WO2015157509A1 - Compositions et methodes de traitement de maladies associées aux recepteurs des opioides - Google Patents

Compositions et methodes de traitement de maladies associées aux recepteurs des opioides Download PDF

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Publication number
WO2015157509A1
WO2015157509A1 PCT/US2015/025090 US2015025090W WO2015157509A1 WO 2015157509 A1 WO2015157509 A1 WO 2015157509A1 US 2015025090 W US2015025090 W US 2015025090W WO 2015157509 A1 WO2015157509 A1 WO 2015157509A1
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dezocine
composition
subject
opioid
addiction
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PCT/US2015/025090
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English (en)
Inventor
Renyu Liu
Geoffrey KRUG
Feixiang Wu
Julie BLENDY
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The Trustees Of The University Of Pennsylvania
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Priority to US15/303,221 priority Critical patent/US9956187B2/en
Publication of WO2015157509A1 publication Critical patent/WO2015157509A1/fr
Priority to US15/967,526 priority patent/US20190099386A1/en

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the invention relates to dezocine ( i ' ,.J ; > > Ni > ⁇ compositions and uses thereof. Specifically, the invention relates to dezocine compositions, including nano-dezocine compositions and methods for preventing or treating opioid receptor associated diseases, including neuropathic pain; addiction, such as opioid or cocaine addiction; and depression.
  • opioid analgesics have contributed to an increasing number of deaths in the United States.
  • the number of fatal opioid analgesic poisonings has increased by 91% between 1999 and 2002.
  • Methadone-related deaths have increased by 390% from 1999 to 2004.
  • Drug overdoses and brain damage associated with long-term drug abuse killed an estimated 37,485 people in 2009. This surpassed the number of deaths attributed to traffic accidents of that year by 1,201.
  • opioid abuse has been estimated to contribute up to $300 billion per year in direct healthcare costs.
  • buprenorphine is becoming the dominant medication for pain management as a partial agonist and partial antagonist of the mu opioid receptor.
  • DEA Drug Enforcement Administration
  • buprenorphine can cause addition by itself and such addiction is very difficult to manage.
  • its tight binding with the opioid receptor makes it difficult to titrate and it takes 3-5 days for the medication to be eliminated from the body when full agonist opioids are needed for acute pain management and other opioid receptor associated diseases or disorders.
  • methods for preventing or treating an opioid receptor associated disease or disorder in a subject, the methods comprising: administering to said subject a therapeutically effective amount of dezocine or a pharmaceutical composition thereof (e.g. , compositions of the dezocine nanoparticles or microparticles described herein).
  • a therapeutically effective amount of dezocine or a pharmaceutical composition thereof e.g. , compositions of the dezocine nanoparticles or microparticles described herein.
  • NP neuropathic pain
  • methods for preventing or treating neuropathic pain (NP) in a subject, the methods comprising: administering to said subject a therapeutically effective amount of dezocine or a pharmaceutical composition thereof (e.g. , compositions of the dezocine nanoparticles or microparticles described herein).
  • a therapeutically effective amount of dezocine or a pharmaceutical composition thereof e.g. , compositions of the dezocine nanoparticles or microparticles described herein.
  • methods for preventing or preventing or treating an addiction disease (e.g. , addition to heroin or cocaine) in a subject, the methods comprising: administering to said subject a therapeutically effective amount of dezocine or a pharmaceutical composition thereof (e.g. , compositions of the dezocine nanoparticles or microparticles described herein).
  • an addiction disease e.g. , addition to heroin or cocaine
  • a pharmaceutical composition thereof e.g. , compositions of the dezocine nanoparticles or microparticles described herein.
  • methods for preventing or treating depression in a subject, the methods comprising: administering to said subject a therapeutically effective amount of dezocine or a pharmaceutical composition thereof (e.g. , compositions of the dezocine nanoparticles or microparticles described herein).
  • a therapeutically effective amount of dezocine or a pharmaceutical composition thereof e.g. , compositions of the dezocine nanoparticles or microparticles described herein.
  • compositions comprising: dezocine and a second active agent selected from serotonin receptor inhibitors (e.g. , ondansetron); or a opioid receptor antagonist, including but not limited to naloxone or naltrexone; or a mu opioid receptor agonist, including but not limited to morphine, methadone, or fentanyl; or a partial mu agonist; or a serotonin transporter inhibitor.
  • the dezocine is present in an amount effective to treat an opioid receptor associated disease or disorder in a subject and the second agent is present in an effective amount to reduce a dezocine related adverse effect or in an effect effective amount to enhance the effect of the dezocine.
  • the dezocine is present in an effective amount to reduce an adverse effect of the second active agent (e.g. , the second active agent is an opioid agonist and the adverse effect is addiction) or in an effective amount to enhance the effect of the second active agent.
  • compositions comprising opioid nanoparticles, wherein the nanoparticle size is on the order of nanometers (nm).
  • compositions comprising opioid nanoparticles, wherein the nanoparticle size is on the order of micrometers ( ⁇ ).
  • the opioid nanoparticles are dezocine nanoparticles.
  • the forgoing compositions are adapted for extended or controlled release.
  • the foregoing compositions further comprise one or more additional active agents.
  • processes for preparing opioid (e.g. , dezocine) nanoparticles, the processes comprising the steps of: (a) preparing opioid (e.g. , dezocine) in solution, (b) preparing a solution comprising poly(vinyl alcohol) (PVOH) and Propylene Glycol; (c) adding opioid (e.g.
  • dezocine to said solution comprising PVOH and Propylene Glycol; (d) homogenizing the resulting mixture until forming a nano-emulsion; (e) freezing and thawing said nano-emulsion for a predetermined time to produce hydrogel opioid nanoparticles or opioid nanoparticles; (f) filtering the opioid nanoparticles; and (g) suspending the opioid nanoparticles in solution.
  • compositions of opioids e.g. , dezocine
  • the compositions comprising: an aqueous solution of the opioid and a cyclodextrin.
  • methods for preventing or preventing or treating opioid addiction in a subject, the methods comprising: administering to said subject a therapeutically effective amount of dezocine nanoparticles.
  • FIG. 1 A) Dezocine (magenta) overlaps with beta-Funaltrexamine (orange) a mu receptor antagonist and the ligand found in the crystal structure of the mu opioid receptor (4DKL), in the binding pocket. Polar interaction with ASP147 and TYR326 is predicted.
  • FIG. 3 A) Nalbuphine and salvinorin A, full agonists of kappa opioid receptors, concentration dependently activate the G protein in the presence of kappa receptor. Dezocine fails to induce any G protein activation, indicating receptor antagonism. Based on the activity of the G protein in its presence, nor-binaltorphimine is an inverse agonist of kappa opioid receptor. B) G protein was pre-activated with a full agonist (Nalbuphine, 250 nM or Salvinorin A, 20 nM) and then increasing amounts of dezocine was added.
  • a full agonist Nalbuphine and salvinorin A, full agonists of kappa opioid receptors
  • Dezocine inhibited the agonist effects of nalbuphine and salvinorin A concentration-dependently with a total blockage at high concentration, confirming the kappa receptor antagonism effect of dezocine.
  • FIG. 5 Docking result of dezocine and nisoxetine in the model of norepinephrine transporter (NET).
  • Dezocine magenta
  • cyan binding site of nisoxetine
  • Dezocine is located in close proximity to TRP103, TYR127, GLU281, and LEU368 which are all colored in yellow.
  • FIG. 6 A) Dezocine (magenta) sits in the preformed ligand binding pocket for selective serotonin reuptake inhibitors in the model of human serotonin transporter. The key interacting residues lining the pocket (Y95, D98, 1172, Y176, F335, F341, and S438) are colored in yellow. This binding pocket has been demonstrated to be the binding site for many important clinical drugs such as fluoxetine, sertraline, and amitriptyline. B) Dezocine (magenta) shares the same binding pocket and overlap well with desiprimine (orange), the ligand in the LeuT crystal structure (2QJU).
  • FIG. 7 Changes of paw withdrawal latency (PWL) after injection of dezocine on CCI rats. Rats were administered with dezocine one day before CCI, and then PWL was measured. Following administration of dezocine, PWL was significantly increased comparing to that in the NS group (*P ⁇ 0.05).
  • FIG. 8 Changes of paw withdrawal threshold (PWT) after injection of dezocine on CCI rats. PWT was monitored one day before CCI and 1, 3, 7, and 10 day after surgery. At the 1 st , 3 rd , 7 th and 10 th day, PWT showed markedly increased comparing to that in the NS group (*P ⁇ 0.05).
  • Figure 9 Relative affinities of dezocine with three opioid receptors as compared with morphine, a classic opioid receptor agonist to all three receptors.
  • Mu-R mu opioid receptor
  • Delta-R delta opioid receptor
  • kappa_R kappa opioid receptor.
  • NET Norepinephrine Transporter
  • FIG. 12 Left panel: the affinity determination of dezocine (24899, 111 nM) as compared with amitriptyline, a clinical antidepressant which interacts with SERT. Right panel: the binding site of dezocine (D) in SERT overlaps well with amitriptyline (A).
  • FIG. 13 Left panel: The affinity of dezocine (24899, 1 ⁇ ) with NET.
  • Right panel The binding site of dezocine (D) in NET overlaps with desipramine (DSM), an antidepressant.
  • DSM desipramine
  • FIG. 16 Forced Swim Test: The group administered a 0.1 mg/kg dezocine dose shows lower immobility time, suggesting anti-depressant activity.
  • Figure 17 Scanning electron microscope images of PVA-dezocine particles with various sizes (100 nM ⁇ 25 ⁇ ) for different drug carrying and releasing properties can be generated.
  • FIG. HPLC chromatogram of dezocine in 20% 2-Hydroxypropyl-P-cyclodextrin (HPBCD) or 20% 2-Hydroxypropyl)-y-cyclodextrin (HPGCD).
  • HPBCD 2-Hydroxypropyl-P-cyclodextrin
  • HPGCD 2-Hydroxypropyl-y-cyclodextrin
  • the invention relates to dezocine compositions and uses thereof. Specifically, the invention relates to dezocine compositions, including nano-dezocine compositions and methods for preventing or treating opioid receptor associated diseases, including neuropathic pain, addiction, and depression. The present inventors surprisingly and unexpectedly found that dezocine compositions can be used to treat opioid receptor associated diseases, including neuropathic pain, addiction, and depression.
  • Dezocine is a well-known compound and described in U.S. Patent 4,605,671, which is incorporated by reference herein in its entirety.
  • Dezocine [(-)-13 -amino-5, 6,7,8, 9, 10, 11,12- octahydro-5a-methyl-5,l l-methanobenxocyclodecen-31-ol, hydrobromide] is a pale white crystal powder. It has no apparent odor.
  • the salt is soluble at 20 mg/mL, and a 2% solution has a pH of 4.6. Methods of synthesis for dezocine are well known in the art.
  • dezocine or its derivative can be used for preventing or treating opioid receptor associated diseases or disorders.
  • dezocine of any pharmaceutically acceptable salt, alcohol, hydrate, ester, amide, derivative, analog, polymorph, metabolite, isomer, or prodrug or combination thereof can be used.
  • This invention may also extend to a dezocine analog, which has a similar pharmacological profile as a partial mu receptor agonist, kappa receptor antagonist, and norepinephrine and serotonin transporter protein inhibitor.
  • a dezocine analog includes dezocine where one or more of the hydrogens on the methyl substituent is replaced with another moiety (e.g. , with a halogen or an alkyl group) and has the following structure, where at least one of the R groups is not hydrogen:
  • compositions of an opioid such as dezocine
  • the compositions comprising: an aqueous solution of dezocine and a cyclodextrin.
  • the cyclodextrin is a 2-hydroxypropyl-cyclodextrin, such as 2-hydroxypropyl- - cyclodextrin (HPBCD) or 2-hydroxypropyl-y-cyclodextrin (HPGCD). More preferably, the cyclodextrin is 2-hydroxypropyl-y-cyclodextrin (HPGCD).
  • the composition is adapted for intravenous administration.
  • the composition is adapted for oral administration.
  • the composition is adapted for transmucosal, such as intranasal, administration.
  • the HPBCD or HPGCD concentration in the aqueous opioid, such as dezocine, solution is at least 1% (w/v), at least 2.5% (w/v), at least 5% (w/v), at least 7.5% (w/v), at least 10% (w/v), at least 12.5% (w/v), at least 15% (w/v), at least 17.5% (w/v), at least 20% (w/v), at least 22.5% (w/v), or at least 25% (w/v).
  • the HPBCD or HPGCD concentration in the aqueous opioid, such as dezocine, solution is less than 50% (w/v), less than 45% (w/v), less than 40% (w/v), less than 35% (w/v), less than 30% (w/v), less than 25% (w/v), less than 22.5% (w/v), less than 20% (w/v), less than 17.5% (w/v), less than 15% (w/v).
  • the HPBCD or HPGCD has a concentration in the aqueous dezocine solution of about at least 20% (w/v).
  • the invention relates to opioid nanoparticles, such as dezocine nanoparticles.
  • the size of the nanoparticles may range from about 1 nm to about 200 nm. In one embodiment, the size of the nanoparticles may range from about 5 nm to about 150 nm. In another embodiment, the size of the nanoparticles may range from about 10 nm to about 100 nm. In yet another embodiment, the size of the nanoparticles may range from about 50 nm to about 100 nm. In some embodiments, the size of the nanoparticles is about 1 , 5, 10, 20, 30, 50, 80, 100, 150, 200, 500, 600, 700, 800 or 900 nm. In a particular embodiment, the size of the nanoparticles is less than or equal to 100 nm.
  • the invention relates to opioid microparticles, such as dezocine microparticles.
  • the size of the particles may range from about 1 ⁇ to about 200 ⁇ . In one embodiment, the size of the particles may range from about 5 ⁇ to about 150 ⁇ . In another embodiment, the size of the particles may range from about 10 ⁇ to about 100 ⁇ . In yet another embodiment, the size of the particles may range from about 50 ⁇ to about 100 ⁇ . In some embodiments, the size of the particles is about 1, 5, 10, 20, 30, 50, 80, 100, 150, 200, 500, 600, 700, 800 or 900 ⁇ . In a particular embodiment, the size of the particles is less than or equal to 100 ⁇ .
  • Opioid nanoparticles or microparticles can be prepared by a process that comprises the steps of: (a) preparing an opioid, such as dezocine, in solution, (b) preparing a solution comprising poly(vinyl alcohol) (PVOH) and propylene glycol; (c) adding the opioid, such as dezocine, to said solution comprising PVOH and propylene glycol; (d) homogenizing the resulting mixture until forming a nano-emulsion or a micro-emulsion; (e) freezing and thawing said nano- emulsion or micro-emulsion for a predetermined time to produce hydrogel opioid nanoparticles, opioid nanoparticles, hydrogel opioid microparticles, opioid microparticles; (f) filtering said nanoparticles or microparticles; and (g) suspending the opioid nanoparticles or opioid microparticles in solution.
  • the nanoparticle such as an opioid, such as dezocine, in solution
  • PVOH poly(vin
  • One or more additional therapeutically effective agent(s) may be conjugated to the dezocine, incorporated into the same composition as the dezocine (e.g. , the additional agent(s) is incorporated into the dezocine nanoparticles or microparticles), or may be administered as a separate composition.
  • the other therapeutically agent or treatment may be administered prior to, during and/or after the administration of dezocine.
  • the invention relates to a composition
  • a composition comprising dezocine in combination with another compound capable of preventing, inhibiting, or reducing an adverse effect associated with dezocine.
  • the other compound is ondansetron.
  • the composition comprises dezocine and ondansetron, wherein dezocine may be present in an amount effective to treat an opioid receptor associated disease or disorder in a subject and ondansetron may be present in an effective amount to reduce a dezocine related adverse effect.
  • adverse effects include, for example, but are not limited to, nausea and vomiting.
  • Ondansetron (INN), originally marketed under the brand name Zofran, which is a serotonin 5-HT 3 receptor antagonist.
  • Ondansetron is an anti-emetic agent used to prevent nausea and vomiting.
  • Ondansetron is a well-known compound and described in U.S. Patents 7,288,660 and 4,695,578, each of which is incorporated by reference herein in its entirety. Methods of synthesis for ondansetron are known in the art. Any form of ondansetron or its derivative, known to one of skilled in the art, can be used.
  • ondansetron of any pharmaceutically acceptable salt, alcohol, hydrate, ester, amide, derivative, analog, polymorph, metabolite, isomer, or prodrug or combination thereof can be used.
  • the dezocine compositions describe herein can be administered adjunctively with other active agents such as analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti- narcoleptics.
  • active agents such as analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antihistamines, antimigraine drugs, antimuscarinics, anxioltyics, sedatives, hypnotics, antipsychotics, bronchod
  • compounds that can be adjunctively administered with dezocine include, but are not limited to, aceclofenac, acetaminophen, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amlodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate
  • the invention further provides methods of preventing or treating a disease or condition.
  • the methods may include the step of administering to a mammal in need thereof a therapeutically effective amount of dezocine, ondansetron, or a combination thereof.
  • the invention provides a method for preventing or treating opioid receptor associated diseases, in a subject, the method comprising: administering to said subject a therapeutically effective amount of dezocine or a pharmaceutical composition thereof (e.g. , compositions of the dezocine nanoparticles or microparticles described herein).
  • a therapeutically effective amount of dezocine or a pharmaceutical composition thereof e.g. , compositions of the dezocine nanoparticles or microparticles described herein.
  • the method further comprises administering a therapeutically effective amount of ondansetron or a pharmaceutical composition thereof.
  • opioid receptor associated diseases are treated by administering a pharmaceutical composition (e.g. , compositions of the dezocine nanoparticles or microparticles described herein) that comprises a therapeutically effective amount of both dezocine and ondansetron.
  • An opioid receptor can be a mu opioid receptor, a kappa receptor, a delta opioid receptor, or combinations thereof.
  • dezocine treats opioid receptor associated disease by interacting with a norepinephrine transporter (NET), a serotonin transporter (SERT), or a combination thereof.
  • NET norepinephrine transporter
  • SERT serotonin transporter
  • opioid receptor associated diseases or disorders include, for example, but are not limited to, pain (e.g. , neuropathic pain), addiction (e.g. , addiction to a substance or a drug, such as heroin or cocaine), and depression.
  • pain e.g. , neuropathic pain
  • addiction e.g. , addiction to a substance or a drug, such as heroin or cocaine
  • depression e.g. , depression
  • methods for preventing or preventing or treating opioid addiction in a subject, the methods comprising: administering to said subject a therapeutically effective amount of dezocine nanoparticles described herein.
  • the pharmaceutical compositions may include a "therapeutically effective amount.”
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of a molecule may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the molecule to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which toxic or detrimental effects of the molecule are outweighed by the therapeutically beneficial effects.
  • the terms “treat” and “treatment” refer to therapeutic treatment, including prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change associated with a disease or condition.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease or condition, stabilization of a disease or condition (i. e. , where the disease or condition does not worsen), delay or slowing of the progression of a disease or condition, amelioration or palliation of the disease or condition, and remission (whether partial or total) of the disease or condition, whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition or those in which the disease or condition is to be prevented.
  • the compounds and pharmaceutical compositions comprising the same can be administered to a subject by any method known to a person skilled in the art, such as parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intra-dermally, subcutaneously, intra-peritonealy, intra-ventricularly, intra-cranially, intra- vaginally, intrathecally, intranasally, and inhalationally.
  • compositions can be administered orally, and thus can be formulated in a form suitable for oral administration, i.e. as a solid or a liquid preparation.
  • suitable solid oral formulations include, for example, but are not limited to, tablets, capsules, pills, granules, pellets and the like.
  • Suitable liquid oral formulations include, for example, but are not limited to, solutions, suspensions, dispersions, emulsions, oils and the like.
  • the active ingredient is formulated in a capsule.
  • the compositions of the present invention comprise, in addition to the active compound and the inert carrier or diluent, a hard gelating capsule.
  • the pharmaceutical compositions can also be administered by intravenous, intraarterial, or intra-muscular injection of a liquid preparation.
  • suitable liquid formulations include, for example, but are not limited to, solutions, suspensions, dispersions, emulsions, oils and the like.
  • the pharmaceutical compositions are administered intravenously and are thus formulated in a form suitable for intravenous administration.
  • the pharmaceutical compositions are administered intra- arterially and are thus formulated in a form suitable for intra- arterial administration.
  • the pharmaceutical compositions are administered intra-muscularly and are thus formulated in a form suitable for intra-muscular administration.
  • compositions can also be administered topically to body surfaces and are thus formulated in a form suitable for topical administration.
  • Topical formulations include, in another embodiment, gels, ointments, creams, lotions, drops and the like.
  • the pharmaceutical composition is administered as a suppository, for example a rectal suppository or a urethral suppository.
  • the pharmaceutical composition is administered by subcutaneous implantation of a pellet.
  • the pellet provides for controlled release of active agent over a period of time.
  • the active compound is delivered in a vesicle, e.g. , a liposome.
  • compositions of the invention may include carriers or diluents.
  • carriers or diluents include, but are not limited to, a gum, a starch (e.g. , corn starch, pregeletanized starch), a sugar (e.g. , lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. , microcrystalline cellulose), an acrylate (e.g. , polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
  • a gum e.g. , corn starch, pregeletanized starch
  • a sugar e.g. , lactose, mannitol, sucrose, dextrose
  • a cellulosic material e.g. , microcrystalline cellulose
  • an acrylate e.g. , polymethylacrylate
  • calcium carbonate magnesium oxide
  • magnesium oxide magnesium oxide
  • talc or mixtures
  • Pharmaceutically acceptable carriers for liquid formulations can be aqueous or nonaqueous solutions, suspensions, emulsions or oils.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • oils are those of animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, olive oil, sunflower oil, fish-liver oil, another marine oil, or a lipid from milk or eggs.
  • Parenteral vehicles for subcutaneous, intravenous, intra- arterial, or intramuscular injection
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like.
  • sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
  • water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • oils are those of animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, olive oil, sunflower oil, fish- liver oil, another marine oil, or a lipid from but not limited to milk or eggs.
  • compositions may further comprise binders (e.g. , acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g. , cornstarch, potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g. , Tris-HCI., acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g.
  • binders e.g. , acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone
  • disintegrating agents e.g. , cornstarch, potato star
  • aspartame, citric acid preservatives (e.g. , Thimerosal, benzyl alcohol, parabens), lubricants (e.g. , stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. , colloidal silicon dioxide), plasticizers (e.g. , diethyl phthalate, triethyl citrate), emulsifiers (e.g. , carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g. , poloxamers or poloxamines), coating and film forming agents (e.g. , ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.
  • preservatives e.g. , Thimerosal, benzyl alcohol, parabens
  • lubricants e.g. , stea
  • the pharmaceutical compositions provided herein are controlled-release compositions, i.e. compositions in which the active compound is released over a period of time after administration.
  • Controlled- or sustained-release compositions include formulation in lipophilic depots (e.g. , fatty acids, waxes, oils).
  • the composition is an immediate-release composition, i.e. a composition in which of the active compound is released immediately after administration.
  • the pharmaceutical composition is delivered in a controlled release system.
  • the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • a pump may be used (see Langer; Sefton, CRC Crit. Ref. Biomed. Eng.
  • polymeric materials are used; e.g. , in microspheres in or an implant.
  • a controlled release system is placed in proximity to the target cell, thus requiring only a fraction of the systemic dose (see, e.g. ,
  • compositions also include, in another embodiment, incorporation of the active material into or onto particulate preparations of polymeric compounds such as polylactic acid or polylactide (PLA), polyglycolic acid, PLGA or poly(lactic-co-glycolic acid) hydrogels, etc, or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.
  • PVA polylactic acid or polylactide
  • PLGA polyglycolic acid
  • hydrogels etc
  • liposomes emulsions
  • micelles unilamellar or multilamellar vesicles
  • erythrocyte ghosts erythrocyte ghosts
  • spheroplasts spheroplasts.
  • particulate compositions coated with polymers e.g. , poloxamers or poloxamines
  • polymers e.g. , poloxamers or poloxamines
  • Also comprehended by the invention are compounds modified by the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, cyclodextrin, cucurbituril, polyvinylpyrrolidone or polyproline.
  • the modified compounds are known to exhibit substantially longer half-lives in blood following intravenous injection than do the corresponding unmodified compounds (Abuchowski et al., 1981 ; Newmark et al., 1982; and Katre et al., 1987).
  • Such modifications may also increase the compound's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound.
  • the desired in vivo biological activity may be achieved by the administration of such polymer-compound abducts less frequently or in lower doses than with the unmodified compound.
  • the methods of the present invention comprise administering an active compound as the sole active ingredient.
  • methods for preventing or treating diseases and disorders that comprise administering the active compound in combination with one or more therapeutic agents.
  • the administration of dezocine with other agents and/or treatments may occur simultaneously, or separately, via the same or different route, at the same or different times. Dosage regimens may be adjusted to provide the desired response (e.g. , a therapeutic or prophylactic response).
  • Effective doses of the compositions of the present invention, for treatment of conditions or diseases as described herein vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic.
  • the patient is a human but non-human mammals including transgenic mammals can also be treated.
  • Treatment dosages may be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.
  • a single bolus may be administered.
  • several divided doses may be administered over time.
  • a dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for treating mammalian subjects. Each unit may contain a predetermined quantity of active compound calculated to produce a desired therapeutic effect. In some embodiments, the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic or prophylactic effect to be achieved.
  • compositions of the invention may be administered only once, or it may be administered multiple times or continuous infusion.
  • the compositions may be, for example, administered three times a day, twice a day, once a day, once every two days, twice a week, weekly, once every two weeks, or monthly.
  • Dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • administering to a subject is not limited to a particular delivery system and may include, without limitation, parenteral (including subcutaneous, intravenous, intramedullary, intraarticular, intramuscular, or intraperitoneal injection) rectal, topical, transdermal or oral (for example, in capsules, suspensions or tablets), intrathecal, and inhaltional.
  • Administration to a host may occur in a single dose or in repeat administrations or continuous infusion, and in any of a variety of physiologically acceptable salt forms, and/or with an acceptable pharmaceutical carrier and/or additive as part of a pharmaceutical composition (described earlier).
  • physiologically acceptable salt forms and standard pharmaceutical formulation techniques are well known to persons skilled in the art (see, e.g. , Remington's Pharmaceutical Sciences, Mack Publishing Co.).
  • the term "about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviations, per practice in the art.
  • a measurable value such as an amount, a temporal duration, a concentration, and the like, may encompass variations of ⁇ 20% or ⁇ 10%, more preferably ⁇ 5%, even more preferably ⁇ 1%, and still more preferably ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
  • the methods of treatment described herein can be used to treat a suitable mammal, including primates, such as monkeys and humans, horses, cows, cats, dogs, rabbits, and rodents such as rats and mice.
  • a suitable mammal including primates, such as monkeys and humans, horses, cows, cats, dogs, rabbits, and rodents such as rats and mice.
  • the mammal to be treated is human.
  • dezocine is a partial mu opioid receptor agonist, it is not a controlled substance. Thus, the characterization of the molecular targets of dezocine has significant scientific and clinical implications. The goal of this study is to characterize molecular targets for dezocine and their implications.
  • a binding screen for dezocine was performed on 44 available receptors and transporter proteins. Functional assays for the novel targets were performed along with computation calculations to locate the binding site.
  • a G protein activation study was performed for the human kappa opioid receptor to determine whether dezocine is a kappa antagonist. Data are presented as mean + SE. The affinities for dezocine were 3.7+0.7 nM for the mu receptor, 527+70 nM for the delta receptor, and 31.9+1.9 nM for the kappa receptor.
  • Dezocine failed to induce G protein activation with kappa opioid receptor and concentration dependently inhibited kappa agonist (salvinorin A and nalbuphine) induced receptor activation, indicating that dezocine is a kappa antagonist.
  • kappa opioid receptor concentration dependently inhibited kappa agonist (salvinorin A and nalbuphine) induced receptor activation, indicating that dezocine is a kappa antagonist.
  • Two novel molecular targets norepinephrine transporter, NET; and serotonin transporter, SERT
  • the half maximal inhibitory concentrations were 5.68+0.11 for NET and 5.86 + 0.17 for SERT.
  • Dezocine occupied the binding site for known NET and SERT inhibitors.
  • a primary binding screen for dezocine was performed on 44 available receptors (mostly GPCRs, see Table 1). Evidence for interaction was based on the inhibition of the reference ligand-binding signal.
  • Dezocine was diluted in standard binding buffer (50mM Tris-HCl, lOmM MgCl 2 , O.lmM EDTA, pH 7.4) to a final concentration of 10 ⁇ . Briefly, 50 ⁇ , aliquots of radioactive ligand (5nM) were added to wells of a 96- well plate, which contained 25 ⁇ L ⁇ of the reference or test ligands.
  • the secondary binding assay was performed only when the inhibition in the primary screen was over 50%. A secondary binding assay was utilized to determine the binding affinity for the identified receptor. Dezocine was prepared in standard binding buffer and serially diluted to the desired concentrations.
  • 5-HT5A 5-HT6, 5-HT7
  • Betal Beta2, Beta3
  • GABA receptors GABA-A, rat benzodiazepine site GABA receptors GABA-A, rat benzodiazepine site
  • Biogenic amine transporters serotonin transporter; norepinephrine transporter;
  • Opioid receptors mu receptor; kappa receptor; delta receptor
  • HT Serotonin receptor
  • alpha alpha adrenergic receptor
  • Beta beta-adrenergic receptor
  • D dopamine receptor
  • GABA gamma-aminobutyric acid receptor
  • H histamine receptor
  • M muscarinic receptor
  • Sigma sigma receptor.
  • Membrane preparations of recombinant human kappa opioid receptor expressed in the mammalian cell line Chem-5 were obtained from MiUipore (Billerica, MA). The effects of specific kappa opioid receptor ligands on the activation of the recombinant receptor were investigated by measuring G protein activation in vitro. Nalbuphine and salvinorin A (full agonist) and nor-binaltorphimine (antagonist) were utilized as controls.
  • the assay reports the initial rates of activation of heterotrimeric G proteins ( ⁇ 2 ) on an agonist-bound receptor by measuring the accumulation of [ 35 S]-GTPYS (non-hydrolyzable analog of GTP) bound to the activated Gocn subunit.
  • Myristoylated Gocn was expressed in E. coli and purified as previously described.
  • Recombinant human ⁇ 2 subunits of G protein were expressed in baculovirus-infected Sf9 cells and purified as previously described.
  • the G protein activation assay was conducted as follows (final concentrations in 50 ⁇ reaction mixture are given in parentheses): the membrane sample was diluted into ice-cold 10 mM 3-(N- morpholino)propanesulfonic acid (MOPS) buffer to reach a protein concentration of 40 ng/ ⁇ . 10 ⁇ L of the diluted dispersion were dispensed into pre-siliconized glass tubes and mixed with the ligand in MOPS buffer containing 0.1% (w/v) BSA. Upon addition of a mixture of G a n (100 nM) and Gpiy2 (500 nM), the tubes were incubated on ice for 30 minutes.
  • MOPS 3-(N- morpholino)propanesulfonic acid
  • reaction mixture was rapidly filtered through nitrocellulose filters (MiUipore). Filters were washed four times with 2 mL each of cold TNMg buffer, dried, placed in scintillation vials filled with ScintiSafe Econo F scintillation liquid (Fisher, Waltham, MA), and the radioactivity counted. Duplicate samples corresponding to every ligand concentration point were counted.
  • the kappa receptor was preactivated with either nalbuphine (250 nM) or salvinorin A (20 nM), a highly selective non- opioid kappa receptor agonists with strong affinity. The kappa receptor was then treated with increasing concentrations of dezocine. Norepinephrine transporter (NET) and serotonin transporter (SERT) reuptake assay
  • Dezocine docking calculation on a LeuT crystal coupled with desipramine was also performed to identify the potential overlap of the binding sites.
  • Semi-empirical charges calculated by MOPAC2009 were added to the ligand atoms.
  • Essential hydrogen atoms, Kollman united atom type charges, and solvation parameters were added to the receptor using AutoDock tools provided by the server.
  • Grid maps of 30x30x30 A grid points with 0.375 A spacing centered at the known ligand binding site were generated using the Autogrid program. All the ligand searches were performed using the Solis and Wets local search method with a Lamarckian genetic algorithm. Initial position, orientation, and torsions of the ligand molecules were set randomly. The three-dimensional coordinates of the tested compound were obtained from the PubChem database. PyMOL (Version 1.5.0.4, Schrodinger LLC, New York, NY) was used to render the graphics for presentation. Data analysis
  • dezocine binds to all three major subtypes of opioid receptors (Table 2), it only weakly interacts with the delta receptor.
  • Table 3 affinities for dezocine as 3.7+0.7 nM for the human mu receptor, 527+70 nM for the human delta receptor, and 31.9+1.9 nM for the human kappa receptor (Table 3).
  • dezocine docks to the known binding site for opioid ligands in both the mu and kappa receptor.
  • Hydrogen bonding with ASP 147 (149 in human mu) contributes to the strong affinity of dezocine to the mu receptor.
  • TYR326 also has polar interaction with dezocine in the mu receptor as demonstrated in Figure 1A.
  • dezocine hydrogen bonds with ASP 138 as predicted by docking calculations ( Figure 2B).
  • Betal 10 14.7 Beta2 -4.5 -2.6
  • 5-HT Serotonin receptor
  • alpha alpha adrenergic receptor
  • Beta beta- adrenergic receptor
  • D dopamine receptor
  • DAT dopamine transporter
  • GABA gamma-aminobutyric acid receptor
  • H histamine receptor
  • M muscarinic receptor
  • NET norepinephrine transporter
  • SERT serotonin transporter
  • Sigma sigma receptor
  • MOR mu opioid receptor
  • DOR delta opioid receptor
  • KOR kappa opioid receptor Kappa receptor antagonism
  • nalbuphine behaved as a full kappa receptor agonist and fully activated the G protein in the presence of membranes containing kappa receptor as indicated in Figure 3A.
  • the G protein was pre-activated with a full agonist (Nalbuphine or Salvinorin A), and then increasing amounts of dezocine were added.
  • dezocine inhibited the agonist effect concentration-dependently with a total blockage at high concentration. This finding correlated the lack of G protein activation observed in Figure 3A.
  • nor-binaltorphimine acted as an inverse kappa agonist.
  • dezocine in addition to binding to the opioid receptor, dezocine also inhibits the norepinephrine transporter (NET) with p3 ⁇ 4 of 6.00 + 0.10 and the serotonin transporter (SERT) with p3 ⁇ 4 of 6.96+0.08. These interactions were further confirmed by norepinephrine and serotonin reuptake studies.
  • the pICsoS at NET were 7.57+0.23 for nisoxetine (positive control) and 5.68+0.11 for dezocine (Figure 4A).
  • the pICsoS of SERT were 5.99 + 0.07 for nisoxetine and 5.86 + 0.17 for dezocine ( Figure 4B).
  • dezocine is predicted to share the same binding site with nisoxetine in the norepinephrine transporter as indicated in Figure 5.
  • Dezocine is located in close proximity to TRP103, TYR127, GLU281, and LEU368 and might form hydrogen bonds with these residues. Based on the docking prediction shown in Figure 6 A, dezocine binds to the preformed ligand-binding pocket in the model of human serotonin transporter.
  • This pocket has been demonstrated to be the binding site for many selective serotonin reuptake inhibitors including fluoxetine, citalopram, sertraline, fluvoxamine and tricyclic antidepressants such as amitriptyline, desipramine, and imipramine. Mutation of the residues lining this pocket (Y95, D98, 1172, Y176, F335, F341and S438) changed the binding capability of these ligands significantly. Dezocine shares the same binding site for desipramine found in the crystal structure of LeuT as indicated in Figure 6B. Both findings indicate that dezocine may share the same site as selective serotonin reuptake inhibitors or tricyclic antidepressants.
  • Buprenorphine a partial mu agonist and kappa antagonist
  • buprenorphine itself is an addictive Schedule III medication and its chronic use creates significant difficulty for optimal perioperative pain management due to its high affinity to the receptor and long half-life.
  • dezocine is also a partial mu agonist and a kappa antagonist based on our current findings. Its shorter half-life allows for easier titration to an optimal effect as well as rapid removal when full agonism is required during the perioperative period.
  • Dezocine interacts with NET and inhibits the norepinephrine reuptake.
  • the competitive binding assay and the computational docking calculation suggest that dezocine interacts with NET directly at the binding site for the intrinsic NET ligand
  • NP neuropathic pain
  • CCI Chronic constriction injury
  • CCI procedures on the sciatic nerve of male SD rats were performed as previously described. Briefly, after rats were anesthetized by i.p. injection of sodium pentobarbital (40 mg/kg), the right sciatic nerve of the mid- thigh level was exposed. Chromic gut 4-0 was loosely tied around the nerve for 4 ligatures with about 1 mm between knots. The ligation was performed to just barely reduce the diameter of sciatic nerve. The ligatures caused intraneural edema and resulted in constriction of nerve. In the sham group, the sciatic nerve was exposed without ligation. The incisions of rats were closed in layers. After recovery from anesthesia, rats were housed individually in the clear plastic cages with soft bedding covered with 3-6 cm of sawdust. Experimental Protocol
  • Rats were randomly assigned to three groups (6 rats in each group): a sham group (IP normal saline, IP NS), an NS group (CCI+ IP NS) and a Dezocine group (CCI+ IP dezocine).
  • IP intraperitoneal
  • rats of CCI model received intraperitoneal (IP) injection of 3 mg/kg (in 2ml of volume) body weight of dezocine at 9:00 AM per day starting for the day of the surgery. Same volume of normal saline (2ml) was injected in the other two groups at the same time. Evaluation of thermal hyperalgesia
  • the paw withdrawal latency (PWL) to radiant heat was used to evaluate thermal hyperalgesia for nociceptive response as previously described. Rats were placed in transparent plexiglass cage (23x18x13cm) with a piece of 3-mm-thick glass floor and received heat radiation after acclimating to the environments for 30 minutes.
  • the radiant heat source consists of a high- intensity projection lamp bulb (8V, 50W), which was located 40 mm below the glass floor beneath the right hind paw of the rats.
  • the heat source projected through a 5xl0-mm aperture on the top of a movable case.
  • a digital timer automatically measured the duration between the starting of heat and the paw withdrawal, which was considered as the PWL.
  • the PWL was measured in 0.1 second and a maximum of 20 seconds exposure to radiation was set to avoid injury. Three repeated measurements were performed in each rat with a 5-minute interval between each measurement. PWL tests were performed at 11 :00 AM starting from 1 day before CCI surgery and 1, 3, 7, 10 days after surgery.
  • the paw withdrawal threshold was used to evaluate mechanical allodynia for nociceptive response with Von Frey filaments.
  • the rats were placed in transparent plexiglass cage with a wire mesh floor. After acclimating to their environments for 30 minutes, each filament was applied perpendicularly to the plantar surface of the right hind paw. The end point was determined as paw withdrawal accompanied by biting, head turning and/or licking. The force (in gram, g) needed for this reaction was recorded.
  • the PWT was taken though increasing and decreasing the stimulus strength sequentially with the 'up-and-down' method as described by Chaplan. Similar to PWL test, PWT tests were performed at 1 day before and 1, 3, 7, 10 days after CCI surgery.
  • PWT was utilized to measure mechanical allodynia. Mechanical allodynia was induced by CCI, as evidenced by the reduction of PWT ( Figure 8). CCI rats receiving intraperitoneal injection of dezocine, PWT was increased markedly in the dezocine group comparing to the NS group (P ⁇ 0.05), which suggested an attenuation of allodynia by dezocine ( Figure 8). Similar to PWL, the improvement of PWT was found during the entire experiment period. Taken together, the anti-nociception effect by dezocine started immediately after administration and lasted for 10 days without signs of tolerance.
  • dezocine can be used for NP treatment through opioid system and norepinephrine/serotonin system.
  • dezocine significantly attenuated the nociception effect in a neuropathic pain model in rats; indicating that dezocine could be an alternative medication for neuropathic pain management.
  • This invention relates to a combination of two clinical medications (dezocine and ondansetron) for pain management.
  • dezocine is an opioid receptor partial agonist, and has the equivalent potency and similar pharmacokinetic profile as that of morphine and has been used for pain management in clinical practice since the 1970s.
  • the usage of dezocine can therefore reduce the prevalence of opioid addiction.
  • Dezocine and ondansetron are both FDA approved medication for different clinical indications. Consistent with reported data, dezocine has affinity with all three opioid receptors. It has comparable affinity to mu opioid receptor and kappa receptor with morphine, however, it has much weaker affinity with delta opioid receptor as indicated in Figure 9.
  • Dezocine is not only a mu opioid receptor partial agonist, but it also interacts with norepinephrine transportor (NET) protein, an important pathway for pain regulation as indicated in Figure 10.
  • NET norepinephrine transportor
  • dezocine is a kappa antagonist, rather than a kappa receptor agonist as initially reported. This is a finding explains the lack of addiction reported with clinical usage of dezocine. As indicated in Figure 11, dezocine did not cause any G protein activation for human kappa receptor.
  • nalbuphine was used as a positive control which is a kappa receptor agonist and induced G protein activation.
  • dezocine is not a DEA controlled medication and has no reported addiction to date. All the other commonly used clinical opioids for either pain management or addiction treatment are DEA controlled medications and have addictive properties. In addition, all the other opioids are associated with death. No death reports have been associated with dezocine to date.
  • Buprenorphine has a very long half-life, which makes it difficult to be titrated for optimal management and difficult to rescue during overdose.
  • naloxone has been added into the composition for buprenorphine, the half-life time for naloxone is short relative to buprenorphine. Therefore, the combination of these two compounds results is a poor pharmacological match.
  • the pharmacokinetic profile of dezocine matches well with naloxone.
  • dezocine has a ceiling effect on respiratory depression.
  • Dezocine is also a mu opioid receptor partial antagonist, which ensures a better side-effect profile than other full opioid receptor agonists. It is also a kappa antagonist, giving it the potential to treat opioid addiction.
  • dezocine could be an effective therapeutics for neuropathic pain.
  • ondansetron may prevent the most common side effects related to dezocine: nausea and vomiting, a common side effect from most of opioid medication.
  • This invention relates to a combination of current clinical medications (dezocine with ondansetron) for addiction management.
  • dezocine has the equivalent potency and similar pharmacokinetic profile of morphine and has been used in clinical practice for pain management since 1970s. Similar to buprenorphine, dezocine is also a kappa antagonist and should have the property to treat opioid addiction as buprenorphine has. It is not a DEA controlled medication. Thus, the usage of dezocine can reduce the prevalence of opioid addiction. Adding ondansetron will prevent the most common dezocine-related nausea and vomiting.
  • dezocine has affinity with all three opioid receptors. It has comparable affinity to mu opioid receptor and kappa receptor with morphine, however, it has much weaker affinity with delta opioid receptor as indicated in Figure 9. As discussed above, we recently confirmed that dezocine is a kappa antagonist, rather than a kappa receptor agonist as initially reported.
  • dezocine did not cause any G protein activation for human kappa receptor.
  • nalbuphine as a positive control which is a kappa receptor agonist and induced G protein activation.
  • the morphine dependent model was constructed by subcutaneous administration of daily ascending doses of morphine three times/day for 6 consecutive days (5, 10, 20, 40, 50, 60 mg/kg) in all animals except these in the naive group.(l) The same volumes of normal saline (NS) were received subcutaneously in the naive group. All other interventional drugs are administered by intraperitoneal injection. Rats were randomly assigned to three groups (15 rats in each group): a naive group (no morphine will be administered), a normal saline (NS) group (morphine+ NS), and a Dez (dezocine) group (morphine +dezocine 5mg/kg).
  • naloxone (2mg/kg) is administered to reduce morphine withdrawal syndrome.
  • the symptoms of morphine withdrawal syndrome in each animal were observed for 30 min after naloxone injection.
  • the scores of withdrawal symptoms were determined according to Maldonado's modified method as described in our previous work (Table 4).
  • dezocine shows a significant reduction of morphine withdrawal syndrome in a morphine dependent rat model, indicating its important therapeutic role in opioid dependent subjects.
  • dezocine a mu opioid receptor partial agonist approved by the FDA for perioperative acute pain management (IV form only), binds strongly with both the norepinephrine transporter (NET) and serotonin transporter (SERT), two of the major cellular targets for antidepressant drugs. Further study indicates that dezocine is a kappa opioid receptor antagonist, explaining why there is no abuse liability related to dezocine so far and it is not listed as a DEA controlled substance.
  • dezocine is a FDA approved medication for different clinical indications. Consistent with reported data, dezocine has affinity for all three opioid receptors. It has comparable affinity to mu opioid receptor and kappa receptor with morphine, however, it has much weaker affinity with delta opioid receptor as indicated in Figure 9.
  • dezocine is a kappa antagonist, rather than a kappa receptor agonist as initially reported. This finding explains the lack of addiction reported with clinical usage of dezocine. As indicated in Figure 11, dezocine did not cause any G protein activation for human kappa receptor. We used nalbuphine as a positive control which is a kappa receptor agonist and induced G protein activation. [00143] After screening known opioid compounds for novel targets, we discovered that dezocine interacts with both the norepinephrine transporter (NET) and serotonin transporter (SERT). The interaction of dezocine with both NET and SERT indicates that it can have antidepressant properties. The affinity and binding site of dezocine for SERT are indicated in Figure 12, while the affinity and binding site of dezocine for NET are indicated in Figure 13.
  • NET norepinephrine transporter
  • SERT serotonin transporter
  • mice were used for this study. In some instances multiple behavioral tests were performed in a single cohort of mice: forced swim test, tail suspension test, and hot plate test were all performed on the same cohort with a week's time separated each test. Animals were maintained on a 12 h light-dark cycle with food and water available ad libitum in accordance with the University of Pennsylvania Institutional Animal Care and Use Committee. Dezocine was dissolved in 0.9% saline solution and 10 ⁇ acetic acid. The solutions were prepared immediately before use and injected intraperitoneally (i.p.). For forced swim test the drug was administered sub-chronically, 24 hours, 5 hours, and 10 minutes prior to testing.
  • mice were placed in water (30 cm depth, 23 °C) in plastic cylinders (46 cm tall x 20 cm diameter) for 6 minutes. The plastic cylinders were filled with water the night before the testing in order to acclimate to room temperature. Using Viewpoint automated scoring (Viewpoint), the duration of immobility was measured. Mice were administered three injections of Dezocine before testing: one 23.5 hours before the swim test, a second injection 5 hours before the swim test, and a third injection 10 minutes before the swim test. Twenty-four mice were tested and separated into three groups. One group received three injections of saline at the three different time points. Another group received three injections 0.1 mg/kg Dezocine at the three different time points. The last group received three injections of 1.0 mg/kg Dezocine at the three different points outlined previously. Results
  • dezocine may have anti-depressive effect and can be used to treat patients who have both pain and depression.
  • This invention relates to dezocine nanoparticles, named as Nano-Dezocine, as therapeutics for pain, depression, and addiction treatment.
  • dezocine is FDA approved for pain management in the perioperative period.
  • dezocine is a serotonin and norepinephrine transporter protein inhibitor and kappa opioid receptor antagonist. It is known that dezocine is a mu opioid receptor partial agonist.
  • Nanoparticles of dezocine, Nano-Dezocine for clinical usages in various forms: oral, injectable, and transmucosal, including intranasal administration and other depository administration methods.
  • Nano-Dezocine includes two major procedures: (i) solubilizing dezocine and (ii) nano-dezocine creation.
  • Dezocine is very hydrophobic and is not soluble in water. All solutions attempted in this experiment had concentrations >1 mg/mL. A formulation that was not completely soluble at >1 mg/mL was labeled insoluble. Dezocine was found to be insoluble in water, 5% poly (vinyl alcohol) (PVOH) solution, and 31% propylene glycol (PG) solution. Dezocine was found to be soluble at 1 mg/mL in 200-proof ethanol, but no further solutions were made with ethanol, due to its limited usefulness for medical application. Dezocine was found to be soluble at 2 mg/mL in 50% PG, but precipitated at 3 mg/mL.
  • PVOH poly (vinyl alcohol)
  • PG propylene glycol
  • Dezocine was soluble at 10 mg/mL in pure PG, and no higher concentrations were attempted. When a solution of 31% PG, 1% lactic acid was used, dezocine was found to be soluble up to 3 Omg/mL, which was the highest concentration attempted. All further solutions were created at about pH 4. Later parts of the experiment involving PVOH solutions found dezocine to be soluble at lOmg/mL in a 31% PG, 6% PVOH solution buffered to pH 4. Later parts of the experiment involving PVOH solutions found dezocine to be soluble at lOmg/mL in a 31% PG, 6% PVOH solution buffered to pH 4. No higher concentrations were attempted with this formulation.
  • the buffer solution for this application has a pH of around 4.0, and contains propylene glycol (PG). Lactic acid was used to lower pH, and was buffered with sodium hydroxide (NaOH). In 1 mL, the buffer contains the following amounts:
  • the desired amount of water or buffer, and PVOH is measured out.
  • a 9-10% solution is suitable for use in this application.
  • 60 mL of buffer and 6g of PVOH was used in this experiment.
  • the buffer is placed in a 100-250 mL beaker along with a magnetic stir-rod, and covered in aluminum foil to prevent loss of water to evaporation.
  • a small hole (-0.5 cm) is poked in the aluminum foil to allow a temperature probe to be placed inside.
  • the beaker is placed on a hot plate with the temperature probe suspended in such a way as to ensure that it is in the buffer solution, but not interfering with the stir rod or touching the glass.
  • the solution is heated to about 85 °C with stirring.
  • the pouring was done in small increments, with a wait in between each successive amount to allow all of the liquid to settle to the bottom of the tube, and allow accurate measurement of total volume. Once the solution reaches 5 mL, the tube is mixed again with the vortex until homogenized. These amounts can be scaled up or down to create various volumes of solution.
  • the dezocine-PVOH solution is placed in silicone oil at a 1:3 volume ratio of solution to oil, with around 1 ⁇ 7 ⁇ of Tween 80 added to assist disruption and homogenization. This is manually disrupted into small particles. Then, additional silicone oil is added to bring the volume ratio of solution to oil to 1:20. This is homogenized with a blender, forming a nano-emulsion. Once a water-in-oil emulsion is achieved, it is subjected to 2-3 freeze- thaw cycles of 20 hours of freezing followed by 4 hours of thawing. This will turn the dezocine-PVOH solution droplets in the emulsion into hydrogel nanoparticles of around 600-700 nm size.
  • the solution is placed in acetone at a 1:10 volume ratio of emulsion to acetone. This is then vacuum filtered through a PTFE filter with ⁇ 0.1 ⁇ pore size, and then the filter is then washed with acetone to remove silicone oil residue. The nanoparticles are then collected and suspended in saline solution at whatever ratio provides the desired drug concentration.
  • Nano-Dezocine can be made in water or normal saline solution or encapsulated for various formula preparations (transmucosal, oral, implant etc.), which may include controlled release purposes. Nano-dezocine itself has mucoadhesive properties that could allow it to stay on the surface of mucosal membrane for a prolonged period of time.
  • HPBCD 2-Hydroxypropyl-P-cyclodextrin
  • HPGCD 2-Hydroxypropyl-y-cyclodextrin

Abstract

L'invention porte sur des compositions de dézocine et sur leurs utilisations. Spécifiquement, l'invention concerne des compositions de dézocine incluant des compositions de nanodézocine et des méthodes de prévention ou de traitement de maladies associées aux récepteurs des opioïdes, y compris la douleur neuropathique; l'addiction, telle que l'addiction à un opiacé ou à la cocaïne; et la dépression.
PCT/US2015/025090 2014-04-10 2015-04-09 Compositions et methodes de traitement de maladies associées aux recepteurs des opioides WO2015157509A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106018584A (zh) * 2016-05-12 2016-10-12 华润双鹤利民药业（济南）有限公司 一种地佐辛有关物质的检测方法
CN111606816A (zh) * 2017-05-22 2020-09-01 扬子江药业集团有限公司 一种地佐辛晶型及其制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5118528A (en) * 1986-12-31 1992-06-02 Centre National De La Recherche Scientifique Process for the preparation of dispersible colloidal systems of a substance in the form of nanoparticles
US20020150616A1 (en) * 1997-06-05 2002-10-17 Roger Petrus Gerebern Vandecruys Pharmaceutical compositions comprising cyclodextrins
US20040156872A1 (en) * 2000-05-18 2004-08-12 Elan Pharma International Ltd. Novel nimesulide compositions
US20040209850A1 (en) * 2003-04-15 2004-10-21 Theraquest Biosciences, Llc Methods of treating pain and compositions for use therefor
US20080058362A1 (en) * 2006-08-31 2008-03-06 Singh Chandra U Novel pharmaceutical compositions for treating chronic pain and pain associated with neuropathy
WO2008070268A2 (fr) * 2006-10-09 2008-06-12 Charleston Laboratories, Inc. Compositions pharmaceutiques
US20120302592A1 (en) * 2007-01-31 2012-11-29 University Of Virginia Patent Foundation Topiramate plus naltrexone for the treatment of addictive disorders

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5118528A (en) * 1986-12-31 1992-06-02 Centre National De La Recherche Scientifique Process for the preparation of dispersible colloidal systems of a substance in the form of nanoparticles
US20020150616A1 (en) * 1997-06-05 2002-10-17 Roger Petrus Gerebern Vandecruys Pharmaceutical compositions comprising cyclodextrins
US20040156872A1 (en) * 2000-05-18 2004-08-12 Elan Pharma International Ltd. Novel nimesulide compositions
US20040209850A1 (en) * 2003-04-15 2004-10-21 Theraquest Biosciences, Llc Methods of treating pain and compositions for use therefor
US20080058362A1 (en) * 2006-08-31 2008-03-06 Singh Chandra U Novel pharmaceutical compositions for treating chronic pain and pain associated with neuropathy
WO2008070268A2 (fr) * 2006-10-09 2008-06-12 Charleston Laboratories, Inc. Compositions pharmaceutiques
US20120302592A1 (en) * 2007-01-31 2012-11-29 University Of Virginia Patent Foundation Topiramate plus naltrexone for the treatment of addictive disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIU ET AL., NOVEL MOLECULAR TARGETS OF DEZOCINE AND THEIR CLINICAL IMPLICATIONS IN ANESTHESIOLOGY, vol. 120, 2014, pages 714 - 723, XP055231360 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106018584A (zh) * 2016-05-12 2016-10-12 华润双鹤利民药业（济南）有限公司 一种地佐辛有关物质的检测方法
CN111606816A (zh) * 2017-05-22 2020-09-01 扬子江药业集团有限公司 一种地佐辛晶型及其制备方法

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