CN105327349A - Medical purpose of NMDA acceptor antagonist and pharmaceutical composition thereof - Google Patents
Medical purpose of NMDA acceptor antagonist and pharmaceutical composition thereof Download PDFInfo
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- CN105327349A CN105327349A CN201410272815.5A CN201410272815A CN105327349A CN 105327349 A CN105327349 A CN 105327349A CN 201410272815 A CN201410272815 A CN 201410272815A CN 105327349 A CN105327349 A CN 105327349A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention discloses a medical purpose of an NMDA acceptor antagonist and a pharmaceutical composition thereof. The invention concretely discloses a medicine for using the NMDA acceptor antagonist, a pharmaceutically acceptable salt or a pharmaceutical composition thereof for treating or preventing central nervous system disease and/or mental diseases, and the NMDA acceptor antagonist is delivered to a human central nervous system through target administration. An application of the pharmaceutical composition can increase the concentration of the NMDA acceptor antagonist in brain tissue, medicine amount is greatly reduced, and systematic side effect is reduced; biology availability in the brain is high, autonomous drug administration can be carried out by patients, no pain is generated, usage is convenient, and thus the pharmaceutical composition has good patient compliance, and has wide clinical medical science application.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to a kind of medical usage of nmda receptor antagonist, and comprise the pharmaceutical composition of nmda receptor antagonist.
Background technology
Depression is a kind of mental disorder disease, with remarkable and lasting depressed for main clinical characteristics, is the main Types of affective disorder.Clinical depressed unbecoming with its situation as seen, the downhearted of emotion can from depressed to extremely grieved, and depression of feeling oneself inferior is even pessimistic and worldweary, can have suicidal attempt or behavior; Even occur numb; Some cases have obvious anxiety and mobility intense; The psychotic symptoms such as hallucination, vain hope can be there is in severe patient.Even each outbreak continues at least 2 weeks more than, elder's several years, majority of cases has the tendency of recurrent exerbation, and each outbreak great majority can be alleviated, and part can have residual symptoms or transfer to chronic.
The whole world about has 1.2 hundred million people to suffer from depression.WHO prediction is the main cause causing disability to the year two thousand twenty depression.Asia mental science summit (APNS) of being sponsored by psychiatry branch of Chinese Medical Association from June, 2005 is learned: state-owned at present suffer from depression more than 2,600 ten thousand people, but only receive relevant Drug therapy less than the patient of 10%, total financial burden that depression brings China reaches 62,200,000,000 yuans.
At present, Cure of depression is carried out mainly through pharmacotherapy and non-drug therapy two kinds of strategies.Non-drug therapy comprises electromagnetotherapy, shock therapy and psychotherapy etc.The types of drugs that pharmacotherapy uses is more, is mainly divided into three major types, serotonin reuptake inhibitor (SSRI), 5-hydroxy tryptamine and NRI (SNRI) and Iricyclic antidepressants.The antidepressants of a line mainly comprise selective serotonin reuptake inhibitor (SSRI clinically at present, represent agents fluoxetine, paroxetine, Sertraline, fluvoxamine, citalopram and escitalopram), 5-hydroxy tryptamine and NRI (SNRI, represent medicine venlafaxine and duloxetine), norepinephrine and specificity 5-hydroxy tryptamine energy antidepressants (NaSSA represents medicine mirtazapine) etc.Traditional tricyclic antidepressants, tetracyclic antidepressants and oxidase inhibitor are comparatively large due to untoward reaction, apply and obviously reduce.Although these medicines have certain antidepressant curative effect, huge space is also had to have much room for improvement.Such as, these medicines have more toxic and side effects, as felt sick, putting on weight, insomnia etc.; For another example, only have small part patient to respond to it, a lot of patient is to these medicine Low Responses or produce tolerance opposing; In addition, these antidepressant drug onset times used at present are all slow, even increase the risk of suicide.Therefore, market in urgent need exploitation safety, effective and rapid-action antidepressant drug.
N-methyl D aspartate receptor (NMDAR) is a class ionotropic glutamate receptor, and its function mainly participates in the refinement of neural circuit in growth course and triggers the synaptic plasticity of various ways.Important physiological action is played in study, memory and emotion regulation process.Increasing research finds, NMDAR take part in multiple pathological process, comprises brain cell death, neural degenerative disease and the nerve/mental sickness such as schizophrenia, depression that apoplexy causes.Nmda receptor has two regulatory sites: glutamate, Glu (glutamate) and glycine (glycine) regulatory site.In vivo, the activity of NMDAR regulates by glutamic acid and glycine simultaneously.
Increasing evidence display NMDARs regulator (modulator) demonstrates great potential in depression.Main and direct source of evidence is in research ketamine (ketamine) being also referred to as to KET.Ketamine is the channel inhibitor (channelblocker) of nmda receptor, uses clinically at first as anaesthetic.Large quantifier elimination found afterwards, and the ketamine of low dosage has quick antidepressant effect (onset after a few hours of taking medicine), and antidepressant effect can continue long period (1-3 week).The fast long-acting antidepressant function of ketamine causes everybody interest and research widely.But the side effect that ketamine causes comprises the symptom of hallucination and schizophrenia and additively limits its application at depression.
The little peptide (structural formula is as follows) that GLYX-13 is made up of four aminoacid, GLYX-13 also has quick and durable antidepressant effect.With ketamine unlike, GLYX-13 is combined with the Glycine site of nmda receptor, works by regulating the activity of nmda receptor.In addition, GLYX-13 avoids the serious toxic and side effects of picture ketamine and the control used.Preclinical research prompting, except antidepressant, GLYX-13 still has auxiliary therapeutic action to other nervous system disease.These diseases comprise infantile autism, schizophrenia, bipolar affective disorder, anxiety and alzheimer's disease, neuralgia and treating narcotic addiction etc.Because GLYX-13 is in the superior performance of anti-depression aspect, one of 10 top (TOP10) medicines being cited as neural field for 2013, and pushed away as fast Development passage medicine in 2014 by U.S. FDA.
The little peptide (structural formula is as follows) that GLYX-13 is made up of four aminoacid is easily eliminated in vivo.Clinical laboratory data shows (MoskalJR, BruchR, BurgdorfJS, etal.GLYX-13, anNMDAreceptorglycinesitefunctionalpartialagonistenhance scognitionandproducesantidepressanteffectswithoutthepsyc hotomimeticsideeffectsofNMDAreceptorantagonists.ExpertOp in.Investig.Drugs (2014) 23 (2): 243-254), human body is very fast to the supersession rate of GLYX-13, and intravenously administrable plasma half-life is 10 minutes or shorter.And it is reported (MoskalJR, KuoAG, WeissC, etal.GLYX-13:amonoclonalantibody-derivedpeptidethatactsa sanN-methyl-D-aspartatereceptormodulator.Neuropharmacolo gy2005; 49 (7): 1077-87), GLYX-13 is metastable in big rat brain tissue homogenate, and the half-life, at 18 hours, infers that this medicine may be metastable in brain group.Research also shows that GLYX-13 is easy to through blood brain barrier.Therefore, the Main Bottleneck that GLYX-13 enters brain is the high clearance rate in body circulation.The main administering mode of current GLYX-13 is intravenous administration, but this administering mode cannot reduce the quick elimination of (human or animal) body to medicine, thus the medicine arriving cerebral tissue is significantly reduced.
Current nmda receptor antagonist such as GYLX-13 mainly passes through intravenous administration, in addition, WO201104089A2 discloses the multiple possible administering mode of GLYX-13: 1, by oral administration, such as this medicine is made tablet, capsule, granule, powder and syrup.2, by parenterai administration, as injection comprises, intravenous injection, intramuscular injection, subcutaneous injection, intravenous drip.3, by dosing eyes mode, as made Eye ointments and collyrium.4, comprised by topical modes, buccal administration, sublingual administration, rectally, vagina administration.5, by Transdermal absorption administration, ointment etc. is made.
It should be noted that above-mentioned administering mode is all that drug delivery is arrived central nervous system by body circulation again to blood, so GLYX-13 is before arrival brain, can is eliminated by body major part and cannot brain tissue be arrived.In addition, itself also there is patient compliance problem in intravenous administration mode, because patient cannot intravenous injection voluntarily, medical institutions must be gone to just to complete administration, bring great inconvenience to patient.
Therefore extremely it may be necessary the problem that new administering mode and preparation solve the high and administration compliance difference of medicine elimination factor that current medication causes.
Summary of the invention
In order to overcome the deficiencies in the prior art part, inventor finds through further investigation the application that a kind of nmda receptor antagonist such as GYLX-13 is new, by nmda receptor antagonist, its pharmaceutically-acceptable salts or its pharmaceutical composition targeted delivery to mammiferous central nervous system, and without body circulation, be used for the treatment of or prevent central nervous system disease and/or mental sickness.This application improves the concentration of nmda receptor antagonist in cerebral tissue, significantly reduces the consumption of medicine and decreases the side effect of general.
First aspect that the present invention relates to is to provide nmda receptor antagonist for the preparation for the treatment of or the purposes of preventing central nervous system disease and/or mental sickness medicine, and nmda receptor antagonist, its pharmaceutically-acceptable salts or its pharmaceutical composition are delivered to the central nervous system of mammal (such as people) by target administration; Described central nervous system and/or mental sickness are selected from depression, senile dementia, alzheimer's disease, epilepsy, neuralgia or treating narcotic addiction symptom.
As further preferred scheme, described targeting drug administration method directly enters the central nervous system of mammal (such as people) without body circulation or blood brain barrier.
As further preferred scheme, described targeting drug administration method is intracerebroventricular administration, nasal-cavity administration.
Other target administration modes also comprise carotid injection, and it is the same with direct intracerebroventricular administration, and administering mode is invasive, may there is patient's compliance poor, easy infection risk.Nasal-cavity administration, makes absorbed medicine walk around blood brain barrier, directly enters central nervous system, is conducive to improving the nmda receptor antagonist such as concentration of GLYX-13 in cerebral tissue, significantly reduces the consumption of medicine and reduces the side effect of general.
After nasal-cavity administration, drug molecule is stranded in olfactory region mucosa and easily absorbs and enter cerebrospinal fluid, thus can bypass blood brain barrier and enters central nervous system, plays therapeutical effect.Nasal-cavity administration approach is the route of administration with brain targeting, and in this medication brain, bioavailability is high, easy to use, and can avoid stimulates and liver first-pass effect gastrointestinal, and medicine can enter central nervous system fast through blood brain barrier.
In the present invention, targeting administering mode refers to and the major part of medicine is delivered directly to central nervous system, and does not need make medicine through body circulation and arrive central nervous system through blood brain barrier.
As further preferred scheme, described nmda receptor antagonist is selected from ground
xiping, Pethidine, methadone, dextropropoxyphene, tramadol, phenol send acetone, dextromethorphan, phencyclidine, amantadine hydrochloride, isobutyl acetate, dextrorphan, gacyclidine, ibogaine, memantine, rolicyclidine, tinoridine, Tiletamine, Yi Liluo, remacemide, N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine, Ramulus Uncariae cum Uncis alkali, kynurenic acid, scheme for lacosamide, GLYX-13, AP5, AP7, WMS2539 or its combination.
As further preferred scheme, described nmda receptor antagonist is selected from GLYX-13.As further preferred scheme, the dosage of described targeting drug administration method is 0.001-500mg/kg/ days; Preferred dosage is 0.01-100mg/kg/ days; More preferably dosage is 0.1-20mg/kg/ days.
As further preferred scheme, described nasal-cavity administration mode is: nmda receptor antagonist, its pharmaceutically-acceptable salts or its pharmaceutical composition and pharmaceutic adjuvant are made pharmaceutically acceptable pharmaceutical preparation, by pharmaceutical preparation directly or put on nasal cavity by device, medicine is absorbed at nasal cavity position, directly enter central nervous system, be used for the treatment of or prevent central nervous system disease and/or mental sickness.Medicament administration in nasal cavity, can by doser can be squash type, spray-type, atomizing, metered dose absorption plant.
Nmda receptor plays Main Function in the plasticity of synapse, and this plasticity forms the basis of a lot of more senior cognitive function, the acquisition such as remembered, reservation and study, and plays Main Function in some cognition path and in the sensation of pain.In addition, some character of nmda receptor implies that they may relate to the information processing forming self consciousness basis in brain.Because it shows as the CNS obstacle relating to broad spectrum, nmda receptor has caused special interest.Such as, during the cerebral ischaemia caused by apoplexy or traumatic damage, excessive excitatory amino acid glutamate from damage or anoxia neuron release.This excessive glutamate is combined with nmda receptor, described their ligand-gated ion channel of receptor opening; The in turn inflow of calcium produces high-caliber intracellular Ca2+, and it activates the biochemical cascade causing protein degradation and cell death.This phenomenon, known to excitotoxicity, be also considered to cause to from hypoglycemia and asystole to the reason of the relevant nerve injury of other obstacle within the scope of epilepsy.In addition, existing preliminary report shows the similar HD relating to chronic neurodegenative, parkinson disease and Alzheimer.The activation having shown nmda receptor is the reason of fainting from fear after apoplexy, and in some epilepsy model, the activation having shown nmda receptor is required for the generation of epilepsy.In the mankind, produce similar schizoid psychotic state owing to blocking nmda receptor Ca++ passage by Animal Anesthesia agent PCP (phencyclidine), also identify the neuropsychiatry relating to nmda receptor.In addition, nmda receptor also relates to the space learning of some type.
Second aspect that the present invention relates to is, the pharmaceutically acceptable pharmaceutical preparation of described nasal-cavity administration mode can be nasal drop, nasal in-situ gel, nose aerosol, nasal spray, powder nose inhalant, nose microsphere, nose microcapsule, nasal nanometer microgranule, nose liposome, nose Emulsion, nose unguentum, nose membrane or nose cyclodextrin preparation; Preferred nose nasal drop, nasal spray, nasal in-situ gel and nasal powder.
As preferred scheme, described nasal in-situ gel includes nmda receptor antagonist or its pharmaceutically-acceptable salts, gel-type vehicle, water and one or more other pharmaceutic adjuvants of effective amount.Described nasal drop, nasal spray include nmda receptor antagonist or its pharmaceutically-acceptable salts, water and one or more other pharmaceutic adjuvants of effective amount.
As further preferred scheme, wherein other pharmaceutic adjuvant aforementioned is selected from penetration enhancer, osmotic pressure regulator, pH adjusting agent or antiseptic.
As further preferred scheme, described gel-type vehicle is selected from poloxamer188, PLURONICS F87, sodium alginate, gellan gum, Chitosan-phospholipid complex, methylcellulose, hydroxypropyl cellulose, polylactic acid-polyethylene glycol block copolymer, polycaprolactone polyethyleneglycol block copolymer, poly-N-isopropyl acrylamide or its combination, preferred poloxamer188, PLURONICS F87, gellan gum or its combination, described penetration enhancer is selected from oleyl alcohol, lauryl alcohol, hexadecanol, linoleic acid, Brij30, isopropyl cetylate, isopropyl myristate, lanoline, cineole, menthol, saponin, dodecane nitrogen
ketone, Camphora, liquid paraffin, dimethicone, glycerol, Polyethylene Glycol, cyclodextrin, HP-β-CD, Sulfated β-cyclodextrin, sodium laurylsulfate, tween 80, SUNSOFT 700P-2, azone, cholate, Calculus Bovis NaTDC, NaGC, NaTDC, sweet ammonia gallbladder deoxidation acid sodium, fusidinic acid, Salicylate, N-acetyl-L-cysteine, sodium ethylene diamine tetracetate, citrate, collagen N-acetyl derivative, LYSOLECITHIN SUNLECITHIN A, palmityl LYSOLECITHIN SUNLECITHIN A, stearoyl LYSOLECITHIN SUNLECITHIN A, sodium glycyrrhetate, glycyrrhizic acid dipotassium, carbene oxo disodium, dihydro steroid mycin sodium, Calculus Bovis dihydro steroid mycin sodium, Oct Carn, lauroyl carnitine, chitosan, cetylpyridinium chloride, poly-left-handed brilliant propylhomoserin or its combination, preferably from azone, Calculus Bovis NaTDC or its combination, described osmotic pressure regulator is selected from glycerol, sodium chloride, potassium chloride, glucose or its combination, preferred sodium chloride, described pH adjusting agent is selected from hydrochloric acid, sodium hydroxide, potassium hydroxide, acetic acid, sodium acetate, citric acid, sodium citrate, phosphoric acid, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate or its combination, preferably phosphoric acid sodium dihydrogen, sodium hydrogen phosphate or its combination, described antiseptic is selected from chlorobutanol, benzalkonium chloride, benzalkonium bromide, potassium sorbate, methyl salicylate, sodium salicylate, ethylparaben, methyl parahydroxybenzoate, benzyl p-hydroxybenzoate, resorcinol, phenethanol, benzoic acid, sodium benzoate, benzyl alcohol, phenol, metacresol, thimerosal or its combination, preferred ethylparaben, methyl parahydroxybenzoate or its combination.
As further preferred scheme; described nasal in-situ gel includes the nmda receptor antagonist of effective amount or its pharmaceutically-acceptable salts, gel-type vehicle is selected from poloxamer188, PLURONICS F87, gellan gum or its combination, penetration enhancer is selected from azone or Calculus Bovis NaTDC, osmotic pressure regulator is selected from sodium chloride, pH adjusting agent is selected from hydrochloric acid or sodium hydroxide, antiseptic are selected from ethylparaben, and all the other are water.
Nmda receptor antagonist such as GLYX-13 is by the situ-gel of nasal-cavity administration, and become liquid condition in vitro, dosage easily accurately controls, easy to use, sprays into nasal cavity and can be uniformly dispersed in nasal mucosal surface, and diffuse to form gel mutually with snotter.Medicine was increased in the nasal cavity time of staying, not easily runs off, add medicine and directly enter by nose nicergoline road the probability that brain plays drug effect.In addition, medicine by nasal absorption, avoids and is eliminated in body circulation, thus significantly can reduce consumption, and patient can self administration in addition, and painless, therefore has good patient compliance.
As most preferred scheme, each component composition of gel for nose and content (W/V) are:
As most preferred scheme, each component composition of gel for nose and content (W/V) are:
As preferred scheme, described nasal powder includes the nmda receptor antagonist of effective amount or its pharmaceutically-acceptable salts and one or more other pharmaceutic adjuvants.
As further preferred scheme, other pharmaceutic adjuvant described is selected from carrier powder body, penetration enhancer, binder, fluidizer, surfactant, diluent.
As further preferred scheme, described carrier powder body is selected from starch, lactose, mannitol, sorbitol, pregelatinized Starch, cyclodextrin or its combination, described binder, fluidizer are selected from sodium alginate, arabic gum, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, starch, carboxymethyl starch sodium, pregelatinized Starch, cyclodextrin or its combination, described surfactant is selected from Polysorbate, poloxamer, Brij or its combination, described diluent is selected from starch, lactose, mannitol, sorbitol, pregelatinized Starch, cyclodextrin or its combination, described penetration enhancer is selected from oleyl alcohol, lauryl alcohol, hexadecanol, linoleic acid, Brij30, isopropyl cetylate, isopropyl myristate, lanoline, cineole, menthol, saponin, dodecane nitrogen
ketone, Camphora, liquid paraffin, dimethicone, glycerol, Polyethylene Glycol, cyclodextrin, HP-β-CD, Sulfated β-cyclodextrin, sodium laurylsulfate, tween 80, SUNSOFT 700P-2, azone, cholate, Calculus Bovis NaTDC, NaGC, NaTDC, sweet ammonia gallbladder deoxidation acid sodium, fusidinic acid, Salicylate, N-acetyl-L-cysteine, sodium ethylene diamine tetracetate, citrate, collagen N-acetyl derivative, LYSOLECITHIN SUNLECITHIN A, palmityl LYSOLECITHIN SUNLECITHIN A, stearoyl LYSOLECITHIN SUNLECITHIN A, sodium glycyrrhetate, glycyrrhizic acid dipotassium, carbene oxo disodium, dihydro steroid mycin sodium, Calculus Bovis dihydro steroid mycin sodium, Oct Carn, lauroyl carnitine, chitosan, cetylpyridinium chloride, poly-left-handed brilliant propylhomoserin or its combination.
The 3rd aspect that the present invention relates to is, described nmda receptor antagonist pharmaceutical composition is nmda receptor antagonist and other any one or the pharmaceutical composition that forms of multiple medicine for central nervous system.
As preferred scheme, other medicines for central nervous system described are selected from sedative hypnotic, antiepileptic, psychosis, antidepressants, analgesic or neurodegenerative disease therapeutic agent.
As further preferred scheme, other medicines for central nervous system can be benzodiazepine
class medicine is (as chlorine nitrogen
diazepam, clobazam, lorazepam, estazolam), or barbiturates (as allobarbital, amobarbital, allopropylbarbital, phenallymal, barbital, brallobarbital, phenobarbital, penthiobarbital), or non-benzodiazepine
class, γ-aminobutyric acid (GABA) receptor stimulating agent (as zolpidem, Zaleplon, zopiclone), or ureide derivative (as phenytoin Sodium) in ring, or dibenzo is mixed nitrogen
class is (as carbamazepine, oxcarbazepine), GABA derivant is (as Pu Luojia amine, gabapentin, vigabatrin), fat carboxylic acid is (as valproic acid, sodium valproate, valpromide), phenothiazines, thioxanthene class, butyrophenones, opioid receptor agonist, opiate receptor partial agonist, opiate receptor antagonist, glutamate receptor antagonists, acetylcholine receptor antagonists, neuropeptide receptor antagonists, k receptor stimulating agent, tricyclic antidepressant (as amitriptyline), selectivity serotonin reuptake inhibitors is (as fluorobenzene oxygen aniline, Paroxetine and Sertraline), tetracyclic antidepressants (as maprotiline), and monoamine oxidase, MAO (MAO) inhibitor (as phenelzine), excited corticocerebral medicine, excited medullary respiratory center medicine, promote the medicine that brain function recovers.
The 4th aspect that the present invention relates to is, there is provided a kind of and include the nmda receptor antagonist of effective amount or the pharmaceutical preparation of its pharmaceutically-acceptable salts, described pharmaceutical preparation is selected from nose nasal drop, nasal spray, nasal in-situ gel and nasal powder, and the mode being delivered to mammiferous central nervous system by target administration carries out administration; Preferably be delivered to mammiferous central nervous system in nasal-cavity administration mode.
As further preferred scheme, described nasal in-situ gel includes nmda receptor antagonist or its pharmaceutically-acceptable salts, gel-type vehicle, water and one or more other pharmaceutic adjuvants of effective amount; Described nasal drop, nasal spray include nmda receptor antagonist or its pharmaceutically-acceptable salts, water and one or more other pharmaceutic adjuvants of effective amount; Described nasal powder includes the nmda receptor antagonist of effective amount or its pharmaceutically-acceptable salts and one or more other pharmaceutic adjuvants.
As further preferred scheme, described gel-type vehicle, other pharmaceutic adjuvant can be the ranges of choice that second aspect present invention provides, and also can be pharmaceutic adjuvants well known by persons skilled in the art.
Compared with prior art, nmda receptor antagonist such as GYLX-13 is delivered to mammiferous central nervous system by target administration by the present invention, and be cycled to used in treatment without body or prevent central nervous system disease and/or mental sickness, improve the concentration of nmda receptor antagonist in cerebral tissue, significantly reduce the consumption of medicine and decrease the side effect of general.The formation of the component in pharmaceutical composition of the present invention or preparation and content is made to be different from prior art by this special administering mode.
In medication brain of the present invention, bioavailability is high, easy to use, can avoid being subject to effect to gastrointestinal stimulation and liver, and medicine can enter central nervous system fast through blood brain barrier.Especially situ-gel, by nasal-cavity administration, become liquid condition in vitro, dosage easily accurately controls, easy to use, can be uniformly dispersed in nasal mucosal surface, and diffuse to form gel mutually with snotter after spraying into nasal cavity.Medicine was increased in the nasal cavity time of staying, not easily runs off, add medicine and directly enter by nose nicergoline road the probability that brain plays drug effect.
In addition, medicine by nasal absorption, avoids medicine and is eliminated in body circulation, compared with existing preparation or administering mode, significantly can reduce the consumption of medicine, and patient can self administration in addition, and painless, therefore has good patient compliance.
In sum, the present invention solves the problem of the high and administration compliance difference of medicine elimination factor that prior art medication causes very targetedly, has clinical medicine widely and applies.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail and completely, but limit the present invention by no means, and the present invention is also not only confined to the content of embodiment.
Embodiment 1
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/V, %) |
| GLYX-13 | 200 | 20 |
| Poloxamer188 | 100 | 10 |
| PLURONICS F87 | 10 | 1 |
| Azone | 5 | 0.5 |
| Sodium chloride | 9 | 0.9 |
| Ethylparaben | 1 | 0.1 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and azone, stirring and dissolving.Get recipe quantity poloxamer188 and PLURONICS F87, be scattered in above-mentioned solution, make that appearance is swollen becomes clear solution completely.Add recipe quantity GLYX-13, after dissolving, adjust pH to 5.0-7.4.Subpackage and get final product.
Embodiment 2
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/V, %) |
| GLYX-13 | 200 | 20 |
| Poloxamer188 | 200 | 20 |
| PLURONICS F87 | 50 | 5 |
| Azone | 15 | 1.5 |
| Sodium chloride | 9 | 0.9 |
| Ethylparaben | 3 | 0.3 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and azone, stirring and dissolving.Get recipe quantity poloxamer188 and PLURONICS F87, be scattered in above-mentioned solution, make that appearance is swollen becomes clear solution completely.Add recipe quantity GLYX-13, after dissolving, adjust pH to 5.0-7.4.Divide and be filled to squash type intranasal medicator and get final product.
Embodiment 3
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/V, %) |
| GLYX-13 | 50 | 5 |
| Poloxamer188 | 255 | 25.5 |
| PLURONICS F87 | 50 | 5 |
| Calculus Bovis NaTDC | 50 | 5 |
| Sodium chloride | 9 | 0.9 |
| Ethylparaben | 1 | 0.1 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and Calculus Bovis NaTDC, stirring and dissolving.Get recipe quantity poloxamer188 and PLURONICS F87, be scattered in above-mentioned solution, make that appearance is swollen becomes clear solution completely.Add recipe quantity GLYX-13, after dissolving, adjust pH to 5.0-7.4.Divide and be filled to atomizing intranasal medicator and get final product.
Embodiment 4
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/V, %) |
| GLYX-13 | 25 | 2.5 |
| Poloxamer188 | 200 | 20 |
| PLURONICS F87 | 100 | 10 |
| Azone | 25 | 2.5 |
| Sodium chloride | 9 | 0.9 |
| Ethylparaben | 5 | 0.5 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and azone, stirring and dissolving.Get recipe quantity poloxamer188 and PLURONICS F87, be scattered in above-mentioned solution, make that appearance is swollen becomes clear solution completely.Add recipe quantity GLYX-13, after dissolving, adjust pH to 5.0-7.4.Divide and be filled to metered dose absorption plant and get final product.
Embodiment 5
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/V, %) |
| GLYX-13 | 25 | 2.5 |
| Poloxamer188 | 100 | 10 |
| PLURONICS F87 | 50 | 5 |
| Azone | 15 | 1.5 |
| Sodium chloride | 9 | 0.9 |
| Ethylparaben | 5 | 0.5 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and azone, stirring and dissolving.Get recipe quantity poloxamer188 and PLURONICS F87, be scattered in above-mentioned solution, make that appearance is swollen becomes clear solution completely.Add recipe quantity GLYX-13, after dissolving, adjust pH to 5.0-7.4.Divide and be filled to metered dose absorption plant and get final product.
Embodiment 6
1, pharmaceutical formulation
| 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 |
| Ethylparaben | 1 | 0.1 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and azone, stirring and dissolving.Get recipe quantity gellan gum, be scattered in above-mentioned solution, make that appearance is swollen becomes clear solution completely.Add recipe quantity GLYX-13, after dissolving, adjust pH to 5.0-7.4.Divide and be filled to atomizing intranasal medicator and get final product.
Embodiment 7
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/V, %) |
| GLYX-13 | 20 | 2 |
| Gellan gum | 25 | 2.5 |
| Azone | 10 | 1 |
| Sodium chloride | 9 | 0.9 |
| Ethylparaben | 2 | 0.2 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and azone, stirring and dissolving.Get recipe quantity gellan gum, be scattered in above-mentioned solution, make that appearance is swollen becomes clear solution completely.Add recipe quantity GLYX-13, after dissolving, adjust pH to 5.0-7.4.Divide and be filled to spray-type intranasal medicator and get final product.
Embodiment 8
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/V, %) |
| GLYX-13 | 25 | 2.5 |
| Gellan gum | 50 | 5 |
| Azone | 20 | 2 |
| Sodium chloride | 9 | 0.9 |
| Ethylparaben | 5 | 0.5 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and azone, stirring and dissolving.Get recipe quantity gellan gum, be scattered in above-mentioned solution, make that appearance is swollen becomes clear solution completely.Add recipe quantity GLYX-13, after dissolving, adjust pH to 5.0-7.4.Divide and be filled to metered dose absorption plant and get final product.
Embodiment 9
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/V, %) |
| GLYX-13 | 25 | 2.5 |
| Oxazepam | 10 | 1 |
| Poloxamer188 | 200 | 20 |
| PLURONICS F87 | 100 | 10 |
| Azone | 25 | 2.5 |
| Sodium chloride | 9 | 0.9 |
| Ethylparaben | 5 | 0.5 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and azone, stirring and dissolving.Get recipe quantity poloxamer188 and PLURONICS F87, be scattered in above-mentioned solution, make that appearance is swollen becomes clear solution completely.Add recipe quantity GLYX-13 and oxazepam, after dissolving, adjust pH to 5.0-7.4.Divide and be filled to atomizing intranasal medicator and get final product.
Embodiment 10
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/W, %) |
| GLYX-13 | 55 | 55 |
| Hydroxypropyl cellulose | 23 | 23 |
| Calculus Bovis NaTDC | 5 | 5 |
| Lactose | 17 | 17 |
2, preparation method
GLYX-13, hydroxypropyl cellulose, lactose, Calculus Bovis NaTDC are micronized to particle diameter 0.1-10 micron, fully mix, be sub-packed in single dose nasal cavity applied medicine device and get final product.
Embodiment 11
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/V, %) |
| GLYX-13 | 1 | 0.1 |
| Azone | 5 | 0.5 |
| Sodium chloride | 9 | 0.9 |
| Ethylparaben | 1 | 0.1 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and azone, stirring and dissolving.Add recipe quantity GLYX-13, after dissolving, adjust pH to 5.0-7.4.Divide and be filled to squash type intranasal medicator and get final product.
Embodiment 12
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/V, %) |
| GLYX-13 | 50 | 5 |
| Azone | 2 | 0.2 |
| Sodium chloride | 9 | 0.9 |
| Ethylparaben | 3 | 0.3 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and azone, stirring and dissolving.Add recipe quantity GLYX-13, after dissolving, adjust pH to 5.0-7.4.Divide and be filled to atomizing intranasal medicator and get final product.
Embodiment 13
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/V, %) |
| GLYX-13 | 50 | 5 |
| Estazolam | 1 | 0.1 |
| Azone | 10 | 1 |
| Sodium chloride | 9 | 0.9 |
| Ethylparaben | 5 | 0.5 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and azone, stirring and dissolving.Add recipe quantity GLYX-13 and estazolam, after dissolving, adjust pH to 5.0-7.4.Divide and be filled to squash type intranasal medicator and get final product.
Embodiment 14
1, pharmaceutical formulation
| Component | Quality (g) | Composition (W/V, %) |
| GLYX-13 | 30 | 3 |
| Diazepam | 5 | 0.5 |
| Azone | 1 | 0.1 |
| Sodium chloride | 9 | 0.9 |
| Ethylparaben | 2 | 0.2 |
| Hydrochloric acid/sodium hydroxide | In right amount | / |
| Water for injection | Add to 1000ml | / |
2, preparation method
Get water for injection 900ml, add recipe quantity ethylparaben, sodium chloride and azone, stirring and dissolving.Add recipe quantity GLYX-13 and diazepam, after dissolving, adjust pH to 5.0-7.4.Divide and be filled to atomizing intranasal medicator and get final product.
Finally should be noted that, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted the present invention, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to the technical scheme of invention or equivalent replacement, described technical scheme also can not depart from the spirit and scope of technical solution of the present invention, and it all should be encompassed in right of the present invention.
Claims (24)
1. nmda receptor antagonist is for the preparation for the treatment of or a purposes of preventing central nervous system disease and/or mental sickness medicine, and described nmda receptor antagonist, its pharmaceutically-acceptable salts or its pharmaceutical composition are delivered to the central nervous system of people by target administration.
2. purposes as claimed in claim 1, it is characterized in that, described central nervous system and/or mental sickness are selected from depression, infantile autism, senile dementia, alzheimer's disease, epilepsy, neuralgia or treating narcotic addiction symptom.
3. purposes as claimed in claim 1, is characterized in that, described target administration directly enters the central nervous system of people without body circulation or blood brain barrier.
4. purposes as claimed in claim 3, it is characterized in that, described target administration is intracerebroventricular administration or nasal-cavity administration.
5. purposes as claimed in claim 1, it is characterized in that, described nmda receptor antagonist is selected from ground
xiping, Pethidine, methadone, dextropropoxyphene, tramadol, phenol send acetone, dextromethorphan, phencyclidine, amantadine hydrochloride, isobutyl acetate, dextrorphan, gacyclidine, ibogaine, memantine, rolicyclidine, tinoridine, Tiletamine, Yi Liluo, remacemide, N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine, Ramulus Uncariae cum Uncis alkali, kynurenic acid, scheme for lacosamide, GLYX-13, AP5, AP7, WMS2539 or its combination.
6. purposes as claimed in claim 5, it is characterized in that, described nmda receptor antagonist is selected from GLYX-13.
7. purposes as claimed in claim 1, it is characterized in that, the dosage of described target administration is 0.001-500mg/kg/ days; Preferred dosage is 0.01-100mg/kg/ days; More preferably dosage is 0.1-20mg/kg/ days.
8. purposes as claimed in claim 4, it is characterized in that, described nasal-cavity administration mode is: nmda receptor antagonist, its pharmaceutically-acceptable salts or its pharmaceutical composition and pharmaceutic adjuvant are made pharmaceutically acceptable pharmaceutical preparation, by pharmaceutical preparation directly or put on nasal cavity by device, medicine is absorbed at nasal cavity position, directly enter central nervous system, be used for the treatment of or prevent central nervous system disease and/or mental sickness.
9. purposes as claimed in claim 8, it is characterized in that, described pharmaceutically acceptable pharmaceutical preparation is selected from nasal drop, nasal in-situ gel, nose aerosol, nasal spray, powder nose inhalant, nose microsphere, nose microcapsule, nasal nanometer microgranule, nose liposome, nose Emulsion, nose unguentum, nose membrane or nose cyclodextrin preparation; Preferred nose nasal drop, nasal spray, nasal in-situ gel and nasal powder.
10. include the nmda receptor antagonist of effective amount or the nasal in-situ gel of its pharmaceutically-acceptable salts, gel-type vehicle, water and one or more other pharmaceutic adjuvants.
11. include the nmda receptor antagonist of effective amount or the nasal drop of its pharmaceutically-acceptable salts, water and one or more other pharmaceutic adjuvants or nasal spray.
12. nasal in-situ gels as claimed in claim 10 or nasal drop according to claim 11 or nasal spray, it is characterized in that, other pharmaceutic adjuvant described is selected from penetration enhancer, osmotic pressure regulator, pH adjusting agent or antiseptic.
13. nasal in-situ gels as claimed in claim 10, it is characterized in that, described gel-type vehicle is selected from poloxamer188, PLURONICS F87, sodium alginate, gellan gum, Chitosan-phospholipid complex, methylcellulose, hydroxypropyl cellulose, polylactic acid-polyethylene glycol block copolymer, polycaprolactone polyethyleneglycol block copolymer, poly-N-isopropyl acrylamide or its combination; Preferred poloxamer188, PLURONICS F87, gellan gum or its combination.
14. nasal in-situ gel, nasal drop or nasal sprays as claimed in claim 12, it is characterized in that, described penetration enhancer is selected from oleyl alcohol, lauryl alcohol, hexadecanol, linoleic acid, Brij30, isopropyl cetylate, isopropyl myristate, lanoline, cineole, menthol, saponin, dodecane nitrogen
ketone, Camphora, liquid paraffin, dimethicone, glycerol, Polyethylene Glycol, cyclodextrin, HP-β-CD, Sulfated β-cyclodextrin, sodium laurylsulfate, tween 80, SUNSOFT 700P-2, azone, cholate, Calculus Bovis NaTDC, NaGC, NaTDC, sweet ammonia gallbladder deoxidation acid sodium, fusidinic acid, Salicylate, N-acetyl-L-cysteine, sodium ethylene diamine tetracetate, citrate, collagen N-acetyl derivative, LYSOLECITHIN SUNLECITHIN A, palmityl LYSOLECITHIN SUNLECITHIN A, stearoyl LYSOLECITHIN SUNLECITHIN A, sodium glycyrrhetate, glycyrrhizic acid dipotassium, carbene oxo disodium, dihydro steroid mycin sodium, Calculus Bovis dihydro steroid mycin sodium, Oct Carn, lauroyl carnitine, chitosan, cetylpyridinium chloride, poly-left-handed brilliant propylhomoserin or its combination, preferably from azone, Calculus Bovis NaTDC or its combination, described osmotic pressure regulator is selected from glycerol, sodium chloride, potassium chloride, glucose or its combination, preferred sodium chloride, described pH adjusting agent is selected from hydrochloric acid, sodium hydroxide, potassium hydroxide, acetic acid, sodium acetate, citric acid, sodium citrate, phosphoric acid, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate or its combination, preferably phosphoric acid sodium dihydrogen, sodium hydrogen phosphate or its combination, described antiseptic is selected from chlorobutanol, benzalkonium chloride, benzalkonium bromide, potassium sorbate, methyl salicylate, sodium salicylate, ethylparaben, methyl parahydroxybenzoate, benzyl p-hydroxybenzoate, resorcinol, phenethanol, benzoic acid, sodium benzoate, benzyl alcohol, phenol, metacresol, thimerosal or its combination, preferred ethylparaben, methyl parahydroxybenzoate or its combination.
15. nasal in-situ gels as claimed in claim 10; it is characterized in that; include the nmda receptor antagonist of effective amount or its pharmaceutically-acceptable salts, gel-type vehicle is selected from poloxamer188, PLURONICS F87, gellan gum or its combination, penetration enhancer is selected from azone or Calculus Bovis NaTDC, osmotic pressure regulator is selected from sodium chloride, pH adjusting agent is selected from hydrochloric acid or sodium hydroxide, antiseptic are selected from ethylparaben, all the other are water.
16. nasal in-situ gels as claimed in claim 15, is characterized in that, each component composition of described gel and content (W/V) are:
17. nasal in-situ gels as claimed in claim 15, is characterized in that, each component composition of described gel and content (W/V) are:
18. nasal in-situ gel comprising nmda receptor antagonist, nasal drop or nasal sprays as described in claim 10-17 any one are for the preparation of the purposes for the treatment of or prevention central nervous system disease and/or mental sickness medicine, and described nmda receptor antagonist, its pharmaceutically-acceptable salts or its pharmaceutical composition are delivered to the central nervous system of people by target administration.
19. include the nmda receptor antagonist of effective amount or the nasal powder of its pharmaceutically-acceptable salts and one or more other pharmaceutic adjuvants.
20. nasal powders as claimed in claim 19, it is characterized in that, other pharmaceutic adjuvant described is selected from carrier powder body, penetration enhancer, binder, fluidizer, surfactant and/or diluent.
21. nasal powders as claimed in claim 20, is characterized in that, described carrier powder body is selected from starch, lactose, mannitol, sorbitol, pregelatinized Starch, cyclodextrin or its combination, described binder, fluidizer are selected from sodium alginate, arabic gum, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, starch, carboxymethyl starch sodium, pregelatinized Starch, cyclodextrin or its combination, described surfactant is selected from Polysorbate, poloxamer, Brij or its combination, described diluent is selected from starch, lactose, mannitol, sorbitol, pregelatinized Starch, cyclodextrin or its combination, described penetration enhancer is selected from oleyl alcohol, lauryl alcohol, hexadecanol, linoleic acid, Brij30, isopropyl cetylate, isopropyl myristate, lanoline, cineole, menthol, saponin, dodecane nitrogen
ketone, Camphora, liquid paraffin, dimethicone, glycerol, Polyethylene Glycol, cyclodextrin, HP-β-CD, Sulfated β-cyclodextrin, sodium laurylsulfate, tween 80, SUNSOFT 700P-2, azone, cholate, Calculus Bovis NaTDC, NaGC, NaTDC, sweet ammonia gallbladder deoxidation acid sodium, fusidinic acid, Salicylate, N-acetyl-L-cysteine, sodium ethylene diamine tetracetate, citrate, collagen N-acetyl derivative, LYSOLECITHIN SUNLECITHIN A, palmityl LYSOLECITHIN SUNLECITHIN A, stearoyl LYSOLECITHIN SUNLECITHIN A, sodium glycyrrhetate, glycyrrhizic acid dipotassium, carbene oxo disodium, dihydro steroid mycin sodium, Calculus Bovis dihydro steroid mycin sodium, Oct Carn, lauroyl carnitine, chitosan, cetylpyridinium chloride, poly-left-handed brilliant propylhomoserin or its combination.
22. nasal powders as described in claim 19-21 any one are for the preparation of the purposes for the treatment of or prevention central nervous system disease and/or mental sickness medicine, and described nmda receptor antagonist, its pharmaceutically-acceptable salts or its pharmaceutical composition are delivered to the central nervous system of people by target administration.
23. comprise nmda receptor antagonist and other any one or the pharmaceutical composition of multiple medicine for central nervous system, and described nmda receptor antagonist is delivered to the central nervous system of people by target administration; Preferably, described target administration is intracerebroventricular administration or nasal-cavity administration.
24. pharmaceutical compositions as claimed in claim 23, it is characterized in that, described medicine for central nervous system is selected from sedative hypnotic, antiepileptic, psychosis, antidepressants, analgesic or neurodegenerative disease therapeutic agent.
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| CN201410272815.5A CN105327349A (en) | 2014-06-18 | 2014-06-18 | Medical purpose of NMDA acceptor antagonist and pharmaceutical composition thereof |
| CN201580028785.6A CN106413708A (en) | 2014-06-18 | 2015-06-17 | Medical application of nmda receptor antagonist and pharmaceutical composition thereof |
| PCT/CN2015/081637 WO2015192772A1 (en) | 2014-06-18 | 2015-06-17 | Medical application of nmda receptor antagonist and pharmaceutical composition thereof |
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| CN201410272815.5A CN105327349A (en) | 2014-06-18 | 2014-06-18 | Medical purpose of NMDA acceptor antagonist and pharmaceutical composition thereof |
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| CN106668865A (en) * | 2017-01-23 | 2017-05-17 | 牡丹江医学院 | Medicinal composition for treating cerebral ischemia, preparation and application of medicinal composition |
| CN109890371A (en) * | 2016-08-26 | 2019-06-14 | 斯瑞尼瓦萨饶·韦帕切杜 | Composition and its method |
| CN110433133A (en) * | 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 | The cannabidiol nasal formulations for treating posttraumatic stress disorder |
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| CN108969478A (en) * | 2018-08-29 | 2018-12-11 | 江南大学 | A kind of Memantine difficulty soluble salt is slow-release injected and preparation method thereof |
| CN114828848A (en) * | 2019-06-28 | 2022-07-29 | 宾夕法尼亚大学理事会 | Intranasal dantrolene administration for the treatment of alzheimer's disease |
| CN113117080A (en) * | 2019-12-30 | 2021-07-16 | 珠海沅芷健康科技有限公司 | Delivery of beta to brain2Methods of adrenergic receptor agonists |
| CN116265016B (en) * | 2022-12-21 | 2024-03-22 | 大连医科大学 | Composition of epileptic disease medicine and application of composition in preparation of epileptic disease medicine |
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| US20120178695A1 (en) * | 2009-07-02 | 2012-07-12 | Joseph Moskal | Methods of treating neuropathic pain |
| EP2985032B1 (en) * | 2009-10-05 | 2019-01-02 | Northwestern University | Glyx for use in the treatment of alzheimer's disease, parkinson's disease or huntington's disease |
| CN102283801B (en) * | 2010-06-17 | 2015-05-27 | 江西中医学院 | Nasal drug delivery gel preparation for curing cerebral diseases |
| SG10202010665YA (en) * | 2011-04-27 | 2020-11-27 | Univ Northwestern | Methods of treating alzheimer's disease, huntington's disease, autism, or other disorders |
| CN103169649A (en) * | 2013-04-11 | 2013-06-26 | 中国人民解放军总医院 | Temperature and ion dual-sensitive in-situ gel nasal cavity drug delivery system |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109890371A (en) * | 2016-08-26 | 2019-06-14 | 斯瑞尼瓦萨饶·韦帕切杜 | Composition and its method |
| CN106668865A (en) * | 2017-01-23 | 2017-05-17 | 牡丹江医学院 | Medicinal composition for treating cerebral ischemia, preparation and application of medicinal composition |
| CN106668865B (en) * | 2017-01-23 | 2019-07-23 | 牡丹江医学院 | For treating pharmaceutical composition, preparation and its application of cerebral ischemia |
| CN110433133A (en) * | 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 | The cannabidiol nasal formulations for treating posttraumatic stress disorder |
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| CN106413708A (en) | 2017-02-15 |
| WO2015192772A1 (en) | 2015-12-23 |
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