WO2018106339A1 - Neurotoxines botuliques destinées à être utilisées dans un traitement chirurgical de réparation de tendon - Google Patents

Neurotoxines botuliques destinées à être utilisées dans un traitement chirurgical de réparation de tendon Download PDF

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Publication number
WO2018106339A1
WO2018106339A1 PCT/US2017/055773 US2017055773W WO2018106339A1 WO 2018106339 A1 WO2018106339 A1 WO 2018106339A1 US 2017055773 W US2017055773 W US 2017055773W WO 2018106339 A1 WO2018106339 A1 WO 2018106339A1
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Prior art keywords
neurotoxin
hours
administration
less
procedure
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PCT/US2017/055773
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English (en)
Inventor
Kenton Abel
Sawsan ABU-SHAKRA
Wajdie AHMAD
Fauad HASAN
Michael Jarpe
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Bonti, Inc.
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Publication of WO2018106339A1 publication Critical patent/WO2018106339A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Clostridium (G)

Definitions

  • the present specification relates to the use of botulinum neurotoxins in conjunction with surgeries related to tendon repair and/or reattachment.
  • Tendons are load-bearing structures that transmit forces from muscle to bone or cartilage. Their hierarchical collagen structure is interlaced with numerous non- fibrillar proteins, which are essential to the ability of tendons to support a load. Tenocytes, the main resident cells of the tendon, "sense" mechanical loads from the extracellular matrix (ECM), and in turn modulate the ECM. Loading is essential for the maintenance of tendon homeostasis, but can also result in remodeling or degeneration.
  • ECM extracellular matrix
  • compositions and methods for use in conjunction with surgical treatments for example tendon repair treatments.
  • Embodiments disclosed herein can locally reduce muscular activity and thereby reduce tension for a limited duration, for example in conjunction with surgical re-attachment or repair of a tendon.
  • An embodiment comprises a method for reducing mechanical loading on a tendon, comprising administering a botulinum neurotoxin to a muscle attached to that tendon.
  • Disclosed embodiments comprise use of a "fast-acting" botulinum toxin.
  • Disclosed embodiments comprise use of a "fast-recovery" botulinum toxin.
  • the "fast-acting" botulinum toxin is also a “fast-recovery” toxin.
  • disclosed methods comprise administration of a fast-acting botulinum neurotoxin prior to a surgical procedure, for example a tendon repair procedure.
  • disclosed methods comprise administration of a fast-acting botulinum neurotoxin prior to a surgical procedure.
  • disclosed methods comprise administration of a fast-acting botulinum neurotoxin following a surgical procedure.
  • disclosed methods comprise administration of a fast- recovery botulinum neurotoxin prior to a surgical procedure.
  • disclosed methods comprise administration of a fast- recovery botulinum neurotoxin following a surgical procedure.
  • Figure 1 shows a depiction of the primary structure of a botulinum neurotoxin (BoNT).
  • Embodiments disclosed herein can reduce local nerve and muscle activity and thereby reduce the mechanical load on a particular tendon, for example after surgical re-attachment of a tendon such as occurs in rotator cuff surgery (e.g., reattachment of the supraspinatus tendon). This can reduce or eliminate tension overload on the repaired tendon, and also allow the patient to begin therapy with other muscles near the point of repair but not attached to the damaged tendon.
  • the disclosed methods can also provide improved collagen fiber organization at the tendon/bone interface. This improved collagen fiber organization is indicative of healthier tissue.
  • administering means the step of giving (i.e. administering) a pharmaceutical composition or active ingredient to a subject.
  • the pharmaceutical compositions disclosed herein can be administered via a number of appropriate routs, including intramuscular or subcutaneous routes of administration, such as by injection or use of an implant.
  • Botulinum toxin or "botulinum neurotoxin” means a neurotoxin derived from Clostridium botulinum, as well as modified, recombinant, hybrid and chimeric botulinum toxins.
  • a recombinant botulinum toxin can have the light chain and/or the heavy chain thereof made recombinantly by a non-Clostridial species.
  • Botulinum toxin encompasses the botulinum toxin serotypes A, B, C, D, E, F, G and H.
  • Botulinum toxin as used herein, also encompasses both a botulinum toxin complex (i.e.
  • purified botulinum toxin means a pure botulinum toxin or a botulinum toxin complex that is isolated, or substantially isolated, from other proteins and impurities which can accompany the botulinum toxin as it is obtained from a culture or fermentation process.
  • a purified botulinum toxin can have at least 95%, and more preferably at least 99% of the non-botulinum toxin proteins and impurities removed.
  • Clostridial neurotoxin means a neurotoxin produced from, or native to, a Clostridial bacterium, such as Clostridium botulinum, Clostridium butyricum or Clostridium beratti, as well as a Clostridial neurotoxin made recombinantly by a non- Clostridial species.
  • “Fast-acting” as used herein refers to a botulinum toxin that produces effects in the patient more rapidly than those produced by, for example, a botulinum neurotoxin type A.
  • the effects of a fast-acting botulinum toxin can be produced within 36 hours.
  • “Fast-recovery” as used herein refers to a botulinum toxin that whose effects diminish in the patient more rapidly than those produced by, for example, a botulinum neurotoxin type A.
  • the effects of a fast-recovery botulinum toxin can diminish within, for example, 120 hours, 150 hours, 300 hours, 350 hours, 400 hours, 500 hours, 600 hours, 700 hours, 800 hours, or the like. It is known that botulinum toxin type A can have an efficacy for up to 12 months (European J.
  • Neurology 6 (Supp 4): S1 1 1 -S1 150: 1999), and in some circumstances for as long as 27 months, when used to treat glands, such as in the treatment of hyperhidrosis. See e.g. Bushara K., Botulinum toxin and rhinorrhea, Otolaryngol Head Neck Surg 1996; 1 14(3):507, and The Laryngoscope 109: 1344-1346: 1999.
  • the usual duration of an intramuscular injection of a botulinum neurotoxin type A is typically about 3 to 4 months.
  • Intermediate-acting refers to a botulinum toxin that produces effects more slowly than would a fast-acting toxin.
  • Neurotoxin means a biologically active molecule with a specific affinity for a neuronal cell surface receptor.
  • Neurotoxin includes Clostridial toxins both as pure toxin and as complexed with one to more non-toxin, toxin associated proteins.
  • Patient means a human or non-human subject receiving medical or veterinary care.
  • “Pharmaceutical composition” means a formulation in which an active ingredient can be a botulinum toxin.
  • formulation means that there is at least one additional ingredient (such as, for example and not limited to, an albumin [such as a human serum albumin or a recombinant human albumin] and/or sodium chloride) in the pharmaceutical composition in addition to a botulinum neurotoxin active ingredient.
  • a pharmaceutical composition is therefore a formulation which is suitable for diagnostic, therapeutic or cosmetic administration to a subject, such as a human patient.
  • the pharmaceutical composition can be: in a lyophilized or vacuum dried condition, a solution formed after reconstitution of the lyophilized or vacuum dried pharmaceutical composition with saline or water, for example, or; as a solution that does not require reconstitution.
  • a pharmaceutical composition can be liquid, semi-solid, or solid.
  • a pharmaceutical composition can be animal-protein free.
  • substantially free means present at a level of less than one percent by weight of a culture medium, fermentation medium, pharmaceutical composition or other material in which the weight percent of a substance is assessed.
  • “Supplemental administration” as used herein refers to a botulinum administration that follows an initial neurotoxin administration.
  • Therapeutic formulation means a formulation that can be used to treat and thereby alleviate a disorder or a disease and/or symptom associated thereof, such as a disorder or a disease characterized by an activity of a peripheral muscle.
  • “Therapeutically effective amount” means the level, amount or concentration of an agent (e.g. such as a botulinum toxin or pharmaceutical composition comprising botulinum toxin) needed to treat a disease, disorder or condition without causing significant negative or adverse side effects.
  • "Treat,” “treating,” or “treatment” means an alleviation or a reduction (which includes some reduction, a significant reduction a near total reduction, and a total reduction), resolution or prevention (temporarily or permanently) of an disease, disorder or condition, so as to achieve a desired therapeutic or cosmetic result, such as by healing of injured or damaged tissue, or by altering, changing, enhancing, improving, ameliorating and/or beautifying an existing or perceived disease, disorder or condition.
  • "Unit” or "U” means an amount of active botulinum neurotoxin standardized to have equivalent neuromuscular blocking effect as a Unit of commercially available a botulinum neurotoxin type A.
  • Wild refers to a disruption to the skin, for example caused by injury or intentionally.
  • Embodiments disclosed herein comprise neurotoxin compositions, for example fast-acting, fast-recovery neurotoxins, for example botulinum type E compositions.
  • Such neurotoxins can be formulated in any pharmaceutically acceptable formulation in any pharmaceutically acceptable form.
  • the neurotoxin can also be used in any pharmaceutically acceptable form supplied by any manufacturer.
  • the neurotoxin can be made by a Clostridial bacterium, such as by a Clostridium botulinum, Clostridium butyricum, or Clostridium beratti bacterium. Additionally, the neurotoxin can be a modified neurotoxin; that is a neurotoxin that has at least one of its amino acids deleted, modified or replaced, as compared to the native or wild type neurotoxin. In embodiments, the neurotoxin can be a recombinantly produced neurotoxin or a derivative or fragment thereof.
  • a disclosed type E composition has 40% amino acid homology compared with type A, and they share the same basic domain structure consisting of 2 chains, a 100 kDa heavy chain (HC) and a 50 kDa light chain (LC), linked by a disulfide bond (Whelan 1992).
  • the HC contains the receptor binding domain and the translocation domain while the LC contains the synaptosomal- associated protein (SNAP) enzymatic activity.
  • the domain structure is the same structure shared by all botulinum neurotoxin serotypes.
  • the neurotoxin is formulated in unit dosage form; for example, it can be provided as a sterile solution in a vial or as a vial or sachet containing a lyophilized powder for reconstituting in a suitable vehicle such as saline for injection.
  • the botulinum toxin is formulated in a solution containing saline and pasteurized human serum albumin, which stabilizes the toxin and minimizes loss through non-specific adsorption.
  • the solution can be sterile filtered (0.2 pm filter), filled into individual vials, and then vacuum-dried to give a sterile lyophilized powder.
  • the powder can be reconstituted by the addition of sterile unpreserved normal saline (sodium chloride 0.9% for injection).
  • botulinum type E is supplied in a sterile solution for injection with a 5-mL vial nominal concentration of 20 ng/mL in 0.03 M sodium phosphate, 0.12 M sodium chloride, and 1 mg/mL Human Serum Albumin (HSA), at pH 6.0.
  • HSA Human Serum Albumin
  • compositions may only contain a single type of neurotoxin, for example botulinum type E
  • disclosed compositions can include two or more types of neurotoxins, which can provide enhanced therapeutic effects.
  • a composition administered to a patient can include botulinum types A and E. Administering a single composition containing two different neurotoxins can permit the effective concentration of each of the neurotoxins to be lower than if a single neurotoxin is administered to the patient while still achieving the desired therapeutic effects.
  • composition administered to the patient can also contain other pharmaceutically active ingredients, such as, protein receptor or ion channel modulators, in combination with the neurotoxin or neurotoxins. These modulators may contribute to the reduction in neurotransmission between the various neurons.
  • a composition may contain gamma aminobutyric acid (GABA) type A receptor modulators that enhance the inhibitory effects mediated by the GABA A receptor.
  • GABA A receptor inhibits neuronal activity by effectively shunting current flow across the cell membrane.
  • GABA A receptor modulators may enhance the inhibitory effects of the GABA A receptor and reduce electrical or chemical signal transmission from the neurons.
  • GABA A receptor modulators include benzodiazepines, such as diazepam, oxaxepam, lorazepam, prazepam, alprazolam, halazeapam, chordiazepoxide, and chlorazepate.
  • Compositions may also contain glutamate receptor modulators that decrease the excitatory effects mediated by glutamate receptors.
  • glutamate receptor modulators include agents that inhibit current flux through AMPA, NMDA, and/or kainate types of glutamate receptors.
  • Methods disclosed herein can comprise administration of a neurotoxin, for example a botulinum neurotoxin, to a patient.
  • a neurotoxin for example a botulinum neurotoxin
  • the neurotoxin is BoNT/E.
  • Methods disclosed herein can comprise supplemental administration of a fast- acting neurotoxin to a patient.
  • Embodiments comprising supplemental administration can further comprise doctor or patient evaluation of the results of a prior neurotoxin administration.
  • Embodiments comprise administration of a fast-acting neurotoxin prior to a surgical procedure, for example a tendon repair procedure.
  • the administration is performed, for example, within 48 hours before the procedure, within 47 hours before the procedure, within 46 hours before the procedure, within 45 hours before the procedure, within 44 hours before the procedure, within 43 hours before the procedure, within 42 hours before the procedure, within 41 hours before the procedure, within 40 hours before the procedure, within 39 hours before the procedure, within 38 hours before the procedure, within 37 hours before the procedure, within 36 hours before the procedure, within 35 hours before the procedure, within 34 hours before the procedure, within 33 hours before the procedure, within 32 hours before the procedure, within 31 hours before the procedure, within 30 hours before the procedure, within 29 hours before the procedure, within 28 hours before the procedure, within 27 hours before the procedure, within 26 hours before the procedure, within 25 hours before the procedure, within 24 hours before the procedure, within 23 hours before the procedure, within 22 hours before the procedure, within 21 hours before the procedure, within 20 hours before the procedure, within 19 hours
  • Embodiments comprise administration of a fast-acting neurotoxin prior to a surgical procedure, for example a tendon repair procedure.
  • the administration is performed, for example, within 48 hours or less before the procedure, within 47 hours or less before the procedure, within 46 hours or less before the procedure, within 45 hours or less before the procedure, within 44 hours or less before the procedure, within 43 hours or less before the procedure, within 42 hours or less before the procedure, within 41 hours or less before the procedure, within 40 hours or less before the procedure, within 39 hours or less before the procedure, within 38 hours or less before the procedure, within 37 hours or less before the procedure, within 36 hours or less before the procedure, within 35 hours or less before the procedure, within 34 hours or less before the procedure, within 33 hours or less before the procedure, within 32 hours or less before the procedure, within 31 hours or less before the procedure, within 30 hours or less before the procedure, within 29 hours or less before the procedure, within 28 hours or less before the procedure, within 27 hours or less before the procedure, within 26 hours or less before the procedure
  • Embodiments comprise administration of a fast-acting neurotoxin following an injury, for example an injury to a tendon.
  • the fast- acting neurotoxin can be administered within 5 minutes of an injury occurring, within 10 minutes an injury, within 15 minutes of an injury, within 20 minutes of an injury, within 25 minutes of an injury, within 30 minutes of an injury, within 35 minutes of an injury, within 40 minutes of an injury, within 45 minutes of an injury, within 50 minutes of an injury, within 55 minutes of an injury, within 60 minutes of an injury, within 65 minutes of an injury, within 70 minutes of an injury, within 75 minutes of an injury, within 80 minutes of an injury, within 85 minutes of an injury, within 90 minutes of an injury, within 95 minutes of an injury, within 100 minutes of an injury, within 1 10 minutes of an injury, within 2 hours of an injury, within 2 hours of an injury, within 3 hours of an injury, within 4 hours of an injury, within 5 hours of an injury, within 6 hours of an injury, within 7 hours of an injury, within 8 hours of an
  • administration of the fast-acting neurotoxin is performed concurrently with a surgical procedure.
  • evaluation of the results of the initial neurotoxin administration can be performed within, for example, 6 hours of the initial administration of neurotoxin, 8 hours of the initial administration, 10 hours of the initial administration, 12 hours of the initial administration, 14 hours of the initial administration, 16 hours of the initial administration, 18 hours of the initial administration, 24 hours of the initial administration, 30 hours of the initial administration, 36 hours of the initial administration, 42 hours of the initial administration, 48 hours of the initial administration, 54 hours of the initial administration, 60 hours of the initial administration, 66 hours of the initial administration, 72 hours of the initial administration, 78 hours of the initial administration, 84 hours of the initial administration, 90 hours of the initial administration, 96 hours of the initial administration, 102 hours of the initial administration, 108 hours of the initial administration, 1 14 hours of the initial administration, 120 hours i of the initial administration, 1 week of the initial administration, 2 weeks of the initial administration, 3 weeks of the initial administration, 4 weeks of the initial administration, 5 weeks of the initial administration, 6 weeks of
  • Methods disclosed herein can provide rapid-onset effects (for example, using a fast-acting neurotoxin).
  • disclosed embodiments can reduce muscle activity, nerve activity, and pain sensation within, for example, 30 minutes after administration, 45 minutes after administration, 60 minutes after administration, 75 minutes after administration, 90 minutes after administration, 2 hours after administration, 3 hours after administration, 4 hours after administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 8 hours after administration, 9 hours after administration, 10 hours after administration, 1 1 hours after administration, 12 hours after administration, 13 hours after administration, 14 hours after administration, 15 hours after administration, 16 hours after administration, 17 hours after administration, 18 hours after administration, 19 hours after administration, 20 hours after administration, 21 hours after administration, 22 hours after administration, 23 hours after administration, 24 hours after administration, 30 hours after administration, 36 hours after administration, 42 hours after administration, 48 hours after administration, 3 days after administration, 4 days after administration, 5 days after administration, 6 days after administration, 7 days after administration, or the like.
  • Methods disclosed herein can provide rapid-onset effects (for example, using a fast-acting neurotoxin).
  • disclosed embodiments can reduce muscle activity, nerve activity, and pain sensation within, for example, 30 minutes or less after administration, 45 minutes or less after administration, 60 minutes or less after administra tion, 75 minutes or less after administration, 90 minutes or less after administra tion, 2 hours or less after administration, 3 hours or less after administra tion, 4 hours or less after administration, 5 hours or less after administra tion, 6 hours or less after administration, 7 hours or less after administra tion, 8 hours or less after administration, 9 hours or less after administra tion, 10 hours or less after administration, 1 1 hours or less after administra tion, 12 hours or less after administration, 13 hours or less after administra tion, 14 hours or less after administration, 15 hours or less after administra tion, 16 hours or less after administration, 17 hours or less after administra tion, 18 hours or less after administration, 19 hours or less after administr
  • Methods disclosed herein can provide reduction in muscle activity, nerve activity, and pain sensation for a shorter duration (for example, using a fast-recovery neurotoxin).
  • disclosed embodiments can provide a reduction in muscle activity and pain sensation that subsides within, for example, 3 days or less after administration, 4 days or less after administration, 5 days or less after administration, 6 days or less after administration, 7 days or less after administration, 8 days or less after administration, 9 days or less after administration, 10 days or less after administration, 1 1 days or less after administration, 12 days or less after administration, 13 days or less after administration, 14 days or less after administration, 15 days or less after administration, 16 days or less after administration, 17 days or less after administration, 18 days or less after administration, 19 days or less after administration, 20 days or less after administration, 21 days or less after administration, 22 days or less after administration, 23 days or less after administration, 24 days or less after administration, 25 days or less after administration, 26 days or less after administration, 27 days or less after administration, 28 days or less after administration, 29 days
  • Disclosed embodiments can provide neurotoxin treatments that result in fewer side effects, or side effects of a shorted duration, than conventional neurotoxin treatments. For example, disclosed embodiments can result in fewer (or shorter duration) instances of double vision or blurred vision, eyelid paralysis (subject cannot lift eyelid all the way open), loss of facial muscle movement, hoarseness, loss of bladder control, shortness of breath, difficulty in swallowing, difficulty speaking, death, and the like.
  • Disclosed methods comprise administration to an area in the proximity of surgical treatment.
  • disclosed embodiments can provide reduced muscle and nerve activity and reduced pain sensation of a more-certain duration. For example, with a longer acting neurotoxin, a 20% variance in duration of effects can result in a month's difference in effective duration. With the disclosed fast-recovery neurotoxins, this 20% variance produces a much less drastic difference in effective duration.
  • Disclosed fast-acting neurotoxin compositions can be injected into the patient using a needle or a needleless device.
  • the method comprises sub-dermally injecting the composition in the individual.
  • administering may comprise injecting the composition through a needle no greater than about 30 gauge.
  • the method comprises administering a composition comprising a botulinum toxin type E.
  • compositions can be carried out by syringe, catheters, needles and other means for injecting.
  • the injection can be performed on any area of the mammal's body that is in need of treatment, including, but not limited to, face, neck, torso, arms, hands, legs, and feet.
  • the injection can be into any position in the specific area such as epidermis, dermis, fat, muscle, or subcutaneous layer.
  • Methods disclosed herein can comprise administration of the neurotoxin to a muscle, for example a muscle attached to a tendon.
  • methods can comprise administration to the rotator cuff, the quadriceps, the Achilles, the biceps, or the like.
  • methods can comprise administration to any of the muscles of the rotator cuff group, including the supraspinatus muscle, the infraspinatus muscle, the teres minor muscle, and the subscapularis muscle.
  • Methods can comprise administration to any of the muscles of the quadriceps group, including the vastus medialis, the intermedius, the lateralis, and the rectus femoris.
  • Methods can comprise administration to any of the muscles of the Achilles group, including the plantaris, gastrocnemius (calf), and soleus muscles.
  • Methods can comprise administration to any of the muscles of the biceps, including either head of the biceps brachii.
  • skeletal muscles suitable for administration of disclosed compositions can comprise, for example, the occipitofrontalis, nasalis, orbicularis oris, depressor anguli oris, platysma, sternohyoid, serratus anterior, rectus abdominis, external oblique, tensor fasciae latae, brachioradialis, lliacus, psoas major, pectineus, adductor longus, sartorius, gracillis, vastus lateralis, rectus femoris, vastus medialis, tendon of quadriceps femoris, patella, gastroctnemius, soleus, tibia, fibularis longus, tibialis anterior, patellar ligament, iliotibial tract, hypothenar muscles, thenar muscles, flexor carpi ulnaris, flexor digitorum superficialis,
  • compositions can comprise injection into or in the vicinity of one or more of the following nerves, for example, the axillary nerve, phrenic nerve, spinal ganglion, spinal cord, sypathetic ganglia chain, pudendal nerve, common palmar digital nerve, ulnar nerve, deep branch of the ulnar nerve, sciatic nerve, peroneal nerve, tibial nerve, saphenous nerve, interosseous nerve, superficial peroneal nerve, intermediate dorsal cutaneous nerve, medial plantar nerve, medial dorsal cutaneous nerve, deep peroneal nerve, muscular branches of tibial nerve, infrapatellar branch of saphenous nerve, common peroneal nerve, muscular branch of femoral nerve, anterior cutaneous branches of femoral nerve, muscular branches of sciatic nerve, femoral nerve, ilioinguinal, filum terminate, iliohypogastric, obturator, ulnar, radial, obturator,
  • Smooth muscles suitable for administration of disclosed compositions can comprise any of walls of blood vessels, walls of stomach, ureters, intestines, in the aorta (tunica media layer), iris of the eye, prostate, gastrointestinal tract, respiratory tract, small arteries, arterioles, reproductive tracts (both genders), veins, glomeruli of the kidneys (called mesangial cells), bladder, uterus, arrector pili of the skin, ciliary muscle, sphincter, trachea, bile ducts, and the like.
  • the frequency and the amount of injection under the disclosed methods can be determined based on the nature and location of the particular area being treated. In certain cases, however, repeated injection may be desired to achieve optimal results. The frequency and the amount of the injection for each particular case can be determined by the person of ordinary skill in the art.
  • the appropriate route of administration and dosage are generally determined on a case by case basis by the attending physician. Such determinations are routine to one of ordinary skill in the art (see for example, Harrison's Principles of Internal Medicine (1998), edited by Anthony Fauci et al., 14th edition, published by McGraw Hill).
  • the route and dosage for administration of a Clostridial neurotoxin according to the present disclosed invention can be selected based upon criteria such as the solubility characteristics of the neurotoxin chosen as well as the intensity and scope of the condition being treated.
  • the fast-acting neurotoxin can be administered in an amount of between about 10 "3 U/kg and about 35 U/kg. In an embodiment, the neurotoxin is administered in an amount of between about 10 "2 U/kg and about 25 U/kg. In another embodiment, the neurotoxin is administered in an amount of between about 10 "1 U/kg and about 15 U/kg. In another embodiment, the neurotoxin is administered in an amount of between about 1 U/kg and about 10 U/kg. In many instances, an administration of from about 1 unit to about 500 units of a neurotoxin, such as a botulinum type E, provides effective therapeutic relief.
  • a neurotoxin such as a botulinum type E
  • a neurotoxin such as a botulinum type E
  • a neurotoxin such as a botulinum type E
  • from about 10 units to about 100 units of a neurotoxin, such as a botulinum type E can be locally administered into a target tissue such as a muscle.
  • administration can comprise a dose of about 10 units of a neurotoxin, or about 20 units of a neurotoxin, or about 30 units of a neurotoxin, or about 40 units of a neurotoxin, or about 50 units of a neurotoxin, or about 60 units of a neurotoxin, or about 70 units of a neurotoxin, or about 80 units of a neurotoxin, or about 90 units of a neurotoxin, or about 100 units of a neurotoxin, or about 1 10 units of a neurotoxin, or about 120 units of a neurotoxin, or about 130 units of a neurotoxin, or about 140 units of a neurotoxin, or about 150 units of a neurotoxin, or about 160 units of a neurotoxin, or about 170 units of a neurotoxin, or about 180 units of a neurotoxin, or about 190 units of a neurotoxin, or about 200 units of a neurotoxin
  • the dose of the neurotoxin is expressed in protein amount or concentration.
  • the neurotoxin can be administered in an amount of between about .2ng and 20 ng.
  • the neurotoxin is administered in an amount of between about .3 ng and 19 ng, about .4 ng and 18 ng, about .5 ng and 17 ng, about .6 ng and 16 ng, about .7 ng and 15 ng, about .8 ng and 14 ng, about .9 ng and 13 ng, about 1 .0 ng and 12 ng, about 1 .5 ng and 1 1 ng, about 2 ng and 10 ng, about 5 ng and 7 ng, and the like into a target tissue such as a muscle or nerve.
  • administration can comprise a total dose of between 5 and 7 ng, between 7 and 9 ng, between 9 and 1 1 ng, between 1 1 and 13 ng, between 13 and 15 ng, between 15 and 17 ng, between 17 and 19 ng, or the like.
  • administration can comprise a total dose of not more than 5 ng, not more than 6 ng, not more than 7 ng, not more than 8 ng, not more than 9 ng, not more than 10 ng, not more than 1 1 ng, not more than 12 ng, not more than 13 ng, not more than 14 ng, not more than 15 ng, not more than 16 ng, not more than 17 ng, not more than 18 ng, not more than 19 ng, not more than 20 ng, or the like.
  • administration can comprise a total dose of not less than 5 ng, not less than 6 ng, not less than 7 ng, not less than 8 ng, not less than 9 ng, not less than 10 ng, not less than 1 1 ng, not less than 12 ng, not less than 13 ng, not less than 14 ng, not less than 15 ng, not less than 16 ng, not less than 17 ng, not less than 18 ng, not less than 19 ng, not less than 20 ng, or the like.
  • administration can comprise a total dose of about 0.1 ng of a neurotoxin, 0.2 ng of a neurotoxin, 0.3 ng of a neurotoxin, 0.4 ng of a neurotoxin, 0.5 ng of a neurotoxin, 0.6 n of a neurotoxin, 0.7 ng of a neurotoxin, 0.8 ng of a neurotoxin, 0.9 ng of a neurotoxin, 1 .0 ng of a neurotoxin, 1 .1 ng of a neurotoxin, 1.2 ng of a neurotoxin, 1 .3 ng of a neurotoxin, 1 .4 ng of a neurotoxin, 1.5 ng of a neurotoxin, 1.6 ng of a neurotoxin, 1 .7 ng of a neurotoxin, 1 .8 ng of a neurotoxin, 1.9 ng of a neurotoxin
  • administration can comprise a dose per injection of about 0.1 ng of a neurotoxin, 0.2 ng of a neurotoxin, 0.3 ng of a neurotoxin, 0.4 ng of a neurotoxin, 0.5 ng of a neurotoxin, 0.6 n of a neurotoxin, 0.7 ng of a neurotoxin, 0.8 ng of a neurotoxin, 0.9 ng of a neurotoxin, 1 .0 ng of a neurotoxin, 1.1 ng of a neurotoxin, 1.2 ng of a neurotoxin, 1 .3 ng of a neurotoxin, 1 .4 ng of a neurotoxin, 1.5 ng of a neurotoxin, 1 .6 ng of a neurotoxin, 1 .7 ng of a neurotoxin, 1.8 ng of a neurotoxin, 1.9 ng of a neurotoxin,
  • the patient's total bi-monthly protein dose can be limited to, for example, 5 ng of a neurotoxin, 6 ng of a neurotoxin, 7 ng of a neurotoxin, 8 ng of a neurotoxin, 9 ng of a neurotoxin, 10 ng of a neurotoxin, 1 1 ng of a neurotoxin, 12 ng of a neurotoxin, 13 ng of a neurotoxin, 14 ng of a neurotoxin, 15 ng of a neurotoxin, 16 ng of a neurotoxin, 17 ng of a neurotoxin, 18 ng of a neurotoxin, 19 ng of a neurotoxin, 20 ng of a neurotoxin, or the like.
  • the patient's total monthly protein dose can be limited to, for example, 5 ng of a neurotoxin, 6 ng of a neurotoxin, 7 ng of a neurotoxin, 8 ng of a neurotoxin, 9 ng of a neurotoxin, 10 ng of a neurotoxin, 1 1 ng of a neurotoxin, 12 ng of a neurotoxin, 13 ng of a neurotoxin, 14 ng of a neurotoxin, 15 ng of a neurotoxin, 16 ng of a neurotoxin, 17 ng of a neurotoxin, 18 ng of a neurotoxin, 19 ng of a neurotoxin, 20 ng of a neurotoxin, or the like.
  • the patient's total yearly protein dose can be limited to, for example, 25 ng of a neurotoxin, 35 ng of a neurotoxin, 45 ng of a neurotoxin, 55 ng of a neurotoxin, 65 ng of a neurotoxin, 75 ng of a neurotoxin, 85 ng of a neurotoxin, 95 ng of a neurotoxin, 105 ng of a neurotoxin, 125 ng of a neurotoxin, 145 ng of a neurotoxin, 165 ng of a neurotoxin, 185 ng of a neurotoxin, 200 ng of a neurotoxin, or the like.
  • a controlled release system can be used in the embodiments described herein to deliver a neurotoxin in vivo at a predetermined rate over a specific time period.
  • release rates are determined by the design of the system, and can be largely independent of environmental conditions such as pH.
  • Controlled release systems which can deliver a drug over a period of several years are known.
  • sustained release systems typically deliver drug in 24 hours or less and environmental factors can influence the release rate.
  • the release rate of a neurotoxin from an implanted controlled release system is a function of the physiochemical properties of the carrier implant material and of the drug itself.
  • the implant is made of an inert material which elicits little or no host response.
  • a controlled release system can be comprised of a neurotoxin incorporated into a carrier.
  • the carrier can be a polymer or a bio-ceramic material.
  • the controlled release system can be injected, inserted or implanted into a selected location of a patient's body and reside therein for a prolonged period during which the neurotoxin is released by the implant in a manner and at a concentration which provides a desired therapeutic efficacy.
  • Polymeric materials can release neurotoxins due to diffusion, chemical reaction or solvent activation, as well as upon influence by magnetic, ultrasound or temperature change factors. Diffusion can be from a reservoir or matrix. Chemical control can be due to polymer degradation or cleavage of the drug from the polymer. Solvent activation can involve swelling of the polymer or an osmotic effect.
  • Implants may be prepared by mixing a desired amount of a stabilized neurotoxin into a solution of a suitable polymer dissolved in methylene chloride.
  • the solution may be prepared at room temperature.
  • the solution can then be transferred to a Petri dish and the methylene chloride evaporated in a vacuum desiccator.
  • a suitable amount of the dried neurotoxin incorporating implant is compressed at about 8000 p.s.i. for 5 seconds or at 3000 p.s.i. for 17 seconds in a mold to form implant discs encapsulating the neurotoxin.
  • the implant material used is substantially non-toxic, non- carcinogenic, and non-immunogenic.
  • Suitable implant materials include polymers, such as poly(2-hydroxy ethyl methacrylate) (p-HEMA), poly(N-vinyl pyrrolidone) (p- NVP)+, polyvinyl alcohol) (PVA), poly(acrylic acid) (PM), polydimethyl siloxanes (PDMS), ethylene-vinyl acetate (EVAc) copolymers, polyvinylpyrrolidone/methylacrylate copolymers, polymethylmethacrylate (PMMA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyanhydrides, poly(ortho esters), collagen and cellulosic derivatives and bioceramics, such as hydroxyapatite (HPA), tricalcium phosphate (TCP), and aliminocalcium phosphate (ALCAP). Lactic acid, glycolic acid and
  • An implant material can be biodegradable or bioerodible.
  • An advantage of a bioerodible implant is that it does not need to be removed from the patient.
  • a bioerodible implant can be based upon either a membrane or matrix release of the bioactive substance.
  • Biodegradable microspheres prepared from PLA-PGA are known for subcutaneous or intramuscular administration.
  • kits for practicing disclosed embodiments are also encompassed by the present disclosure.
  • the kit can comprise a 30 gauge or smaller needle and a corresponding syringe.
  • the kit can also comprise a Clostridial neurotoxin composition, such as a botulinum type E toxin composition.
  • the neurotoxin composition may be provided in the syringe.
  • the composition is injectable through the needle.
  • the kits are designed in various forms based the sizes of the syringe and the needles and the volume of the injectable composition contained therein, which in turn are based on the specific deficiencies the kits are designed to treat.
  • a 65 year-old worker is diagnosed with a rotator cuff tear. His doctor recommends arthroscopic surgery to repair the supraspinatus tendon. During surgery, 50 U of BoNT/E is injected into the supraspinatus muscle. The injection reduces mechanical loading on the supraspinatus tendon during the initial healing period. At 2 weeks post-surgery, the patient starts non-load bearing physical therapy to increase range of motion. At 4 weeks post-surgery the supraspinatus muscle recovers function and patient starts load bearing physical therapy.
  • a 35 year-old dancer is diagnosed with an Achilles tendon tear. Her doctor recommends arthroscopic surgery to reattach the Achilles tendon to the heel bone. During surgery, 300 U of BoNT/E is injected into the gastrocnemius muscle. The injection reduces mechanical loading on the Achilles tendon while the reattachment heals. At 4 weeks the patient starts physical therapy.
  • a 25 year-old athlete is diagnosed with a quadriceps tear.
  • Her doctor recommends arthroscopic surgery to reattach the quadriceps tendon to the patella.
  • 200 U of BoNT/E is injected into the quadriceps muscle. The injection reduces mechanical loading on the tendon while the reattachment heals.
  • the patient starts non-load bearing physical therapy to increase range of motion.
  • the supraspinatus muscle recovers function and patient starts load bearing physical therapy.
  • a 50 year-old construction worker is diagnosed with a proximal biceps tendon tear. His doctor recommends arthroscopic surgery to reattach the bicep tendon to the corocoid process. Following surgery, 100 of BoNT/E biceps muscle. The injection reduces mechanical loading on the tendon while the reattachment heals. At 4 weeks the patient starts physical therapy.
  • Example 5 [090] Applicants performed the first-in-human, randomized, double-blind, placebo- controlled, ascending dose cohort, Phase 2a study to evaluate safety and efficacy of a single treatment cycle of a disclosed fast-acting type E composition in subjects with glabellar frown lines. This study was conducted in compliance with this protocol and all applicable Federal and State regulations. Subsequent studies will further evaluate the safety and efficacy of EB-001 ("EB-001 " refers to a botulinum type E composition disclosed herein) in glabellar line treatment with multiple treatment cycles. EB-001 is expected to show improvement in severity of glabellar lines with fast onset of action, and with a favorable safety and tolerability profile.

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Abstract

L'invention concerne des compositions et des méthodes destinées à être utilisées conjointement à des traitements chirurgicaux de réparation de tendon. Des modes de réalisation de l'invention permettent de réduire localement l'activité musculaire et de réduire ainsi la tension, par exemple après un acte chirurgical de rattachement ou de réparation de tendon.
PCT/US2017/055773 2016-12-06 2017-10-09 Neurotoxines botuliques destinées à être utilisées dans un traitement chirurgical de réparation de tendon WO2018106339A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018195474A1 (fr) * 2017-04-21 2018-10-25 Bonti, Inc. Initiation de traitements par neurotoxines
US20200046814A1 (en) * 2017-03-22 2020-02-13 Bonti, Inc. Botulinum neurotoxins for use in therapy
EP3600385A4 (fr) * 2017-03-22 2021-04-07 Bonti, Inc. Neurotoxines de botulinum pour le traitement de lésions traumatiques

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Publication number Priority date Publication date Assignee Title
US6423319B1 (en) * 2000-10-04 2002-07-23 Allergan Sales, Inc. Methods for treating muscle injuries
US20120065143A1 (en) * 2008-10-14 2012-03-15 Dt Scimed, Llc Dose and localization of botulinum toxins in skin and muscle
US20150250724A1 (en) * 2012-09-21 2015-09-10 Kansai Medical University Educational Corporation Long-lasting, controlled-release local anesthetic liposome preparation
WO2015188944A1 (fr) * 2014-06-13 2015-12-17 Merz Pharma Gmbh & Co. Kgaa Nouvelles utilisations de neurotoxines clostridiales de recombinaison à durée d'effet réduite
US20150359721A1 (en) * 2013-01-17 2015-12-17 Jeffrey Hagel Increasing muscular volume in a human using hyaluronic acid

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6423319B1 (en) * 2000-10-04 2002-07-23 Allergan Sales, Inc. Methods for treating muscle injuries
US20120065143A1 (en) * 2008-10-14 2012-03-15 Dt Scimed, Llc Dose and localization of botulinum toxins in skin and muscle
US20150250724A1 (en) * 2012-09-21 2015-09-10 Kansai Medical University Educational Corporation Long-lasting, controlled-release local anesthetic liposome preparation
US20150359721A1 (en) * 2013-01-17 2015-12-17 Jeffrey Hagel Increasing muscular volume in a human using hyaluronic acid
WO2015188944A1 (fr) * 2014-06-13 2015-12-17 Merz Pharma Gmbh & Co. Kgaa Nouvelles utilisations de neurotoxines clostridiales de recombinaison à durée d'effet réduite

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200046814A1 (en) * 2017-03-22 2020-02-13 Bonti, Inc. Botulinum neurotoxins for use in therapy
EP3600385A4 (fr) * 2017-03-22 2021-04-07 Bonti, Inc. Neurotoxines de botulinum pour le traitement de lésions traumatiques
US11260114B2 (en) * 2017-03-22 2022-03-01 Bonti, Inc. Botulinum neurotoxins for use in therapy
WO2018195474A1 (fr) * 2017-04-21 2018-10-25 Bonti, Inc. Initiation de traitements par neurotoxines

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