Classifications

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  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
  • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
• • A—HUMAN NECESSITIES
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  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • A—HUMAN NECESSITIES
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  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
• • A—HUMAN NECESSITIES
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  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1682—Processes
• • A—HUMAN NECESSITIES
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  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/51—Nanocapsules; Nanoparticles
  • A61K9/5107—Excipients; Inactive ingredients
  • A61K9/513—Organic macromolecular compounds; Dendrimers
  • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/51—Nanocapsules; Nanoparticles
  • A61K9/5107—Excipients; Inactive ingredients
  • A61K9/513—Organic macromolecular compounds; Dendrimers
  • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
  • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• compositions, methods, and kits for treating acute, postoperative, or chronic pain in a subject are provided herein.
• opioids e.g. morphine
• local anesthetics e.g.
• bupivacaine and/or steroids (e.g. methylprednisolone).
• steroids e.g. methylprednisolone.
• 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, 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
• Toxicity also limits therapeutic regiments of steroids for management of chronic pain indications.
• 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.
• compositions for treating acute, post-operative, or chronic pain in a subject comprise an anticonvulsant agent and a biodegradable carrier.
• Methods of treating acute, post-operative, or chronic pain comprising administering to a subject having the pain a composition comprising an anticonvulsant agent and a biodegradable carrier are also disclosed herein.
• kits for producing compositions for treating acute, postoperative, or chronic pain in a subject are provided.
• FIG. 1 illustrates an exemplary biodegradable, polymeric nanoparticle or microparticle releasing an anticonvulsant agent.
• FIG. 2 shows a representative scanning electron micrograph of PLGA microparticles incorporating the anticonvulsant carbamazepine.
• FIG. 3 shows examples of sustained, controlled release kinetic profiles of the anticonvulsant carbamazepine from PLGA microparticles comprising PLGA with inherent viscosities of (a) 0.15-0.25 dL/g and (b) 0.55-0.75 dL/g.
• FIG. 4 shows an example of a sustained, controlled release kinetic profile of the anticonvulsant carbamazepine from poly(D,L-lactide) (PLA) microparticles.
• 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.
• 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.
• administering to said subject and similar terms indicate a procedure by which the described anticonvulsant agents or compositions, together or separately, are introduced into, implanted in, 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.
• administration of the described anticonvulsant agents or compositions should be understood by those skilled in the art to mean administered to the anatomical area of interest within the limits of traditionally practiced surgical and image-guided surgical procedures.
• administration "near" the relevant anatomical site refers to a location that is not directly within or on the site, but sufficiently close to the site to provide a therapeutically relevant effect thereon.
• Those of ordinary skill in the art can readily determine the maximum distance from a given anatomical site that will be sufficient to provide a therapeutically relevant effect using a composition according to the present disclosure having a known concentration of active ingredient.
• “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.
• “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.
• 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.
• results may include, but are not limited to, the treatment of acute, post-operative or chronic pain, as determined by any means suitable in the art.
• treating refers 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.
• 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.
• 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.
• 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.
• 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.
• Biodegradable, polymeric microparticles and nanoparticles represent an attractive means to achieve the desired local delivery of therapeutic agents, often by
• a depot formulation containing these particles can be fabricated by a variety of techniques to incorporate neurologically active therapeutic agents, including, anticonvulsants.
• the fabrication technique dictates the physical, chemical, and mechanical properties of the resulting particles.
• the fabrication technique and polymer must be selected appropriately.
• 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
• the anticonvulsant carbamazepine
• 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 acute, post-operative, or chronic pain indications..
• the intentional high, micro-scale porosity of the microparticles fabricated by Klose et al. limits the ability for sustained, long-term release applications.
• 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.
• Pepic et al utilized an oil-in-water (o/w) single emulsification technique to fabricate large, porous poly(e-caprolactone) (PCL) microspheres incorporating carbamazepine.
• 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 acute, postoperative, or chronic 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.
• 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.
• 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 release for an extended period of time, such as two weeks or more, from nanoparticles or microparticles that have sufficiently small mean and/or median hydrodynamic diameters up to 25 microns, inclusive, as measured by laser diffraction or dynamic light scattering in aqueous solution, to enable clinical administration as an injectable.
• Suitable instrumentation for aqueous solution phase laser diffraction includes the Malvern InstrumentsTM Masters izer® 3000 equipped with the Hydro MV unit.
• Suitable instrumentation for aqueous solution phase dynamic light scattering includes the Malvern InstrumentsTM ZetaSizer® Nano ZS. Also described herein are methods for using these specifically designed compositions for the treatment of acute, post-operative, or chronic pain.
• compositions for treating acute, post-operative, or chronic pain in a subject comprise an anticonvulsant agent and a biodegradable carrier.
• the composition consists of an anticonvulsant agent and a biodegradable carrier.
• Suitable anticonvulsant agents include, but are not limited to, carbamazepine, pregablin, phenytoin, gabapentin, topiramate, oxcarbazepine, or any combination thereof.
• the anticonvulsant is carbamazepine.
• the anticonvulsant is gabapentin.
• the anticonvulsant is pregabalin.
• Suitable biodegradable carriers include, but are not limited to, a nanoparticle, a microparticle, or any combination thereof.
• the biodegradable carrier is a nanoparticle.
• the biodegradable carrier is a microparticle.
• the biodegradable carrier is a nanoparticle.
• the biodegradable carrier is a nanoparticle.
• 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.
• compositions can comprise an anticonvulsant agent and a biodegradable carrier.
• the composition comprises carbamazepine and a nanoparticle.
• the composition comprises carbamazepine and a microparticle.
• the composition comprises phenytoin and a nanoparticle.
• the composition comprises phenytoin and a microparticle.
• the composition comprises gabapentin and a nanoparticle.
• the composition comprises gabapentin and a microparticle.
• the composition comprises pregablin and a nanoparticle.
• the composition comprises pregablin and a microparticle.
• the composition comprises topiramate and a nanoparticle. In some embodiments, the composition comprises topiramate and a microparticle. In some embodiments, the composition comprises oxcarbazepine and a nanoparticle. In some embodiments, the composition comprises oxcarbazepine and a microparticle.
• Anticonvulsant agents also include mixtures of carbamazepine, pregablin, phenytoin, gabapentin, topiramate, and/or oxcarbazepine within the same biodegradable carrier.
• the composition can comprise carbamazepine and pregablin within a microparticle.
• the phrase "the anticonvulsant agent” can refer to more than one anticonvulsant agent if more than one such agent is present in the composition.
• a reference to release of "60% of the anticonvulsant agent” means that there is release of 60% of the sole present anticonvulsant.
• language referring to release of "60% of the anticonvulsant agent” means that 60% of the total complement of anticonvulsant agents is released.
• composition includes 3 mg of a first anticonvulsant agent and 3 mg of a second anticonvulsant agent
• release of "60% of the anticonvulsant agent” can mean that 60% of the total complement of 6 mg of anticonvulsant agents is released.
• Biodegradable carriers can comprise 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.
• the biodegradable carrier comprises or consists of a synthetically derived biodegradable polymer.
• the synthetically derived biodegradable polymer can be poly(lactic-co-glycolic acid) (PLGA), having a lactic acid and glycolic acid content ranging from 0-100% for each monomer.
• PLGA poly(lactic-co-glycolic acid)
• the biodegradable polymer can be a 50:50 PLGA, where 50:50 refers to the ratio of lactic to glycolic acid.
• the biodegradable carrier comprises or consists of a copolymer.
• 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.
• PEG poly(ethylene glycol)
• PLGA poly(lactic- co-glycolic acid)
• Biodegradable carriers can be configured to be injected into a subject.
• the biodegradable carrier comprises a nanoparticle that is configured to be injected into a subject.
• the biodegradable carrier comprises a
• microparticle that is configured to be injected into a subject.
• the microparticle or nanoparticle must have a mean or median hydrodynamic diameter of not more than 25 microns, inclusive, as measured by the aforementioned aqueous solution phase laser diffraction or dynamic light scattering instrumentation.
• Biodegradable carriers can be configured to be implanted into a subject.
• Implants can be any size and shape suitable for delivering an anticonvulsant to or near the site of pain.
• Biodegradable carriers can further comprise one or more surface modifications.
• suitable surface modification include, but are not limited to, functional group modifications, PEGylation or affinity-based targeting moieties.
• 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.
• 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.
• the process of incorporation may be accomplished using solvent extraction/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.
• 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.
• 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.
• the biodegradable carrier can begin to degrade upon resuspension in aqueous media.
• the biodegradable carrier can begin to degrade upon administration of the composition to a subject.
• 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.
• 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.
• 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 21 days.
• the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 28 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 35 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 42 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 56 days. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 3 months. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 4 months.
• the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 5 months. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 6 months. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 7 months. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 8 months. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 9 months. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 10 months. In some embodiments, the biodegradable carrier releases less than 60% of the anticonvulsant agent over about 12 months.
• 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.
• the biodegradable carrier provides a therapeutically effective dose of the agent for up to 3 hours.
• the biodegradable carrier provides a therapeutically effective dose of the agent for up to 6 hours.
• the biodegradable carrier provides a therapeutically effective dose of the agent for up to 12 hours.
• the biodegradable carrier provides a therapeutically effective dose of the agent for up to 1 day.
• the biodegradable carrier provides a therapeutically effective dose of the agent for up to 2 days.
• 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
• 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
• 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
• the biodegradable carrier provides a therapeutically effect dose of the agent for up to 12 days.
• the biodegradable carrier provides a therapeutically effect dose of the agent for up to 14 days.
• the biodegradable carrier provides a therapeutically effect dose of the agent for up to 18 days.
• the biodegradable carrier provides a therapeutically effective dose of the agent for up to 3 weeks.
• the biodegradable carrier provides a therapeutically effective dose of the agent for up to 1 month.
• the biodegradable carrier provides a therapeutically effective dose of the agent for up to 2 months.
• the biodegradable carrier provides a therapeutically effective dose of the agent for up to 3 months.
• the biodegradable carrier provides a therapeutically effective dose of the agent for up to 4 months. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 5 months. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 6 months. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 7 months. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 8 months. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 9 months. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 10 months. In some embodiments, the biodegradable carrier provides a therapeutically effective dose of the agent for up to 12 months.
• compositions described herein may also be included in the compositions described herein.
• the pharmaceutical agents may stabilize the composition, allow it to be readily administered to a subject, increase its ability to treat acute, chronic, or post-operative pain, or otherwise make the composition suitable for therapeutic use in a subject.
• the described composition may further comprise a pharmaceutically acceptable carrier or excipient, as would be known to an individual skilled in the relevant art.
• pharmaceutical compositions having an anticonvulsant and a biodegradable carrier, as provided herein.
• the described pharmaceutical compositions for delivery or injection of the described compositions may be administered to a subject in order to maintain the ability to treat chronic 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.
• the described pharmaceutical compositions may be formulated as any of various preparations that are known and suitable in the art, including those described and exemplified herein.
• 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.
• 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).
• 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).
• a hydrogel may function as an excipient in which the biodegradable carrier and active agent are dispersed.
• compositions may also be prepared as liquid formulations and solid form preparations which are intended to be converted, shortly before use, to liquid preparations.
• 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).
• 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
• compositions may contain, in addition to the active agent, stabilizers, buffers, dispersants, thickeners, solubilizing agents, and the like.
• the 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.
• 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.
• kits for treating a subject having acute, postoperative, or chronic pain comprising administering to a subject having acute, post-operative, or chronic pain any one of the compositions disclosed herein.
• the methods of treating a subject having acute, post-operative, or chronic pain can comprise administering to a subject having the pain a composition comprising an anticonvulsant agent and a biodegradable carrier.
• the methods of treating a subject having acute, post-operative, or chronic pain can comprise administering to a subject having the pain a composition consisting of an anticonvulsant agent and a biodegradable carrier.
• compositions can be administered by injection or implantation.
• the composition can be injected or surgically placed on or near the nerve of interest.
• Local delivery allows a therapeutic concentration of the composition to be delivered to the nerve in question, without the systemic levels 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.
• compositions can be injected by a number of routes, including, but not limited to, epidurally, intravenously, intra-arterially, transdermally, subcutaneously, intra- articularly, intramuscularly, perineurally, or any combination thereof.
• routes including, but not limited to, epidurally, intravenously, intra-arterially, transdermally, subcutaneously, intra- articularly, intramuscularly, perineurally, or any combination thereof.
• the compositions can be implanted at or near a site of acute, post-operative, or chronic pain.
• the composition can be administered to a sensory neuron.
• the composition can be injected near a sensory neuron.
• the composition can be surgically implanted near a sensory neuron.
• the composition can be administered to a synapse. In some aspects, the composition can be injected near a synapse. In other aspects, the composition can be surgically implanted near a synapse. In yet other embodiments, the composition can be administered near or to a dorsal root ganglion. In some aspects, the composition can be injected near a dorsal root ganglion. In other aspects, the composition can be surgically implanted near a dorsal root ganglion. In yet other embodiments, the composition can be administered near or to sensory nerve. In some aspects, the composition can be injected near a sensory nerve. In other aspects, the composition can be surgically implanted near a sensory nerve.
• the composition can be administered near or to a peripheral nerve. In some aspects, the composition can be injected near a peripheral nerve. In other aspects, the composition can be surgically implanted near a peripheral nerve. In yet other embodiments, the composition can be administered near or to a medial nerve branch. In some aspects, the composition can be injected near a medial nerve branch. In other aspects, the composition can be surgically implanted near a medial nerve branch. In yet other embodiments, the composition can be administered into or around intramuscular tissue. In some aspects, the composition can be injected into or around intramuscular tissue. In other aspects, the composition can be surgically implanted into intramuscular tissue. In yet other embodiments, the composition can be administered into or around an intra-articular joint.
• the composition can be injected into or around an intra-articular joint. In other aspects, the composition can be surgically implanted into an intraarticular joint. In yet other embodiments, the composition can be administered into or around a facet joint. In some aspects, the composition can be injected into or around a facet joint. In other aspects, the composition can be surgically implanted into a facet joint. In yet other
• the composition can be administered near or to the femoral nerve. In some aspects, the composition can be injected near the femoral nerve. In other aspects, the composition can be surgically implanted near the femoral nerve. In yet other embodiments, the composition can be administered near or to the sciatic nerve. In some aspects, the composition can be injected near the sciatic nerve. In other aspects, the composition can be surgically implanted near the sciatic nerve. In yet other embodiments, the composition can be administered near or to the brachial plexus. In some aspects, the composition can be injected near the brachial plexus. In other aspects, the composition can be surgically implanted near the brachial plexus.
• the composition can be administered into and around the epidural space. In some aspects, the composition can be injected into and around the epidural space. In other aspects, the composition can be surgically implanted into and around the epidural space. In yet other embodiments, the composition can be administered near or to the inferior alveolar nerve. In some aspects, the composition can be injected near the inferior alveolar nerve. In other aspects, the composition can be surgically implanted near the inferior alveolar nerve. In yet other embodiments, the composition can be administered near or to the trigeminal nerve. In some aspects, the composition can be injected near the trigeminal nerve. In other aspects, the composition can be surgically implanted near the trigeminal nerve.
• the disclosed methods can be used to treat acute, post-operative, or chronic pain caused by a number of ailments, diseases, and/or injuries including, but not limited to pain caused by trauma, post-operative pain, dental pain, degenerative disk disease, spinal stenosis, spinal disc herniation, radiculopathy, radiculitis, arachnoiditis, trigeminal neuralgia, postherpetic neuralgia, shingles, occipital neuralgia, cervicogenic headache, migraine headaches, cluster headaches, back pain, facet joint pain, intra-articular joint pain, intramuscular pain, complex regional pain syndrome, cancer associated pain, neuropathy, diabetic neuropathic pain, tabetic neuralgia, sciatic neuralgia, sciatica, or any combination thereof.
• the disclosed compositions can be used to treat acute or chronic pain associated with back pain or facet joint pain by, for example, administering the composition on or near the nerve root or the medial branch nerves near the source of the pain.
• compositions can be used to treat chronic pain associated with cervicogenic headache, migraine headaches, and cluster headaches by, for example,
• composition onto or near the greater occipital nerve.
• compositions can be used to treat chronic pain associated with trigeminal neuralgia and the trigeminal nerve by, for example, administering the composition onto or near the Gasserian ganglion or into Meckel's Cave.
• compositions can be used to treat chronic pain associated with postherpetic neuralgia by, for example, administering the composition onto or near the nerve root, the dorsal nerve root ganglion, or distal to the dorsal nerve root ganglion.
• compositions can be used to treat acute or chronic pain associated with sciatic neuralgia and the sciatic nerve by, for example, administering the composition onto or near the sciatic nerve.
• compositions can be used to treat acute or post-operative pain associated with knee surgery or knee-replacement surgery by, for example, administering the composition onto or near the femoral nerve.
• compositions can be used to treat acute or post-operative pain associated with hip surgery or hip-replacement surgery by, for example, administering the composition onto or near the femoral or sciatic nerve.
• compositions can be used to treat acute or post-operative pain associated with shoulder surgery by, for example, administering the composition onto or near the brachial plexus.
• compositions can be used to treat acute or post-operative pain associated with dental procedures or surgery by, for example, administering the composition onto or near the inferior alveolar nerve or trigeminal nerve.
• Any chronic, acute, or post-operative pain that can be temporarily relieved by a local anesthetic nerve block or corticosteroid injection can potentially be treated long term by delivering the disclosed compositions to the same location that the local anesthetic is applied.
• compositions can be used to treat acute, post-operative, or chronic pain that can be relieved by a sensory and/or peripheral nerve block.
• kits for producing a composition to treat acute, postoperative, or chronic pain in a subject comprising an anticonvulsant agent, a
• the instructions may describe the steps and reagents for producing the composition by solvent extraction/evaporation, oil-in-water single emulsification, by spray drying, or by precipitation using a solvent/non- solvent system.
• steps and reagents may be in accordance with those that the present application discloses for solvent extraction/evaporation, oil-in-water single emulsification, spray drying, and precipitation using a solvent/non-solvent system.
• Microencapsulated anticonvulsant agent by solvent extraction/evaporation, single oil-in-water emulsification Biodegradable, polymeric microparticles were fabricated using a solvent extraction/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.
• PVA surfactant
• the resulting stable microemulsion was subsequently added to an evaporation bath containing 100 mL of deionized water containing a trace concentration (0-0.5% (w/v)) of surfactant (PVA) under stirring at 350 rpm for 3 hours to effectively extract and evaporate the organic solvent.
• PVA surfactant

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  • 2015-02-23 US US14/628,563 patent/US20160136179A1/en not_active Abandoned
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