treating surgical incisional pain or wound pain in a subject.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 illustrates the stepwise release of an anticonvulsant agent from a biodegradable, polymeric nanoparticle or microparticle.

[0009] FIG. 2A shows a representative scanning electron micrograph (SEM) of poly(D,L-lactide-co-glycolide) (PLGA) microparticles incorporating the anticonvulsant carbamazepine fabricated by solvent extraction and evaporation single oil-in-water emulsification. FIG. 2B shows a cross section of the microparticles depicted in FIG. 2A..

[0010] FIG. 3 shows a representative particle size distribution of PLGA

microparticles incorporating the anticonvulsant carbamazepine fabricated by solvent extraction and evaporation single oil-in-water emulsification, as measured by aqueous solution phase laser diffraction (d[50]=2.66 microns and d[3,2]=2.51 microns, median and mean

hydrodynamic diameters, respectively).

[0011] FIG. 4 A shows a sustained, controlled release kinetic profile of the anticonvulsant carbamazepine from PLGA microparticles comprising 50:50 PLGA with an inherent viscosity of 0.15-0.25 dL/g, and FIG. 4B shows a sustained, controlled release kinetic profile of the anticonvulsant carbamazepine from PLGA microparticles comprising 50:50 PLGA with an inherent viscosity of 0.55-0.75 dL/g.

[0012] FIG. 5 shows a sustained, controlled release kinetic profile of the

anticonvulsant carbamazepine from PLGA microparticles comprising 50:50 PLGA with an inherent viscosity of 0.55-0.75 dL/g, and with a d[50]=2.66 microns and d[3,2]=2.51 microns, median and mean hydrodynamic diameters, respectively, as measured by aqueous solution phase laser diffraction.

[0013] FIG. 6 shows an example of a sustained, controlled release kinetic profile of the anticonvulsant carbamazepine from poly(D,L-lactide) (PLA) microparticles comprising PLA with a molecular weight of 75-120 kDa.

[0014] FIG. 7 shows the evaluation of therapeutic efficacy of sciatic nerve block following perineural, depot injection of carbamazepine-loaded microparticles. Pain scoring was assessed by comparison of pre- and post-treatment electronic von Frey measurements of the ligated hindlimb for treatments of either carbamazepine-loaded microparticles (20 mg and 10 mg , 2.6 urn, 4.8% carbamazepine by weight, 50:50 PLGA (i.v. 0.55-0.75 dL/g)) (solid circles and solid squares, respectively), or saline (open circles). Pain relief scores greater than 20 grams were indicative of therapeutic efficacy. Error analysis is presented as S.E.M.

[0015] FIG. 8 shows pharmacokinetic analysis of the carbamazepine released from the microparticle depot into circulation. The detection limit was 10 ng/mL. Error analysis is presented as S.D. for n=6 replicates.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0016] The disclosed compositions, methods, and kits may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed compositions, methods, and kits are not limited to the specific compositions, methods, and kits described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed compositions, methods, and kits. Also, as used in the specification including the appended claims, the singular forms "a," "an," and "the" include the plural, and reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value.

Further, reference to values stated in ranges include each and every value within that range. All ranges are inclusive and combinable. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment.

[0017] It is to be appreciated that certain features of the disclosed compositions, methods, and kits which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions, methods, and kits that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any

subcombination.

[0018] The term "about" when used in reference to numerical ranges, cutoffs, or specific values is used to indicate that the recited values may vary by up to as much as 25% from the listed value. As many of the numerical values used herein are experimentally determined, it should be understood by those skilled in the art that such determinations can, and often times will, vary among different experiments. The values used herein should not be considered unduly limiting by virtue of this inherent variation. The term "about" is used to encompass variations of ±25% or less, variations of ± 20% or less, variations of 10% or less, variations of ± 5% or less, variations of ± 1% or less, variations of ± 0.5% or less, or variations of ± 0.1% or less from the specified value.

[0019] As used herein, "administering to said subject" and similar terms indicate a procedure by which the described anticonvulsant agents or compositions, together or separately, are introduced into, sprinkled into, dispersed into via aerosol, used as a cream or paste, injected into, or applied onto a subject such that target cells, tissues, or segments of the body of the subject are contacted with the agent.

[0020] For purposes of the present disclosure, a substance is "biodegradable" if it is capable of being at least partially broken down within and cleared by the human body over time by natural biological, biochemical, and/or physiological processes. For example, carriers comprising polyesters, such as, poly(lactide-co-glyoclides) (PLGA), poly(lactides) (PLA), or copolymers of PLGA or PLA with poly(ethylene glycol) (PEG), which are broken down by the human body by hydrolytic and enzymatic cleavage, through interaction with water and esterases, respectively, are thus referred to as biodegradable carriers.

[0021] "Pharmaceutically acceptable" refers to those properties and substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance, and bioavailability.

[0022] "Pharmaceutically acceptable carrier" refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredient(s) and is not toxic to the host to which it is administered.

[0023] "Therapeutically effective dose" refers to an amount of a composition, as described herein, effective to achieve a particular biological or therapeutic result such as, but not limited to, biological or therapeutic results disclosed, described, or exemplified herein. The therapeutically effective dose may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to cause a desired response in a subject. Such results may include, but are not limited to, the treatment of surgical incisional or wound pain, as determined by any means suitable in the art.

[0024] The terms "treating" or "treatment" refer to any success or indicia of success in the attenuation or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement, remission, diminishing of symptoms or making the injury, pathology, or condition more tolerable to the patient, slowing in the rate of inflammation, making the final point of inflammation less debilitating, improving a subject's physical or mental well-being, or prolonging the length of survival. The treatment may be assessed by objective or subjective parameters; including the results of a physical examination, neurological examination, or psychiatric evaluations.

[0025] As used herein, "exposed on the surface" means that at least a portion of the anticonvulsant agent is not covered or encased by the biodegradable carrier and is accessible from the exterior of the biodegradable carrier. The anticonvulsant agent exposed on the surface can be fully exposed, such that the entire agent is on the surface of the biodegradable carrier, or can be partially exposed, such that only a portion of the agent is on the surface of the biodegradable carrier. The anticonvulsant agent that is exposed on the surface of the biodegradable carrier can be bound to the surface of the biodegradable carrier through, for example, covalent or non-covalent bonds, or can be incorporated within the biodegradable carrier such that a portion of the agent is exposed on the surface.

[0026] As used herein, "incorporated within" means that the anticonvulsant agent is at least partially covered by, contained within, encased in, or entrapped by the biodegradable carrier. In such circumstances, the anticonvulsant agent may or may not be exposed on the surface of the biodegradable carrier. Depending on the type of biodegradable carrier present in the composition, the anticonvulsant agent may be located in a void space, such as a core, of the biodegradable carrier or dispersed within the biodegradable carrier with the potential for being exposed on the surface, or any combination thereof. In some embodiments, the anticonvulsant agent can be dispersed or distributed within the biodegradable carrier, and not partially exposed on the surface of the biodegradable carrier. In other embodiments, the anticonvulsant agent can be partially exposed on the surface of the biodegradable carrier. In other embodiments, the anticonvulsant agent can be both dispersed or distributed within the biodegradable carrier and partially exposed on the surface of the biodegradable carrier. In yet other embodiments, the anticonvulsant agent can be located in a void space of the

biodegradable carrier. In yet other embodiments, the anticonvulsant agent can be both located in a void space of the biodegradable carrier and exposed on the surface of the biodegradable carrier.

[0027] Biodegradable, polymeric microparticles and nanoparticles represent an attractive means to achieve the desired local delivery of therapeutic agents, often by

administration of a depot formulation. These particles can be fabricated by a variety of techniques to incorporate neurologic ally active therapeutic agents, including, anticonvulsants. The fabrication technique dictates the physical, chemical, and mechanical properties of the resulting particles. Thus, to achieve desired therapeutically efficacious concentrations and durations, the fabrication technique and polymer must be selected appropriately. For example, buoyant poly(D,L-lactide-co-glycolide) (PLGA) microspheres were created by oil- in-oil emulsification to encapsulate and deliver hydrophilic small-molecule agents (e.g., inosine) for intrathecal administration for the treatment of central nervous system disorders (WO 2004/047768).

[0028] The formulation of anticonvulsants within different biodegradable implants or carriers has been examined for achieving sustained therapeutic efficacy in epilepsy [see, e.g., Halliday et al, Adv Drug Deliv Rev., 2012, 64(10):953-64]. To these ends, the anticonvulsant, carbamazepine, has been studied as a model drug for incorporation within these types of devices [Klose et al, Inter J Pharmaceutics., 2011, 404:75-82; Barakat et al, Drug Deliv., 2006, 13(1):9- 18; Pepic et al, J Microencapsulation., 2013, 30(2): 151-160]; however, in these reports, the fabrication technique, polymer, and size were not selected appropriately to yield a clinically relevant drug delivery system for the treatment of surgical incisional or wound pain indications. For example, different water-in-oil-in-water (w/o/w) double emulsification techniques have been utilized to fabricate either large, highly porous [Klose et al, Inter J Pharmaceutics., 2011, 404:75-82] or large, solid matrix [Barakat et al, Drug Deliv., 2006, 13(1):9-18] biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microparticles incorporating carbamazepine. In both reports, the large particle size is necessary to extend the release duration, however, these forms are impractical for clinical translation as an injectable or topical application. Additionally, the intentional high, micro- scale porosity of the microparticles fabricated by Klose et al, limits the ability for sustained, long-term release applications. Further, the carbamazepine within the solid matrix microparticles fabricated by Barakat et al. , is predominantly distributed on or within close proximity to the microparticle surface. This predominantly surface-associated carbamazepine gives rise to the observed high initial burst release and inability to sustain the release of therapeutically relevant concentrations. Additionally, neither study was able to achieve a size range that is suitable for injection without resorting to mechanical sieving of high- poly dispersity populations of particles, which results in non-uniform particle distributions.

Furthermore, Pepic et al. , utilized an oil-in-water (o/w) single emulsification technique to fabricate large, porous poly(e-caprolactone) (PCL) microspheres incorporating carbamazepine. In this report, the high hydrophobic character and crystallinity of the PCL causes extremely slow biodegradation that is too slow to be clinically relevant as a biodegradable carrier for therapeutic delivery in the treatment of surgical incisional or wound pain indications. This slow biodegradation combined with the porosity inherent to the PCL polymer matrix causes the carbamazepine release mechanism to be solely diffusion-based, rather than biodegradation- based, necessitating large particle sizes to extend release. These large particle sizes reported are also impractical for clinical translation as an injectable. Further, the carbamazepine within the polymer matrix was observed to be predominantly distributed on or within close proximity to the microparticle surface. This predominantly surface-associated carbamazepine gives rise to the observed high initial burst release and inability to sustain the release of therapeutically relevant concentrations.

[0029] The present disclosure describes compositions that are formulated specifically to enable 1) control of anticonvulsant agent incorporation, including substantially even distribution throughout the polymer matrix, 2) control over anticonvulsant agent release rate, 3) clinically relevant biodegradation rates, and 4) control over the duration of anticonvulsant agent release at therapeutically efficacious concentrations, including sustained efficacious release for an extended period of time, such as one day or more, from nanoparticles, microparticles, or any combination thereof. Also described herein are methods for using these specifically designed compositions for the treatment of surgical incisional pain or wound pain.

[0030] Further, the present disclosure describes compositions that are formulated specifically to enable control over hydrodynamic diameter. The hydrodynamic diameter of the biodegradable carrier represents an important characteristic which influences 1) anticonvulsant incorporation, 2) anticonvulsant release rate, 3) biodegradation and clearance rate, 4) administration site residence duration, and 5) the ability to enable clinical

administration of the composition to said subject as a topical application such as, but not limited to, a sprinkled powder, dispersed via aerosol, cream, or paste, and subsequently in situ reconstitutable or as an injectable without necessitating a change to the standard of care.

[0031] Sprinkling and subsequent in situ re constitution as a route of administration has been exploited in the clinical setting for the mitigation of infection in the post-surgical incisional site. For example, sprinkling of vancomycin into the surgical site has been performed prophylactically to minimize the potential for surgical site infection [Kim et al. , Case Reports in Surgery. 2015, Vol. 2015, Article ID 321682].

[0032] Disclosed herein are compositions for treating surgical incisional pain or wound pain in a subject. In some embodiments, the compositions comprise an anticonvulsant agent and a biodegradable carrier. In some embodiments, the compositions consist of an anticonvulsant agent and a biodegradable carrier. In yet other embodiments, the compositions consist essentially of an anticonvulsant agent and a biodegradable carrier.

[0033] Suitable biodegradable carriers include, but are not limited to, nanoparticles, microparticles, or any combination thereof. In some embodiments, the biodegradable carrier comprises nanoparticles. In some embodiments, the biodegradable carrier comprises microparticles. In some embodiments, the biodegradable carrier is a combination of microparticles and nanoparticles.

[0034] Suitable classes of nanoparticles or microparticles include, but are not limited to, polymeric. Further, said nanoparticles or microparticles may be solid, hollow, or a mixture thereof. Further, said nanoparticles or microparticles may be porous, wherein the porosity is defined solely by the density and packing arrangement of the polymer matrix and the incorporated anticonvulsant agent.

[0035] Polymeric nanoparticles can have a mean hydrodynamic diameter up to 1 micron, as measured by dynamic light scattering in aqueous suspension, wherein the hydrodynamic diameter is derived solely from the fabrication process in the absence of sieving the lyophilized product. Suitable instrumentation for aqueous suspension phase dynamic light scattering includes the Malvern Instruments™ ZetaSizer® Nano ZS, wherein the mean is derived from the intensity distribution obtained with cumulants analysis. Polymeric microparticles can have a median and/or mean hydrodynamic diameter greater than or equal to 1 micron and up to about 25 microns, inclusive, and can have a maximum hydrodynamic diameter of about 40 microns, as measured by laser diffraction in aqueous suspension, wherein the hydrodynamic diameter is derived solely from the fabrication process in the absence of sieving the lyophilized product. Suitable instrumentation for aqueous suspension phase laser diffraction includes the Malvern Instruments™ Mastersizer® 3000 equipped with the Hydro MV unit, where median and mean hydrodynamic diameter are calculated as d[50] and d[3,2], respectively. For example, microparticles can be fabricated via solvent extraction and evaporation single oil-in-water emulsification to have a median hydrodynamic diameter (d[50]) of 18 microns, as measured by laser diffraction in aqueous suspension, by precisely controlling the shear-rate and viscosity of the emulsion. Further, the disclosed compositions have sufficiently small median and/or mean hydrodynamic diameters up to 25 microns, inclusive, to enable clinical administration as an injectable without changing the standard of care. In addition, the polydispersity of particles produced (measured by range from d[10] and d[90]) is narrow enough that, in certain embodiments, no particles fall above 40 microns, and follows a normal distribution about the mean.

[0036] Suitable anticonvulsant agents include, but are not limited to,

carbamazepine, pregabalin, phenytoin, gabapentin, topiramate, oxcarbazepine, or any combination thereof. In some embodiments, the anticonvulsant agent is carbamazepine. In some embodiments, the anticonvulsant agent is phenytoin. In some embodiments, the anticonvulsant agent is gabapentin. In some embodiments, the anticonvulsant agent is pregabalin.

[0037] The disclosed compositions can comprise, consist of, or consist essentially of an anticonvulsant agent and a biodegradable carrier. In some embodiments, the composition comprises, consists of, or consists essentially of carbamazepine and a nanoparticle. In some embodiments, the composition comprises, consists of, or consists essentially of carbamazepine and a microparticle. In some embodiments, the composition comprises, consists of, or consists essentially of phenytoin and a nanoparticle. In some embodiments, the composition comprises, consists of, or consists essentially of phenytoin and a microparticle. In some embodiments, the composition comprises, consists of, or consists essentially of gabapentin and a nanoparticle. In some embodiments, the composition comprises, consists of, or consists essentially of gabapentin and a microparticle. In some embodiments, the composition comprises, consists of, or consists essentially of pregabalin and a nanoparticle. In some embodiments, the composition comprises, consists of, or consists essentially of pregabalin and a microparticle. In some embodiments, the composition comprises, consists of, or consists essentially of topiramate and a nanoparticle. In some embodiments, the composition comprises, consists of, or consists essentially of topiramate and a microparticle. In some embodiments, the composition comprises, consists of, or consists essentially of oxcarbazepine and a nanoparticle. In some embodiments, the composition comprises, consists of, or consists essentially of oxcarbazepine and a microparticle.

[0038] Anticonvulsant agents also include mixtures of carbamazepine, pregabalin, phenytoin, gabapentin, topiramate, and/or oxcarbazepine within the same biodegradable carrier. For example, and without intent to be limiting, in some aspects the composition can comprise carbamazepine and pregabalin within a microparticle.

[0039] In some embodiments, the anticonvulsant agent can be formulated to comprise up to 1% by weight, inclusive, of the biodegradable carrier. In some embodiments, the anticonvulsant agent can be formulated to comprise up to 5% by weight, inclusive, of the biodegradable carrier. In some embodiments, the anticonvulsant agent can be formulated to comprise up to 10% by weight, inclusive, of the biodegradable carrier. In some embodiments, the anticonvulsant agent can be formulated to comprise up to 15% by weight, inclusive, of the biodegradable carrier. In some embodiments, the anticonvulsant agent can be formulated to comprise up to 20% by weight, inclusive, of the biodegradable carrier. In some embodiments, the anticonvulsant agent can be formulated to comprise up to 25% by weight, inclusive, of the biodegradable carrier. In some embodiments, the anticonvulsant agent can be formulated to comprise up to 50% by weight, inclusive, of the biodegradable carrier.

[0040] Throughout the present disclosure, the phrase "the anticonvulsant agent" can refer to more than one anticonvulsant agent if more than one such agent is present in the composition. For example, when only one anticonvulsant agent is contained within the biodegradable carrier, a reference to release of "60% of the anticonvulsant agent" means that there is release of 60% of the sole present anticonvulsant. When more than one anticonvulsant agent is contained within the biodegradable carrier, language referring to release of "60% of the anticonvulsant agent", means that 60% of the total complement of anticonvulsant agents is released. Thus, if the composition includes 3 mg of a first anticonvulsant agent and 3 mg of a second anticonvulsant agent, then release of "60% of the anticonvulsant agent" can mean that 60% of the total complement of 6 mg of anticonvulsant agents is released.

[0041] Biodegradable carriers can comprise, consist of, or consist essentially of a number of materials suitable for delivering an anticonvulsant agent to a subject, including synthetically derived, biodegradable polymers. Exemplary polymers include, but are not limited to, poly(lactides) (PLA), poly(glycolides) (PGA), poly(lactide-co-glycolides) (PLGA), or copolymers of said polymers with poly(ethylene glycol)(PEG), or any combination thereof. In some embodiments, the biodegradable carrier comprises, consists of, or consists essentially of a synthetically derived biodegradable polymer. Additionally, in some embodiments, the synthetically derived biodegradable polymer can be poly(lactic-co-glycolic acid) (PLGA), having a lactic acid and gly colic acid content ranging from 0-100% for each monomer. For example, in some aspects, the biodegradable polymer can be a 50:50 PLGA, where 50:50 refers to the ratio of lactic to glycolic acid. In some embodiments, the biodegradable carrier comprises, consists of, or consists essentially of a copolymer. For example, in some embodiments, the biodegradable polymer can be a copolymer of poly(ethylene glycol) (PEG) and poly(lactic-co- glycolic acid) (PLGA), having a lactic acid and glycolic acid content ranging from 0-100% for each monomer.

[0042] Biodegradable carriers can be configured to be injected into a surgical incision or wound of a subject. For example, in some aspects, the biodegradable carrier comprises a nanoparticle that is configured to be injected into a surgical incision or wound of a subject. In other aspects, the biodegradable carrier comprises a microparticle that is configured to be injected into a surgical incision or wound of a subject. For injection into a surgical incision or wound of a subject, the microparticle must have a median and/or mean hydrodynamic diameter of not more than 25 microns, inclusive, and a maximum

hydrodynamic diameter of about 40 microns, as measured by the aforementioned aqueous solution phase laser diffraction instrumentation.

[0043] Biodegradable carriers can also be configured to be sprinkled into a surgical incision or wound of a subject, or prepared as a paste for topical application at the wound site. For example, in some aspects, the biodegradable comprises a lyophilized nanoparticle that can be sprinkled into a surgical incision or wound of a subject. In other aspects, the biodegradable comprises a lyophilized microparticle that can be sprinkled into a surgical incision or wound of a subject. In other aspects, lyophilized nanoparticles and/or microparticles can be resuspended in a liquid to form a paste for application. In other aspects, lyophilized nanoparticles and/or microparticles can be sprayed onto the wound site in an aerosol.

[0044] Biodegradable carriers can further comprise one or more surface modifications. Examples of suitable surface modification include, but are not limited to, functional group modifications, PEGylation or affinity -based targeting moieties. In some embodiments, the biodegradable carrier can be PEGylated. Surface modifications can prevent the carrier from migrating from the site of administration, abrogate the foreign body response, and/or minimize clearance by immune system cells.

[0045] The anticonvulsant agent can be exposed on the surface of the

biodegradable carrier, incorporated within the biodegradable carrier, or both. In some embodiments, the anticonvulsant agent is incorporated within the biodegradable carrier.

[0046] When the anticonvulsant agent is incorporated within the biodegradable carrier, the process of incorporation may be accomplished using solvent extraction and evaporation oil-in-water (o/w) single emulsification in the presence of a stabilizing surfactant. Suitable surfactants for stabilizing this oil-in-water emulsion include, but are not limited to, poly(vinyl alcohol) (PVA), polysorbate 80, polysorbate 85, poly(ethylene glycol), or any combination thereof.

[0047] When the anticonvulsant agent is incorporated within the biodegreadable carrier, exemplary polymers for forming the biodegradable carrier include, but are not limited to, PLGA, PLA, PLGA-PEG and PLA-PEG block copolymers, or any combination thereof.

[0048] The biodegradable carrier for use in an incorporated system can be chosen to begin to degrade within any suitable time frame following preparation for administration of the composition to a subject. In some embodiments, the biodegradable carrier can begin to degrade upon resuspension in aqueous media. In some embodiments, the biodegradable carrier can begin to degrade upon administration of the composition to a subject.

[0049] Degradation, diffusion, or any combination thereof, can lead to the controlled release of the anticonvulsant agent from the biodegradable carrier. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 3 hours. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 6 hours. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 12 hours. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 1 day. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 2 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 3 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 4 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 5 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 6 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 7 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 8 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 9 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 10 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 12 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 14 days. In some

embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 18 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 3 weeks. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 1 month. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 2 months. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 3 months.

[0050] Degradation of the biodegradable carrier can lead to the controlled release of and/or delivery of the anticonvulsant agent, thus providing a therapeutically effective dose of the agent to the subject. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 3 hours. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 6 hours. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 12 hours. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 1 day. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 2 days. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 3 days. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 4 days. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 5 days. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 6 days. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 7 days. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 8 days. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 9 days. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 10 days. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 12 days. In some embodiments, the biodegradable carrier provides a therapeutically effect dose of the agent for up to 14 days. In some embodiments, the biodegradable carrier provides a therapeutically effect dose of the agent for up to 18 days. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 3 weeks. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 1 month. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 2 months. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 3 months.

[0051] Degradation of the biodegradable carrier can lead to the controlled release of and/or delivery of the anticonvulsant agent, providing a therapeutically effective dose of the agent to the subject, while maintaining systemic blood plasma concentrations of the anticonvulsant agent that are lower than those associated with oral dosing or administration. In some embodiments, the blood plasma concentration of the anticonvulsant agent can be 1/1000 or less than the blood plasma concentration associated with oral dosing or administration. In some embodiments, the blood plasma concentration of the anticonvulsant agent can be 1/500 or less than the blood plasma concentration associated with oral dosing or administration. In some embodiments, the blood plasma concentration of the anticonvulsant agent can be 1/100 or less than the blood plasma concentration associated with oral dosing or administration. In other embodiments, the blood plasma concentration of the anticonvulsant agent can be below detection limits of analytical measurements.

[0052] Pharmaceutical agents may also be included in the compositions disclosed herein. In some aspects, the pharmaceutical agents may stabilize the composition, allow it to be readily administered to a subject, increase its ability to treat surgical incisional pain or wound pain, or otherwise make the composition suitable for therapeutic use in a subject.

Accordingly, the described composition may further comprise a pharmaceutically acceptable carrier or excipient, as would be known to an individual skilled in the relevant art. In view of the inclusion of pharmaceutical agents in some of the described compositions, disclosed herein are also pharmaceutical compositions having an anticonvulsant and a biodegradable carrier, as provided herein. The disclosed pharmaceutical compositions for delivery or injection of the described compositions may be administered to a subject in order to maintain the ability to treat incisional or wound pain in the subject over a prolonged period of time. For example, composition viscosity and concentration of the agent may be altered to increase the half-life of composition's active ingredients.

[0053] The disclosed pharmaceutical compositions may be formulated as any of various preparations that are known and suitable in the art, including those described and exemplified herein. In some embodiments, the pharmaceutical compositions are aqueous formulations. Aqueous solutions may be prepared by admixing the described compositions in water or suitable physiologic buffer, and optionally adding suitable colorants,

preservatives, stabilizing and thickening agents, ions such as calcium or magnesium, and the like as desired. Aqueous suspensions may also be made by dispersing the described compositions in water or physiologic buffer with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well- known suspending agents.

[0054] When the disclosed compositions are prepared as aqueous suspensions, the suspensions may be formulated by dispersing the present biodegradable carrier and active agent within injectable, in situ cross-linking hydrogel solution precursors, including, but not limited to, naturally derived polymers (e.g. polysaccharides) and/or synthetically derived polymers (e.g. PEG, PGA-PEG-PGA, PLA-PEG-PLA, PLGA-PEG-PLGA). The resulting compositions may then be administered to a subject, for example, by injection. Accordingly, a hydrogel may function as an excipient in which the biodegradable carrier and active agent are dispersed.

[0055] The disclosed compositions may also be prepared as liquid formulations and solid form preparations which are intended to be converted, shortly before use, to liquid preparations. Such liquids include solutions, suspensions, syrups, slurries, and emulsions. Liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats or oils); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl- p-hydroxybenzoates or sorbic acid). These preparations may contain, in addition to the active agent, stabilizers, buffers, dispersants, thickeners, solubilizing agents, and the like. The disclosed compositions may be in powder or lyophilized form for constitution with a suitable vehicle such as sterile water, physiological buffer, saline solution, or alcohol, before use. The compositions may be formulated for injection into a subject. For injection, the compositions described may be formulated in aqueous solutions such as water or alcohol, or in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.

The solution may contain one or more formulatory agents such as suspending, stabilizing or dispersing agents. Injection formulations may also be prepared as solid form preparations which are intended to be converted, shortly before use, to liquid form preparations suitable for injection, for example, by constitution with a suitable vehicle, such as sterile water, saline solution, or alcohol before use.

[0056] Provided herein are methods of treating a subject surgical incisional pain or wound pain comprising administering to a subject having surgical incisional pain any one of the compositions disclosed herein. In some embodiments, the methods of treating a subject having surgical incisional pain or wound pain can comprise administering to a subject having the pain a composition comprising an anticonvulsant agent and a biodegradable carrier. In other embodiments, the methods of treating a subject surgical incisional pain or wound pain can comprise administering to a subject having the pain a composition consisting of an anticonvulsant agent and a biodegradable carrier. In yet other embodiments, the methods of treating a subject having surgical incisional pain or wound pain can comprise administering to a subject having the pain a composition consisting essentially of an anticonvulsant agent and a biodegradable carrier.

[0057] The disclosed compositions can be administered by sprinkling or injection. For example, the composition can be sprinkled into or injected into a surgical incision, wound, or laceration. Local delivery allows a therapeutic concentration of the composition to be delivered to the nerve in question, without the systemic levels, including, but not limited to, blood plasma concentrations, rising as high as when oral or systemic delivery is used for the same effect.

Consequently, the systemic side effects can be greatly reduced or entirely eliminated.

[0058] The disclosed compositions can be administered to a surgical incision, laceration, or wound by sprinkling, applications as a cream or paste, aerosol dispersal, injection, or any combination thereof. In some embodiments, the composition can be sprinkled into a surgical incision. In some embodiments, the composition can be sprinkled into a laceration or wound. In some embodiments, the composition can be injected into a surgical incision. In some embodiments, the composition can be injected into a laceration or wound.

[0059] In the scenario wherein the disclosed composition is administered to a surgical incision or wound by sprinkling of the sterile, lyophilized powder, the composition is intended to be reconstituted in situ by the surrounding physiological fluid.

[0060] The disclosed methods can be used to treat acute pain such as that arising from surgical incisions, wounds, lacerations, or any combination thereof.

EXAMPLES

[0061] Microencapsulated anticonvulsant agent by solvent extraction and evaporation single oil-in-water emulsification. Biodegradable, polymeric microparticles were fabricated using a solvent extraction and evaporation single oil-in-water (o/w) emulsification method. PLGA (0-20 wt%) and carbamazepine (0-20 wt%) were dissolved in a suitable, volatile organic solvent (e.g. dichloromethane, ethyl acetate). The resulting polymer solution dispersant phase was added to an aqueous continuous phase containing 1-5% (w/v) of surfactant (PVA) under constant shear rate mixing to create a single o/w microemulsion. The resulting stable microemulsion was subsequently added to an evaporation bath containing deionized water containing a trace concentration (0-0.5% (w/v)) of surfactant (PVA) under stirring to effectively extract and evaporate the organic solvent. The hardened microparticles were then collected, purified with deionized water, and lyophilized.

[0062] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.