WO1998024428A1 - Anesthesiques locaux a effet de longue duree - Google Patents

Anesthesiques locaux a effet de longue duree Download PDF

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Publication number
WO1998024428A1
WO1998024428A1 PCT/US1997/021855 US9721855W WO9824428A1 WO 1998024428 A1 WO1998024428 A1 WO 1998024428A1 US 9721855 W US9721855 W US 9721855W WO 9824428 A1 WO9824428 A1 WO 9824428A1
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Prior art keywords
pain
tetracaine
composition
butyl
pharmaceutically acceptable
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PCT/US1997/021855
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English (en)
Inventor
Ging Kuo Wang
Wai Man Mok
Johann Georg Thalhammer
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Brigham & Women's Hospital, Inc.
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Publication of WO1998024428A1 publication Critical patent/WO1998024428A1/fr

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine

Definitions

  • This invention relates to methods for the treatment of pain and, in particular, to the alleviation of chronic pain and its varieties, e.g., neuropathic pain, and acute persistent pain by administration of an N-butyl tetracaine and/or an N- ⁇ -phenylethyl lidocaine.
  • chronic pain is associated with a known tissue pathology (e.g., cancer pain, arthritic pain) and may be associated with inflammation of an injured body tissue (e.g., surgery).
  • Neuropathic pain is thought to be a consequence of damage to peripheral nerves or to regions of the central nervous system. Neuropathic pain frequently occurs as a form of chronic pain, although neuropathic pain also can present as an acute pain.
  • Pain relief research during the last two decades has focused on the identification of new local anesthetics to produce analgesia of long duration with minimal impairment of autonomic function and low toxicity.
  • each of these local anesthetics also is highly cardiotoxic.
  • the development of alternative "long-acting" local anesthetics has met with limited success.
  • Pain relief research also has focussed on the identification of new neurolytic agents for the treatment of chronic pain and intractable cancer pain.
  • spinal opiate administration, surgical intervention, or both have been used to alleviate chronic and intractable cancer pain.
  • phenol or absolute alcohol reportedly have been used as neurolytic agents to destroy the pathogenic nerve regions that are responsible for pain manifestation.
  • these agents exert only weak local anesthetic effects and, accordingly, have been difficult to administer to alert patients without inducing additional pain.
  • a long-acting local anesthetic with a neurolytic activity has not been available for the treatment of chronic and intractable cancer pain.
  • the invention involves in one respect the discovery of two novel long-acting local anesthetics that are useful for pain management: an N-butyl tetracaine and a N- ⁇ -phenyl ethyl lidocaine.
  • the methods for preparing the preferred compounds of the invention are provided in the Examples and are summarized below.
  • These anesthetics exhibit unexpectedly improved analgesic properties compared to related compounds that previously have been used for pain management.
  • the anesthetics disclosed herein act by blocking voltage-gated sodium channels and inhibiting the propagation of action potentials in excitable membranes.
  • neurolytic compounds with strong local anesthetic properties such as N-butyl tetracaine described herein, are advantageous over the existing compounds for pain management because conventional neurolytic agents typically exert only weak local anesthetic effects or none at all.
  • a "neurolytic agent” refers to a chemical that is capable of irreversibly damaging the axonal membranes, i.e., these agents are locally neurotoxic;
  • a "local anesthetic” refers to a chemical that is capable of inhibiting the propagation of action potentials in excitable membranes.
  • N-butyl tetracaine is a long-acting anesthetic that also displays neurolytic properties at concentrations ⁇ 1%.
  • a composition containing an N-butyl tetracaine is provided.
  • the preferred N-butyl tetracaine derivative is illustrated in Figure 1.
  • the composition further includes a pharmaceutically acceptable carrier and the N-butyl tetracaine is present in the composition in a therapeutically effective amount.
  • a therapeutically effective amount is that amount necessary to alleviate pain in a subject.
  • the pharmaceutically acceptable carrier is a pharmaceutically acceptable topical or intrathecal carrier.
  • the pharmaceutically acceptable carrier is a topical or intrathecal carrier that is not suitable for oral delivery to the subject.
  • a composition containing N- ⁇ - phenylethyl lidocaine (also referred to herein as a "tonicaine”) is provided.
  • the preferred tonicaine is illustrated in Figure 2.
  • the composition further includes a pharmaceutically acceptable carrier and the tonicaine is present in the composition in a therapeutically effective amount.
  • the pharmaceutically acceptable carrier is a pharmaceutically acceptable topical or intrathecal carrier.
  • the pharmaceutically acceptable carrier is a topical or intrathecal carrier that is not suitable for oral delivery to the subject.
  • a method for alleviating pain e.g., a localized pain
  • the method involves administering to the subject a therapeutically effective amount of the above-described N-butyl tetracaine and/or the above- described tonicaine, alone or together with another therapeutically useful ingredient.
  • the subject is a mammal that is either exhibiting pain or is about to be subjected to a pain-causing event.
  • the subject to whom the compounds of the invention are administered is diagnosed as having a localized pain that is attributable to a condition selected from the group consisting of phantom pain, rheumatoid arthritis or osteoarthritis, post-operative analgesia, intractable cancer pain, chronic pain, shingles, and painful diabetic neuropathy.
  • the method for alleviating pain is used to treat a subject who is diagnosed as having localized pain that is a nociceptor-mediated pain.
  • the method of this invention can be applied to alleviate chronic pain (e.g., chronic neuropathic) as well as to alleviate acute pain (e.g., inflammatory pain resulting from surgery, injuries, bronchial asthma, and so forth).
  • the method of the invention can be applied to the treatment of pain that is associated with a skin condition such as psoriasis, seborrheic dermatitis and eczema, and shingles (Herpes zoster).
  • novel intermediate compounds used in the preparation of the above-described compounds of the invention and the methods for making and using these intermediate compounds to formulate the above-described compounds of the invention are provided.
  • the intermediates and related methods for making and using such compounds are provided in the Examples.
  • a method for making a medicament for alleviating pain is provided. The method involves placing at least one of the above-identified compounds of the invention is a pharmaceutically acceptable carrier.
  • Figure 1 shows the chemical formula for the preferred N-butyl tetracaine compound of the invention.
  • Figure 2 shows the chemical structure for the preferred N- ⁇ -phenyl ethyl lidocaine compound of the invention.
  • FIG. 3 shows the chemical structure of tetracaine and its derivatives.
  • the present invention in one aspect involves the discovery of two novel long-acting local anesthetics for pain management: an N-butyl tetracaine and an N- ⁇ -phenylethyl lidocaine.
  • an N-butyl tetracaine and an N- ⁇ -phenylethyl lidocaine.
  • the in vitro and in vivo activities of the compounds of the invention are significantly greater than the activities of the base compounds, tetracaine and lidocaine.
  • the potency of the compounds of the invention in blocking sodium channels is vastly improved over the local anesthetics that are known in the art.
  • Applicants' discovery represents the first identification of compounds which exhibit both local anesthetic and neurolytic properties.
  • the results presented herein demonstrate that the novel compounds disclosed herein elicit sensory and motor block properties that are vastly improved compared to the properties of the existing local anesthetics. Accordingly, it is believed that the compounds of the invention are particularly useful for alleviating chronic and intractable cancer pain, phantom pain, rheumatoid arthritis, bronchial asthma, shingles, and various neuropathic pain.
  • the compounds of the invention are believed to be useful for alleviating topical pain that is, for example, associated with a skin condition such as psoriasis, seborrheic dermatitis, eczema, shingles, and post-operative pain.
  • a composition including an N-butyl tetracaine is provided.
  • the composition further includes a pharmaceutically acceptable carrier and the N-butyl tetracaine is present in the composition in a therapeutically effective amount.
  • an "N-butyl tetracaine” refers to the compound having the chemical structure shown in Figure 1.
  • the N-butyl tetracaines of the invention include the particularly preferred N- butyl tetracaine (also referred to as an N-butyl tetracaine quaternary ammonium bromide) shown in Figure 1, as well as derivatives of this N-butyl tetracaine chemical structure.
  • N- butyl tetracaine derivatives include N-pentyl and N-hexyl tetracaine (i.e., N-pentyl and N-hexyl groups are substituted for the N-butyl group attached to the quaternary ammonium nitrogen), as well as other amphipathic tetracaine derivatives such as N- ⁇ -phenyl ethyl tetracaine (i.e., a phenyl ethyl group is substituted for the N-butyl group attached to the quaternary ammonium nitrogen).
  • N-pentyl and N-hexyl tetracaine i.e., N-pentyl and N-hexyl groups are substituted for the N-butyl group attached to the quaternary ammonium nitrogen
  • other amphipathic tetracaine derivatives such as N- ⁇ -phenyl ethyl tetracaine (i.e., a phen
  • N-butyl groups that can be substituted for this N-butyl include: an alkyl, aryl or cyclic functional group containing from four to twelve carbon atoms (e.g., heptyl-, octyl-, nonyl-, decyl-, aryl-, cyclopentyl-, cyclohexyl-, propylphenyl-, butyl-phenyl-, hexylphenyl-), provided that the derivative compound is amphipathic.
  • the foregoing chemical terms have their common meaning known to one of ordinary skill in the art.
  • the above-noted functional groups that can be used in place of N-butyl can be saturated or unsaturated, straight-chained or branched.
  • one or more hydrogen atoms of the functional group can be replaced by a substituent group, such as a chloride, an amino group or a thio group.
  • the particularly preferred N-butyl tetracaine is a quaternary ammonium salt that has been synthesized from a tetracaine base (Sigma chemical company, St. Louis, MO) and 1-bromo butane (Aldrich, Milwaukee, WI) in accordance with the procedure provided in the Example (see, also, Wang, G. K. et al., Biophys. J. 67:1851-1860 (1994)).
  • tetracaine base Sigma chemical company, St. Louis, MO
  • 1-bromo butane Aldrich, Milwaukee, WI
  • other salts of this compound and other N-butyl tetracaines alternatively can be used for practicing the invention.
  • chloride, phosphate, sulfate, citrate, and acetate salts can be used.
  • bromide is the counter ion for this positively charged quaternary ammonium compound.
  • N-butyl tetracaine at 37 mM elicited prolonged sciatic nerve block of the withdrawal response to noxious pinch in rats for more than two weeks with this withdrawal response being fully restored after nine weeks. Motor functions of the hind legs were similarly blocked by injection of this N-butyl tetracaine. Morphological examinations at three and five weeks after a single injection of this drug revealed degeneration of many sciatic nerve fibers and were consistent with the results of the functional tests.
  • the results of the Example demonstrate that N-butyl tetracaine exhibits the requisite local anesthetic and neurolytic properties to render this agent particularly useful as a long-acting local anesthetic for pain management in humans.
  • the results demonstrate that N-butyl tetracaine is a potent sodium channel blocker in vitro and produced strong tonic and use-dependent inhibition of sodium channels in vitro.
  • the animal model used in the Example is illustrative of an early stage of neuropathic pain and is, in particular, predictive of neuropathic and chronic pain in humans.
  • the results obtained using this animal model demonstrate that the nociceptive functions of rat sciatic nerves were completely blocked for 14 days following injection of 37 mM N-butyl tetracaine with full functional recovery occurring after 60 days. Since similar symptoms occur in humans months and years after the original injury, these animal model experiments also are predictive of chronic pain conditions and can be used to predict the efficacy of the compounds of the invention in alleviating chronic as well as acute pain in humans.
  • N-butyl tetracaine for pain management in the central nervous system, where myelinated nerve fibers do not regenerate to the extent documented in the peripheral nervous system.
  • N-butyl tetracaine can relieve pain in the central nervous system for as long as phenol or absolute alcohol and that N-butyl tetracaine appears to display significantly stronger local anesthetic properties in vivo compared to these conventional drugs.
  • intrathecal delivery of N-butyl tetracaine is not accompanied by the sharp burning sensation associated with intrathecal delivery of conventional agents such as phenol or alcohol.
  • a composition containing a therapeutically effective amount of N-butyl tetracaine in a pharmaceutically acceptable intrathecal carrier represents a particularly preferred aspect of the invention.
  • an alternative long-acting local anesthetic namely, N- ⁇ -phenyl ethyl lidocaine
  • the composition further includes a pharmaceutically acceptable carrier and the tonicaine is present in the composition in a therapeutically effective amount.
  • a "tonicaine” refers to the compound having the chemical structure shown in Figure 2.
  • the tonicaines of the invention include the particularly preferred tonicaine (also referred to as N- ⁇ -phenyl ethyl lidocaine quaternary ammonium bromide) shown in Figure 2, as well as derivatives of this tonicaine chemical structure.
  • Exemplary tonicaine derivatives include N- ⁇ -aminophenyl ethyl lidocaine and N- ⁇ - chlorophenyl ethyl lidocaine and other amphipathic derivatives such as N-hexyl lidocaine.
  • phenylethyl group examples include: an alkyl, aryl or cyclic functional group containing from four to twelve carbon atoms (e.g., heptyl-, octyl-, nonyl-, decyl-, aryl-, cyclopentyl-, cyclohexyl-, propylphenyl-, butyl-phenyl-, hexylphenyl-), provided that the derivative compound is amphipathic.
  • the above-noted functional groups that can be used in place of the N- ⁇ -phenyl ethyl group can be saturated or unsaturated, straight-chained or branched.
  • one or more hydrogen atoms of the functional group can be replaced by a substituent group, such as a chloride, an amino group or a thio group.
  • the preferred tonicaine has the chemical structure shown in Figure 2.
  • the method for synthesizing this tonicaine is provided in the Example. (See, also, Wang, G. K., et al.,
  • this preferred tonicaine was synthesized from lidocaine (base) and (2-bromo ethyl) benzene.
  • various counter ions e.g., phosphate, sulfate, citrate, acetate and so forth
  • phosphate, sulfate, citrate, acetate and so forth can be used in place of bromide for synthesizing this compound.
  • GH 3 cells was tested in vitro under whole-cell voltage clamp conditions. Neurologic evaluations of sciatic nerve block of sensory and motor functions in vivo for tonicaine also were determined in rats. The results demonstrate that tonicaine is a potent sodium channel blocker in vitro and that tonicaine produced both tonic and use-dependent blocks of sodium currents that were significantly greater than the corresponding effects induced by the underivatized lidocaine base compound. In vivo, tonicaine elicited a prolonged and complete sciatic nerve block of motor function with a withdrawal response to noxious pinch that was significantly greater than that of the corresponding lidocaine base compound.
  • tonicaine achieved complete sciatic neural blockade for more than three hours with sensory blockage being prolonged to a greater extent than the motor blockade.
  • compositions of the invention are useful for alleviating pain in a subject.
  • "alleviating pain” refers to treating a subject so as to remove existing pain as well as to suppress or inhibit pain which would otherwise ensue from a pain-causing event.
  • the above-described compounds of the invention are administered in therapeutically effective amounts.
  • a therapeutically effective amount means that amount necessary to delay the onset of, inhibit the progression of , or halt altogether the particular condition being treated.
  • the method of this invention can be applied to the treatment of chronic (e.g., neuropathic) pain as well as the acute pain (e.g., inflammatory pain) that can occur following trauma to body tissues, e.g., surgery, injury and so forth.
  • the condition being treated is a localized pain that is associated with, for example, postoperative analgesia, intractable cancer pain, chronic pain, bronchial asthma, shingles, phantom pain, rheumatoid arthritis, and painful diabetic neuropathy.
  • localized pain or “local pain” refers to sensory processes signaling tissue injury (nociceptor).
  • the compounds of the invention are administered to a subject who is diagnosed as having a localized pain that is a nociceptor-mediated pain.
  • Exemplary conditions that are manifested by a nociceptor-mediated pain include cutaneous, deep somatic or visceral pain.
  • a therapeutically amount of the compounds of the invention will vary with the subject's age, condition, and sex, as well as the nature and extent of the disease in the subject, all of which can be determined by one of ordinary skill in the art.
  • the dosage may be adjusted by the individual physician or veterinarian, particularly in the event of any complication.
  • a therapeutically effective amount typically varies from 0.01 mg/kg to about 1000 mg/kg, preferably from about 0.1 mg/kg to about 200 mg/kg and most preferably from about 0.2 mg/kg to about 20 mg/kg, in one or more dose administrations daily, for one or more days.
  • the therapeutics of the invention are "nontoxic", i.e., the therapeutics have been approved by the United States Food and Drug Administration (“FDA") for administration to humans or, in keeping with established criteria, are susceptible to approval by the FDA for administration to humans.
  • FDA United States Food and Drug Administration
  • the therapeutics of the invention can be administered to a patient immediately before the patient is subjected or exposed to a pain-causing event (i.e., as preemptive analgesia), or while the patient is experiencing pain.
  • the therapeutics of the invention can be administered by any conventional route, including injection, gradual infusion over time, infiltration anesthesia, regional anesthesia, or spinal anesthesia.
  • the administration may, for example, be oral, intravenous, intraperitoneal, intramuscular, intra cavity, subcutaneous, or transdermal.
  • the compounds of the invention are administered in a pharmaceutically acceptable topical carrier or a pharmaceutically acceptable intrathecal carrier.
  • pharmaceutically acceptable carriers include components which will not significantly impair the biological properties of the compounds of the invention.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, R nger's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like.
  • the compounds of the invention alternatively can be delivered using controlled release drug delivery systems. Preferably such systems are biodegradable and bioerodible. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • the compounds of the invention may also be used in combination with other therapeutic agents, for example, bronchodilators or anti-inflammatory agents.
  • the therapeutics of the invention are sterile preparations and can be sterilized, for example, by gamma irradiation.
  • the preferred pharmaceutical composition is contained in an implant that is suitable for implantation into the mammalian recipient.
  • implant that is suitable for implantation into the mammalian recipient.
  • Exemplary bioerodible implants that are useful in accordance with this method are described in PCT International application no. PCT/US/03307 (Publication No. WO 95/24929, entitled “Polymeric Gene Delivery System", claiming priority to U.S. patent application serial no. 213,668, filed March 15, 1994).
  • PCT/US/03307 describes a biocompatible, preferably biodegradable polymeric matrix for sustained release of an exogenous agent in the patient.
  • the compositions described herein are encapsulated or dispersed within the biocompatable, preferably biodegradable polymeric matrix disclosed in PCT/US/03307.
  • the polymeric matrix preferably is in the form of a micro particle such as a micro sphere (wherein the composition is dispersed throughout a solid polymeric matrix) or a microcapsule (wherein the composition is stored in the core of a polymeric shell).
  • Other forms of the polymeric matrix for containing the composition include films, coatings, gels, implants, and stents.
  • the size and composition of the polymeric matrix device is selected to result in favorable release kinetics in the tissue into which the matrix device is implanted.
  • the size of the polymeric matrix devise further is selected according to the method of delivery which is to be used, typically injection into a tissue or administration of a suspension by aerosol into the nasal and/or pulmonary areas.
  • the polymeric matrix composition can be selected to have both favorable degradation rates and also to be formed of a material which is bioadhesive, to further increase the effectiveness of transfer when the devise is administered to a mucosal or other surface.
  • the matrix composition also can be selected not to degrade, but rather, to release by diffusion over an extended period of time.
  • Both non-biodegradable and biodegradable polymeric matrices can be used to deliver the compositions of the invention to the subject.
  • Biodegradable matrices are preferred.
  • Such polymers may be natural or synthetic polymers. Synthetic polymers are preferred.
  • the polymer is selected based on the period of time over which release is desired, generally in the order of a few hours to a year or longer. Typically, release over a period ranging from between a few hours and three to twelve months is most desirable.
  • the polymer optionally is in the form of a hydrogel that can absorb up to about 90% of its weight in water and further, optionally is cross- linked with multi-valent ions or other polymers.
  • compositions of the invention are delivered using the bioerodible implant by way of diffusion, or more preferably, by degradation of the polymeric matrix.
  • exemplary synthetic polymers which can be used to form the biodegradable delivery system include: polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, poly-vinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate,
  • biodegradable polymers include synthetic polymers such as polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butic acid), poly(valeric acid), and poly(lactide-cocaprolactone), and natural polymers such as alginate and other polysaccharides including dextran and cellulose, collagen, chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins, copolymers and mixtures thereof. In general, these materials degrade either by enzymatic hydrolysis or exposure to water in vivo, by surface or bulk erosion.
  • Bioadhesive polymers of particular interest include bioerodible hydrogels described by H.S. Sawhney, C.P. Pathak and J.A. Hubell in Macromolecules. 1993, 26, 581-587, the teachings of which are incorporated herein, polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
  • the invention provides a composition of the above-described therapeutic agents for use as a
  • compositions of the invention are to be used to alleviate epidural or intrathecal pain
  • injection or administration of the compositions through a catheter is the most simple mode of administration.
  • the compounds of the invention can be administered, for example, in an aqueous medium, such as an isotonic solution, or in a non-aqueous medium, such as glycerol or an oil.
  • the compounds of the invention can be administered as an injectable suspension to achieve a more prolonged effect.
  • the preferred medium for intrathecal injection is isotonic dextrose.
  • Other exemplary pharmaceutically acceptable intrathecal carriers include hypobaric (e.g., 50% normal saline) and hyperbaric (e.g., 5-8% glucose) solutions.
  • the compounds of the invention are present in an intrathecal formulation in an amount ranging from about 0.1% to about 10%) by weight, based upon the total weight of the composition.
  • the compounds of the invention are present in an amount ranging from about 0.25% to about 2.5% by weight and, most preferably, the compounds are present in an amount ranging from about 0.5% to about 1% by weight.
  • compositions of the invention When the compositions of the invention are to be used to alleviate a topical pain, the compounds can be administered as a pure dry chemical (e.g., by inhalation of a fine powder via an insufflator) or, more preferably, as a pharmaceutical composition further including a pharmaceutically acceptable topical carrier.
  • the pharmaceutical compositions of the invention include those suitable for administration by inhalation or insufflation or for nasal, intraocular or other topical (including buccal and sub-lingual) administration.
  • the compounds of the invention can be delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray.
  • the compounds of the invention can be delivered as a dry powder composition containing, for example, the pure compound together with a suitable powder base (e.g., lactose, starch).
  • the compounds of the invention can be administered via nose drops, a liquid spray, such as via a plastic bottle atomizer or metered-dose inhaler.
  • a liquid spray such as via a plastic bottle atomizer or metered-dose inhaler.
  • Exemplary atomizers are known to those of ordinary skill in the art.
  • Drops, such as eye drops or nose drops can be formulated with an aqueous or non-aqueous base which optionally further includes one or more dispersing agents, solubihzing agents or suspending agents. Apparatus and methods for delivering liquid sprays and/or drops are well known to those of ordinary skill in the art.
  • the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch or intraocular insert or iontophoresis.
  • ointments and creams can be formulated with an aqueous or oily base alone or together with suitable thickening and/or gelling agents.
  • Lotions can be formulated with an aqueous or oily base and, typically, further include one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. (See, e.g., U.S.
  • the compounds of the invention are present in a topical formulation in an amount ranging from about 0.01% to about 30.0% by weight, based upon the total weight of the composition.
  • the compounds of the invention are present in an amount ranging from about 0.5 to about 30% by weight and, most preferably, the compounds are present in an amount ranging from about 0.5 to about 10% by weight.
  • the compositions of the invention comprise a gel mixture to maximize contact with the surface of the localized pain and minimize the volume and dosage necessary to alleviate the localized pain.
  • GELFOAM ® (a methylcellulose-based gel manufactured by Upjohn Corporation) is a preferred pharmaceutically acceptable topical carrier.
  • Other pharmaceutically acceptable carriers include iontophoresis for transdermal drug delivery.
  • the compounds of the invention are formulated in a composition to alleviate pain in the oral cavity.
  • An exemplary pharmaceutically acceptable topical carrier for the sustained release of a pain relieving substance in the oral cavity is a polyvinyl alcohol matrix such as that described in U.S. 5,520,924, entitled “Methods and articles for administering drug to the oral cavity", issued to Chapman, R., et al.
  • Alternative formulations suitable for topical administration in the mouth or throat include lozenges comprising the compound(s) of the invention in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the compound(s) in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • lozenges comprising the compound(s) of the invention in a flavored base, usually sucrose and acacia or tragacanth
  • pastilles comprising the compound(s) in an inert base such as gelatin and glycerin or sucrose and acacia
  • mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • suitable carriers for delivery to the oral cavity or other topical surface and/or for the sustained release of a pain alleviating compound are l ⁇ iown to one of ordinary skill in the art.
  • N-butyl tetracaine and tonicaine compounds of the invention can be administered in accordance with known methods for administering the base compounds tetracaine and lidocaine, respectively.
  • exemplary pharmaceutically acceptable carriers and modes of administration for administering the tetracaine and/or the lidocaine base compounds to a subject are described in at least the following United States patents: U.S. 5,502,058 (entitled “Method for the treatment of pain", issued to Mayer, D., et al.); U.S.
  • DMSO dimethylsulfoxide
  • Batrachotoxin Batrachotoxin
  • Lidocaine base was purchased from Sigma Chemical Co. (St. Louis, MO); 1- bromododecane and (2-bromoethyl) benzene were from Aldrich, Chemical Company, Inc. (Milwaukee, WI).
  • QX-314 chloride was donated by Astra Pharmaceutical Products (Worcester,
  • Silica gel G was obtained from Brinkmann Instruments, Inc. (Westbury, NY). All chemicals were reagent grade from commercial sources.
  • a 1 :2 molar ratio of tetracaine base and 1-bromobutane (Aldrich, Milwaukee. WI) was mixed in 15 ml of absolute ethanol and refiuxed at 85 °C for 30 h. The reaction was stopped and excess ethanol was evaporated. The jelly-like residue was washed several times with warm hexane to remove the remaining starting reactants, and the product was dried under a vacuum.
  • N-butyl tetracaine QA was -90%, and the product was >97% pure was judged with a thin layer chromatography system.
  • N-Butyl tetracaine QA was dissolved in DMSO at 100 mM as a stock solution.
  • the chemical structures of tetracaine and its derivatives are shown in Figure
  • the conventional method for QA synthesis was used to modify the lidocaine structure.
  • Tonicaine was synthesized from lidocaine (base) and (2-bromoethyl) benzene. A 2:1 molar ratio of lidocaine and (2-bromoethyl) benzene were refiuxed at 80-90°C in absolute ethanol for 5 days.
  • N- ⁇ -phenylethyl lidocaine bromide diethyl-(2,6-dimethylanilinocarbonyl) methyl- ⁇ -phenylethyl ammonium bromide
  • the mobile phases were chloroform/ethyl acetate (13/1, vol/vol) followed by chloroform/ethanol (80/20, vol/vol). Tonicaine was eluted in the chloroform/ethanol.
  • N-dodecyl lidocaine was synthesized from lidocaine (base) and 1 -bromododecane by the method similar to that for tonicaine synthesis (see above). The product was >98% pure as judged by thin layer chromatography systems. Structural analysis of N-dodecyl lidocaine QA by mass spectrometry yielded a molecular mass of 403.2, which agreed with the structure of N-dodecyl lidocaine.
  • Nociception was evaluated by measurement of the different degree of the withdrawal response to noxious pinch. Care was taken to avoid tissue injury resulting in hyperalgesia by properly spacing the stimulations.
  • the fifth toe was pinched (to 300 g) with a force-calibrated serrated forceps for 2 s, and the withdrawal response was graded as 4 (normal, brisk, generalized motor reaction; withdrawal of the stimulated hind limb; attempts to bite the forceps; and vocalization); 3 (the same as 4, but slower than on the control side); 2 (the same as 3, but with one of the responses lacking); 1 (only a weak attempt to withdraw); or 0 (no response). Morphologic Changes in Treated Sciatic Nerves
  • Rat clonal pituitary GH 3 cells were purchased from the American Type Culture Collection (Rockville, MD) and maintained as described by Cota and Armstrong (Cota G. Et al., J Gen Physiol 1989; 94:213-32) in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (Hyclone Labs, Logan, UT). For Na + current recording, cells were grown in a 35 -mm culture dish, which was then used as a recording chamber.
  • the whole-cell variant of the patch-clamp method was used to measure Na + currents in rat clonal GH 3 cells (Cota G. Et al., J Gen Physiol 1989; 94:213-32).
  • the external solution contained 150 mM choline Cl, 0.2 mM CdCl 2 , 2 mM CaCl 2 , and 10 mM hydroxyethylpiperazine-ethane sulfonic acid adjusted to pH 7.4 with tetramethylammonium hydroxide.
  • Micropipettes were fabricated and had a tip resistance of ⁇ 1 M ⁇ when filled with an Na + solution containing 100 mM NaF, 300 mM NaCl, 10 mM EGTA, and 10 mM hydroxyethylpiperazine-ethane sulfonic acid adjusted to pH 7.2 with CsOH.
  • the junction potential of electrodes was nulled before seal formation. After the patch membrane ruptured, the cell was allowed to equilibrate with the pipette solution for at least 15 min at a holding potential of -100 mV.
  • Tetracaine and N-butyl tetracaine QA at appropriate concentrations were applied to cells with a flow rate of about 0.12 ml/min through a series of narrow-bored capillary tubes positioned within 200 ⁇ m of the cell (Wang GK et al, ANESTHESIOLOGY 1995; 83:1293- 1301). Washout of drugs was performed using a tube containing the external solution without drug. Voltage clamp protocols were created with pClamp software (Axon Instruments, Foster City, CA). Leak and capacitance were subtracted by a leak and capacitance compensator, as described by Hille and Campbell (Hille B et al., J Gen Physiol 1976; 67:265-93).
  • Typical tertiary amine LAs including tetracaine, block voltage-gated Na + channels in a complicated manner. Generally they elicit tonic inhibition of Na + currents when the nerve is stimulated infrequently (Butterworth JF et al., ANESTHESIOLOGY 1990; 72:71 1-34). We observed show the tonic inhibition of Na + currents by N-butyl tetracaine and tetracaine, respectively.
  • the rapid wash-in tetracaine block at 100 ⁇ M was characteristic of tertiary amine LAs. Within 1 to 2 min, the block reached its steady-state level of about 80% of the control current. The wash-off of tetracaine was equally rapid, reaching its completion within 2 min.
  • N- butyl tetracaine at 100 ⁇ M had a significantly slower wash-in effect than did tetracaine (P ⁇ 0.0001); an interval of more than 20 min was required to reach the steady-state block of up to 80% to 90% of Na + current. The drug's wash-off effect was also very slow. After 30 min of continuous perfusion of drug-free solution, about 40%> of Na + current remained blocked. This wash-out time course of N-butyl tetracaine was significantly longer than that for tetracaine (P ⁇ 0.0001).
  • N-butyl tetracaine For N-butyl tetracaine, a concentration of 100 ⁇ M is used because of its slow wash-in time course. Use-dependent block by this drug significantly exceeded the control value as early as 5 min after application (PO.0001). Between 20 and 30 min, only about 20% of the peak Na + current remains. However, approximately 50% of this remaining current is blocked after repetitive pulses. The rate of use-dependent block for N-butyl tetracaine is significantly slower than that for tetracaine (P ⁇ 0.0001). A similar rate difference has been found for tonicaine (a QA derivative of lidocaine) and for lidocaine (Wang GK et al., ANESTHESIOLOGY 1995; 83:1293-1301). Clearly, N-butyl tetracaine QA retains the ability of its parent compound, tetracaine, to elicit tonic and use-dependent block.
  • N-butyl tetracaine possesses strong neurolytic properties that elicit prolonged block of the sciatic nerve functions.
  • Quaternary Ammonium N-butyl tetracaine QA exhibits not only neurolytic but also LA characteristics. It blocks voltage-gated Na + channels effectively when applied externally to GH 3 cells in vivo.
  • this drug produces profound tonic block of Na + current by more than 80%. Only 0.21% of the concentration is used in experiments conducted in vitro (37 mM versus 100 ⁇ M).
  • the wash-in of this drug is relatively slow; it takes more than 30 min to reach steady state. The wash-out is equally slow; again, at least 30 min is required for partial removal of the block. These slow kinetics are to be expected because this compound has a permanent positive charge.
  • tetracaine as a tertiary amine drug, can penetrate the membrane barrier rapidly and complete is blocking effect within 2 min. Similarly, tetracaine can be washed out of the cell within 2 to 5 min.
  • N-butyl tetracaine elicits profound use-dependent block of Na + current at 2Hz. This is not surprising because QA compounds produce use-dependent block in the same manner as their tertiary amine LA counterparts (Strichartz GR, J Gen Physiol 1973; 62:37-57). Without repetitive pulses, closed Na + channels may not be able to interact with N- butyl tetracaine efficiently. For example, after 5 min of wash-in, the first single pulse elicits about 65% block of Na + current, whereas the tenth pulse elicits about 50% block (with pulses applied every 30 mins).
  • N-butyl tetracaine QA at low concentrations (100 ⁇ M) is an LA that, like typical tertiary amine LAs, elicits both tonic and use-dependent block of Na + currents.
  • N-Butyl Tetracaine Quaternary Ammonium as a Dual Local Anesthetic and Neurolytic Agent Our results show that the nociceptive functions of rat sciatic nerves are completely blocked for 14 days by 37 mM N-butyl tetracaine and that full functional recovery occurs after 60 days.
  • N-butyl tetracaine may be used intrathecally as a neurolytic agent to substitute for currently used drugs such as phenol and absolute alcohol.
  • N-butyl tetracaine may relieve pain in the central nervous system for as long as phenol or absolute alcohol; in addition, it may display much stronger LA properties in vivo than these currently available drugs.
  • N-butyl tetracaine Treatment with N-butyl tetracaine may also prove less distressing to patients than intrathecal injection of alcohols, which causes burning sharp pain. Such burning pain, usually lasting for several hours after alcohol injection, will not be a potential problem for N-butyl tetracaine injection because of its strong and fast LA effect.

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Abstract

L'invention porte sur des compositions contenant de la N-butyle tétracaïne et/ou de la N-β-phényléthyle lidocaïne servant à calmer la douleur, due par exemple à une analgésie post-opératoire ou à un cancer incurable ou à une douleur chronique. Les méthodes et composition selon l'invention s'avèrent particulièrement utiles pour le traitement de douleurs localisées par exemple induites par le nocicepteur. Les composés selon la présente invention possèdent une activité anesthésique de longue durée et la N-butyle tétracaïne possède également une activité neurolytique.
PCT/US1997/021855 1996-12-02 1997-11-26 Anesthesiques locaux a effet de longue duree WO1998024428A1 (fr)

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EP1182193A1 (fr) * 1999-04-09 2002-02-27 Mochida Pharmaceutical Co., Ltd. Remedes pour douleurs neurogenes
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EP2446903A3 (fr) * 2006-11-20 2012-11-14 President and Fellows of Harvard College Procédés, compositions et kits de traitement de la douleur et du prurit
US8337883B2 (en) 2006-11-03 2012-12-25 Durect Corporation Transdermal delivery systems
RU2563837C1 (ru) * 2014-09-16 2015-09-20 Федеральное государственное бюджетное учреждение "Российский онкологический научный центр имени Н.Н. Блохина" Российской академии медицинских наук (ФГБУ "РОНЦ им. Н.Н. Блохина" РАМН) Способ мультимодального безопиоидного послеоперационного обезболивания у больных с опухолями головы и шеи
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US10927096B2 (en) 2019-03-11 2021-02-23 Nocion Therapeutics, Inc. Ester substituted ion channel blockers and methods for use
US10934263B2 (en) 2019-03-11 2021-03-02 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10933055B1 (en) 2019-11-06 2021-03-02 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10968179B2 (en) 2019-03-11 2021-04-06 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
WO2021087113A1 (fr) * 2019-10-30 2021-05-06 Children's Medical Center Corporation Anesthésiques locaux avec blocage nerveux sensoriel sélectif
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WO1999063985A1 (fr) * 1998-06-09 1999-12-16 Nortran Pharmaceuticals, Inc. Compositions et procedes antitussifs
EP1182193A1 (fr) * 1999-04-09 2002-02-27 Mochida Pharmaceutical Co., Ltd. Remedes pour douleurs neurogenes
EP1182193A4 (fr) * 1999-04-09 2002-09-11 Mochida Pharm Co Ltd Remedes pour douleurs neurogenes
US6642257B2 (en) 1999-04-09 2003-11-04 Mochida Pharmaceutical Co., Ltd. Agents for treating neuropathic pain
US8337883B2 (en) 2006-11-03 2012-12-25 Durect Corporation Transdermal delivery systems
US8956644B2 (en) 2006-11-03 2015-02-17 Durect Corporation Transdermal delivery systems
EP2446903A3 (fr) * 2006-11-20 2012-11-14 President and Fellows of Harvard College Procédés, compositions et kits de traitement de la douleur et du prurit
US9603817B2 (en) 2006-11-20 2017-03-28 President And Fellows Of Harvard College Methods, compositions, and kits for treating pain and pruritis
US10179116B2 (en) 2006-11-20 2019-01-15 President And Fellows Of Harvard College Methods, compositions, and kits for treating pain and pruritis
US10729664B2 (en) 2009-07-10 2020-08-04 President And Fellows Of Harvard College Permanently charged sodium and calcium channel blockers as anti-inflammatory agents
US8865741B2 (en) * 2011-02-18 2014-10-21 Asana Biosciences, Llc Aminoindane compounds and use thereof in treating pain
US20120214809A1 (en) * 2011-02-18 2012-08-23 Scott Kevin Thompson Aminoindane Compounds and Use Thereof in Treating Pain
RU2563837C1 (ru) * 2014-09-16 2015-09-20 Федеральное государственное бюджетное учреждение "Российский онкологический научный центр имени Н.Н. Блохина" Российской академии медицинских наук (ФГБУ "РОНЦ им. Н.Н. Блохина" РАМН) Способ мультимодального безопиоидного послеоперационного обезболивания у больных с опухолями головы и шеи
US11021443B2 (en) 2015-08-03 2021-06-01 President And Fellows Of Harvard College Charged ion channel blockers and methods for use
EP3331609A4 (fr) * 2015-08-03 2019-03-27 President and Fellows of Harvard College Bloqueurs de canal d'ions chargés et procédés d'utilisation
AU2016301282B2 (en) * 2015-08-03 2022-03-17 Children's Medical Center Corporation Charged ion channel blockers and methods for use
JP2018530518A (ja) * 2015-08-03 2018-10-18 プレジデント アンド フェローズ オブ ハーバード カレッジ 荷電イオンチャネル遮断薬及び使用方法
US10934263B2 (en) 2019-03-11 2021-03-02 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10828287B2 (en) 2019-03-11 2020-11-10 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10927096B2 (en) 2019-03-11 2021-02-23 Nocion Therapeutics, Inc. Ester substituted ion channel blockers and methods for use
US11512058B2 (en) 2019-03-11 2022-11-29 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11643404B2 (en) 2019-03-11 2023-05-09 Nocion Therapeutics, Inc. Ester substituted ion channel blockers and methods for use
US10968179B2 (en) 2019-03-11 2021-04-06 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10786485B1 (en) 2019-03-11 2020-09-29 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10780083B1 (en) 2019-03-11 2020-09-22 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11603355B2 (en) 2019-03-11 2023-03-14 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11377422B2 (en) 2019-03-11 2022-07-05 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
WO2021087113A1 (fr) * 2019-10-30 2021-05-06 Children's Medical Center Corporation Anesthésiques locaux avec blocage nerveux sensoriel sélectif
US10842798B1 (en) 2019-11-06 2020-11-24 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10933055B1 (en) 2019-11-06 2021-03-02 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11696912B2 (en) 2019-11-06 2023-07-11 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US11332446B2 (en) 2020-03-11 2022-05-17 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use

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