[go: up one dir, main page]

WO2015192772A1 - Application médicale d'un antagoniste des récepteurs nmda et composition pharmaceutique basée sur ce dernier - Google Patents

Application médicale d'un antagoniste des récepteurs nmda et composition pharmaceutique basée sur ce dernier Download PDF

Info

Publication number
WO2015192772A1
WO2015192772A1 PCT/CN2015/081637 CN2015081637W WO2015192772A1 WO 2015192772 A1 WO2015192772 A1 WO 2015192772A1 CN 2015081637 W CN2015081637 W CN 2015081637W WO 2015192772 A1 WO2015192772 A1 WO 2015192772A1
Authority
WO
WIPO (PCT)
Prior art keywords
nasal
sodium
group
nmda receptor
receptor antagonist
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2015/081637
Other languages
English (en)
Chinese (zh)
Inventor
王培全
张磊
周夏君
李成海
包如迪
徐耀昌
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Hansoh Biomedical Co Ltd
Original Assignee
Shanghai Hansoh Biomedical Co Ltd
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
Application filed by Shanghai Hansoh Biomedical Co Ltd filed Critical Shanghai Hansoh Biomedical Co Ltd
Priority to CN201580028785.6A priority Critical patent/CN106413708A/zh
Publication of WO2015192772A1 publication Critical patent/WO2015192772A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides

Definitions

  • the invention belongs to the technical field of medicines, and in particular relates to a medical use of an NMDA receptor antagonist, and a pharmaceutical composition comprising the NMDA receptor antagonist.
  • Depression is a mental disorder characterized by significant and persistent depression as the main clinical feature and the main type of affective disorder. Clinically, the depression is not commensurate with its situation.
  • the depression of emotions can range from sullen to grief, inferiority depression, and even pessimistic, may have suicide attempts or behaviors; even stupor; some cases have obvious anxiety and motor agitation; In severe cases, psychotic symptoms such as hallucinations and delusions may occur. Each episode lasts for at least 2 weeks, and the elderly or even years. Most cases have a tendency to recurrent. Most of the episodes can be relieved, and some may have residual symptoms or become chronic.
  • Non-pharmacological therapies include electromagnetic therapy, shock therapy, and psychotherapy.
  • Drug therapy uses a wide variety of drugs, mainly divided into three categories, serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI) and tricyclic antidepressants.
  • SSRI serotonin reuptake inhibitors
  • SNRI norepinephrine reuptake inhibitors
  • tricyclic antidepressants tricyclic antidepressants.
  • the first line of clinical antidepressants mainly include selective serotonin reuptake inhibitors (SSRI, representing the drugs fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram and escitalopram) , serotonin and norepinephrine reuptake inhibitors (SNRI, representing the drugs venlafaxine and duloxetine), norepinephrine and specific serotoninergic antidepressants (NaSSA, representing the drug rice nitrogen equality.
  • SSRI selective serotonin reuptake inhibitors
  • SNRI serotonin and norepinephrine reuptake inhibitors
  • NaSSA norepinephrine and specific serotoninergic antidepressants
  • Traditional tricyclic, tetracyclic antidepressants and monoamine oxidase inhibitors have significantly reduced adverse effects due to their adverse reactions. Although these drugs have certain antidepressant effects, there is still much room for improvement.
  • these drugs have more toxic side effects, such as nausea, weight gain, insomnia, etc.; for example, only a small number of patients respond to them, many patients have poor response to these drugs or produce tolerance; in addition, currently used These antidepressants have a slower onset of action and even increase the risk of suicide. Therefore, there is an urgent need to develop anti-depressant drugs that are safe, effective, and effective.
  • NMDAR N-methyl-D-aspartate receptor
  • the NMDA receptor has two regulatory sites: glutamate and glycine regulatory sites. In vivo, the activity of NMDAR is regulated by both glutamate and glycine.
  • ketamine also known as K powder.
  • Ketamine is a channel blocker for NMDA receptors and was originally used clinically as an anesthetic. Later, a large number of studies found that low doses of ketamine have a rapid antidepressant effect (onset after taking the drug for several hours), and the antidepressant effect can last for a long time (1-3 weeks). The rapid and long-lasting antidepressant function of ketamine has aroused widespread interest and research. However, the side effects caused by ketamine, including the symptoms of hallucinations and schizophrenia, and addiction limit its use in depression.
  • GLYX-13 is a small peptide composed of four amino acids (the structural formula is as follows), and GLYX-13 also has a rapid and long-lasting antidepressant effect. Unlike ketamine, GLYX-13 binds to the glycine site of the NMDA receptor and acts by modulating the activity of the NMDA receptor. In addition, GLYX-13 avoids serious side effects like ketamine and regulation of use. Preclinical studies suggest that in addition to antidepressant, GLYX-13 also has an adjuvant therapeutic effect on other neurological diseases. These diseases include autism, schizophrenia, bipolar disorder, anxiety and Alzheimer's disease, neuralgia and detoxification. Due to its superior performance in antidepressant, GLYX-13 was named one of the top 10 (TOP10) drugs in the neurological field in 2013, and was promoted by the US FDA as a rapid development channel drug in 2014.
  • TOP10 top 10
  • GLYX-13 is a small peptide composed of four amino acids (the structural formula is as follows) which is easily eliminated in the body.
  • Clinical experimental data indicate (Moskal JR, Bruch R, Burgdorf JS, et al. GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists.ExpertOpin.Investig.Drugs (2014) 23(2): 243-254), the human body has a rapid elimination rate of GLYX-13, and the plasma half-life of intravenous administration is 10 minutes or less. According to reports (Moskal JR, Kuo AG, Weiss C, et al.
  • GLYX-13 a monoclonal antibody-derived peptide, acts as an N-methyl-D-aspartate receptor modulator.
  • Neuropharmacology 2005; 49(7): 1077-87 GLYX-13 is relatively stable in rat brain homogenate, with a half-life of about 18 hours. It is concluded that the drug may be relatively stable in the brain group.
  • the main mode of administration of GLYX-13 is intravenous administration, but this mode of administration cannot reduce the rapid elimination of the drug by the human (human or animal) body, so that the drug reaching the brain tissue is significantly reduced.
  • NMDA receptor antagonists such as GYLX-13 are mainly administered by intravenous injection.
  • WO201104089A2 discloses various possible administration modes of GLYX-13: 1.
  • oral administration for example, the drug is tableted. , capsules, granules, powders and syrups.
  • parenteral administration such as injection, intravenous, intramuscular, subcutaneous, intravenous drip.
  • eye administration such as eye ointment and eye drops.
  • topical administration buccal administration, sublingual administration, rectal administration, vaginal administration. 5.
  • An ointment or the like is prepared by transdermal absorption administration.
  • the above-mentioned modes of administration are to transfer the drug to the blood and then to the central nervous system through the systemic circulation. Therefore, before reaching the brain, GLYX-13 is mostly eliminated by the body and cannot reach the brain tissue.
  • the intravenous administration method itself has a problem of patient compliance, because the patient cannot administer the vein by himself, and must go to the medical institution to complete the administration, which brings great inconvenience to the patient.
  • an NMDA receptor antagonist such as GYLX-13, that is, an NMDA receptor antagonist, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. It is delivered to the central nervous system of mammals without undergoing systemic circulation for the treatment or prevention of central nervous system diseases and/or mental illnesses. This application increases the concentration of NMDA receptor antagonists in brain tissue, significantly reducing the amount of drug used and reducing systemic side effects.
  • a first aspect of the present invention relates to the use of an NMDA receptor antagonist for the preparation of a medicament for the treatment or prevention of diseases of the central nervous system and/or psychiatric disorders, an NMDA receptor antagonist, a pharmaceutically acceptable salt thereof or a pharmaceutical combination thereof
  • the substance is delivered to the central nervous system of a mammal (eg, a human) by targeted administration; the central nervous system and/or mental illness is selected from the group consisting of depression, Alzheimer's disease, Alzheimer's disease, seizures, neuralgia Or detoxification symptoms.
  • the targeted administration method directly enters the central nervous system of a mammal (e.g., a human) without undergoing systemic circulation or blood-brain barrier.
  • a mammal e.g., a human
  • the targeted administration method is intraventricular injection, nasal administration.
  • NMDA receptor antagonists such as GLYX-13 in brain tissue, greatly reducing the amount of drugs and reducing systemic side effect.
  • the nasal administration route is a brain-targeted administration route, and the administration method has high bioavailability in the brain, is convenient to use, can avoid stimulation to the gastrointestinal tract and liver first pass effect, and the drug can pass through the blood brain barrier. Quickly enter the central nervous system.
  • the targeted administration mode in the present invention means that most of the drug is directly delivered to the central nervous system without It is necessary to pass the drug through the systemic circulation and through the blood-brain barrier to the central nervous system.
  • the NMDA receptor antagonist is selected from the group consisting of Xiping, pethidine, methadone, dextropropoxyphene, tramadol, phenolic acetonide, dextromethorphan, phencyclidine, amantadine hydrochloride, isobutyl acetate, dextrorphan, gacyclidine, Ibogine, memantine, cyclacycline, tenoline, thietylamine, elilol, remicarbamide, atatina, rhynchophylline, kynurenic acid, lacosamide, GLYX- 13. AP5, AP7, WMS2539 or a combination thereof.
  • the NMDA receptor antagonist is selected from the group consisting of GLYX-13.
  • the targeted administration method is administered at a dose of 0.001 to 500 mg/kg/day; preferably, the administered dose is 0.01 to 100 mg/kg/day; more preferably, the administered dose is 0.1-20 mg/kg. /day.
  • the nasal administration method is: preparing the NMDA receptor antagonist, the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof and the medicinal auxiliary into a pharmaceutically acceptable pharmaceutical preparation, and directly adopting the pharmaceutical preparation
  • the drug is absorbed into the nasal cavity and directly enters the central nervous system for treating or preventing central nervous system diseases and/or mental diseases.
  • the drug can be administered to the nasal cavity, and the drug delivery device that can be used can be a squeeze type, a spray type, a spray type, or a pressure quantitative absorption device.
  • NMDA receptors play a major role in synaptic plasticity, which forms the basis of many more advanced cognitive functions, such as memory acquisition, retention, and learning, as well as in certain cognitive pathways and in painful sensations. main function.
  • certain properties of NMDA receptors suggest that they may involve information processing that forms the basis of their own consciousness in the brain.
  • NMDA receptors have attracted particular interest because of their manifestations of a wide range of CNS disorders. For example, during brain ischemia caused by stroke or traumatic injury, excess excitatory amino acid glutamate is released from damaged or hypoxic neurons.
  • NMDA receptor The excess glutamate binds to the NMDA receptor, which opens their ligand-gated ion channels; in turn calcium influx produces high levels of intracellular calcium that activate biochemical grades that lead to protein degradation and cell death. Union. This phenomenon, known as excitotoxicity, is also believed to be responsible for nerve damage associated with other disorders ranging from hypoglycemia and cardiac arrest to epilepsy. In addition, preliminary reports have shown similar Huntington's disease, Parkinson's disease, and Alzheimer's disease involving chronic neurodegeneration. Activation of the NMDA receptor has been shown to be the cause of post-stroke convulsions, and in some epilepsy models it has been shown that activation of NMDA receptors is essential for the production of seizures.
  • NMDA receptors Neuropsychiatry involving NMDA receptors has also been identified as a disorder-like schizophrenia-like psychotic state is produced in humans by blocking the NMDA receptor Ca++ channel by the animal anesthetic PCP (phenepidine).
  • PCP phenepidine
  • NMDA receptors are also involved in certain types of spatial learning.
  • the pharmaceutically acceptable pharmaceutical preparation for nasal administration may be a nasal drop, a nasal in situ gel, a nasal aerosol, a nasal spray, or a nasal spray.
  • the nasal in situ gelling agent comprises an effective amount of an NMDA receptor antagonist, or a pharmaceutically acceptable salt thereof, a gel matrix, water, and one or more other pharmaceutical excipients.
  • the nasal drops, nasal sprays comprise an effective amount of an NMDA receptor antagonist or a pharmaceutically acceptable salt thereof, water, and one or more other pharmaceutical excipients.
  • the aforementioned other pharmaceutical excipients are selected from the group consisting of permeation enhancers, osmotic pressure regulators, pH adjusters or preservatives.
  • the gel matrix is selected from the group consisting of poloxamer 407, poloxamer 188, sodium alginate, gellan gum, chitosan and derivatives thereof, methylcellulose, hydroxypropyl Cellulose, polylactic acid-polyethylene glycol block copolymer, polycaprolactone polyethylene glycol block copolymer, poly N-isopropyl acrylamide or a combination thereof; preferably poloxamer 407, Polo Sam 188, gellan gum or a combination thereof; the penetration enhancer is selected from the group consisting of oleyl alcohol, lauryl alcohol, cetyl alcohol, linoleic acid, polyoxyethylene lauryl ether, isopropyl palmitate, isopropyl meat Stigmaster, lanolin, eucalyptol, menthol, saponin, dodecane nitrogen Ketone, camphor, liquid paraffin, dimethicone, glycerin, polyethylene glycol, cyclodextr, poloxamer 40
  • the nasal in situ gelling agent comprises an effective amount of an NMDA receptor antagonist or a pharmaceutically acceptable salt thereof
  • the gel matrix is selected from the group consisting of poloxamer 407, poloxamer 188,
  • the gellan gum or a combination thereof
  • the penetration enhancer is selected from the group consisting of azone or sodium berdeoxycholate
  • the osmotic pressure adjusting agent is selected from sodium chloride
  • the pH adjuster is selected from hydrochloric acid or sodium hydroxide
  • the preservative is selected from the group consisting of p-hydroxybenzoic acid. Ethyl ester, the rest is water.
  • NMDA receptor antagonists such as GLYX-13 are administered in situ by intranasal gel, which is easily inoculated in vitro.
  • the dosage is easy to control, easy to use, sprayed into the nasal cavity and evenly dispersed on the surface of the nasal mucosa, and diffused with nasal mucus. A gel is formed.
  • the drug stays in the nasal cavity for a longer period of time, which is less prone to loss, and increases the probability that the drug will directly enter the brain through the nasal brain pathway to exert its efficacy.
  • the drug is absorbed through the nasal cavity, avoiding The systemic circulation is eliminated, so that the dosage can be drastically reduced.
  • the patient can be administered autonomously and is painless, and thus has good patient compliance.
  • composition and content (W/V) of each component of the nasal gel is:
  • composition and content (W/V) of each component of the nasal gel is:
  • the nasal powder comprises an effective amount of an NMDA receptor antagonist or a pharmaceutically acceptable salt thereof, and one or more other pharmaceutical excipients.
  • the other pharmaceutical excipient is selected from the group consisting of a carrier powder, a penetration enhancer, an adhesive, a glidant, a surfactant, and a diluent.
  • the carrier powder is selected from the group consisting of starch, lactose, mannitol, sorbitol, pregelatinized starch, cyclodextrin or a combination thereof;
  • the adhesion agent and the glidant are selected from the group consisting of sodium alginate, Acacia gum, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, starch, sodium carboxymethyl starch, pregelatinized starch, cyclodextrin or a combination thereof;
  • the surfactant is selected from the group consisting of a polysorbate, a poloxamer, a benzide or a combination thereof;
  • the diluent is selected from the group consisting of starch, lactose, mannitol, sorbitol, pregelatinized starch, cyclodextrin or a combination thereof;
  • the penetration enhancer is selected from the group consisting of starch, lactose, manni
  • the NMDA receptor antagonist pharmaceutical composition is a pharmaceutical composition comprising an NMDA receptor antagonist and any other one or more central nervous system drugs.
  • the other central nervous system drug is selected from the group consisting of a sedative hypnotic, an anti-epileptic drug, an antipsychotic, an antidepressant, an analgesic or a neurodegenerative drug.
  • other central nervous system drugs may be benzodiazepines Drugs such as chloronitrogen , diazepam, chlorobakjane, lorazepam, estazolam, or barbiturates (eg, albbital, isobarbital, aprabital, phenidate, bar Betato, bromide, phenobarbital, thiopental), or non-benzodiazepine a gamma-aminobutyric acid (GABA) receptor agonist (such as zolpidem, zaleplon, zopiclone), or a cyclic ureide (such as phenytoin), or dibenzo nitrogen Classes (such as carbamazepine, oxcarbazepine), GABA derivatives (such as progaol, gabapentin, aminohexenoic acid), fatty carboxylic acids (such as valproic acid, sodium valproate, valproic acid), Pheno
  • Drugs such as
  • a fourth aspect of the present invention provides a pharmaceutical preparation comprising an effective amount of an NMDA receptor antagonist or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of nasal nasal drops, nasal sprays, Nasal in situ gels and nasal powders are administered by targeted administration to the central nervous system of a mammal; preferably delivered to the central nervous system of a mammal by nasal administration.
  • an NMDA receptor antagonist or a pharmaceutically acceptable salt thereof which is selected from the group consisting of nasal nasal drops, nasal sprays, Nasal in situ gels and nasal powders are administered by targeted administration to the central nervous system of a mammal; preferably delivered to the central nervous system of a mammal by nasal administration.
  • the nasal in situ gelling agent comprises an effective amount of an NMDA receptor antagonist, or a pharmaceutically acceptable salt thereof, a gel matrix, water, and one or more other pharmaceutical excipients;
  • Nasal drops, nasal sprays comprising an effective amount of an NMDA receptor antagonist or a pharmaceutically acceptable salt thereof, water, and one or more other pharmaceutical excipients;
  • the nasal powder comprising an effective amount of an NMDA receptor An antagonist or a pharmaceutically acceptable salt thereof, and one or more other pharmaceutical excipients.
  • the gel matrix and other pharmaceutically acceptable excipients may be the second in the present invention.
  • the range of options provided by the aspects may also be pharmaceutical excipients known to those skilled in the art.
  • the present invention delivers an NMDA receptor antagonist such as GYLX-13 to a mammalian central nervous system by targeted administration without undergoing systemic circulation for treating or preventing central nervous system diseases and/or spirits.
  • the disease increases the concentration of NMDA receptor antagonists in brain tissue, significantly reducing the amount of drug used and reducing systemic side effects.
  • the composition and content of the components in the pharmaceutical composition or formulation of the present invention are different from the prior art by this particular mode of administration.
  • the method of administration of the invention has high bioavailability in the brain and is convenient to use, can avoid stimulation of the gastrointestinal tract and liver effect, and the medicine can quickly enter the central nervous system through the blood-brain barrier.
  • the in situ gel, administered through the nasal cavity is in a liquid state in vitro, the dosage is easily and accurately controlled, and is convenient to use, and can be uniformly dispersed on the surface of the nasal mucosa after being sprayed into the nasal cavity, and diffused with the nasal mucus to form a gel.
  • the drug stays in the nasal cavity for a longer period of time, which is less prone to loss, and increases the probability that the drug will directly enter the brain through the nasal brain pathway to exert its efficacy.
  • the drug is absorbed through the nasal cavity, which avoids the elimination of the drug in the systemic circulation.
  • the dosage of the drug can be greatly reduced, and the patient can be administered autonomously and is painless, so that the patient has a good patient. Compliance.
  • the present invention solves the problem of high drug elimination rate and poor drug compliance caused by the prior art drug delivery method, and has a wide range of clinical medical applications.
  • Component Quality (g) Composition (W/V, %) GLYX-13 200 20 Poloxamer 407 100 10 Polosham 188 10 1 Azone 5 0.5 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 1 0.1 Hydrochloric acid/sodium hydroxide Moderate amount / Water for Injection Add to 1000ml /
  • Component Quality (g) Composition (W/V, %) GLYX-13 200 20 Poloxamer 407 200 20 Polosham 188 50 5 Azone 15 1.5 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 3 0.3 Hydrochloric acid/sodium hydroxide Moderate amount / Water for Injection Add to 1000ml /
  • 900 ml of water for injection was taken, and a prescribed amount of ethyl p-hydroxybenzoate, sodium chloride and azone were added and stirred to dissolve.
  • a prescription of poloxamer 407 and poloxamer 188 was taken and dispersed in the above solution to complete the bulk expansion into a clear solution.
  • Component Quality (g) Composition (W/V, %) GLYX-13 50 5 Poloxamer 407 255 25.5 Polosham 188 50 5 Sodium fulvate 50 5 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 1 0.1 Hydrochloric acid/sodium hydroxide Moderate amount / Water for Injection Add to 1000ml /
  • 900 ml of water for injection was taken, and a prescribed amount of ethyl p-hydroxybenzoate, sodium chloride, and sodium taurodeoxycholate was added, and the mixture was stirred and dissolved.
  • a prescription of poloxamer 407 and poloxamer 188 was taken and dispersed in the above solution to complete the bulk expansion into a clear solution.
  • Component Quality (g) Composition (W/V, %) GLYX-13 25 2.5 Poloxamer 407 200 20 Polosham 188 100 10 Azone 25 2.5 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 5 0.5 Hydrochloric acid/sodium hydroxide Moderate amount / Water for Injection Add to 1000ml /
  • Component Quality (g) Composition (W/V, %) GLYX-13 25 2.5 Poloxamer 407 100 10 Polosham 188 50 5 Azone 15 1.5 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 5 0.5 Hydrochloric acid/sodium hydroxide Moderate amount /
  • Component Quality (g) Composition (W/V, %) GLYX-13 25 2.5 Gellan gum 1 0.1 Azone 5 0.5 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 1 0.1 Hydrochloric acid/sodium hydroxide Moderate amount / Water for Injection Add to 1000ml /
  • Component Quality (g) Composition (W/V, %) GLYX-13 20 2 Gellan gum 25 2.5 Azone 10 1 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 2 0.2 Hydrochloric acid/sodium hydroxide Moderate amount / Water for Injection Add to 1000ml /
  • Component Quality (g) Composition (W/V, %) GLYX-13 25 2.5 Gellan gum 50 5 Azone 20 2 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 5 0.5 Hydrochloric acid/sodium hydroxide Moderate amount / Water for Injection Add to 1000ml /
  • Component Quality (g) Composition (W/V, %) GLYX-13 25 2.5 Oxah 10 1 Poloxamer 407 200 20 Polosham 188 100 10 Azone 25 2.5 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 5 0.5 Hydrochloric acid/sodium hydroxide Moderate amount /
  • 900 ml of water for injection was taken, and a prescribed amount of ethyl p-hydroxybenzoate, sodium chloride and azone were added and stirred to dissolve.
  • a prescription of poloxamer 407 and poloxamer 188 was taken and dispersed in the above solution to complete the bulk expansion into a clear solution.
  • Component Quality (g) Composition (W/W, %) GLYX-13 55 55 Hydroxypropyl cellulose twenty three twenty three Sodium fulvate 5 5 lactose 17 17
  • GLYX-13 hydroxypropylcellulose, lactose, sodium taurodeoxycholate are micronized to a particle size of 0.1-10 micron, fully mixed, and dispensed into a single-dose nasal drug delivery device.
  • Component Quality (g) Composition (W/V, %) GLYX-13 1 0.1 Azone 5 0.5 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 1 0.1 Hydrochloric acid/sodium hydroxide Moderate amount / Water for Injection Add to 1000ml /
  • Component Quality (g) Composition (W/V, %) GLYX-13 50 5 Azone 2 0.2 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 3 0.3 Hydrochloric acid/sodium hydroxide Moderate amount / Water for Injection Add to 1000ml /
  • Component Quality (g) Composition (W/V, %) GLYX-13 50 5 Estazolam 1 0.1 Azone 10 1 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 5 0.5 Hydrochloric acid/sodium hydroxide Moderate amount / Water for Injection Add to 1000ml /
  • Diazepam 5 0.5 Azone 1 0.1 Sodium chloride 9 0.9 Ethyl p-hydroxybenzoate 2 0.2 Hydrochloric acid/sodium hydroxide Moderate amount / Water for Injection Add to 1000ml /
  • 900 ml of water for injection was taken, and a prescribed amount of ethyl p-hydroxybenzoate, sodium chloride and azone were added and stirred to dissolve.
  • the prescription amounts of GLYX-13 and diazepam were added, and the pH was adjusted to 5.0-7.4 after dissolution. Dispense into a nebulized nasal delivery device.
  • PK and distribution test of nasal drug In this experiment, SD rats weighing 200-300 g were selected, and the rats were intranasally instilled with drugs at a dose of 10 mg/kg body weight. The rats were inhaled by themselves to simulate the active autonomous drug administration process.
  • the experimental method is as follows:
  • GLYX-13 can be detected in the blood and brain tissues of rats after nasal administration, which proves that the nasal administration mode can make GLYX-13 smoothly enter the brain, and the drug is unexpectedly found to be relatively gentle. Entering the brain, metabolic clearance is relatively slow and persists in the brain for a long time.
  • GLYX-13 can be rapidly distributed to mammalian brain tissue. As shown in the above results, after nasal administration, most of the drugs entered the brain tissue, and the proportion of cerebral blood drug distribution (B/P) was about 3.3, which was proportional to the proportion of cerebral blood drugs administered intravenously (B/P). For 0.32, there has been a great improvement. Therefore, nasal administration can more specifically target GLYX-13 into brain tissue and improve drug intake. The efficiency of the brain, which can significantly reduce the amount of drugs used.
  • Nasal administration increases the probability that the drug directly enters the brain through the nasal passage to exert its efficacy, avoids the elimination of the drug in the systemic circulation, and prolongs the half-life of the drug, thereby facilitating the bioavailability of the drug in the brain.
  • GLYX-13 is rapidly eliminated in the body, it requires a large dose to ensure that the drug can be delivered to the brain, so the blood concentration of the drug fluctuates greatly, which inevitably gives Psychiatric patients bring irritation and overreaction.
  • the concentration of the drug is extended to 1 hour in the brain, and the blood concentration is sustained and stable, thereby avoiding the stimulation or over-excitation of the mentally ill and facilitating the intravenous injection.
  • Administration results in the disadvantage of poor compliance of the mental patient.
  • nasal administration allows the patient to be administered autonomously anytime and anywhere, and is safe and non-invasive, thereby making the use of the drug more convenient.
  • the convenience of this application method has a very positive benefit for the timely treatment and disease control of patients suffering from mental illness, and therefore has a wide clinical application value.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une application pharmaceutique d'un antagoniste des récepteurs NMDA. L'antagoniste des récepteurs NMDA et un sel pharmaceutiquement acceptable ou d'une composition pharmaceutique de ces derniers sont utilisés pour préparer des médicaments destinés au traitement ou à la prévention de maladies du système nerveux central et/ou de maladies mentales, et l'antagoniste des récepteurs NMDA est transporté vers le système nerveux central humain par l'intermédiaire d'une administration ciblée de médicament. L'invention concerne également une composition pharmaceutique contenant l'antagoniste des récepteurs NMDA. La composition est un gel nasal in situ, des gouttes nasales, un aérosol nasal ou une poudre nasale.
PCT/CN2015/081637 2014-06-18 2015-06-17 Application médicale d'un antagoniste des récepteurs nmda et composition pharmaceutique basée sur ce dernier Ceased WO2015192772A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201580028785.6A CN106413708A (zh) 2014-06-18 2015-06-17 Nmda受体拮抗剂的医药用途及其药物组合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410272815.5A CN105327349A (zh) 2014-06-18 2014-06-18 Nmda受体拮抗剂的医药用途及其药物组合物
CN201410272815.5 2014-06-18

Publications (1)

Publication Number Publication Date
WO2015192772A1 true WO2015192772A1 (fr) 2015-12-23

Family

ID=54934877

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/081637 Ceased WO2015192772A1 (fr) 2014-06-18 2015-06-17 Application médicale d'un antagoniste des récepteurs nmda et composition pharmaceutique basée sur ce dernier

Country Status (2)

Country Link
CN (2) CN105327349A (fr)
WO (1) WO2015192772A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108969478A (zh) * 2018-08-29 2018-12-11 江南大学 一种美金刚难溶盐缓释注射剂及其制备方法

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7096813B2 (ja) * 2016-08-26 2022-07-06 エクシーバ ゲーエムベーハー 組成物及びその方法
CN106668865B (zh) * 2017-01-23 2019-07-23 牡丹江医学院 用于治疗脑缺血的药物组合物、制剂及其应用
JP2022538608A (ja) * 2019-06-28 2022-09-05 ザ トラスティーズ オヴ ザ ユニヴァーシティー オヴ ペンシルバニア アルツハイマー病の治療のための鼻腔内ダントロレン投与
CN110433133A (zh) * 2019-08-19 2019-11-12 中国人民解放军军事科学院军事医学研究院 治疗创伤后应激障碍的大麻二酚鼻用制剂
CN113117080A (zh) * 2019-12-30 2021-07-16 珠海沅芷健康科技有限公司 一种向脑部递送β2肾上腺素受体激动剂的方法
CN116265016B (zh) * 2022-12-21 2024-03-22 大连医科大学 癫痫疾病药物的组合物及其用于制备治疗癫痫疾病药物的用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011003064A2 (fr) * 2009-07-02 2011-01-06 Naurex, Inc. Procédés de traitement d'une douleur neuropathique
CN102283801A (zh) * 2010-06-17 2011-12-21 江西中医学院 一种治疗脑部疾病的鼻腔给药凝胶制剂
WO2012149389A2 (fr) * 2011-04-27 2012-11-01 Northwestern University Procédés de traitement de la maladie d'alzheimer, de la maladie de huntington, de l'autisme ou autres troubles
CN103169649A (zh) * 2013-04-11 2013-06-26 中国人民解放军总医院 温度和离子双重敏感型原位凝胶鼻腔给药系统

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HRP20140784T1 (hr) * 2009-10-05 2014-10-10 Northwestern University Glyx-13 za uporabu u postupku tretiranja refraktornih depresija

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011003064A2 (fr) * 2009-07-02 2011-01-06 Naurex, Inc. Procédés de traitement d'une douleur neuropathique
CN102283801A (zh) * 2010-06-17 2011-12-21 江西中医学院 一种治疗脑部疾病的鼻腔给药凝胶制剂
WO2012149389A2 (fr) * 2011-04-27 2012-11-01 Northwestern University Procédés de traitement de la maladie d'alzheimer, de la maladie de huntington, de l'autisme ou autres troubles
CN103169649A (zh) * 2013-04-11 2013-06-26 中国人民解放军总医院 温度和离子双重敏感型原位凝胶鼻腔给药系统

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108969478A (zh) * 2018-08-29 2018-12-11 江南大学 一种美金刚难溶盐缓释注射剂及其制备方法

Also Published As

Publication number Publication date
CN105327349A (zh) 2016-02-17
CN106413708A (zh) 2017-02-15

Similar Documents

Publication Publication Date Title
WO2015192772A1 (fr) Application médicale d'un antagoniste des récepteurs nmda et composition pharmaceutique basée sur ce dernier
US20200253894A1 (en) Intranasal administration of ketamine to treat depression
Khosrow Tayebati et al. Intranasal drug delivery to the central nervous system: present status and future outlook
US11602521B2 (en) N,N-dimethyltryptamine compositions and methods
US20130072532A1 (en) Topical transdermal dexmedetomidine compositions and methods of use thereof
WO2025098365A1 (fr) Pulvérisation nasale de lévodopa, son procédé de préparation et son utilisation
CN114028335A (zh) 一种阿戈美拉汀溶液鼻喷剂及其应用
CN114366714A (zh) 一种阿戈美拉汀混悬鼻喷剂及其应用
RS60554B1 (sr) Intranazalna kompozicija koja sadrži betahistin
CN117771181A (zh) 一种人参皂苷f1的鼻黏膜制剂及其制备方法和用途
JP2021513977A (ja) レストレスレッグズ症候群を治療するための治療薬
CN1961879A (zh) 组成石杉碱甲鼻用原位凝胶喷雾剂的药物组合物、其制备方法及用途
JP2024520510A (ja) 薬物抵抗性てんかんを処置する方法
WO2024026463A1 (fr) Composition pour l'administration nasale d'un composé actif
CN119326740A (zh) 一种治疗生物节律失调的鼻脑递释制剂
AU2023222825A1 (en) Medication
WO2022123607A1 (fr) Formulations pharmaceutiques d'eskétamine
CA3042013C (fr) Composition pharmaceutique et methode de traitement de dysfonctions sexuelles feminines
EP4329722A1 (fr) Utilisation d'alcool périllylique pour améliorer l'administration de levo-dopa
KR20070017136A (ko) 정신과적 질환의 치료를 위한 ｎｍｄａ 수용체 길항제와항우울제 ｍａｏ 억제제 또는 ｇａｄｐｈ 억제제의 조합물

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: 15810118

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: 15810118

Country of ref document: EP

Kind code of ref document: A1