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WO2023091469A1 - Ciblage de tissu périostique à des fins d'administration d'agents thérapeutiques - Google Patents

Ciblage de tissu périostique à des fins d'administration d'agents thérapeutiques Download PDF

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Publication number
WO2023091469A1
WO2023091469A1 PCT/US2022/050077 US2022050077W WO2023091469A1 WO 2023091469 A1 WO2023091469 A1 WO 2023091469A1 US 2022050077 W US2022050077 W US 2022050077W WO 2023091469 A1 WO2023091469 A1 WO 2023091469A1
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WIPO (PCT)
Prior art keywords
oxytocin
individual
periosteum
composition
cases
Prior art date
Application number
PCT/US2022/050077
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English (en)
Inventor
David C. Yeomans
Vimala Nagabhushana BHARADWAJ
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The Board Of Trustees Of The Leland Stanford Junior University
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Publication of WO2023091469A1 publication Critical patent/WO2023091469A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/0012—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
    • 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
    • A61K9/1605—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)

Definitions

  • TBI post-traumatic headache
  • PTH post-traumatic headache
  • About 95% of all TBIs may account for mild TBI.
  • Cumulative incidence of new or worsening of pre-existing headaches in patients with mTBI has been reported to be 91%.
  • PTH is very difficult to treat, largely due to the lack of understanding of the pathophysiology.
  • Most common headache phenotype in PTH are migraine-like and tension-type-like headaches. Physicians consider the phenotype of the PTH and then prescribe the medications used to treat the phenotype of the primary headache disorder.
  • 40% of patients with acute PTH later develop persistent PTH (long lasting headaches). Early intervention may be necessary to avoid the persistent PTH.
  • the calvarial periosteum is a dense fibrous membrane covering the surface of the skull. It has been reported that a network of sensory fibers bifurcate from dural nociceptors and reach extracranial tissues such as periosteum and pericranial muscles.
  • compositions and methods for using periosteal tissue as a local target for therapeutics such as oxytocin.
  • periosteal tissue e.g., calvarial periosteum
  • direct calvarial periosteum delivery of nanoparticles (or, e.g., microparticles) to deliver a therapeutic such as oxytocin will significantly reduce the activation and sensitization of primary afferents and thus, reduce the likelihood of post traumatic headache (PTH) generation.
  • Nanoparticles or biomaterials as such can act as a local drug depot for prolonged drug delivery. Such prolonged delivery of therapeutics offers a tremendous advantage compared to free drug delivery.
  • compositions and methods disclosed herein will impact the treatment of patients (e.g., those with PTH) and help reduce the likelihood of developing persistent symptoms (e.g., persistent PTH).
  • kits for treating an individual in need thereof include administering a composition for controlled drug release via local delivery (e.g., injection) to an individual’s periosteum.
  • a composition for controlled drug release via local delivery e.g., injection
  • the individual has a headache such as a PTH.
  • the individual has a traumatic brain injury (TBI) (e.g., closed-head TBI).
  • TBI traumatic brain injury
  • the individual is a human.
  • the individual is a rodent, a pet, or a farm animal.
  • the local delivery includes injection into or onto an individual’s calvarial periosteum.
  • local delivery e.g., injection into or onto the calvarial periosteum
  • a skull suture i.e. , peri-skull-suture
  • TBI closed-head traumatic brain injury
  • the periosteum is long bone periosteum.
  • the composition for controlled drug release includes a therapeutic agent.
  • the therapeutic agent is oxytocin, an oxytocin analog, or a combination thereof.
  • the composition for controlled drug release includes a hydrogel, a fiber/conduit, a nanoparticle, a microparticle, or any combination thereof. In some cases, the composition for controlled drug release includes a hydrogel, a fiber/conduit, a nanoparticle, or any combination thereof. In some cases, the composition for controlled drug release includes microparticles loaded with a therapeutic agent (e.g., oxytocin, an oxytocin analog, or a combination thereof, e.g., oxytocin-loaded microspheres). In some cases, oxytocin-loaded microspheres are oxytocin-loaded sustained-release poly (lactide-co-glycolide) (PLGA) microspheres. In some cases, the composition for controlled drug release includes nanoparticles loaded with a therapeutic agent (e.g., oxytocin, an oxytocin analog, or a combination thereof).
  • a therapeutic agent e.g., oxytocin, an oxytocin analog
  • FIG. 1 Post-Traumatic Headache (PTH) is the most common symptom after TBI and is very difficult to treat.
  • FIG. 2 Top: Schematic of Calvarial Periosteum in migraine-like pain.
  • FIG. 3 Top: oxytocin receptors are expressed on trigeminal ganglia neurons (Tzabazis et aL, Cephalalgia 36, 943-950 (2016)). Bottom: Oxytocin can inhibit electrically evoked activity of trigeminal ganglia neurons, oxytocin can reduce capsaicin-induced release of calcitonin gene-related peptide (CGRP) from dura in vitro, and intra-nasal oxytodcin delivery reduces facial and hind paw allodynia acutely after mTBI (Meidahl et aL, Headache: The Journal of Head and Face Pain 58, 545-558 (2016)).
  • CGRP calcitonin gene-related peptide
  • FIG. 4 Periosteal tissue as a local target for therapeutics (such as oxytocin).
  • FIG. 5 Direct calvarial periosteum delivery of formulations for prolonged local delivery (e.g., controlled drug release, e.g., hydrogels, fibers/conduits, nanoparticles, microparticles) (e.g., oxytocin) to significantly reduce the activation and sensitization of primary afferents and thus, reduce the likelihood of PTH generation.
  • formulations for prolonged local delivery e.g., controlled drug release, e.g., hydrogels, fibers/conduits, nanoparticles, microparticles
  • nanoparticles encapsulated with drugs such as oxytocin
  • FIG. 6 PTH and PPTH-related pain - effect of direct OT or vehicle injection:
  • OT oxytocin
  • Two-way ANOVA (Tukey’s post-hoc test). Graphs show mean S.E.M. (****p ⁇ 0.0001 ).
  • FIG. 8 Results from OT-loaded microparticle size determined using dynamic light scattering technique that showed the average diameter and polydispersity index of 1 .7 ⁇ 0.13 pm and 0.196, respectively.
  • FIG. 9 OT-loaded or blank microparticles were injected into the CP of mTBI mice on day 2 post-injury. Mice injected with OT-microparticles showed sustained reduction in allodynia for at least up to 24-hour post-injection compared to the control group. Two- way ANOVA (Tukey’s post-hoc test). Graphs show mean S.E.M. (““ p ⁇ 0.0001 , ** p ⁇ 0.001).
  • TBI Traumatic Brain Injury
  • mTBI Mild Traumatic Brain Injury OT
  • OTR Oxytocin Receptor
  • CGRP Calcitonin-gene related peptide CP: Calvarial Periosteum
  • compositions and methods for using periosteal tissue e.g., calvarial periosteum
  • periosteal tissue e.g., calvarial periosteum
  • therapeutics such as oxytocin
  • the present disclosure provides local delivery (e.g., injection) that targets an individual’s periosteum.
  • the targeted periosteum is calvarial periosteum.
  • the periosteum is long bone periosteum.
  • the local delivery e.g., injection
  • a therapeutic such as oxytocin into the calvarial periosteum.
  • Such delivery can be to any convenient location of the skull (e.g., crown of the skull, along or near a skull suture, and the like).
  • local delivery e.g., injection
  • local delivery is into the crown of the skull.
  • local delivery e.g., injection
  • local delivery is along or near a skull suture.
  • local delivery e.g., injection
  • the site of a closed-head TBI In some cases, the TBI is an mTBI.
  • the local delivery (e.g., injection) is into, onto, or near the calvarial periosteum.
  • the phrase “into, onto, or near the calvarial periosteum” (which can also be referred to as “pericranial”) is intended to mean “500mm or less” (e.g., 450mm or less, 400mm or less, 350mm or less, 300mm or less, 250mm or less, 200mm or less, or 150mm or less) from the periosteum.
  • the delivery is 400mm or less (e.g., 350mm or less, 300mm or less, 250mm or less, 200mm or less, or 150mm or less) from the periosteum.
  • the delivery is 300mm or less (e.g., 250mm or less, 200mm or less, or 150mm or less) from the periosteum. In some cases, the delivery is 200mm or less (e.g., 150mm or less) from the periosteum. In some cases, the delivery is 100mm or less (e.g., 50mm or less) from the periosteum.
  • the term “into” is intended to mean passing through the periosteum (which is a thin membrane) and deposition under it - between the membrane and the bone of the skull (e.g., an injection where the needle is inserted such that it passes through the periosteum).
  • delivery “onto” the periosteum the term “onto” is intended to mean delivery in which the skin is penetrated, but the periosteum is not (e.g., an injection where the needle penetrates the skin but does not penetrate the periosteum) - in such a case, the delivered (e.g., injected) compound will still reach the pericranium via diffusion.
  • the local delivery (e.g., injection) is into or onto the calvarial periosteum. In some cases, the local delivery (e.g., injection) is into the calvarial periosteum. In some cases, the local delivery (e.g., injection) is onto the calvarial periosteum. In some cases, the delivery will be into the crown of the skull.
  • the delivery is at or near the site of a closed-head TBI.
  • the phrase “at or near the site of a closed-head TBI” is intended to mean “500mm or less” (e.g., 450mm or less, 400mm or less, 350mm or less, 300mm or less, 250mm or less, 200mm or less, or 150mm or less) from the site of a closed-head TBI.
  • the delivery is 400mm or less (e.g., 350mm or less, 300mm or less, 250mm or less, 200mm or less, or 150mm or less) from the site of a closed-head TBI.
  • the delivery is 300mm or less (e.g., 250mm or less, 200mm or less, or 150mm or less) from the site of a closed-head TBI. In some cases, the delivery is 200mm or less (e.g., 150mm or less) from the site of a closed-head TBI. In some cases, the delivery is 100mm or less (e.g., 50mm or less) from the site of a closed- head TBI. In some cases, the delivery is at the site of a closed-head TBI.
  • the local delivery is along or near a skull suture (e.g., coronal suture, sagittal suture, lambdoid suture), as this area is heavily innervated by periosteal afferents that are branches of the trigeminal nerve.
  • a skull suture e.g., coronal suture, sagittal suture, lambdoid suture
  • the phrase “along or near a skull suture” or “at or near a skull suture” or “peri-skull-suture” is intended to mean “500mm or less” (e.g., 450mm or less, 400mm or less, 350mm or less, 300mm or less, 250mm or less, 200mm or less, or 150mm or less) from a skull suture.
  • the delivery is 400mm or less (e.g., 350mm or less, 300mm or less, 250mm or less, 200mm or less, or 150mm or less) from a skull suture.
  • the delivery is 300mm or less (e.g., 250mm or less, 200mm or less, or 150mm or less) from a skull suture.
  • the delivery is 200mm or less (e.g., 150mm or less) from a skull suture.
  • the delivery is 100mm or less (e.g., 50mm or less) from a skull suture.
  • the delivery is along a skull suture.
  • local delivery is topical delivery for targeting periosteal tissue, e.g., without injecting into the skin.
  • a therapeutic agent such as oxytocin (e.g., as part of a controlled release formulation such as a microsphere, nanoparticle, hydrogel, and the like) is delivered (e.g., injected) into or onto calvarial periosteum of an individual who has a headache such as a post-traumatic headache (PTH).
  • a therapeutic agent such as oxytocin
  • a controlled release formulation such as a microsphere, nanoparticle, hydrogel, and the like
  • the delivery is into the crown of the skull, and in some cases along or near a skull suture.
  • a therapeutic agent such as oxytocin (e.g., as part of a controlled release formulation such as a microsphere) is injected into or onto calvarial periosteum of an individual who has a traumatic brain injury (TBI), e.g., a closed-head TBI. In some such cases, the delivery at or near the site of the TBI.
  • TBI traumatic brain injury
  • targeting the periosteum is used for headache-related diagnostics and/or prognosis purposes.
  • imaging agent e.g., free agent or biomaterial-based formulations encapsulated/decorated with imaging agent
  • MRI/PET approaches can be used when targeting the periosteum.
  • targeting the periosteum e.g., calvarial periosteum
  • one can evaluate/target specific receptors or other proteins linked to mechanistic activity of disease progression e.g., receptor expression or the drug of action.
  • targeting the periosteum e.g., calvarial periosteum
  • periosteum e.g., calvarial periosteum
  • biomaterial encapsulation e.g., hydrogel, fiber/conduit, microparticles, nanoparticles, and the like.
  • AAV adeno-associated virus
  • CRISPR-based gene therapeutics e.g., Cas effector protein or nucleic acid encoding the Cas effector protein, and/or a guide RNA or nucleic acid encoding the guide RNA, and the like.
  • targeting the periosteum is used to target therapies (free drug or biomaterial based) towards the microenvironment of the periosteum.
  • therapies free drug or biomaterial based
  • such delivery can be used to target immune cells (e.g., mast cells, macrophages, and the like) and/or blood vessel associated factors (e.g., fibrinogen), that would activate periosteal afferents using free drug and/or microparticles loaded with drugs.
  • immune cells e.g., mast cells, macrophages, and the like
  • blood vessel associated factors e.g., fibrinogen
  • the therapeutic agent to be delivered is an analgesic.
  • the therapeutic agent is oxytocin (OT).
  • the therapeutic agent to be delivered is oxytocin or an analog thereof.
  • the therapeutic agent to be delivered is oxytocin, an oxytocin analog, or a mixture thereof.
  • Oxytocin is a short-lived, fast acting peptide hormone (9 amino acids long) with two cysteine residues that form a disulfide bridge between positions 1 and 6: Cys - Tyr - lie - Gin - Asn - Cys - Pro - Leu - Gly (CYIQNCPLG).
  • Oxytocin analogs include, but are not necessarily limited to: 4-threonine-1-hydroxy-deaminooxytocin, 9- Deamidooxytocin, 7-D-proline-oxytocin and its deamino analog, (2,4-Diisoleucine)- oxytocin, deamino oxytocin analog, 1-desamino-1-monocarba-E12-Tyr (OMe)J- OT(dCOMOT), carbetocin, [Thr4-Gly7]-oxytocin (TG-OT), oxypressin, and deamino-6- carba-oxytoxin (dC60).
  • an oxytocin dose will be in a range of from 0.01 to 100 ⁇ g (e.g., 0.01 to 80, 0.01 to 70, 0.01 to 60, 0.01 to 50, 0.01 to 40, 0.01 to 30, 0.05 to 100, 0.05 to 80, 0.05 to 70, 0.05 to 60, 0.05 to 50, 0.05 to 40, 0.05 to 30, 0.1 to 100, 0.1 to 80, 0.1 to 70, 0.1 to 60, 0.1 to 50, 0.1 to 40, 0.1 to 30, 0.5 to 100, 0.5 to 80, 0.5 to 70, 0.5 to 60, 0.5 to 50, 0.5 to 40, 0.5 to 30, 1 to 100, 1 to 80, 0.5 to 70, 0.5 to 60, 0.5 to 50, 0.5 to 40, 0.5 to 30, 1 to 100, 1 to 80, 1 to 70, 1 to 60, 1 to 50, 1 to 40, 1 to 30, 5 to 100, 5 to 80, 5 to 70, 5 to 50, 5 to 70, 5 to
  • an oxytocin dose will be in a range of from 0.1 to 80 ⁇ g (e.g., 0.1 to 70, 0.1 to 60, 0.1 to 50, 0.1 to 40, 0.1 to 30, 0.5 to 80, 0.5 to 70, 0.5 to 60, 0.5 to
  • an oxytocin dose will be in a range of from 1 to 50 pg (e.g., 1 to 40, 1 to 30, 5 to 50, 5 to 40, or 5 to 30 pg).
  • oxytocin analogs are non-peptide compounds or peptidomimetics.
  • oxytocin analogs are fragments of oxytocin, for example peptide cleavage products. Such fragments may be chemically synthesized or derived by any known means. Oxytocin fragments of the present invention retain bioactivity similar to or greater than oxytocin.
  • oxytocin, oxytocin analogs or mixtures thereof are modified to increase stability/ enhance their retention. Such modification may occur through esterification with a steroid or fatty acid, or through covalent attachment of quinines, abenzoquinones, napthoquinones, indolequinones, nitroheterocycles or 1 ,4- dihydrotrigonellinate.
  • the therapeutic agent is a calcitonin gene-related peptide (CGRP) signaling inhibitor such as a CGRP inhibitor or a CGRP receptor antagonist (e.g., erenumab, galcanezumab, fremanezumab, rimegepant, ubrogepant, atogepant, eptinezumab, olcegepant, and the like).
  • a CGRP signaling inhibitor is an anti-CGRP or an anti-CGRP receptor monoclonal antibody.
  • a CGRP signaling inhibitor is a small molecule (e.g., olcegepant).
  • the therapeutic agent is a combination of oxytocin (OT) and a CGRP inhibitor.
  • the therapeutic agent is a sodium channel blocker (e.g., local anesthetics such as bupivicaine, lidocaine, arbamazepine, oxcarbazepine).
  • the therapeutic agent is a combination of oxytocin (OT) and a sodium channel blocker.
  • the therapeutic agent is a drug sometimes used to treat migraine, such as topiramate, and tricyclics (e.g., Amitriptyline, Amoxapine, Desipramine (Norpramin), Doxepin, Imipramine (Tofranil), Nortriptyline (Pamelor), Protriptyline, Trimipramine).
  • the therapeutic agent is a combination of oxytocin (OT) and one or more of the agents listed in this paragraph.
  • the therapeutic agent is an opioid, (e.g., morphine, fentanyl, hydrocodone, oxymorphone, oxycodone, codeine, heroin, tapentadol, tramadol, uprenorphine, meperidine, methadone, nalbuphine, levorphanol, opium, propoxyphene, pentazocine, meperidine, remifentanil, sufentanil, oliceridin, sufentanil, and the like).
  • the therapeutic agent is a combination of oxytocin (OT) and an opioid.
  • the therapeutic agent is a hydrocodone combination (e.g., including hydrocodone-acetaminophen, hydrocodone-ibuprofen, and the like).
  • the therapeutic agent is a combination of oxytocin (OT) and a hydrocodone combination.
  • any of the above treatments can be administered with an additional therapy or agent (e.g., an analgesic).
  • additional therapies or agents include (but are not limited to), in any combination: a CGRP signaling inhibitor such as a CGRP inhibitor or a CGRP receptor antagonist (e.g., erenumab, galcanezumab, fremanezumab, rimegepant, ubrogepant, atogepant, eptinezumab, olcegepant, and the like); an anti-migraine agent (e.g., sumatriptan, eletriptan, rizatriptan, zolmitriptan, frovatriptan, almotriptan, naratriptan, dihydroergotamine, ergotamine, lasmiditan, dihydroergotamine, and the like); a cox-2 inhibitor (e.g., Cele
  • co-administration include the administration of two or more therapies either simultaneously, concurrently or sequentially within no specific time limits.
  • the therapies being co-administered can be administered to the same location (local delivery, e.g., injection into same/similar location) or can be administered via different routes (e.g., one delivered locally, e.g., via injection, and another delivered systemically, e.g., oral, intravenous, etc.).
  • agents are present in the cell or in the subject's body at the same time or exert their biological or therapeutic effect at the same time.
  • therapeutic agents are in the same composition or unit dosage form. In other embodiments, therapeutic agents are in separate compositions or unit dosage forms.
  • a first therapy e.g., agent
  • a second therapy e.g., agent
  • a second therapy e.g., agent
  • an agent e.g., oxytocin
  • an agent or therapy such as those listed above that can be used to treat pain (e.g., headache pain such as migraine pain).
  • Such administration may involve concurrent (/.e. at the same time), prior, or subsequent administration of the agent and/or therapy with respect to the administration of an agent or agents of the disclosure.
  • a person of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence, location, and dosages of administration for particular drugs and compositions of the present disclosure.
  • a therapeutic e.g., oxytocin
  • a controlled release formulation i.e., a “composition for controlled drug release”.
  • controlled release is also referred to herein as “slow release” or “sustained release”.
  • a “composition for controlled drug release” includes a delivery vehicle (e.g., a hydrogel, fibers/conduits, nanoparticles, microparticles) and a therapeutic agent (e.g., oxytocin) to be released.
  • drug is used herein interchangeably with the term “therapeutic agent” and imparts no limitations with respect to the size or type of agent.
  • a composition comprises a hydrogel, a fiber/conduit, a nanoparticle, a microparticle (i.e., microsphere), or any combination thereof loaded with (e.g., encapsulating) a desired therapeutic agent such as oxytocin (or a derivative thereof).
  • aspects of the disclosure include administering a formulation for controlled/gradual drug release (e.g., hydrogels, fibers/conduits, nanoparticles, microparticles to deliver oxytocin) to the periosteum via local delivery (e.g., injection).
  • a formulation for controlled/gradual drug release e.g., hydrogels, fibers/conduits, nanoparticles, microparticles to deliver oxytocin
  • the drug is oxytocin.
  • the gradual release can be over a range of time, e.g., up to 8 months (e.g., up 6 months, up to 5 months, up to 4 months, up to 3 months, up to 2 months, up to 1 month, up to 3 weeks, up to 2 weeks, or up to 1 week).
  • the formulation includes nanoparticles, e.g., nanoparticles that encapsulate the drug (such as oxytocin).
  • the formulation includes microparticles, e.g., microparticles that encapsulate the drug (such as oxytocin).
  • the formulations can be used for peri-skull injection (e.g., for the treatment of headache). Also included are formulations for peri-bone (e.g, long bone) injections. Also included are peri-skull or peri-bone injections (e.g., of other compounds).
  • microparticles or nanoparticles can include a polymer selected from the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polyacetyls, polycyanoacrylates, polyetheresters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and poly(lactide)s or poly(lactide-co- glycolide)s, biodegradable polyurethanes, blends and copolymers thereof.
  • the microparticles are oxytocin-loaded sustained-release poly (lactide- co-glycolide) (PLGA) microspheres.
  • PLGA sustained-release poly
  • oxytocin-loaded microspheres can be embedded within a hydrogel (e.g., a thermosensitive hydrogel).
  • the therapeutic agent e.g., oxytocin, oxytocin analog or mixture thereof
  • the therapeutic agent is associated with (e.g., encapsulated by) microparticles or nanoparticles (i.e. , the microparticles or nanoparticles can be “loaded” with the therapeutic agent).
  • the microparticles or nanoparticles comprise poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polyacetyls, polycyanoacrylates, polyetheresters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and poly(lactide)s or poly(lactide-co-glycolide), biodegradable polyurethanes, and blends and copolymers thereof.
  • a subjectd microparticle comprises poly(lactide -co-glycolide) (PLGA). Hydrophilic Polymers
  • a hydrophilic polymer may be attached to a therapeutic agent (e.g., oxytocin, oxytocin analogs or a mixture thereof.)
  • Hydrophilic polymers are any water-soluble linear or branched polymer including, but not limited to, polyethylene glycol (PEG) and polypropylene glycol and similar linear and branched polymers. In some cases, the molecular weight of the hydrophilic polymer will range from 200 to 40,000 daltons. In addition, such hydrophilic polymers will often have a reactive group incorporated for attachment to the therapeutic agent through amino, carboxyl, sulfhydryl, phosphate or hydroxyl functions. In some cases, there may also be an organic linker between the hydrophilic polymer and the therapeutic agent.
  • hydrophilic polymers are well known in the art. For example, a methoxy group can be added to one end of the polymer while the other end is activated for facile conjugation to active groups on proteins, peptides, nucleic acids and small molecules.
  • a hydrophilic polymer is covalently attached to the amino terminal nitrogen of a therapeutic agent (e.g., oxytocin or peptide analogs of oxytocin having a free amino terminus).
  • a therapeutic agent e.g., oxytocin or peptide analogs of oxytocin having a free amino terminus.
  • the hydrophilic polymer is covalently attached to a non-peptide oxytocin analog.
  • a hydrolysable linker may be included in the attachment of the hydrophilic polymer to the therapeutic agent.
  • the hydrophilic polymers such as PEG, increase the half-life and molecular mass of the therapeutic agent (e.g., oxytocin or oxytocin analog). A longer half-life allows for a lower dose to be administered less frequently to a patient.
  • the agent may be released from the hydrophilic polymer when the attachment site is through a hydrolysable linkage.
  • the PEG can be linked to the agent through a non-hydrolysable bond, whereby the linkage does not substantially interfere with the action of the drug at its binding locus.
  • a hydrophilic polymer can be linked to a therapeutic agent (e.g., oxytocin, oxytocin analogs or a mixture thereof) and is further encapsulated in a microparticle.
  • a polymer can be in the form of a material such as a gel, a hydrogel, and/or an implant.
  • the therapeutic agent e.g., oxytocin, oxytocin analog or mixture thereof
  • a polymer e.g., a biodegradable polymer
  • a microparticle has a diameter of less than 1 .0 mm and in some cases is in a range of from 1 to 200 microns (e.g., 1-100 microns, 1-50 microns, 1-20 microns, 1-10 microns, or 1-5 microns).
  • Microparticles include both microspheres and microcapsules. For purposes of this disclosure, the terms microsphere, microparticle and microcapsule are used interchangeably.
  • microparticles can be made with a variety of polymers.
  • Biodegradable polymers as defined herein, means the polymer will degrade or erode in vivo to form smaller chemical species. Degradation can result, for example, by enzymatic, chemical and/or physical processes.
  • Suitable biocompatible, biodegradable polymers include, for example, poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polyacetyls, polycyanoacrylates, polyetheresters, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and poly(lactide)s or poly(lactide-co-glycolide)s, biodegradable polyurethanes, blends and copolymers thereof.
  • Biodegradable polymers dissolve or degrade within a desired period of time, typically less than about five years, e.g., in less than one year, after exposure to a physiological solution with a pH between 6 and 8 and a temperature of between about 25 C and 38 C.
  • a subject microparticle includes poly(lactide-co-glycolide) (PLGA).
  • PLGA degrades when exposed to physiological pH and hydrolyzes to form lactic acid and glycolic acid, which are normal byproducts of cellular metabolism.
  • the disintegration rate of PLGA polymers can vary depending on the polymer molecular weight, ratio of lactide to glycolide monomers in the polymer chain, and stereoregularity of the monomer subunits. Polymer disintegration rates can be increased by mixtures of L and D stereoisomers that disrupt the polymer crystallinity.
  • microspheres can contain blends of two or more biodegradable polymers, of different molecular weight and/or monomer ratio.
  • derivatized microparticles including hydrophilic polymers attached to PLGA, can be used to form microspheres.
  • Microspheres can be made by any technique known in the art.
  • microspheres are produced by single or double emulsions steps followed by solvent removal.
  • other known methods such as spray drying, solvent evaporation, phase separation and coacervation may be utilized to create microspheres. Such techniques are well known in the art.
  • microspheres can be produced by dissolving approximately 20 mg of the agent (e.g., oxytocin, oxytocin analog or mixture thereof) in a minimal amount of methanol or DMSO, such as 0.2-2 mL.
  • a polymer solution can then prepared by dissolving a biodegradable polymer in a minimal amount of either ethyl acetate or methylene chloride, such as 0.5-2 mL..
  • the two solutions can then be combined to produce the oil or "organic" phase.
  • the combined agent (e.g., oxytocin, oxytocin analog or mixture thereof) and polymer solution can then added to a water or "aqueous" phase.
  • the aqueous phase is a 1% aqueous solution of poly(vinyl alcohol) (PVA), wherein the volume of the aqueous solution is 2-2.5 times the total volume of the combined oxytocin, oxytocin analog or mixture thereof /polymer solution.
  • PVA poly(vinyl alcohol)
  • the aqueous phase may additionally contain an inorganic salt, such as disodium pamoate ( ⁇ 10mM).
  • the combined oil and aqueous phases can then be mixed to produce an emulsion.
  • the resultant emulsion can then added to a large volume (-100-150 L) of acid (pH ⁇ 5.5) with constant stirring (e.g,, for 3-4 hours).
  • the acid is buffered water (pH ⁇ 5.5) or 0.3% PVA.
  • the hardened microspheres can then collected by vacuum filtration, washed with water, and dried overnight.
  • the dried particles can be analyzed for peptide content (coreload) by reverse-phase HPLC, particle size by laser light scattering, residual solvents by gas chromatography, and dissolution rate by standard methods.
  • the therapeutic agent e.g., oxytocin, oxytocin analog or a mixture thereof
  • the therapeutic agent can be associated with submicron particles for controlled release of the oxytocin molecules.
  • a nanoparticle can have a diameter in a range of from 20.0 nanometers (nm) to about 1 micron and is typically between 25 nm - 1 micron.
  • nm nanometers
  • a "nanoparticle” refers to any particle having a diameter of less than 1000 nm.
  • nanoparticles have a diameter of 500 nm or less, e.g., from 25 nm to 35 nm, from 35 nm to 50 nm, from 50 nm to 75 nm, from 75 nm to 100 nm, from 100 nm to 150 nm, from 150 nm to 200 nm, from 200 nm to 300 nm, from 300 nm to 400 nm, or from 400 nm to 500 nm.
  • nanoparticles suitable for use in delivering a subject therapeutic agent e.g., oxytocin
  • a subject therapeutic agent e.g., oxytocin
  • Nanoparticles suitable for use in delivering a therapeutic agent may be provided in different forms, e.g., as solid nanoparticles (e.g., metal such as silver, gold, iron, titanium), non-metal, lipid-based solids, polymers), suspensions of nanoparticles, or combinations thereof.
  • Metal, dielectric, and semiconductor nanoparticles may be prepared, as well as hybrid structures (e.g., core-shell nanoparticles).
  • Nanoparticles made of semiconducting material may also be labeled quantum dots if they are small enough (typically below 10 nm) that quantization of electronic energy levels occurs.
  • nanoscale particles are used in biomedical applications as drug carriers or imaging agents and may be adapted for similar purposes in the present disclosure.
  • Semi-solid and soft nanoparticles are also suitable for use in delivering a therapeutic agent (e.g., oxytocin).
  • a prototype nanoparticle of semi-solid nature is a liposome.
  • a therapeutic agent e.g., oxytocin
  • a therapeutic agent e.g., oxytocin
  • a “bridge” or "spacer” e.g., amino groups can easily be derivatized to provide sites for direct coupling of a compound.
  • spacers i.e. , linking molecules and derivatizing moieties on targeting ligands
  • avidin-biotin are also useful to indirectly couple agents to microparticles or nanoparticles.
  • Nanoparticles can be produced by any convenient technique and many will be known to one of ordinary skill in the art. For example, they can be created in a similar manner as microparticles, except that high-speed mixing or homogenization can be used to reduce the size of the polymer/bioactive agent emulsions. Such methods are well known in the art.
  • lipid nanoparticles can be used to deliver a subject therapeutic agent (e.g., oxytocin).
  • a subject therapeutic agent e.g., oxytocin.
  • ionizable cationic lipids have been focused upon, namely 1 ,2-dilineoyl-3-dimethylammonium-propane (DLinDAP), 1 ,2- dilinoleyloxy-3-N,N-dimethylaminopropane (DLinDMA), 1 ,2-dilinoleyloxy-keto-N,N- dimethyl-3-aminopropane (DLinKDMA), and 1 ,2-dilinoleyl-4-(2-dimethylaminoethyl)- [1 ,3]-dioxolane (DLinKC2-DMA).
  • DLinDAP ,2-dilineoyl-3-dimethylammonium-propane
  • DLinDMA 1 ,2- dil
  • LNPs Preparation of LNPs is described in, e.g., Rosin et al. (2011 ) Molecular Therapy 19:1286-2200).
  • cationic lipids 1 ,2-dilineoyl- 3-dimethylammonium-propane (DLinDAP), 1 ,2-dilinoleyloxy-3-N,N- dimethylaminopropane (DLinDMA), 1 ,2-dilinoleyloxyketo-N,N-dimethyl-3- aminopropane (DLinK-DMA), 1 ,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1 ,3]-dioxolane (DLinKC2-DMA), (3-o-[2"-(methoxypolyethyleneglycol 2000) succinoyl]-1 ,2- dimyristoyl-sn-glycol (PEG-S-DMG), and R-3-[(.omega.-meth
  • Spherical Nucleic Acid (SNATM) constructs and other nanoparticles (particularly gold nanoparticles) can be used to deliver a therapeutic agent (e.g., oxytocin).
  • a therapeutic agent e.g., oxytocin.
  • Cutler et al. J. Am. Chem. Soc. 2011 133:9254-9257, Hao et al., Small. 2011 7:3158- 3162, Zhang et aL, ACS Nano. 2011 5:6962-6970, Cutler et aL, J. Am. Chem. Soc. 2012 134:1376-1391 , Young et aI, Nano Lett. 2012 12:3867-71 , Zheng et aL, Proc.
  • a subject therapeutic agent e.g., oxytocin
  • a subject therapeutic agent e.g., oxytocin
  • a water-swellable, erodible, or soluble polymer which may generally be described as an osmopolymer, hydrogel or water-swellable polymer.
  • Hydrogels are biomaterials consisting of hydrophilic polymer networks, and their polymer chain entanglement or crosslink density may be modified to match the mechanical characteristics of the targeted tissue. Hydrogels may include homopolymers or copolymers.
  • injectable hydrogels are used (and can be used) as drug delivery vehicles - for example, for controlled drug release. Any convenient hydrogel can be used and many different hydrogel formulations and techniques for producing such will be known to one of ordinary skill in the art.
  • Any convenient hydrogel can be used and many different hydrogel formulations and techniques for producing such will be known to one of ordinary skill in the art.
  • they may be synthetic polymers, e.g., derived from vinyl, acrylate, methacrylate, urethane, ester and oxide monomers, they can also be naturally occurring polymers such as polysaccharides or proteins.
  • Naturally occurring polysaccharides include, but are not limited to: chitin, chitosan, dextran and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phosphatides such as lecithin; alginates such as ammonium alginate, sodium, potassium or calcium alginate, propylene glycol alginate; gelatin; collagen; and cellulosics.
  • cellulosics is meant a cellulose polymer that has been modified by reaction of at least a portion of the hydroxyl groups on the saccharide repeat units with a compound to form an ester- linked or an ether-linked substituent.
  • the cellulosic ethyl cellulose has an ether linked ethyl substituent attached to the saccharide repeat unit, while the cellulosic cellulose acetate has an ester linked acetate substituent.
  • hydrogels can fill an injury cavity and simulate mechanical properties of target tissue (see, e.g., Assungao- Silva et aL, 2015).
  • Other hydrogels are colloidal solutions within a syringe but solidify following injection in response to changes in temperature, pH, or other stimuli (see, e.g., Nguyen and Lee, 2010).
  • agarose is an injectable, natural carbohydrate polymer that has been explored for nervous system applications.
  • a hydrogel can be pH and/or thermo sensitive.
  • a hydrogel can be an injectable In Situ-Forming pH/Thermo-Sensitive Hydrogel (see, e.g., Kim et aL, Tissue Eng Part A. 2009 Apr;15(4):923-33).
  • a thermos- and pH- sensitive hydrogel can be chitan-based (see, e.g., Fathi et aL, Int J Biol MacromoL 2019 May 1 ;128:957-964). Also see, e.g., Mai et aL, Acc. Chem. Res. 2018, 51 , 5, 999-1013.
  • Other natural hydrogels such as the protein hydrogel fibrin, can be placed (e.g., as opposed to injected).Through reduction of thrombin concentration (to create a partially solidified hydrogel) or through inclusion of a co-polymer such as alginate (that can interrupt fibrinogen chain entanglement), fibrin hydrogels can also be injected.
  • PEG poly(ethylene glycol)
  • PEG poly(ethylene glycol)
  • Hydrogels can provide a localized delivery of drugs over short periods of time (hours to days due to large hydrogel pore sizes).
  • hydrogels may be engineered to extend the duration of release or combined with other drug delivery vehicles that can extend the duration of release from the hydrogel.
  • Varying the porosity of a hydrogel alters the diffusion rate of drugs from hydrogels. For example, increasing the polymer concentration (see, e.g., Bertz et aL, 2013), monomer concentration, and amount of cross-linking (Kremer et aI, 1994; Bertz et aL, 2013) result in hydrogels with smaller pore sizes.
  • Increasing the polymer concentration leads to decreased drug release (see, e.g., Peppas et aL, 1999).
  • increasing the level of crosslinking decreases the diffusion rate of drug.
  • Surfactants can be used to improve drug solubility in hydrogel materials.
  • Surfactant addition to hydrogel biomaterials can also influence porosity.
  • adding co-polymers can affect the porosity of hydrogels. For example, addition of the polysaccharide carrageenan to gelatin can increase the pore size, ultimately increasing the drug release rate.
  • Post-processing approaches are also used to tune pore size and include particle leaching, lyophilization, and gas foaming.
  • particle leaching a uniformly sized solute can be incorporated within the polymer solution.
  • the polymer can be solidified, and the solute removed by leaching or dissolution in an appropriate solvent, leaving behind a uniformly porous hydrogel.
  • Lyophilization, or freeze-drying involves cooling of the polymer solution under vacuum, which enables sublimation of the solvent. Spaces the solvent previously occupied become pores within the polymer network.
  • Gas foaming can be achieved by incorporating a foaming agent, or compound that produces gas as it decomposes, enabling the formation of pores within the hydrogel (see, e.g., Annabi et aL, 2010).
  • More complex methods of hydrogel degradation control e.g., beta-elimination
  • beta-elimination can be employed to further slow the drug release and maintain hydrogel structure even after release. Release can occur via non-enzymatic drug-hydrogel self-cleavages and hydrogel crosslink self-cleavages. This release can be controlled by the acidity of the proton adjacent to the cleavage sites, enabling high predictability of release rate.
  • Fibrin hydrogels can be modified by first crosslinking peptides to fibrin using transglutaminase, Factor XI I la. These peptides have an affinity for heparin and covalently immobilize heparin to fibrin. Heparin has affinity for growth factors, including FGF and NGF, which ultimately slows the release of these growth factors from fibrin hydrogel. [0099] To circumvent the complication of cooling the hydrogel to solidify it within a lesion, the natural polysaccharide polymer HA is combined with the cellulose derivative, MC. HAMC hydrogels have been modified with SH3 binding peptides to slow protein release.
  • ChABC an enzyme that degrades CSPGs
  • the peptides reversibly bind to SH3, enabling a controlled release of ChABC.
  • the affinity strength for SH3 and SH3 binding peptides was tunable, thus facilitated a tunable release rate (Pakulska et aL, 2013).
  • the system was also studied using rhFGF2, and a release over 10 days was achieved (Vulic and Shoichet, 2012).
  • affinity-based drug delivery can be effective in controlling drug delivery from hydrogels.
  • Other useful materials for use with hydrogels can include, but are not limited to: pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.) and other acrylic acid derivatives such as homopolymers and copolymers of butylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate, (2- dimethylaminoethyl)methacrylate, and (trimethylaminoethyl) methacrylate chloride.
  • pullulan polyvinyl pyrrolidone
  • polyvinyl alcohol polyvinyl acetate
  • glycerol fatty acid esters polyacrylamide
  • polyacrylic acid copolymers of ethacryl
  • a hydrogel may contain a wide variety of the same types of additives and excipients known in the pharmaceutical arts, including osmopolymers, osmagens, solubilityenhancing or -retarding agents and excipients that promote stability or processing of the formulation.
  • hydrophilic polymeric materials include poly(hydroxyalkyl methacrylate), poly(N-vinyl-2-pyrrolidone), anionic and cationic hydrogels, polyelectrolyte complexes, poly(vinyl alcohol) having a low acetate residual and crosslinked with glyoxal, formaldehyde, or glutaraldehyde, methyl cellulose cross-linked with dialdehyde, a mixture of cross-linked agar and carboxymethyl cellulose, a water insoluble, water-swellable copolymer produced by forming a dispersion of finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butylene, or isobutylene cross-linked with from 0.001 to about 0.5 moles of a polyunsaturated cross-linking agent per mole of maleic anhydride in the copolymer, water-swellable polymers of N-vinyl lactam
  • swellable materials include hydrogels exhibiting a cross-linking of 0.05 to 60%, hydrophilic hydrogels known as Carbopol acidic carboxy polymer, CyanamerTM polyacrylamides, cross-linked water-swellable indene-maleic anhydride polymers, Good-riteTM polyacrylic acid, starch graft copolymers, Aqua-KeepsTM acrylate polymer, diester cross-linked polyglucan, and the like.
  • hydrophilic hydrogels known as Carbopol acidic carboxy polymer, CyanamerTM polyacrylamides, cross-linked water-swellable indene-maleic anhydride polymers, Good-riteTM polyacrylic acid, starch graft copolymers, Aqua-KeepsTM acrylate polymer, diester cross-linked polyglucan, and the like.
  • the formulations may comprise additives such as polyethylene oxide polymers, polyethylene glycol polymers, cellulose ether polymers, cellulose ester polymers, homo- and copolymers of acrylic acid cross-linked with a polyalkenyl polyether, poly(meth)acrylates, homopolyers (e.g., polymers of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol), copolymers (e.g., polymers of acrylic acid and C.sub.10-C.sub.30 alkyl acrylate crosslinked with allyl pentaerythritol), interpolymers (e.g., a homopolymer or copolymer that contains a block copolymer of polyethylene glycol and a long chain alkyl acid ester), disintegrants, ion exchange resins, polymers reactive to intestinal bacterial flora (e.g., polysaccharides such as guar gum, inulin obtained from plant or chito)
  • Particles can be incorporated within hydrogels to facilitate localized drug release.
  • Particle size can affects release rates (Wang et aL, 2008). Smaller particles, having a higher surface area to volume ratio, tend to induce faster release kinetics than larger particles. Larger particles can hold more drug than smaller particles, and thus, may be more appropriate for strategies for longer release.
  • Particles within the hydrogels can be modified to adjust drug release rates. For example, the addition of fatty acid esters to PLLA microspheres can increase the release rate, and in some cases, can establish a biphasic response with different release rates (Urata et aI, 1999). As would be known to one of ordinary skill in the art, depending on the desired timescale of release, different particle modifications can be employed to facilitate early, rapid release or delayed, extended release.
  • Hydrogels and particles can be thermo- and pH- sensitive. See, e.g., Boffito et aL, Front Bioeng BiotechnoL 2020 May 19;8:384: Hybrid Injectable Sol- Gel Systems Based on Thermo-Sensitive Polyurethane Hydrogels Carrying pH- Sensitive Mesoporous Silica Nanoparticles for the Controlled and Triggered Release of Therapeutic Agents. For more information related to hydrogels for therapeutic agent delivery, also see, e.g., Ziemba et aL, Front Pharmacol. 2017; 8: 245.
  • a subject therapeutic agent e.g., oxytocin
  • periosteum e.g., calvarial periosteum
  • fiber/conduit e.g. an electrospun fiber
  • Fibers and conduits are polymeric, synthetic scaffolds. Several fibers and conduits are used (and can be used) as drug delivery vehicles - for example, for controlled drug release. Any convenient fiber or conduit can be used and many different formulations and techniques for producing such will be known to one of ordinary skill in the art.
  • Fiber modifications can be used for a brief or sustained delivery of drugs. As would be known to one of ordinary skill in the art, altering fiber diameter and ultimately surface area can change the drug release rate. Smaller diameter fibers have demonstrated a greater burst release, while larger fibers provide a more sustained release, likely due to lower surface area of larger fibers and greater volume of polymer to diffuse through.
  • Fibers and conduits can be made of non- biodegradable polymer, biodegradable polymer, or a combination thereof.
  • Non-biodegradable polymers include, for example, non-degradable synthetic polymers, e.g., polystyrene, polyethylene, polypropylene, polycarbonate, polyethylene terephthalate, polyamide, polyvinyle chloride, etc. and mixtures thereof.
  • non-degradable synthetic polymers e.g., polystyrene, polyethylene, polypropylene, polycarbonate, polyethylene terephthalate, polyamide, polyvinyle chloride, etc. and mixtures thereof.
  • Biodegradable polymers include, for example, polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), polyanhydrides, poly(.beta.-hydroxybutyrate), polydioxanone, poly(DTH iminocarbonate), polypropylene fumarate, etc. copolymers thereof and mixtures thereof.
  • fibers can be made of a material that is resorbable in the human body.
  • resorbable substances include poly lactic acid (PLA), poly glycolic acid (PGA), and PLGA.
  • Resorbable polymers can be based on functional groups such as esters, orthoesters, amides, anhydrides, polycaprolactones or other biodegradable materials as is known in the art. The rates of resorption of these substances can be adjusted by the details of their copolymerization, the molecular weight, chemical nature, resorption mechanism and the like.
  • a porous 3D scaffold e.g., porous polycaprolactone scaffold
  • a porous 3D scaffold e.g., porous polycaprolactone scaffold
  • Electrospun fiber scaffolds have characteristics that include simple preparation, high material universality, and favorable surface chemical properties for drug adsorption.
  • the high porosity and large specific surface area of electrospun fiber scaffolds make them beneficial to increasing drug-loading efficiency and the response speed of stimuli-delivered drugs.
  • the extracellular matrix (ECM)-like morphology of electrospun fibers inherently guides cellular drug uptake.
  • drugs can be released in a fast, sustained, heterogeneous or controlled manner by being combined with polymers, adsorbing on the fiber surface, or indirectly encapsulating onto electrospun fibers.
  • a therapeutic agent such as Oxytocin (or an oxytocin analog or a combination thereof) is delivered locally (e.g., injected) to (into or onto) an individual’s calvarial periosteum using a composition for controlled drug release (e.g., hydrogel, fiber/conduit, nanoparticle, microparticle), where the individual has a headache such as a post-traumatic headache (PTH).
  • a composition for controlled drug release e.g., hydrogel, fiber/conduit, nanoparticle, microparticle
  • PTH post-traumatic headache
  • local delivery e.g., injection
  • local delivery is into the crown of the skull.
  • local delivery e.g., injection
  • local delivery is along or near a skull suture.
  • local delivery e.g., injection
  • the TBI is an mTBI.
  • a therapeutic agent such as Oxytocin (or an oxytocin analog or a combination thereof) is delivered locally (e.g., injected) to (into or onto) an individual’s calvarial periosteum using a composition that includes microparticles (e.g., microspheres) loaded with the agent, where the individual has a headache such as a post-traumatic headache (PTH).
  • the microparticles are oxytocin- loaded sustained-release poly (lactide-co-glycolide) (PLGA) microspheres.
  • local delivery e.g., injection
  • injection is into the crown of the skull.
  • local delivery e.g., injection
  • local delivery is along or near a skull suture.
  • local delivery e.g., injection
  • the site of a closed-head TBI is at or near the site of a closed-head TBI.
  • the TBI is an mTBI.
  • a therapeutic agent such as Oxytocin (or an oxytocin analog or a combination thereof) is delivered locally (e.g., injected) to (into or onto) an individual’s calvarial periosteum using a composition for controlled drug release that includes a hydrogel loaded with the agent, where the individual has a headache such as a post-traumatic headache (PTH).
  • local delivery e.g., injection
  • local delivery is along or near a skull suture.
  • local delivery e.g., injection
  • the TBI is an mTBI.
  • a therapeutic agent such as Oxytocin (or an oxytocin analog or a combination thereof) is delivered locally to (into or onto) an individual’s calvarial periosteum using a composition for controlled drug release that includes a fiber/conduit loaded with the agent, where the individual has a headache such as a post-traumatic headache (PTH).
  • PTH post-traumatic headache
  • local delivery is into the crown of the skull.
  • local delivery is along or near a skull suture.
  • local delivery is at or near the site of a closed-head TBI.
  • the TBI is an mTBI.
  • a therapeutic agent such as Oxytocin (or an oxytocin analog or a combination thereof) is delivered locally (e.g., injected) to (into or onto) an individual’s calvarial periosteum using a composition that includes nanoparticles loaded with the agent, where the individual has a headache such as a post-traumatic headache (PTH).
  • local delivery e.g., injection
  • local delivery is into the crown of the skull.
  • local delivery e.g., injection
  • local delivery is along or near a skull suture.
  • local delivery e.g., injection
  • the TBI is an mTBI. 5. Individual in need and their treatment
  • an individual to be treated has a headache. Accordingly, delivery of the therapeutic agent is to the calvarial periosteum (as opposed to another type of periosteum such as long bong periosteum).
  • the headache is a post- traumatic headache (PTH).
  • the individual has a traumatic brain injury (TBI) (e.g., a closed-head TBI).
  • TBI traumatic brain injury
  • An individual in need can be of any age.
  • the individual in some cases, is an adult, in some cases an adolescent, and in some cases a child.
  • Headache is a common complication of traumatic brain injury.
  • the International Headache Society defines a PTH as a headache attributed to trauma or injury to the head that develops within seven days of the trauma/injury or after regaining consciousness. Different types of headache have been described, but the most common headache resembles migraine (moderate to severe in intensity, pulsating, associated nausea/vomiting or light/sound sensitivity, worsened with routine activity), and tension-type headache (mild to moderate in intensity, non-pulsating headache with either light or sound sensitivity but no nausea or vomiting).
  • PTH is commonly associated with many symptoms including dizziness, insomnia, poor concentration, memory problems, sensitivity to noise or bright lights, fatigue as well as mood and personality changes like depression and nervousness.
  • the individual in need (the individual to be treated) has a PTH, trigemaminal Neuralgia, trigeminal neuropathy, dry socket, eye pain, temporomandibular joint disease pain, Nasopharyngeal carcinoma pain, burning mouth syndrome, optic neuritis, craniofacial post-operative pain, idiopathic facial pain, migraine, chronic migraine, occipital headache, or any combination thereof.
  • the individual in need (the individual to be treated) has trigemaminal Neuralgia, trigeminal neuropathy, dry socket, eye pain, temporomandibular joint disease pain, Nasopharyngeal carcinoma pain, burning mouth syndrome, optic neuritis, craniofacial post-operative pain, idiopathic facial pain, migraine, chronic migraine, occipital headache, or any combination thereof.
  • the individual in need has migraine, chronic migraine, occipital headache, or any combination thereof.
  • the periosteum is targeted to treat the attached bone, e.g., to treat skull bone pain.
  • the individual in need has skull bone pain, skull Base osteomyeliti, or mastoiditis.
  • the individual in need (the individual to be treated) has a symptom such as pain associated with a bone injury other than a head injury, e.g., an injury to a long bone.
  • a symptom such as pain associated with a bone injury other than a head injury, e.g., an injury to a long bone.
  • delivery of the therapeutic agent can be to periosteum such as long bong periosteum (as opposed to calvarial periosteum).
  • the individual in need is a human.
  • the individual is a pet or a farm animal.
  • the individual is a non-human primate.
  • the individual is a rodent (e.g., rat, mouse).
  • treatment used herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect can be prophylactic in terms of completely or partially preventing a disease and/or symptom(s) (e.g., headache paine) and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or symptom(s) (e.g., headache paine) and/or adverse effect attributable to the disease and/or symptom(s).
  • treatment encompasses any treatment of a disease and/or symptom(s) in a mammal, particularly a human, and includes: (a) preventing the disease and/or symptom(s) from occurring in a subject who may be predisposed to the disease or symptom(s) but has not yet been diagnosed as having it (prophylactic); (b) inhibiting the disease and/or symptom(s), i.e. , arresting development of a disease and/or symptoms; or (c) relieving the disease and/or symptom(s), i.e., causing regression of the disease and/or symptom(s).
  • Those in need of treatment can include those already inflicted (e.g., those with headaches, e.g., from a TBI) as well as those in which prevention is desired.
  • a therapeutic treatment is one in which the subject is inflicted (e.g., with a headache) prior to administration and a prophylactic treatment is one in which the subject is not inflicted prior to administration.
  • the terms “recipient”, “individual”, “subject”, “host”, and “patient”, are used interchangeably herein and refer to any mammalian subject for whom diagnosis, treatment, or therapy is desired (e.g., humans). This includes but is not limited to human and non-human primates (simians, apes, gibbons, gorillas, chimpanzees, orangutans, macaques, and the like); mammalian sport animals (e.g., horses); mammalian farm animals (e.g., poultry such as chickens and ducks, horses, cows, goats, sheep, pigs, etc.); mammalian pets (dogs, cats, etc.); and rodents/experimental animals (e.g., mouse, rat, rabbit, guinea pig, etc.) for whom diagnosis, treatment, or therapy is desired, particularly humans.
  • rodents/experimental animals e.g., mouse, rat, rabbit, guinea pig, etc.
  • mammal for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, camels, etc.
  • the mammal is human.
  • the mammal is a rodent (e.g., rat, mouse).
  • the mammal is a non-human primate.
  • Human subjects include fetal, neonatal, infant, juvenile and adult subjects.
  • Subjects include animal disease models, for example, mouse and other animal models of cancer and others known to those of skill in the art.
  • Doses can vary and depend upon whether the treatment is prophylactic or therapeutic, the type, onset, progression, severity, frequency, duration, or probability of the disease and/or symptom(s) treatment is directed to, the clinical endpoint desired, previous or simultaneous treatments, the general health, age, gender, race or immunological competency of the subject and other factors that will be appreciated by the skilled artisan.
  • the dose amount, number, frequency or duration may be proportionally increased or reduced, as indicated by any adverse side effects, complications or other risk factors of the treatment or therapy and the status of the subject. The skilled artisan will appreciate the factors that may influence the dosage and timing required to provide an amount sufficient for providing a therapeutic or prophylactic benefit.
  • an "effective amount” or “sufficient amount” refers to an amount providing, in single or multiple doses, alone or in combination, with one or more other compositions (therapeutic agents such as a drug), treatments, protocols, or therapeutic regimens, a detectable response of any duration of time (long or short term), an expected or desired outcome in or a benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for minutes, hours, days, months, years, or cured). For example, an amount of a subject composition or compound that will elicit the intended biological, physiologic, clinical or medical response of a cell, tissue, organ, system, or subject that is being sought.
  • an effective amount is an amount that reduces headache (e.g., intensity, duration, type, or a combination thereof) in the individual.
  • An effective amount can be determined on an individual basis and can be based, in part, on consideration of the symptoms to be treated and results sought. An effective amount can be determined by one of ordinary skill in the art employing such factors and using no more than routine experimentation, e.g., through routine trials establishing dose response curves.
  • pharmaceutically acceptable and “physiologically acceptable” mean a biologically acceptable formulation, gaseous, liquid or solid, or mixture thereof, suitable for one or more routes of administration, in vivo delivery or contact.
  • a "pharmaceutically acceptable” or “physiologically acceptable” composition is a material that is not biologically or otherwise undesirable, e.g., the material may be administered to a subject without causing substantial undesirable biological effects.
  • unit dosage form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity optionally in association with a pharmaceutical carrier (excipient, diluent, vehicle or filling agent) which, when administered in one or more doses, produces a desired effect (e.g., prophylactic or therapeutic effect).
  • a pharmaceutical carrier excipient, diluent, vehicle or filling agent
  • unit dosage forms may be within, for example, ampules and vials, including a liquid composition, or a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo.
  • Individual unit dosage forms can be included in multi-dose kits or containers.
  • compositions for treatment e.g., pharmaceutical compositions useful in treating subjects according to the methods of the disclosure.
  • dosing regimens for administering the described pharmaceutical compositions comprising: a) therapeutic agent such as oxytocin; and b) a pharmaceutically acceptable carrier, diluent, excipient, or buffer.
  • the pharmaceutically acceptable carrier, diluent, excipient, or buffer is suitable for use in a human.
  • a subject composition e.g., a controlled release formulation such as oxytocin-loaded microspheres
  • a subject composition is for use in treating a headache by injection into an individual’s calvarial periosteum.
  • a subject composition e.g., a controlled release formulation such as oxytocin-loaded microspheres
  • TBI traumatic brain injury
  • a subject composition e.g., a controlled release formulation such as oxytocin-loaded microspheres
  • a subject composition is for use in treating a headache by injection into an individual’s calvarial periosteum at the crown of the skull.
  • a subject composition e.g., a controlled release formulation such as oxytocin- loaded microspheres
  • a subject composition is for use in treating a headache by injection into an individual’s calvarial periosteum at or near a skull suture.
  • a subject composition e.g., a controlled release formulation such as oxytocin-loaded microspheres
  • TBI traumatic brain injury
  • a subject composition e.g., a controlled release formulation such as oxytocin-loaded microspheres
  • a subject composition is for use in treating a PTH by injection into an individual’s calvarial periosteum.
  • a subject composition e.g., a controlled release formulation such as oxytocin-loaded microspheres
  • TBI traumatic brain injury
  • a subject composition e.g., a controlled release formulation such as oxytocin-loaded microspheres
  • a subject composition is for use in treating a PTH by injection into an individual’s calvarial periosteum at the crown of the skull.
  • a subject composition e.g., a controlled release formulation such as oxytocin-loaded microspheres
  • a subject composition is for use in treating a PTH by injection into an individual’s calvarial periosteum at at or near a skull suture.
  • a subject composition e.g., a controlled release formulation such as oxytocin-loaded microspheres
  • TBI traumatic brain injury
  • a therapeutic agent e.g., oxytocin
  • a pharmaceutical composition comprising an active therapeutic agent(s) and a pharmaceutically acceptable excipient.
  • the preferred form depends on the intended mode of administration and therapeutic application.
  • the compositions can also include, depending on the formulation desired, pharmaceutically-acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration.
  • the diluent can be selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solutions, dextrose solution, and Hank's solution.
  • the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
  • compositions can also include large, slowly metabolized macromolecules such as proteins, polysaccharides such as chitosan, polylactic acids, polyglycolic acids and copolymers (such as latex functionalized SepharoseTM, agarose, cellulose, and the like), polymeric amino acids, amino acid copolymers, and lipid aggregates (such as oil droplets or liposomes).
  • a carrier may bear the agents in a variety of ways, including covalent bonding either directly or via a linker group, and non-covalent associations.
  • Suitable covalent-bond carriers include proteins such as albumins, peptides, and polysaccharides such as aminodextran, each of which have multiple sites for the attachment of moieties.
  • a carrier may also bear a subject agent by non-covalent associations, such as non- covalent bonding or by encapsulation.
  • the nature of the carrier can be either soluble or insoluble for purposes of the disclosure. Those skilled in the art will know of other suitable carriers for binding a subject agent, or will be able to ascertain such, using routine experimentation.
  • Acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyidimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, his
  • the active ingredients may also be entrapped in microcapsule prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsule and poly-(methylmethacylate) microcapsule, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules
  • the agents of the disclosure can be administered in the form of a depot injection or implant preparation which can be formulated in such a manner as to permit a sustained or pulsatile release of the active ingredient.
  • the pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration.
  • GMP Good Manufacturing Practice
  • Toxicity of a subject agent can be determined by standard pharmaceutical procedures in cell cultures and/or experimental animals, e.g., by determining the LD 5 o (the dose lethal to 50% of the population) or the LD 100 (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effect is the therapeutic index.
  • the data obtained from these cell culture assays and animal studies can be used in further optimizing and/or defining a therapeutic dosage range and/or a sub- therapeutic dosage range (e.g., for use in humans). The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition.
  • a suitable subject agent can be provided in pharmaceutical compositions suitable for therapeutic use, e.g. for human treatment.
  • pharmaceutical compositions of the present disclosure include one or more therapeutic entities of the present disclosure (e.g., one or subject agents) and can include a pharmaceutically acceptable carrier, a pharmaceutically acceptable salt, a pharmaceutically acceptable excipient, and/or esters or solvates thereof.
  • the use of a subject agent includes use in combination with (co-administration with) another therapeutic agent.
  • Therapeutic formulations comprising a subject agent can be prepared by mixing the agent(s) having the desired degree of purity with a physiologically acceptable carrier, a pharmaceutically acceptable salt, an excipient, and/or a stabilizer (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)) (e.g., in the form of lyophilized formulations or aqueous solutions).
  • a composition having a subject agent can be formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder and/or symptom being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder and/or symptom, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients can be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.
  • “Pharmaceutically acceptable salts and esters” means salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include salts that can be formed where acidic protons present in the compounds are capable of reacting with inorganic or organic bases. Suitable inorganic salts include those formed with the alkali metals, e.g.
  • Suitable organic salts include those formed with organic bases such as the amine bases, e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Such salts also include acid addition salts formed with inorganic acids (e.g., hydrochloric and hydrobromic acids) and organic acids (e.g., acetic acid, citric acid, maleic acid, and the alkane- and arenesulfonic acids such as methanesulfonic acid and benzenesulfonic acid).
  • inorganic acids e.g., hydrochloric and hydrobromic acids
  • organic acids e.g., acetic acid, citric acid, maleic acid, and the alkane- and arenesulfonic acids such as methanesulfonic acid and benzenesulfonic acid.
  • esters include esters formed from carboxy, sulfonyloxy, and phosphonoxy groups present in the compounds, e.g., Ci- 6 alkyl esters.
  • a pharmaceutically acceptable salt or ester can be a mono-acid-mono-salt or ester or a di-salt or ester; and similarly where there are more than two acidic groups present, some or all of such groups can be salified or esterified.
  • Compounds named in this disclosure can be present in unsalified or unesterified form, or in salified and/or esterified form, and the naming of such compounds is intended to include both the original (unsalified and unesterified) compound and its pharmaceutically acceptable salts and esters.
  • compositions, carriers, diluents and reagents are used interchangeably and represent that the materials are capable of administration to or upon a human without the production of undesirable physiological effects to a degree that would prohibit administration of the composition.
  • kits/systems for carrying out a subject method can include various combinations of components useful in any of the methods described elsewhere herein.
  • a subject kit includes a composition for controlled drug release that includes a subject therapeutic agent (e.g., oxytocin) in a unit dosage form appropriate for the subject methods.
  • a subject kit can include oxytocin in a unit dosage form appropriate for injection into or onto the calvarial periosteum.
  • the agent can be in the form of a pre-loaded controlled drug release formulation (e.g., hydrogel, fiber/conduit, nanoparticles, microparticles, and the like), or the agent and a controlled drug release vehicle (e.g., hydrogel, fiber/conduit, nanoparticles, microparticles, and the like) can be packaged separately in the same kit for later mixing/loading prior to administration.
  • a pre-loaded controlled drug release formulation e.g., hydrogel, fiber/conduit, nanoparticles, microparticles, and the like
  • a controlled drug release vehicle e.g., hydrogel, fiber/conduit, nanoparticles, microparticles, and the like
  • a kit can further include one or more additional reagents, where such additional reagents can be any convenient reagent.
  • additional reagents can be any convenient reagent.
  • Components of a subject kit can be in separate containers; or can be combined in a single container. In some cases one or more of a kit’s components are pharmaceutically formulated for administration to a human.
  • a subject kit can further include instructions for using the components of the kit to practice the subject methods (e.g., dosing instructions, instructions to administer the component(s) to an individual.
  • the instructions for practicing the subject methods are generally recorded on a suitable recording medium.
  • the instructions may be printed on a substrate, such as paper or plastic, etc.
  • the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e. , associated with the packaging or subpackaging) etc.
  • the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, diskette, flash drive, etc.
  • the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided.
  • An example of this embodiment is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate.
  • Oxytocin receptor Expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders. Cephalalgia. 2016 Sep;36(10):943-50.
  • CGRP Calcitonin gene-related peptide
  • a method of treating an individual in need thereof, a comprising administering a composition for controlled drug release via local delivery to the periosteum.
  • composition for controlled drug release comprises a hydrogel, a fiber/conduit, a nanoparticle, or any combination thereof.
  • composition for controlled drug release comprises a nanoparticle (e.g., population of nanoparticles) encapsulating a drug.
  • composition from any one of 1 -9.
  • a method of treating an individual in need thereof, a comprising administering a composition for controlled drug release via local delivery to the periosteum.
  • composition for controlled drug release comprises a hydrogel, a fiber/conduit, a nanoparticle, or any combination thereof.
  • composition for controlled drug release comprises a nanoparticle (e.g., population of nanoparticles) encapsulating a drug.
  • composition for controlled drug release comprises a hydrogel, a fiber/conduit, a nanoparticle, a microparticle, or any combination thereof.
  • composition for controlled drug release comprises a microparticle (e.g., population of microparticles) encapsulating a drug.
  • the drug is oxytocin.
  • composition for controlled drug release comprises a hydrogel, a fiber/conduit, a nanoparticle, a microparticle, or any combination thereof.
  • composition for controlled drug release comprises microparticles loaded with a therapeutic agent.
  • composition for controlled drug release comprises nanoparticles loaded with a therapeutic agent.
  • composition for controlled drug release comprises oxytocin, an oxytocin analog, or a combination thereof.
  • composition for controlled drug release comprises a CGRP signaling inhibitor.
  • composition for controlled drug release comprises oxytocin-loaded microspheres.
  • oxytocin-loaded microspheres are oxytocin-loaded sustained-release poly (lactide-co-glycolide) (PLGA) microspheres.
  • TBI closed-head traumatic brain injury
  • a method of treating a mammalian individual in need thereof comprising injecting a composition comprising: (a) oxytocin, an oxytocin analog, or a combination thereof; (b) a CGRP signaling inhibitor; or (c) a combination thereof, into or onto the individual’s calvarial periosteum.
  • TBI closed-head traumatic brain injury
  • composition for controlled drug release comprises a hydrogel, a fiber/conduit, a nanoparticle, a microparticle, or any combination thereof.
  • composition for controlled drug release comprises oxytocin-loaded microspheres.
  • oxytocin-loaded microspheres are oxytocin- loaded sustained-release poly (lactide-co-glycolide) (PLGA) microspheres.
  • a composition comprising a controlled drug release formulation of (a) oxytocin, an oxytocin analog, or a combination thereof; (b) a CGRP signaling inhibitor; or (c) a combination thereof, formulated for use in treating a headache by injection into or onto an individual’s calvarial periosteum.
  • TBI traumatic brain injury
  • composition of 30 or 31 wherein the individual is human.
  • Example 1 Effect of OT (and OTR antagonist) injection into CP for PTH- and Persistent PTH-related pain
  • BLS bright light stress
  • L-368,899 hydrochloride is a nonpeptide, desamino-OT analog, and a competitive OTR antagonist.
  • animals received direct CP injection of L-368,899 (50pl of 50pg Sigma diluted in saline) or vehicle five mins prior to OT (50pl of 25pg) injection into CP.
  • OTR antagonist injection blocked OT induced analgesic effect.
  • mice were exposed to 15 mins of bright light stress (BLS).
  • BLS bright light stress
  • Example 2 Microparticle characterization
  • OT-loaded microspheres were prepared by solvent displacement method (based on Akay et. aL). 100 mg PLGA and 10 mg OT was used to prepare the sample. The production yield was -60%. The particle diameter of the OT-loaded microspheres was 1 .7 ⁇ 0.13 pm, and their polydispersity index was 0.196, obtained from dynamic light scattering technique, Figure 8. The analysis was run in triplicates.
  • Example 3 OT-loaded microparticles injected into CP produced sustained analgesic response
  • mice received 30pl of OT- or blank microparticles injection into CP. Cranial frequency response was tested 2h, 10h, and 24h post-injection. The OT- microparticle injected group showed significantly decreased frequency response compared to blank-microparticle group at least up to 24 hours post-injection. See Figure 9.
  • Retrograde tracer was applied selectively onto the CP of pre-inflamed rats. After two weeks, animals were sacrificed to harvest the TG and perform imaging. TG sections show abundant retrograde tracer (blue) labeling of the CPT neurons that also express OTR (green), Figure 10.
  • Synthetic interstitial fluid (SI F) or an inflammatory mediators (IM) was injected selectively into the CP of mice. 10 mins after application, animals were sacrificed to harvest the TG. Immunohistochemical ( I HC) analysis of phosphor-ERK (pERK) levels that indicates neuronal excitation, increase in the IM group vs SIP group ( Figure 11)
  • Example 5 Effect of CGRP receptor antagonist injection into the calvarial periosteum for treatment od PTH-related pain
  • CGRP is neuropeptide that is known to play a critical role in the pathophysiology of migraine. PTH often mimics a migraine-like headache and anti-CGRP monoclonal antibodies have proven effective for preventive and acute treatments of migraine.
  • a CGRP receptor antagonist, erenumab has been shown to lower frequency of moderate to severe headaches and is well tolerated in patients with persistent PTH.

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Abstract

Des aspects de la divulgation comprennent l'administration d'une formulation pour la libération contrôlée/progressive de médicament (par exemple, hydrogels, fibres/conduits, nanoparticules en vue d'administrer de l'ocytocine) au périoste par administration locale (par exemple, injection). Dans certains cas, le médicament est de l'ocytocine. La libération progressive peut avoir lieu sur une plage de temps, par exemple jusqu'à 8 mois (par exemple jusqu'à 6 mois, jusqu'à 5 mois, jusqu'à 4 mois, jusqu'à 3 mois, jusqu'à 2 mois, jusqu'à 1 mois, jusqu'à 3 semaines, jusqu'à 2 semaines ou jusqu'à 1 semaine). Dans certains cas, la formulation comprend des nanoparticules, par exemple des nanoparticules qui encapsulent le médicament (tel que de l'ocytocine). Les formulations peuvent être utilisées à des fins d'injection péri-crânienne (par exemple, pour le traitement de la céphalée). L'invention concerne également des formulations pour injections péri-osseuses (par exemple, os longs). L'invention concerne également des injections péri-crâniennes ou péri-osseuses (par exemple, d'autres composés).
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6306423B1 (en) * 2000-06-02 2001-10-23 Allergan Sales, Inc. Neurotoxin implant
US20170368095A1 (en) * 2015-01-07 2017-12-28 Trigemina, Inc. Magnesium-containing oxytocin formulations and methods of use
US20180078622A1 (en) * 2008-04-03 2018-03-22 Allergan, Inc. Suture Line Administration Technique Using Botulinum Toxins
US20180229029A1 (en) * 2009-10-05 2018-08-16 The Regents Of The University Of California Extracranial implantable devices, systems and methods for the treatment of medical disorders
US20210128724A1 (en) * 2019-07-05 2021-05-06 Allergan Pharmaceuticals International Limited Cgrp antagonists and clostridial derivatives for the treatment of cortical spreading depression associated disorders
US20210177466A1 (en) * 2017-12-12 2021-06-17 Umc Utrecht Holding B.V. Deformable body and combination of such deformable body and a surgical screw element

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6306423B1 (en) * 2000-06-02 2001-10-23 Allergan Sales, Inc. Neurotoxin implant
US20180078622A1 (en) * 2008-04-03 2018-03-22 Allergan, Inc. Suture Line Administration Technique Using Botulinum Toxins
US20180229029A1 (en) * 2009-10-05 2018-08-16 The Regents Of The University Of California Extracranial implantable devices, systems and methods for the treatment of medical disorders
US20170368095A1 (en) * 2015-01-07 2017-12-28 Trigemina, Inc. Magnesium-containing oxytocin formulations and methods of use
US20210177466A1 (en) * 2017-12-12 2021-06-17 Umc Utrecht Holding B.V. Deformable body and combination of such deformable body and a surgical screw element
US20210128724A1 (en) * 2019-07-05 2021-05-06 Allergan Pharmaceuticals International Limited Cgrp antagonists and clostridial derivatives for the treatment of cortical spreading depression associated disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHAO ET AL.: "The sensory innervation of the calvarial periosteum is nociceptive and contributes to headache-like behavior", PAIN, vol. 155, 2014, pages 1392 - 1400, XP029006365, DOI: 10.1016/j.pain.2014.04.019 *

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