WO2017074903A1 - Utilisation de dimère de buprénorphine dans le traitement de douleur neuropathique périphérique - Google Patents

Utilisation de dimère de buprénorphine dans le traitement de douleur neuropathique périphérique Download PDF

Info

Publication number
WO2017074903A1
WO2017074903A1 PCT/US2016/058593 US2016058593W WO2017074903A1 WO 2017074903 A1 WO2017074903 A1 WO 2017074903A1 US 2016058593 W US2016058593 W US 2016058593W WO 2017074903 A1 WO2017074903 A1 WO 2017074903A1
Authority
WO
WIPO (PCT)
Prior art keywords
dimer
buprenorphine
neuropathic pain
pain
opioid
Prior art date
Application number
PCT/US2016/058593
Other languages
English (en)
Inventor
Nikhilesh Nihala Singh
Original Assignee
Orphomed, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US14/922,373 external-priority patent/US9549924B2/en
Application filed by Orphomed, Inc. filed Critical Orphomed, Inc.
Publication of WO2017074903A1 publication Critical patent/WO2017074903A1/fr

Links

Classifications

    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies

Definitions

  • Pain may be divided into two major categories: "nociceptive” pain (caused by inflamed or damaged tissue that activates specialized pain sensors called nociceptors), and “neuropathic” pain (caused by damage to or malfunction of the nervous
  • Neuropathic pain may either be "peripheral”, which originates in the peripheral nervous system, or "central”, which originates in the brain or spinal cord.
  • Peripheral neuropathic pain is a chronic condition that is very common in clinical practice. Peripheral neuropathic pain can have many underlying causes, including diabetes, alcoholism, vitamin deficiencies, injury, toxic reactions to prescribed drugs, infectious diseases, malignancies, etc.
  • the pain associated with peripheral neuropathy may be severe and, unlike most pain that sufferers have previously experienced, it is characterized by allodynia (pain response from stimuli that do not normally provoke pain), hyperalgesia and in some cases, sensory loss.
  • the pain is often described as "burning, stabbing, raw or sickening". It can be constant or paroxysmal and with or without sensory impairment.
  • the type and severity of pain or sensory loss depends on the underlying cause of the neuropathy.
  • symptoms In chronic forms of neuropathic pain, symptoms begin subtly and progress slowly. Some people may have periods of relief followed by relapse. Others may reach a plateau stage where symptoms stay the same for many months or years. Many chronic neuropathies worsen over time. For the majority of patients with neuropathic pain, the pain will persist for life. Comorbidities such as depression, poor quality of life and employment and domestic issues are very common.
  • peripheral neuropathies are classified according to the type of damage to the nerves. Some forms of neuropathy involve damage to only one nerve and are called mononeuropathies. More frequently, however, multiple nerves are affected, called polyneuropathy.
  • Entrapment neuropathies eg., carpal tunnel syndrome
  • HIV sensory neuropathy Iatrogenic neuralgias eg, postmastectomy pain or
  • Radiculopathy Cervical, thoracic, or lumbosacral
  • opioid analgesics oxycodone and tramadol (UltramTM). None have had complete success and all have significant associated adverse events.
  • a common adverse event of opioid analgesics is sedation, related to the central nervous system effects of these drugs. In many patients, especially elderly patients, treatment with opioid analgesics may result in problems of impairment and mobility, which may increase the risk of hip fractures. All patients that use opioid analgesics on a chronic basis will develop physical dependence and stopping the medication for any reason would require them to be under close medical care.
  • Buprenorphine a partial opioid mu agonist and full opioid delta and kappa antagonist, has been extensively studied in patients with neuropathic pain. As an analgesic, it is approximately 30 times more potent than morphine. Buprenorphine has been shown to not only have an analgesic effect but also to have significant antihyperalgesic
  • Hyperalgesia is a component of neuropathic pain.
  • the major drawback of prescribing buprenorphine for this purpose, however, is that as an opioid mu receptor agonist, it has significant addictive properties and would not be suited for safe long- term use.
  • Peripheral neuropathic pain is by nature local, affecting one or more areas of the body and the doses required to treat the local condition by intravenous delivery would seem to rule out buprenorphine itself for this purpose.
  • buprenorphine has previously been formulated for subcutaneous long-acting depot injection. (See US patents 8,921,387 and 8,975,270).
  • a buprenorphine depot formulation for the treatment of peripheral neuropathic pain would appear to offer irreconcilable choices between, on the one hand, sufficient dose to treat local pain, and on the other concerns about the agent's access to the central nervous system and it's significant consequences.
  • the dimer has been shown to retain the receptor affinity and pharmacologic characteristics of the parent compound, buprenorphine. It maintains potent binding affinities for the mu, delta and kappa receptors. The molecular weight of the dimer is greater than 1000 daltons, which prevents it from being absorbed and entering the central nervous system.
  • a study of the buprenorphine dimer administered intravenously to mice demonstrated rapid elimination. Mice showed no evidence of CNS activity in that there was no change in behavior. More recently, in a rodent study to determine the antihyperalgesic effects of the dimer, significant antihyperalgesic activity was demonstrated, while no evidence of CNS activity was evident, in that there was no change in behavior of test mice.
  • the dimer when administered intramuscularly or subcutaneously, either by immediate-acting formulation or by long-acting depot formulation, based on laboratory data, is expected to have potent systemic analgesic and antihyperalgesic properties excluding the central nervous system.
  • the dimer because of its strong covalent ether ethylene glycol linker, is stable and does not undergo metabolism. No metabolism to buprenorphine has been detected in experiments conducted to date.
  • the potent peripherally acting (non-CNS) drug behavior makes this drug very suitable for the treatment of painful peripheral neuropathies. Its potent mu opioid agonist and kappa antagonist effects and lack of CNS absorption, result in it being unique among analgesic agents.
  • the invention provides for the use of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof in the treatment of peripheral neuropathic pain by subcutaneous or intramuscular administration of a therapeutically effective dose.
  • Injection may be subcutaneous or intramuscular in solution for initial treatment of acute pain.
  • the invention provides a method for the treatment of peripheral neuropathic pain by injecting a depot formulation of a therapeutically effective amount of the dimer for slow release over time.
  • the compound is provided in a slow release formulation for subcutaneous injection.
  • the invention provides pharmaceutical compositions for use in the treatment of peripheral neuropathic pain.
  • Figure 1 provides a bar chart illustrating the stability of buprenorphine dimer when exposed to CYP enzymes in the presence and absence of a co-factor.
  • Figure 2 provides a bar graph showing the stability of buprenorphine dimer to aqueous conditions, as well as acidic and basic condition, each at room temperature and at 140°F for the indicated period of time.
  • Figure 3 provides the results of buprenorphine dimer receptor binding experiments
  • Figure 4 provides the results of buprenorphine dimer receptor binding experiments
  • Figure 5 provides ⁇ agonist functional assay results for the buprenorphine dimer.
  • Figure 6 provides ⁇ antagonist functional assay results for the buprenorphine dimer.
  • Figure 7 provides the results of a demonstration in mice of the antihyperalgesic properties of the dimer.
  • the compound was employed in the form of its hydrochloride salt.
  • the buprenorphine dimer surprisingly retains the pharmacologic receptor activity of the parent opioid, including the anti-hyperalgesia activity thereof. By reason of its size and lipophilicity it is less likely to penetrate the blood brain barrier. Indeed, when
  • the present invention employs a dimeric form of buprenorphine where the two buprenorphine molecules are linked via a covalent bond between the phenolic (3 -hydroxyl) functional group of each buprenorphine molecule and an ethylene linker.
  • the ethylene linker serves as a spacer between the two buprenorphine molecules and is thought to prevent the two bulky buprenorphine molecules from adopting an enclosed ring conformation via either a covalent, ionic or Van der Waal interaction between other functional groups on the molecules.
  • the dimer retains the pharmacological activity of the parent compound.
  • the buprenorphine dimer In contrast to buprenorphine, the buprenorphine dimer, prepared as described herein retains the opioid ⁇ and ⁇ activity not only in form but also direction, viz. neither receptor affinity nor activity is compromised. Additionally, the buprenorphine dimer described herein is relatively stable to metabolism in in vivo and in vitro experiments. The buprenorphine dimer appears metabolically stable, even after exposure to the liver of live mice, following intravenous injection.
  • the buprenorphine dimer retained, selectively, only the ⁇ and the ⁇ functions of buprenorphine, but was significantly stripped of its ⁇ function. Stated differently, the buprenorphine dimer, unlike buprenorphine, is a selective ⁇ and ⁇ active molecule without significant ⁇ activity.
  • Typical, exemplary degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Numerical quantities given herein are approximate unless stated otherwise, meaning that the term "about" or
  • administering refers to the methods that may be used to enable delivery of agents or compositions to the desired site of biological action.
  • chronic pain refers to pain persisting for an extended period of time, for example, greater than three to 6 months, although the characteristic signs of pain can occur earlier or later than this period. Chronic pain may be mild, excruciating, episodic, or continuous.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • terapéuticaally effective amount refers to that amount of the therapeutic agent sufficient to ameliorate the targeted condition or symptoms.
  • treating refers to the treating or treatment of a disease or medical condition (such as pain) in a patient, such as a mammal (particularly a human or an animal) which includes: ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a patient; suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a patient; or alleviating the symptoms of the disease or medical condition in a patient.
  • a disease or medical condition such as pain
  • a patient such as a mammal (particularly a human or an animal) which includes: ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a patient; suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a patient; or alleviating the symptoms of the disease or medical condition in a patient.
  • pharmaceutically acceptable carrier diluent, or excipient is a carrier, diluent, or excipient compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • subject refers to an animal such as a mammal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like.
  • primates e.g., humans
  • cows, sheep, goats horses, dogs, cats, rabbits, rats, mice and the like.
  • Synthesis of the buprenorphine dimer provided herein can proceed by a general O- alkylation reaction in an organic solvent (such as, e.g., acetonitrile, DMF, DMSO, NMP,
  • DCM, THF, 1,4-Dioxane in the presence of inorganic base (such as, e.g., sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate and sodium bicarbonate) or organic base (such as, e.g., triethylamine, Hunig's base, DMAP and pyridine) at room temperature or elevated temperature.
  • inorganic base such as, e.g., sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate and sodium bicarbonate
  • organic base such as, e.g., triethylamine, Hunig's base, DMAP and pyridine
  • Suitable alkylating agents that can be used include diiodo, dibromo, dichloro, ditosylate, dimesylate and ditriflate reagents (e.g., 1,2- ethylene ditosylate, 1,2-ethylene dimesylate).
  • compositions comprising a
  • buprenorphine dimer of Formula A pharmaceutical composition can further comprise a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier Illustrative pharmaceutically acceptable carriers and formulations are described below. Such pharmaceutical compositions can be used to treat peripheral neuropathic pain.
  • a pharmaceutically acceptable salt of a dimer may be used instead of or in addition to a dimer in any or all of the compositions and methods of treating discussed herein.
  • a pharmaceutically acceptable salt of the dimer i.e., any pharmaceutically acceptable salt of any of the dimers
  • These salts can be prepared, for example, in situ during the final isolation and purification of the compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • the pharmaceutically acceptable salt of the buprenorphine dimer is prepared using acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,
  • the buprenorphine dimer can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention. In a specific embodiment, the solvated form of the dimer is a hydrate.
  • salt formation may improve shelf life of the resultant therapeutic agent. Appropriate salt synthesis can afford products that are crystalline, less prone to oxidation and easy to handle. Various salts can be prepared that would afford stable and crystalline compounds. A few examples are hydrochloric, sulfuric, p-toluenesulfonic, methanesulfonic, malonic, fumaric, and ascorbic acid salts.
  • the dimer may be formulated for acute administration or for chronic administration as a depot, long- term injectable or implantable.
  • injectables may be present in the dosage form as a solution, a dispersion in solution, or as a powder or two components to be mixed prior to use.
  • the most basic acute vehicle for injection comprises saline solution, which is comprised of water for injection (WFI) and 0.9% saline solution.
  • suitable aqueous vehicles include Ringer's injection, dextrose solution, dextrose and sodium chloride solution, and Lactated Ringer's Injection.
  • nonaqueous water miscible vehicles may be added including ethanol, propylene glycol, polyethylene glycol 300 or 400.
  • Surfactants such as polysorbate 20 or 80, Cremophor EL, Solutol HS 15 and many others may be added to improve solubility.
  • Oils may be used as nonaqueous vehicles, especially corn oil, cottonseed oil, peanut oil, and sesame oil.
  • nonaqueous vehicles include ethyl oleate, isopropyl myristate, glycerol monoleate, benzyl benzoate and many others.
  • Antimicrobial agents such as cresol, chlorobutanol, phenylmercuric nitrate, thimerosol, benzalkonium chloride, benzethonium chloride, phenol, methyl p- hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, and many others may be added alone or in combination.
  • Antioxidants or chelating agents may be added such as sodium bisulfite, thiourea, EDTA, citric acid or citrate buffer, tocopherol or its derivatives, cysteine, methionine, ascorbic acid or mixtures thereof.
  • the above groups of excipients may be added in combination. All of these additives and potential vehicles may also be used for chronic formulations. Chronic formulations
  • the dimer compound will be delivered in a composition suitable for implantation or injection intramuscularly or, most preferably, by subcutaneous depot injection or implantation,
  • Long acting formulations may be made by incorporation of the dimer in an oil, as listed above, and its slow release from that oil.
  • a salt with a fatty acid may be prepared to lower the solubility and provide a slow rate of dissolution. Both approaches may be combined.
  • a phospholipid depot as taught in US patent 9,132,144, may be formed from the dimer in an oil in water emulsion comprised of a phospholipid and an oil.
  • the emulsion is formed by homogenization and then made into a single phase by microfluidizing.
  • a buffer may be added to maintain the pH.
  • a dry paste is then formed by lyophilization, and ethanol and or isopropanol is added to the paste as 1 to 25% of the formulation to modify the viscosity so that it may be injected through a size 22 needle.
  • NMP N-methyl pyrrolidone
  • the clear gel depot formed is sterilized.
  • Antioxidants and/or chelating agents such as EDTA, citric acid or citrate buffer, tocopherol or its derivatives, cysteine, methionine, ascorbic acid, or mixtures thereof may optionally be added.
  • oils are vegetable oils such as sunflower oil, corn oil, olive oil, peanut oil, cottonseed oil, soybean oil, sesame oil, and the like, or animal oils such as fish oil, or synthetic oils such as glycerol monoleate, propylene glycol monolaurate or monocaprylate, or CAPMULTM.
  • a list of phospholipids that may be used may be found in the referenced patent.
  • a liquid crystalline injectable gel may also be formed by the use of a phospholipid, glycerol dioleate, and ethanol or NMP (US patent 8,097,239).
  • Thermoreversible gels may be made using PoloxamerTM, particularly Poloxamer 407, in about 15 to 25% solutions comprised also of the dimer and physiological saline (0.9% sodium chloride solution). These solutions at room temperature may be passed through a size 22 needle and at body temperature form a gel from which the drug may be slowly released over a period of days or longer. Additional polymer such as 2% hypromellose, or phospholipid such as 1 to 4% lecithin, may be added. Buffer such as citrate, phosphate or acetate buffer at pH 4 to 7, and preferably pH 5 to 6 may be added.
  • Other viscous injectable gels may be formed by polymers or copolymers of lactic (PLA) or lactic and glycolic acids (PLGA) dissolved in N-methyl pyrrolidone (NMP), ethyl benzoate, or benzyl benzoate, as disclosed in US patent 9,044,450.
  • PPA lactic
  • PLGA lactic and glycolic acids
  • NMP N-methyl pyrrolidone
  • SABERTM gel from Durect Corporation comprising sucrose acetate isobutyrate.
  • about 63% NMP has been used with D,L polylactic acid PLA) to produce a biodegradable gel in the body after injection
  • Both microsphere injectables and implants are made from biodegradable polymers that degrade in the body to release drug. These include PLA, PLGA or combinations, polyanhydrides, poly ortho-esters, and others. Drug matrices may be prepared from hyaluronic acid (US 5,716,631). Examples are microspheres containing naltrexone (337 mg/1 g PLGA microspheres, Vivitrol). This is supplied as a kit with the microspheres needing to be suspended in the separate diluent consisting of polysorbate 80, sodium croscarmellose, saline, and WFI.
  • Another depot Leuprolide, also supplies lyophilized microspheres with drug to be resuspended in diluent comprising polysorbate 80, sodium croscarmellose, saline, D-mannitol, glacial acetic acid to control pH, and WFI.
  • PLA or PLGA may be extruded with drug to form an implant as in US patent 6,620,422.
  • Implants may also be made of polymers that are not biodegradable. For example ethylene vinyl acetate (EVA) implants loaded with drug may extruded, implanted in the doctor's office with a trocar and then surgically removed when desired.
  • EVA ethylene vinyl acetate
  • ATRIGELTM Particularly suited for the delivery of the dimer in chronic treatment is the
  • ATRIGEL is the thermoplastic polymer poly(lactide-co-glycolide) (PLG), the thermoplastic polymer poly(lactide-co-glycolide extended with 1,6-hexane diol) (PLG), or PLGH in the organic solvent N-methyl-2-pyrrolidone.
  • PLG thermoplastic polymer poly(lactide-co-glycolide)
  • PLAG thermoplastic polymer poly(lactide-co-glycolide extended with 1,6-hexane diol)
  • PLGH the organic solvent N-methyl-2-pyrrolidone.
  • Buprenorphine itself is formulated in ATRIGEL for the treatment of opioid dependency in US patent 8,921,387, whose disclosure is incorporated herein by reference.
  • a "therapeutically effective amount” refers to that amount of the therapeutic agent, which yields an appreciable and beneficial effect on the treated indication.
  • the patient is a mammal.
  • the patient is a human.
  • the patient may be a domesticated mammal such as a dog, a cat, or a horse.
  • the dose of the buprenorphine dimer provided herein to be administered to a patient is rather widely variable and can be subject to the judgment of a health-care practitioner. Dosage may be properly varied depending on the age, body weight and medical condition of the subject and the type of administration. In any given case, the amount of the dimer provided herein administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.
  • the preferred dose of dimer may be between at least 0.3 and not more than 25 mg, more preferably between at least 1 mg and not more than 20 mg, and still more preferably between at least 2.5 mg and not more than 15 mg.
  • the single use dose can be available as a solution, suspension or as a powder to be reconstituted with an injectable diluent.
  • the preferred dose of dimer may be between about 5 mg and about 120 mg, more preferably between about 10 mg and 100 mg, and still more preferably between about 15 mg and about 80 mg.
  • the weekly depot can be available as an injectable solution, gel, suspension or as a powder to be reconstituted with an injectable diluent.
  • the depot is injectable through a syringe needle gauge 21.
  • the dose of dimer may be about 25 mg to about 200 mg, preferably about 30 mg to about 150 mg, and still more preferably about 40 mg and about 120 mg.
  • the weekly depot can be available as an injectable solution, gel, suspension or as a powder to be reconstituted with an injectable diluent.
  • the depot is injectable through a syringe needle gauge 21.
  • bi-conjugate (buprenorphine dimer-FB) was dissolved in 50 mL of ethyl acetate at room temperature under nitrogen. 3.43 mL (6.9 mmol, 1.2 equiv) of 2N HCl in ether was added drop-wise at room temperature. The reaction mixture was stirred at room temperature for additional hour and filtered to obtain a solid. The solid was further washed with 100 ml of ethyl acetate and dried under vacuum to afford buprenorphine dimer (bis HCl salt) as white solid (5.8 g, 98 %).
  • Example 2 Assays 1. In Vitro Assay: Metabolic Stability of Buprenorphine Dimer
  • Incubations of the dimer (e.g., 1 ⁇ ) with human liver microsomes (e.g., 1 mg protein/mL) was carried out using a Tecan Liquid Handling System (Tecan), or equivalent, at 37 ⁇ 1°C in 0.2-mL incubation mixtures (final volume) containing potassium phosphate buffer (50 mM, pH 7.4), MgC12 (3 mM) and EDTA (1 mM, pH 7.4) with and without a cofactor, NADPH-generating system, at the final concentrations indicated in a 96-well plate format.
  • Tecan Tecan Liquid Handling System
  • the NADPH-generating system consisted of NADP (1 mM, pH 7.4), glucoses- phosphate (5 mM, pH 7.4) and glucose-6-phosphate dehydrogenase (1 Unit/mL).
  • the dimer was dissolved in aqueous methanolic solution (methanol 0.5% v/v, or less). Reactions were started typically by addition of the cofactor, and stopped at four designated time points (e.g., up to 120 min) by the addition of an equal volume of stop reagent (e.g., acetonitrile, 0.2 mL containing an internal standard). Zero-time incubations served as 100% value to determine percent loss of substrate.
  • stop reagent e.g., acetonitrile, 0.2 mL containing an internal standard.
  • Incubations were carried out in triplicate with an exception for zero- time samples (which were incubated in quadruplicate).
  • Zero-cofactor (no NADPH) incubations were performed at zero-time and the longest time point.
  • the samples were subjected to centrifugation (e.g., 920 x g for 10 min at 10°C) and the supernatant fractions analyzed by LC-MS/MS.
  • Additional incubations were carried out with microsomes in which were replaced with a marker substrate (e.g., dextromethorphan to monitor substrate loss) as positive controls to determine if the test system is metabolically competent.
  • a marker substrate e.g., dextromethorphan to monitor substrate loss
  • buprenorphine The dimer was stable in presence of the microsomes, with or without the co- factor.
  • the assay was terminated at 2 hours as enzymes are typically not stable beyond 2 hours at incubation temperatures of 37°C.
  • Example 3 Receptor Binding Activity
  • Membranes from Chinese Hamster Ovary cells expressing the human ⁇ opioid receptor were homogenized in assay buffer (50 mM Tris, pH 7.5 with 5 mM MgC12) using glass tissue grinder, Teflon pestle and Steadfast Stirrer (Fisher Scientific). The concentrates of the membranes were adjusted to 300 ⁇ g/mL in assay plate, a 96 well round bottom polypropylene plate. The compound to be tested was solubilized in DMSO (Pierce), 10 mM, then diluted in assay buffer to 3.6 nM.
  • assay buffer 50 mM Tris, pH 7.5 with 5 mM MgC12
  • a second 96 well round bottom polypropylene plate known as the premix plate
  • 60 ⁇ , of 6X compound was combined with 60 ⁇ , of 3.6 nM 3H-Nalaxone.
  • 60 ⁇ , of 3.6 nM 3H-Nalaxone was transferred to an assay plate containing the membranes, in duplicate.
  • the assay plate was incubated for 2 h at room temperature.
  • a GF/C 96 well filter plate (Perkin Elmer #6005174) was pretreated with 0.3% polyethylenimine for 30 min.
  • the contents of the assay plate were filtered through the filter plate using a Packard Filtermate Harvester, and washed 3 times with 0.9% saline at 4°C.
  • the filter plate was dried, underside sealed, and 30 ⁇ ⁇ Microscint 20 (Packard #6013621) was added to each well.
  • a Topcount-NXT Microplate Scintillation Counter (Packard) was used to measure emitted energies in the range of 2.9 to 35 KeV. Results were compared to maximum binding, wells receiving no inhibitions. Nonspecific binding was determined in presence of 50 uM unlabeled naloxone. The biological activity of the dimer is shown in Figure 3.
  • Results The graphs in Figure 3 show that the dimer has significant affinity for the opioid ⁇ receptor The opioid ⁇ receptor affinity of the buprenorphine dimer at 10-8M (-10 ng) and the profile was similar to that of buprenorphine.
  • Membranes from cloned HEK-293 cells expressing the human kappa opioid receptor were homogenized in assay buffer (50 mM Tris, pH 7.5 with 5 mM MgC12) using glass tissue grinder, Teflon pestle and Steadfast Stirrer (Fisher Scientific). The concentrates of the membranes were adjusted to 300 ⁇ g/mL in assay plate, a 96 well round bottom polypropylene plate. The compound to be tested was solubilized in DMSO (Pierce), 10 mM, then diluted in assay buffer to 3.6 nM.
  • assay buffer 50 mM Tris, pH 7.5 with 5 mM MgC12
  • a second 96 well round bottom polypropylene plate known as the premix plate
  • 60 ⁇ ⁇ of 6X compound was combined with 60 ⁇ ⁇ of 3.6 nM 3H-Diprenorphine (DPN).
  • 50 ⁇ ⁇ was transferred to an assay plate containing the membranes, in duplicate.
  • the assay plate was incubated for 18 h at room temperature.
  • a GF/C 96 well filter plate (Perkin Elmer #6005174) was pretreated with 0.3% polyethylenimine for 30 min.
  • the contents of the assay plate were filtered through the filter plate using a Packard Filtermate Harvester, and washed 3 times with 0.9% saline at 4°C.
  • the filter plate was dried, underside sealed, and 30 ⁇ ⁇ Microscint 20 (Packard #6013621) was added to each well.
  • a Topcount-NXT Microplate Scintillation Counter (Packard) was used to measure emitted energies in the range of 2.9 to 35 KeV. Results were compared to maximum binding, wells receiving no inhibitions.
  • Nonspecific binding was determined in presence of 50 ⁇ unlabeled naloxone.
  • the biological activity of the dimer is shown in Figure 4.
  • buprenorphine monomer and the dimer. Neither the monomer nor the dimer of
  • buprenorphine has lost its affinity for the ⁇ receptor.
  • the binding of the buprenorphine dimer to opioid ⁇ receptor increases with concentration. It is estimated that at about 1 ⁇ g, the profile of the opioid ⁇ receptor affinity of the dimer was similar to that of buprenorphine.
  • the assay was designed to test the ability of a compound to interfere with the binding of tritiated naltrindole to the human ⁇ subtype 2 opioid receptor.
  • Membranes from Chinese Hamster Ovary cells expressing the human ⁇ subtype 2 opioid receptor (Perkin Elmer #RBHODM400UA) were homogenized in assay buffer (50 mM Tris, pH 7.5 with 5 mM MgC12) using a glass tissue grinder, Teflon pestle and Steadfast Stirrer (Fisher
  • the dimer had poor affinity for the ⁇ receptor.
  • This example illustrates the ability of the buprenorphine dimer compound provided herein to stimulate the ⁇ -opioid receptor-mediated signaling.
  • CHO-hMOR Human ⁇ Receptors
  • membranes were added to 15 mL cold binding assay buffer containing 50 mM HEPES, pH 7.6, 5 mM MgC12, 100 mM NaCl, 1 mM DTT and 1 mM EDTA.
  • the membrane suspension was homogenized with a polytron and centrifuged at 3000 rpm for 10 min. The supernatant was done centrifuged at 18,000 rpm for 20 min. The pellet was resuspended in 10 ml assay buffer with a polytron.
  • the membranes were pre-incubated with wheat germ agglutinin coated SPA beads (Amersham) at 25°C, for 45 min in the assay buffer.
  • the SPA bead (5 mg/ml) coupled with membranes (10 ⁇ g/ml) were then incubated with 0.5 nM [35S]GTPyS in the assay buffer.
  • the basal binding was that taking place in the absence of added test compound; this unmodulated binding was considered as 100%, with agonist stimulated binding rising to levels significantly above this value.
  • a range of concentrations of receptor agonist SNC80 was used to stimulate [35S]GTPyS binding. Both basal and non-specific binding were tested in the absence of agonist; non-specific binding determination included 10 ⁇ unlabeled
  • Buprenorphine dimer was tested for function as an antagonist by evaluating its potential to inhibit agonist-stimulated GTPyS binding using D-Phe-Cys-Tyr-D-Trp-Orn-Thr- Pen-Thr-NH2 (CTOP) as the standard. Radioactivity was quantified on a Packard Top Count. The following parameters were calculated:
  • % Stimulation [(test compound cpm- non-specific cpm)/(basal cpm - non-specific cpm)]*100
  • % Inhibition (% stimulation by 1 ⁇ SNC80 -% stimulation by 1 ⁇ SNC80 in presence of test compound)* 100/(%stimulation by 1 ⁇ SNC80- 100).
  • EC50 was calculated using GraphPad Prism. A graph for the compound tested is shown in Figures 5 and 6. Results: Data shown in Figure 5 indicates that the dimer is a potent ⁇ agonist. The results also indicate that the opioid ⁇ receptor activity of the dimer at 10-6M ( ⁇ 1 ⁇ g) is similar to that of buprenorphine. Data in Figure 6 shows that the dimer does not function as a ⁇ - antagonist.
  • Example 5 Anti-Hyperalgesic Properties of the Dimer
  • a weak acetic acid solution administered rectally to neonatal mice results in colonic hypersensitivity when the mice reach maturity, at 8-10 weeks of age.
  • the resulting hyperalgesic condition is similar to that in irritable bowel syndrome (IBS) in humans, where hypersensitivity, and resulting hyperalgesia, is a major component of the disorder.
  • IBS irritable bowel syndrome
  • mice were given a rectal infusion of 20 ul of 0.5% acetic acid or saline at 10 days after birth. After reaching adulthood (8-10 weeks of age), a pair of electrodes was placed in the abdominal external oblique muscle, 5-10 days before the test.
  • VMR visceral motor reflex
  • CCD colonic rectal distention
  • mice were then taken out of the tubes and gavaged with ORP-101 (50mg/kg), or vehicle and were then placed back to the tube.
  • VMR responses to CRD (30 mmHg) were measured 30 and 60 minutes after the administration of ORP-101 or saline. Each measurement was repeated 2 times and the average response was calculated.
  • composition of a vial of the infusion solution contains: a) 20 mg dimer base as the dihydrochloride salt, 400 mg PEG 300, 600 mg Polysorbate 80, 25 mg of soybean oil, and 5 mg of citric acid anhydrous.
  • Example 7 Subcutaneous Solution For Acute Treatment
  • ORP-101 diHCl salt equivalent to 1 g of free base is added to 1 L of sterile water for injection containing 50 g dextrose and mixed until fully dissolved.
  • the 1 mg/mL drug base solution is sterile filtered and aseptically filled into clear glass vials and capped under nitrogen with caps that have no detectable leachables or extractables.
  • a liquid lipid stock solution is prepared by inverted mixing overnight containing soy phosphatidylcholine (PC) 40 g, glycerol monoleate (GMO) 40 g, ethanol 10 g, and tocopherol 0.3 g as an antioxidant. 10 g of the dimer as dihydrochloride salt is added to the stock solution and mixed. The solution is sterile filtered into glass vials capped with Teflon lined caps. The solution can be injected through a 21 gauge needle, and at body temperature in contact with water, it gels to form a viscous depot as the solvent disappears.
  • PC soy phosphatidylcholine
  • GMO glycerol monoleate
  • ethanol 10 g ethanol
  • tocopherol 0.3 g as an antioxidant. 10 g of the dimer as dihydrochloride salt is added to the stock solution and mixed.
  • the solution is sterile filtered into glass vials capped with Teflon lined caps. The solution can be injected

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé et des compositions destinés au traitement de la douleur neuropathique périphérique par administration à un patient d'une quantité thérapeutiquement efficace d'un composé de dimère de buprénorphine, les deux parties de buprénorphine étant liées par un élément d'espacement d'éthylène, et l'élément d'espacement étant lié aux deux molécules opioïdes par l'intermédiaire d'une liaison éther. De préférence, l'agent actif se présente sous la forme d'un médicament retard injectable.
PCT/US2016/058593 2015-10-26 2016-10-25 Utilisation de dimère de buprénorphine dans le traitement de douleur neuropathique périphérique WO2017074903A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14/922,373 2015-10-26
US14/922,373 US9549924B2 (en) 2014-04-28 2015-10-26 Use of buprenorphine dimer in the treatment of peripheral neuropathic pain

Publications (1)

Publication Number Publication Date
WO2017074903A1 true WO2017074903A1 (fr) 2017-05-04

Family

ID=58631771

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/058593 WO2017074903A1 (fr) 2015-10-26 2016-10-25 Utilisation de dimère de buprénorphine dans le traitement de douleur neuropathique périphérique

Country Status (2)

Country Link
TW (1) TW201725040A (fr)
WO (1) WO2017074903A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7759358B2 (en) * 2003-07-23 2010-07-20 Crooks Peter A Oral bioavailable prodrugs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7759358B2 (en) * 2003-07-23 2010-07-20 Crooks Peter A Oral bioavailable prodrugs

Also Published As

Publication number Publication date
TW201725040A (zh) 2017-07-16

Similar Documents

Publication Publication Date Title
US9549924B2 (en) Use of buprenorphine dimer in the treatment of peripheral neuropathic pain
US7736665B2 (en) Implantable polymeric device for sustained release of buprenorphine
US20230312639A1 (en) Gper proteolytic targeting chimeras
ES2930757T3 (es) Una formulación de fármaco para uso en el control eficaz del dolor agudo y/o crónico
WO2017074903A1 (fr) Utilisation de dimère de buprénorphine dans le traitement de douleur neuropathique périphérique
US11464772B2 (en) Methods of treating acute or chronic pain
US20100160364A1 (en) Remedy or preventive for integration dysfunction syndrome
US10118921B2 (en) Diarylmethylidene piperidine derivatives and their use as delta opoid receptor agnists
WO2022175973A1 (fr) Composition injectable pour l'administration à long terme de nalbuphine ou d'un promédicament d'ester de nalbuphine ou de ses sels et son utilisation
US20180305370A1 (en) Ethylene glycol ether of buprenorphine
NZ724989B2 (en) Buprenorphine dimer and its use in treatment of gastrointestinal disorders

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16860597

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16860597

Country of ref document: EP

Kind code of ref document: A1